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1.
Artigo em Inglês | MEDLINE | ID: mdl-32044989

RESUMO

INTRODUCTION: Classifying whether concepts in an unstructured clinical text are negated is an important unsolved task. New domain adaptation and transfer learning methods can potentially address this issue. OBJECTIVE: We examine neural unsupervised domain adaptation methods, introducing a novel combination of domain adaptation with transformer-based transfer learning methods to improve negation detection. We also want to better understand the interaction between the widely used bidirectional encoder representations from transformers (BERT) system and domain adaptation methods. MATERIALS AND METHODS: We use 4 clinical text datasets that are annotated with negation status. We evaluate a neural unsupervised domain adaptation algorithm and BERT, a transformer-based model that is pretrained on massive general text datasets. We develop an extension to BERT that uses domain adversarial training, a neural domain adaptation method that adds an objective to the negation task, that the classifier should not be able to distinguish between instances from 2 different domains. RESULTS: The domain adaptation methods we describe show positive results, but, on average, the best performance is obtained by plain BERT (without the extension). We provide evidence that the gains from BERT are likely not additive with the gains from domain adaptation. DISCUSSION: Our results suggest that, at least for the task of clinical negation detection, BERT subsumes domain adaptation, implying that BERT is already learning very general representations of negation phenomena such that fine-tuning even on a specific corpus does not lead to much overfitting. CONCLUSION: Despite being trained on nonclinical text, the large training sets of models like BERT lead to large gains in performance for the clinical negation detection task.

2.
World Neurosurg ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32001414

RESUMO

BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a recently approved therapy for patients with drug-resistant epilepsy. To date, there is a poor understanding of the mechanism of action and lack of in vivo biomarkers. We propose a method for investigating the in vivo stimulation effects using blood-oxygen-level dependent (BOLD) MRI and present the brain activation pattern associated with ANT DBS. METHODS: Two patients undergoing ANT DBS for epilepsy underwent BOLD MRI using a block design after the DBS was programmed to alternate ON/OFF in 30 second blocks. The scanner was triggered utilizing surface electrophysiological recording to detect the DBS cycle. Nine total runs were obtained and were analyzed using a general linear model. RESULTS: Active ANT stimulation produced activation within several areas of the brain, including the thalamus, bilateral anterior cingulate and posterior cingulate cortex, precuneus, medial prefrontal cortex, amygdala, ventral tegmental area, hippocampus, striatum, and right angular gyrus. CONCLUSIONS: Utilizing block-design BOLD MRI, we were able to show widespread activation resulting from ANT DBS. Overlap with multiple areas of both the default mode and limbic networks was shown suggesting that these nodes may modulate the effect of seizure control with ANT DBS.

3.
J Am Heart Assoc ; 9(2): e013036, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31910780

RESUMO

Background Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease. Heart rhythm complexity analysis has been shown to be useful in predicting outcomes in various diseases; however, data on patients with end-stage renal disease are limited. In this study, we analyzed the association between heart rhythm complexity and long-term cardiovascular outcomes in patients with end-stage renal disease receiving peritoneal dialysis. Methods and Results We prospectively enrolled 133 patients receiving peritoneal dialysis and analyzed linear heart rate variability and heart rhythm complexity variables including detrended fluctuation analysis (DFA) and multiscale entropy. The primary outcome was cardiovascular mortality, and the secondary outcome was the occurrence of major adverse cardiovascular events. After a median of 6.37 years of follow-up, 21 patients (22%) died from cardiovascular causes. These patients had a significantly lower low-frequency band of heart rate variability, low/high-frequency band ratio, total power band of heart rate variability, heart rate turbulence slope, deceleration capacity, short-term DFA (DFAα1); and multiscale entropy slopes 1 to 5, scale 5, area 1 to 5, and area 6 to 20 compared with the patients who did not die from cardiovascular causes. Time-dependent receiver operating characteristic curve analysis showed that DFAα1 had the greatest discriminatory power for cardiovascular mortality (area under the curve: 0.763) and major adverse cardiovascular events (area under the curve: 0.730). The best cutoff value for DFAα1 was 0.98 to predict both cardiovascular mortality and major adverse cardiovascular events. Multivariate Cox regression analysis showed that DFAα1 (hazard ratio: 0.076; 95% CI, 0.016-0.366; P=0.001) and area 1 to 5 (hazard ratio: 0.645; 95% CI, 0.447-0.930; P=0.019) were significantly associated with cardiovascular mortality. Conclusions Heart rhythm complexity appears to be a promising noninvasive tool to predict long-term cardiovascular outcomes in patients receiving peritoneal dialysis.

4.
Int J Biol Markers ; : 1724600819900510, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31992114

RESUMO

OBJECTIVE: α-fetoprotein (AFP) expression is activated during the embryonic stage or hepatocellular carcinogenesis, so it is presumed that AFP is a key endogenous molecule to promote cell proliferation or differentiation. We carried out gene screening in an unknown family with hyper-alpha-fetoproteinemia and some sporadic menopausal women, and discussed the relationship between AFP expression and liver cirrhosis. METHODS: Peripheral blood samples from family members, patients with malignant liver tumors, and normal controls were collected. Full-length sequence of AFP was amplified and directly sequenced, and compared with normal controls. HNF-1α and HNF-1ß in plasma levels of family members, patients with liver cancer, newborns, pregnant women, and normal subjects were detected by ELISA, and the relationship between HNF-1 and AFP mutation or high expression was evaluated. RESULTS: There was a mutation in AFP promoter region at c.-200 C>T, which was located at the binding site of AFP hepatocyte nuclear factor 1 (HNF-1). AFP was higher than 4000 ng/L in all members carrying the mutation, but liver cancer was excluded in the family with hyper-alpha-fetoprotein. However, cirrhosis occurred in post-menopausal women. The cases reviewed showed that unknown hyper-alpha-fetoprotein was closely related to HNF-1 binding point of AFP in post-menopausal women with cirrhosis (7/11), while the plasma levels of HNF-1α and HNF-1ß were not significantly different. CONCLUSION: The mutation of the HNF-1 binding point of AFP may lead to an abnormal high expression of AFP by altering the binding of HNF transcription factors, which is closely related to cirrhosis in menopausal women.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31931328

RESUMO

Fatty acids from 100 randomly selected human serum samples were esterified to fatty acid methyl esters and analyzed by gas chromatography with flame ionization detector. A subset of the 20 samples that spans the variation in the original set of 100 samples were thereafter analyzed by gas chromatography-mass spectrometry (GC-MS). The GC-MS data were acquired using capillary columns with two different stationary phases, BP20 (polyethylene glycol) and BPX70 (cyanopropyl polysilphenylene-siloxane). Equivalent chain lengths on the two columns are reported for 69 compounds that constituted more than 0.1% of the chromatographic area in at least one sample. Of these, 39 compounds were identified as regular fatty acid methyl esters. The remaining 30 compounds were decomposition products from cholesterol, dimethylacetals, three compounds that have been linked to poor kidney function, and 13 compounds that are currently unidentified. The retention index patterns showed that on both columns there were 16 compounds that were separated by less than 0.05 equivalent chain length units from the nearest neighbor, meaning that they were overlapping or poorly resolved. The relationship between the peak threshold level and the number of peaks found above the level predicts a dramatic increase in the number of peaks that have to be resolved if the threshold is lowered below 0.1%.

6.
J Am Heart Assoc ; 9(2): e013784, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31955638

RESUMO

Background Poor engraftment of intramyocardial stem cells limits their therapeutic efficiency against myocardial infarction (MI)-induced cardiac injury. Transglutaminase cross-linked Gelatin (Col-Tgel) is a tailorable collagen-based hydrogel that is becoming an excellent biomaterial scaffold for cellular delivery in vivo. Here, we tested the hypothesis that Col-Tgel increases retention of intramyocardially-injected stem cells, and thereby reduces post-MI cardiac injury. Methods and Results Adipose-derived mesenchymal stem cells (ADSCs) were co-cultured with Col-Tgel in a 3-dimensional system in vitro, and Col-Tgel encapsulated ADSCs were observed using scanning electron microscopy and confocal microscopy. Vitality, proliferation, and migration of co-cultured ADSCs were evaluated. In addition, mice were subjected to MI and were intramyocardially injected with ADSCs, Col-Tgel, or a combination thereof. ADSCs engraftment, survival, cardiac function, and fibrosis were assessed. In vitro MTT and Cell Counting Kit-8 assays demonstrated that ADSCs survive and proliferate up to 4 weeks in the Col-Tgel. In addition, MTT and transwell assays showed that ADSCs migrate outside the edge of the Col-Tgel sphere. Furthermore, when compared with ADSCs alone, Col-Tgel-encapsulated ADSCs significantly enhanced the long-term retention and cardioprotective effect of ADSCs against MI-induced cardiac injury. Conclusions In the current study, we successfully established a 3-dimensional co-culture system using ADSCs and Col-Tgel. The Col-Tgel creates a suitable microenvironment for long-term retention of ADSCs in an ischemic area, and thereby enhances their cardioprotective effects. Taken together, this study may provide an alternative biomaterial for stem cell-based therapy to treat ischemic heart diseases.

7.
RMD Open ; 6(1)2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31958274

RESUMO

OBJECTIVES: This study assessed the psychometric properties of the fatigue numeric rating scale (NRS) and sought to establish values for clinically meaningful change (responder definition). METHODS: Using disease-specific clinician-reported and patient-reported data from two randomised clinical trials of patients with psoriatic arthritis (PsA), the fatigue NRS was evaluated for test-retest reliability, construct validity and responsiveness. A responder definition was also explored using anchor-based and distribution-based methods. RESULTS: Test-retest reliability analyses supported the reproducibility of the fatigue NRS in patients with PsA (intraclass correlation coefficient=0.829). Mean (SD) values at baseline and week 2 were 5.7 (2.2) and 5.7 (2.4), respectively. Supporting construct validity of the fatigue NRS, moderate-to-large correlations with other assessments measuring similar concepts as measured by Sackett's conventions were demonstrated. Fatigue severity was reduced when the underlying disease activity was improved and reductions remained consistent at week 12 and 24. A 3-point improvement was identified as being optimal for demonstrating a level of clinically meaningful improvement in fatigue NRS after 12-24 weeks of treatment. CONCLUSIONS: Fatigue NRS is a valid and responsive patient-reported outcome instrument for use in patients with PsA. The established psychometric properties from this study support the use of fatigue NRS in clinical trials and in routine clinical practice. Robust validation of reliability for use in routine clinical practice in treating patients with active PsA in less active disease states and other more diverse ethnic groups is needed.

8.
JACC Heart Fail ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31926853

RESUMO

Patients with congestive heart failure (CHF) require complex medical management across the continuum of care. Electronic health records (EHR) are currently used for traditional tasks of documentation, reviewing and managing test results, computerized order entry, and billing. Unfortunately many clinicians view EHR as merely digitized versions of paper charts, which create additional work and cognitive burden without improving quality or efficiency of care. In fact, EHR are revolutionizing the care of chronic diseases such as CHF. This review describes how appropriate use of technologies offered by EHR can help standardize CHF care, promote adherence to evidence-based guidelines, optimize workflow efficiency, improve performance metrics, and facilitate patient engagement. This review discusses a number of tools including documentation templates, telehealth and telemedicine, health information exchange, order sets, clinical decision support, registries, and analytics. Where available, evidence of their potential utility in management of CHF is presented. Together these EHR tools can also be used to enhance quality improvement, patient management, and clinical research as part of a learning health care system model. This review describes how existing EHR tools can support patients, cardiologists, and care teams to deliver consistent, high-quality, coordinated, patient-centered, and guideline-concordant care of CHF.

9.
Expert Opin Pharmacother ; 21(3): 275-285, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31790314

RESUMO

Introduction: The prevalence of obesity is increasing worldwide and associated conditions, particularly type 2 diabetes mellitus (T2DM), also show increasing prevalence. Lifestyle intervention should be the first line of management for obesity but additional pharmacotherapy is often required and bariatric surgery is appropriate in more severe cases. Drugs acting as glucagon-like peptide-1 receptor agonists (GLP-1RAs) developed for the management of T2DM reduce body weight and liraglutide is the first GLP-1RA to be approved for the treatment of obesity in patients with and without T2DM.Areas covered: In this review of relevant published material, the authors summarize the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of liraglutide for the treatment of obesity.Expert opinion: Liraglutide effectively reduces body weight and body fat through mechanisms involving reduced appetite and lowered energy intake, independent of its glucose-lowering effects. Like most of the other medications currently available for obesity, liraglutide has some common adverse effects, although generally not serious ones. Liraglutide has additional benefits in reducing cardiovascular events in patients with T2DM but the cost and the need for daily injections may limit its use in obesity. Newer GLP-1RAs, such as semaglutide, or other drugs in development for obesity may have advantages over liraglutide.

10.
J Am Med Inform Assoc ; 27(2): 294-300, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31769835

RESUMO

OBJECTIVE: Real-world data (RWD) are increasingly used for pharmacoepidemiology and regulatory innovation. Our objective was to compare adverse drug event (ADE) rates determined from two RWD sources, electronic health records and administrative claims data, among children treated with drugs for pulmonary hypertension. MATERIALS AND METHODS: Textual mentions of medications and signs/symptoms that may represent ADEs were identified in clinical notes using natural language processing. Diagnostic codes for the same signs/symptoms were identified in our electronic data warehouse for the patients with textual evidence of taking pulmonary hypertension-targeted drugs. We compared rates of ADEs identified in clinical notes to those identified from diagnostic code data. In addition, we compared putative ADE rates from clinical notes to those from a healthcare claims dataset from a large, national insurer. RESULTS: Analysis of clinical notes identified up to 7-fold higher ADE rates than those ascertained from diagnostic codes. However, certain ADEs (eg, hearing loss) were more often identified in diagnostic code data. Similar results were found when ADE rates ascertained from clinical notes and national claims data were compared. DISCUSSION: While administrative claims and clinical notes are both increasingly used for RWD-based pharmacovigilance, ADE rates substantially differ depending on data source. CONCLUSION: Pharmacovigilance based on RWD may lead to discrepant results depending on the data source analyzed. Further work is needed to confirm the validity of identified ADEs, to distinguish them from disease effects, and to understand tradeoffs in sensitivity and specificity between data sources.

11.
Int Immunopharmacol ; 78: 106010, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31806568

RESUMO

Random-pattern flap necrosis is a serious challenge for plastic surgeons. Nobiletin (NOB) is a polymethoxylated flavonoid extracted from citrus fruits reported to have antioxidant, anti-inflammatory and anti-apoptotic effects. Our experiment evaluated the impact of NOB on the viability of random flaps. Thirty six male "McFarlane flap" rat models were separated into two equal groups: a control group and an experimental group treated with 10 mg/kg of NOB. After 7 days, the range of necrosis was calculated, and a histological analysis was performed on tissue specimens. Immunohistochemical staining, lead oxide-gelatin angiography, and a Laser Doppler perfusion imager were used to assess angiogenesis and measure oxidative stress, as indicated by superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. The average survival area of flap was greater in the NOB-treated group than that in the control group. The NOB-treated group mitigated oxidative stress via augmented SOD, reduced MDA, and enhanced vascular endothelial growth factor (VEGF) expression. Hematoxylin and eosin staining indicated that NOB increased blood flow and had anti-inflammatory effects. Our findings revealed that NOB improved random skin flap survival.

12.
Neuroradiology ; 62(1): 81-88, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31676961

RESUMO

PURPOSE: Pilocytic (PA) and pilomyxoid astrocytomas (PMA) are related low-grade tumors which occur predominantly in children. PMAs have a predilection for a supratentorial location in younger children with worse outcomes. However, the two have similar imaging characteristics. Quantitative MR sequences such as dynamic susceptibility contrast (DSC) perfusion and diffusion (DWI) were assessed for significant differences between the two tumor types and locations. METHODS: A retrospective search for MRI with DSC and DWI on pathology-proven cases of PMA and PA in children was performed. Tumors were manually segmented on anatomic images registered to rCBV, K2, and ADC maps. Tumors were categorized as PA or PMA, with subclassification of supratentorial and infratentorial locations. Mean values were obtained for tumor groups and locations compared with Student's t test for significant differences with post hoc correction for multiple comparisons. ROC analysis for significant t test values was performed. Histogram evaluation was also performed. RESULTS: A total of 49 patients met inclusion criteria. This included 30 patients with infratentorial PA, 8 with supratentorial PA, 6 with supratentorial PMA, and 5 with infratentorial PMA. Mean analysis showed significantly increased rCBV for infratentorial PMA (2.39 ± 1.1) vs PA (1.39 ± 0.16, p = 0.0006). ROC analysis for infratentorial PA vs PMA yielded AUC = 0.87 (p < 0.001). Histogram analysis also demonstrated a higher ADC peak location for PMA (1.8 ± 0.2) vs PA (1.56 ± 0.28). CONCLUSION: PMA has a significantly higher rCBV than PA in the infratentorial space. DSC perfusion and diffusion MR imaging may be helpful to distinguish between the two tumor types in this location.

13.
Cytokine ; 126: 154875, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629102

RESUMO

High mobility group protein B2 (HMGB2) is an important protein attributed to tissue function and homeostasis in osteoarthritis (OA), however, its roles in the temporomandibular joint with mechanical pressure are unclear. This study investigated the expression patterns of HMGB2 in chondrocytes of TMJ on OA-related cellular and animal models. The transcriptional level and protein expression of HMGB2 as well as Col- II, MMP-13 and ß-catenin were examined in primary cultured chondrocytes from TMJs with hydrostatic pressures (HP). The immunohistochemistry of HMGB2, Col- II, MMP13 and ß-catenin in rabbits with surgical anterior disc displacement (ADD) were analyzed. The results indicated that HP decreased the mRNA expression of HMGB2, MMP-13, and ß-catenin. HMGB2 knockdown attenuated the sensitivity of chondrocytes response to pressure loading. Immunohistochemical results showed that the rabbits with ADD exhibited thinner condylar cartilage with disordered cell arrangement. The distribution of HMGB2 was chiefly in the fibrous layer and the proliferative layer of the condylar cartilage. In rabbit cartilage with ADD, the expression of HMGB2 and ß-catenin were elevated at 1 week followed by sustained decrease at 2 and 4 weeks. Our findings suggested that HMGB2 is necessary for TMJ chondrocytes to sense pressure loading, which plays an important role in the pathogenesis of chondrogenesis and TMJOA following mechanical loading.

14.
Compr Psychiatry ; 96: 152145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31710880

RESUMO

BACKGROUND: Studies have shown that patients with schizophrenia are at a high risk of developing insulin resistance (IR). We investigated the prevalence of IR and its clinical correlates in hospitalized Chinese patients with schizophrenia. METHODS: A total of 193 patients with schizophrenia (113 males and 80 females) were recruited for the study. We collected their demographic and clinical data, including data on their plasma glucose and lipid levels. All patients were rated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognitive function, while Positive and Negative Syndrome Scale (PANSS) was used to assess psychopathology. The cut-off value for the homeostasis model assessment of insulin resistance (HOMA-IR) was set at 1.7. RESULTS: The prevalence of IR was 37.82% (73/193). The IR patients had significantly higher waist-to-hip ratio and body mass index (BMI), and higher fasting plasma glucose (FPG), triglyceride (TG), and low density lipoprotein (LDL) levels compared to non-IR patients (all p<.05). Binary logistic regression analysis showed that smoking, BMI, and TG and LDL levels are significant predictors of IR. In addition, correlation analysis showed that IR was significantly correlated with the waist-to-hip ratio, BMI, and LDL level (Bonferroni corrected p<.05). The multivariable linear regression analysis indicated that the BMI and FPG are associated with the IR index. There was no significant difference in IR index between patients who were taking different antipsychotics. CONCLUSION: We found a high prevalence of IR and its risk factors in Chinese patients with schizophrenia. Active weight control to reduce the BMI and waist circumference and reducing the number of cigarettes consumed, may be essential to decrease the incidence of IR in patients with schizophrenia.

15.
Toxicol Sci ; 173(1): 100-113, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609387

RESUMO

Exposure to 4,4'-methylene diphenyl diisocyanate (MDI) in the occupational setting may lead to development of occupational asthma (OA), and the underlying molecular mechanisms of MDI-induced disease pathogenesis remain an active area of research. Using a nose-only mouse inhalation model, we find that circulating microRNA (miR)-206-3p and miR-381-3p are downregulated after MDI exposure; however, cellular miR-206-3p and miR-381-3p responses after MDI aerosol exposure and their pathophysiological roles in MDI-OA are unknown. We hypothesize that miR-206-3p and miR-381-3p-regulated mechanisms cause increased expression of the inducible nitric oxide synthase (iNOS) after MDI aerosol exposure. We examined cellular miR-206-3p and miR-381-3p, calcineurins, nuclear factors of activated T cells (NFATs), and iNOS levels from both nose-only exposed murine bronchoalveolar lavage cells (BALCs) and differentiated THP-1 macrophages treated with MDI-glutathione (GSH) conjugates. Both in vivo murine MDI aerosol exposure and in vitro MDI-GSH exposures in THP-1 macrophages result in downregulation of endogenous miR-206-3p and miR-381-3p and upregulation of PPP3CA and iNOS expression. Transfection of THP-1 macrophages with miR-inhibitor-206-3p and miR-inhibitor-381-3p resulted in the upregulation of PPP3CA and iNOS. Using RNA-induced silencing complex immunoprecipitation and translational reporter assays, we verified that PPP3CA, but not iNOS, is directly targeted by both miR-206-3p and miR-381-3p. Downregulation of miR-206-3p and miR-381-3p following by MDI exposure induces calcineurin/NFAT signaling-mediated iNOS transcription in macrophages and BALCs.

16.
Qual Life Res ; 29(2): 369-380, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31655974

RESUMO

PURPOSE: To assess improvements in health-related quality of life (HRQoL) with ixekizumab treatment in patients with moderate-to-severe psoriasis. METHODS: Adults with plaque psoriasis were enrolled in phase III, double-blind, randomised, controlled trials (UNCOVER-1, UNCOVER-2, or UNCOVER-3). All 3 protocols included a 12-week, placebo-controlled induction period; UNCOVER-2 and UNCOVER-3 also had an active-control group (50 mg etanercept) during induction. After induction, patients in UNCOVER-1 and UNCOVER-2 entered a 48-week withdrawal (maintenance) period (Weeks 12-60), during which Week-12 sPGA (0,1) responders were rerandomized to receive placebo, or 80 mg ixekizumab every 4 weeks (Q4W) or 12 weeks. As a secondary objective, HRQoL was measured by the generic Medical Outcomes Survey Short Form-36 (SF-36) at baseline and Weeks 12 and 60. Changes in mean SF-36 Physical and Mental Component Summary (PCS and MCS) and domain scores and proportions of patients reporting improvements ≥ minimal important differences in SF-36 scores were compared between groups. RESULTS: At Week 12, ixekizumab-treated patients (both dose groups in UNCOVER-1, -2, and -3) reported statistically significantly greater improvements in mean SF-36 PCS and MCS and all 8 SF-36 domain scores versus placebo. Further, more ixekizumab-treated patients than placebo-treated patients reported at least minimal treatment responses in SF-36 PCS and MCS scores and domain scores. Overall improvements in SF-36 PCS and MCS scores were maintained through Week 60. CONCLUSIONS: Ixekizumab-treated patients reported statistically significant improvements in HRQoL at 12 weeks that persisted through 1 year.

17.
Pharmacogenomics J ; 20(1): 57-68, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31611591

RESUMO

Although targeted agents are recommended as the first-line treatments for advanced hepatocellular carcinoma (aHCC), systemic chemotherapy or hepatic arterial infusion chemotherapy (HAIC) are still being used in Asian countries. Beside economic considerations, it was found that targeted drugs could not significantly prolong overall survival in aHCC patients with distant metastasis. In addition, chemotherapy could achieve complete response in a small proportion of patients. Here, we aimed to investigate whether combination of three previously identified single nucleotide polymorphism (SNP) predictors (GALNT14-rs9679162, WWOX-rs13338697, and rs6025211) could guide our choice between systemic chemotherapy, HAIC, and targeted agents in aHCC patients. A cohort of 237 real-world aHCC patients (171 receiving systemic chemotherapy followed by various anticancer treatments including sorafenib; 66 receiving HAIC) were included for outcome analysis. By combining the three SNP markers with or without addition of two clinical criteria (tumor diameter <8 cm, neutrophils <80%), small groups of patients were found to harbor high complete response rates to systemic chemotherapy (35.3% if the 3-SNP signature alone matched; 60.0% if clinical criteria also matched). Subsequent sorafenib treatment for chemotherapy non-responders was associated with longer overall survival (P < 0.001). In HAIC-treated patients, GALNT14-rs9679162 genotype "GG" was associated with longer overall survival (P = 0.019, median survival > 10.5 months). In conclusion, pre-test for the 3-SNP signature in aHCC patients could identify potential systemic chemotherapy or HAIC responders. Chemotherapy non-responders still benefited from subsequent sorafenib treatment. Accordingly, we propose a roadmap for aHCC patients when chemotherapy or HAIC is to be used.

18.
Am J Physiol Heart Circ Physiol ; 318(1): H165-H180, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834839

RESUMO

Normal pregnancy involves extensive remodeling of uterine and spiral arteries and matrix metalloproteinases (MMPs)-mediated proteolysis of extracellular matrix (ECM). Preeclampsia is characterized by hypertension in pregnancy (HTN-Preg) and intrauterine growth restriction (IUGR) with unclear mechanisms. Initial faulty placentation and reduced uterine perfusion pressure (RUPP) could release cytoactive factors and trigger an incessant cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent and depth of uterine vascularization and the proteolytic enzymes and ECM proteins involved are unclear. We hypothesized that HTN-Preg involves decreased uterine vascularization and arterial remodeling by MMPs and accumulation of ECM collagen. Blood pressure (BP) and fetal parameters were measured in normal Preg rats and RUPP rat model, and the uteri were assessed for vascularity, MMP levels, and collagen deposition. On gestational day 19, BP was higher, and the uterus weight, litter size, and pup weight were reduced in RUPP vs. Preg rats. Histology of uterine tissue sections showed reduced number (5.75 ± 0.95 vs. 11.50 ± 0.87) and size (0.05 ± 0.01 vs. 0.12 ± 0.02 mm2) of uterine spiral arterioles in RUPP vs. Preg rats. Immunohistochemistry showed localization of endothelial cell marker cluster of differentiation 31 (CD31) and smooth muscle marker α-actin in uterine arteriolar wall and confirmed decreased number/size of uterine arterioles in RUPP rats. The cytotrophoblast marker cytokeratin-7 showed less staining and invasion of spiral arteries in the deep decidua of RUPP vs. Preg rats. Uterine arteries showed less expansion in response to increases in intraluminal pressure in RUPP vs. Preg rats. Western blot analysis, gelatin zymography, and immunohistochemistry showed decreases in MMP-2 and MMP-9 and increases in the MMP substrate collagen-IV in uterus and uterine arteries of RUPP vs. those in Preg rats. The results suggest decreased number, size and expansiveness of spiral and uterine arteries with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg. Decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could be contributing mechanisms to uteroplacental ischemia in HTN-Preg and preeclampsia.NEW & NOTEWORTHY Preeclampsia is a pregnancy-related disorder in which initial inadequate placentation and RUPP cause the release of cytoactive factors and trigger a ceaseless cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent/depth of uterine vascularization and the driving proteolytic enzymes and ECM proteins are unclear. This study shows decreased number, size, and expansiveness of uterine spiral arteries, with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg rats. The decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could contribute to progressive uteroplacental ischemia in HTN-Preg and preeclampsia.

19.
J Psychiatr Res ; 120: 131-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31670261

RESUMO

Illicit drug use contributes to substantial morbidity and mortality. Drug scheduling, a legal measure in drug enforcement, is often structured as a hierarchy based on addiction tendency, abuse trends, and harm, but may lack data-driven evidence when classifying substances. Our study aims to measure addiction tendency and use trends based on real-world data. We used the open access database of National Police Agency, Ministry of the Interior in Taiwan and analyzed all daily criminal cases of illicit drugs from 2013 to 2017 and monthly illicit drug enforcement data from the same database from 2002 to 2017. We hypothesized that repeat and frequent use despite legal consequence may be a reflection of addictive behavior, and empirical mode decomposition was applied in analysis to calculate addiction tendency indices and intrinsic 15-year use trends. Our analysis showed heroin has the highest addiction index, followed by methamphetamine. 3,4-Methyl enedioxy methamphetamine, marijuana, and ketamine had lower addictive propensities. This result is consistent with most drug scheduling hierarchies. 15-year use trends of substances were consistent with previous epidemiological studies.

20.
Neuropharmacology ; 162: 107783, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31541650

RESUMO

Remifentanil is commonly used clinically for perioperative pain relief, but it may induce postoperative hyperalgesia. Low doses of ketamine have remained a common choice in clinical practice, but the mechanisms of ketamine have not yet been fully elucidated. In this study, we examined the possible effects of ketamine on calcium/calmodulin-dependent protein kinase II α (CaMKIIα) and N-methyl-d-aspartate receptor (NMDAR) subunit NR2B in a mouse model of remifentanil-induced postoperative hyperalgesia (RIPH) in the primary somatosensory cerebral cortex (SI) region. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to assess mechanical allodynia and thermal hyperalgesia, respectively, before and after intraoperative remifentanil administration. Before surgery, mice received intrathecal injections of the following drugs: ketamine, NMDA, BayK8644 (CaMKII activator), and KN93 (CaMKII inhibitor). Immunofluorescence was performed to determine the anatomical location and expression of activated CaMKIIα, phosphorylated CaMKIIα (p-CaMKIIα). Additionally, western blotting was performed to assess p-CaMKIIα and NMDAR expression levels in the SI region. Remifentanil decreased the PWMT and PWTL at 0.5 h, 2 h, and 5 h and increased p-CaMKIIα expression in the SI region. Ketamine increased the PWMT and PWTL and reversed the p-CaMKIIα upregulation. Both BayK8644 and NMDA reversed the effect of ketamine, decreased the PWMT and PWTL, and upregulated p-CaMKIIα expression. In contrast, KN93 enhanced the effect of ketamine by reducing hyperalgesia and downregulating p-CaMKIIα expression. These results suggested that ketamine reversed RIPH by inhibiting the phosphorylation of CaMKIIα and the NMDA receptor in the SI region in mice.

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