Assessment of lytic therapy effect in patients with intermediate-high risk pulmonary embolism for prevention of chronic thromboembolic pulmonary hypertension: A randomized, double-blind trial.

Background and Aims: This study aims to compare the effectiveness of thrombolytic therapy and anticoagulation in preventing chronic thromboembolic pulmonary hypertension (CTEPH). Method: A total of 60 patients with intermediate-high risk pulmonary embolism (PE) were randomly assigned to receive either thrombolytic therapy (n = 30) or anticoagulation (n = 30). Results: Echocardiographic assessments demonstrated no significant differences between the two treatment approaches in terms of right ventricular size (RVS) (on discharge in thrombolytic group: 31.17 ± 3.43 vs. anticoagulant group: 32.73 ± 5.27, p = 0.912), tricuspid annular plane systolic excursion (TAPSE) (on discharge in thrombolytic group: 17.66 ± 2.39 vs. anticoagulant group: 16.73 ± 2.93, p = 0.290), and systolic pulmonary artery pressure (SPAP) (on discharge in thrombolytic group: 32.93 ± 9.73 vs. anticoagulant group: 34.46 ± 9.30, p = 0.840). However, significant changes were observed in all assessed parameters within each treatment group (p < 0.001). The 6-month follow-up showed no significant difference between the two groups in terms of CTEPH incidence (p = 0.781) or functional class of the patients (p = 0.135). Conclusion: Based on the findings of this study, neither thrombolytic therapy nor anticoagulation demonstrated superiority over the other in reducing adverse outcomes associated with intermediate-high risk PE, including right ventricular size, SPAP, TAPSE, or CTEPH.

Strong evidence for association between K232A polymorphism of the DGAT1 gene and milk fat and protein contents: A meta-analysis.

The relationship between K232A polymorphism of the DGAT1 gene and milk yield and composition was evaluated by meta-analysis of pooled data of more than 10,000 genotyped cattle. Four genetic models, including dominant (AA+KA vs. KK), recessive (AA vs. KA+KK), additive (AA vs. KK), and co-dominant (AA+KK vs. KA) were used to analyze the data. The standardized mean difference (SMD) was used to measure the size of the effects of the A and K alleles of K232A polymorphism on milk-related traits. The results showed that additive model was the best model for describing the effects of K232A polymorphism on studied traits. Under additive model, milk fat content was strongly decreased in cows having the AA genotype (SMD = -1.320). Furthermore, the AA genotype reduced the protein content of milk (SMD = -0.400). A significant difference in daily milk yield (SMD = 0.225) and lactation yield (SMD = 0.697) was found between cows carrying AA and KK genotypes, suggesting the positive effects of the K allele on these traits. Cook's distance measurement suggested some studies as outliers and sensitivity analyses by removing influential studies revealed that the results of meta-analyses for daily milk yield, fat content and protein content were not sensitive to outliers. However, the outcome of the meta-analysis for lactation yield was strongly influenced by outlier studies. Egger's test and Begg's funnel plots showed no evidence of publication bias in included studies. In conclusion, the K allele of K232A polymorphism showed a tremendous effect on increasing fat and protein contents in the milk of cattle, especially when 2 copies of this allele are inherited together, whereas the A allele of K232A polymorphism had negative effects on these traits.

Genome-wide association study reveals novel candidate genes for litter size in Markhoz goats.

Introduction: The Markhoz goat is the only breed that can produce high-quality fiber called mohair in Iran; however, the size of its population has faced a dramatic decline during the last decades, mainly due to the reluctance of farmers to rear Markhoz goats caused by a reduction in goat production income. Litter size at birth (LSB) and weaning (LSW) are two economically important reproductive traits for local goat breeders and have the potential of increasing the population growth rate. The present study was aimed to identify possible genomic regions that are associated with LSB and LSW in Markhoz goats using a genome-wide association study (GWAS). Methods: To this end, 136 Markhoz goats with record(s) of kidding were selected for GWAS using the Illumina Caprine 50K bead chip. The individual breeding values (BV) of available LSB and LSW records estimated under an animal mixed model were used as the dependent variable in the GWAS, thereby incorporating repeated categorical variables of litter size. Results: Four SNPs on chromosomes 2, 20 and 21 were identified to be significantly associated (FDR p < 0.05) with LSB after multiple testing correction under a Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK) model. Least-square analysis was performed to investigate the effects of detected genotypes on LSB. Ultimately, the GWAS results introduced six candidate genes, including GABRA5, AKAP13, SV2B, PPP1R1C, SSFA2 and TRNAS-GCU in a 100 kb adjacent region of the identified SNPs. Previous studies proposed functional roles of GABRA5 and AKAP13 genes in reproductive processes; however, the role of other candidate genes in reproduction is not clear. Conclusion: These findings warrant further investigation for use in marker-assisted selection programs in Markhoz goats.

Effects of Imported Semen Based on Different Selection Indices on Some Production and Reproduction Traits in Iranian Holstein Cattle.

The aim of the present study was to evaluate the effects of imported semen of Holstein bulls from different countries on the economic traits of their daughters using the Lifetime Net Income (LNI) index in various climates of Iran. The data included the first lactation records of 274,057 Holstein cows collected during 1993 to 2017 by the Animal Breeding Center of Iran from 10 large dairy farms located in various provinces of Iran. The investigated traits included milk, fat and protein yields, calving age and calving interval. Breeding values of progenies were predicted by the Best Linear Unbiased Prediction (BLUP) method under the multi-trait animal model using DMU software. The genetic-economic merit of the progenies was estimated by the LNI index. There were significant differences between the estimated breeding values (EBVs) of sire groups (based on bull semen origin) for milk, fat and protein yields, calving age and calving interval in each climate (p < 0.01). The obtained results showed that the highest least-square means of LNI index in semi-cold, moderate and warm climates belonged to the daughters of French sires; however, daughters of German sires were estimated to have the highest least-square means in the cold climate.

Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia.

In haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), the combination of anti-thymocyte globulin and post-transplant cyclophosphamide (ATG/PTCy) has a synergistic impact in preventing graft-versus-host disease (GvHD). However, little is known about the long-term consequences of the new combination approach. Our goal is to evaluate the efficacy of ATG/PTCy versus a standard ATG regimen by focusing at long-term outcomes in a more homogeneous group of patients. We retrospectively included 118 adult patients up to 60 years with acute leukemia who underwent haplo-PBSCT at our single institution, following the same myeloablative conditioning regimen. From 2010 to 2020, 78 patients received a modified combination of ATG (2.5 mg/kg/day, on days -3, -2, and -1) and PTCy (40 mg/kg/day on days +3 and +4) compared to 40 patients who had a standard ATG-based regimen (2.5 mg/kg/day from days -4 to -1) from 2008 to 2015. The median follow-up time for all patients was 5.36 years, respectively. The cumulative incidence (CI) of neutrophil and platelet engraftment, as well as CMV reactivation, did not differ statistically between the two groups. The CI of the acute GvHD of grades II-IV and III-IV and extensive chronic GvHD were considerably lower in the ATG/PTCy (34.6%, 8.97%, and 13.63%) than in the ATG cohort (57.5%, 30%, and 38.23%) as validated by multivariable modeling. Additionally, compared to the ATG arm, the ATG/PTCy was a hazard factor associated with a higher risk of relapse (HR = 2.23, p = 0.039). The probability of 5-year overall survival, disease-free survival, and GvHD-free relapse-free survival in the ATG/PTCy group (53.34%, 49.77%, and 36.04%) was comparable with the ATG group (47.5%, 42.5%, and 22.5%), respectively. Our finding suggested that a modified ATG/PTCy combination resulted in a lower risk of acute and chronic GvHD and a higher risk of relapse than the standard ATG-based protocol but had no effect on long-term outcomes. However, certain adjustments in the immunosuppression protocol are warranted to improve the outcome.

Constraint-Based, Score-Based and Hybrid Algorithms to Construct Bayesian Gene Networks in the Bovine Transcriptome.

Bayesian gene networks are powerful for modelling causal relationships and incorporating prior knowledge for making inferences about relationships. We used three algorithms to construct Bayesian gene networks around genes expressed in the bovine uterus and compared the efficacies of the algorithms. Dataset GSE33030 from the Gene Expression Omnibus (GEO) repository was analyzed using different algorithms for hub gene expression due to the effect of progesterone on bovine endometrial tissue following conception. Six different algorithms (grow-shrink, max-min parent children, tabu search, hill-climbing, max-min hill-climbing and restricted maximum) were compared in three higher categories, including constraint-based, score-based and hybrid algorithms. Gene network parameters were estimated using the bnlearn bundle, which is a Bayesian network structure learning toolbox implemented in R. The results obtained indicated the tabu search algorithm identified the highest degree between genes (390), Markov blankets (25.64), neighborhood sizes (8.76) and branching factors (4.38). The results showed that the highest number of shared hub genes (e.g., proline dehydrogenase 1 (PRODH), Sam-pointed domain containing Ets transcription factor (SPDEF), monocyte-to-macrophage differentiation associated 2 (MMD2), semaphorin 3E (SEMA3E), solute carrier family 27 member 6 (SLC27A6) and actin gamma 2 (ACTG2)) was seen between the hybrid and the constraint-based algorithms, and these genes could be recommended as central to the GSE33030 data series. Functional annotation of the hub genes in uterine tissue during progesterone treatment in the pregnancy period showed that the predicted hub genes were involved in extracellular pathways, lipid and protein metabolism, protein structure and post-translational processes. The identified hub genes obtained by the score-based algorithms had a role in 2-arachidonoylglycerol and enzyme modulation. In conclusion, different algorithms and subsequent topological parameters were used to identify hub genes to better illuminate pathways acting in response to progesterone treatment in the bovine uterus, which should help with our understanding of gene regulatory networks in complex trait expression.

Variation and frequency of supernumerary teats, litter size, histological features and the fibroblast growth factor 2 (FGF-2) gene expression pattern in goats.

Historically, female domestic goats carrying multiple kids are mostly unable to express sufficient nursing ability due to a limited number of functional teats. Therefore, the functional teat is an important component in prolific goat breeding, and plays a key role in the future health of their kids. With this motivation, we wanted to investigate the phenotypic features, litter size, histology of adult female mammary glands, and the gene expression profile of the fibroblast growth factor 2 (FGF-2) gene in goats. To illustrate this, the initial dataset of the current study consists of an electronic questionnaire that includes 697 individuals (548 does and 149 bucks) of five endemic and three exotic goats from 2015 to 2020 in different geographic areas of Iran, from 59 Markhoz (MARG), 50 Azari (AZAR), 73 Busheri (BUSH), 69 Sarbisheh (SARB), 165 Mahabadi (MOHA) indigenous goats and also exotic breeds, including 183 Saanen (SANN), 39 Alpine (ALPN), and 59 Boer (BORE) goats. The results of this study confirmed that MOHA goats (4.16%), BORE (4.43%) and SANN goat breeds (5.75%) have larger litter sizes. Interestingly, the evidence gathering when SNTs occurred showed that both the BUSH and BORE goat breeds had the highest frequency of SNTs. Moreover, under the same physiological and lactation conditions, there was no statistically significant difference in histological features between the three compared does class consist of the two teats, SNTs, and four functional teats. In addition, the results of the gene expression profile significantly highlight the FGF-2 gene pattern in two teat groups compared to other SNT groups (P < 0.01). In summary, this scenario can be used to generate further research and facts on responsible candidate genes, the variations in teat numbers in goats, examining both the incidence of SNT and litter size.

Meta-analysis of association between c.963A>G single-nucleotide polymorphism on BMP15 gene and litter size in goats.

Litter size is an important economic trait in the goat industry. Previous studies on the bone morphogenetic protein 15 (BMP15) gene detected some single-nucleotide polymorphisms (SNPs) such as c.963A > G that were associated with an increase in ovulation rate and litter size. The aim of this study was to conduct a meta-analysis on the effect of this polymorphism on litter size. We gathered and pooled data from five eligible published studies. To investigate the effect of c.963A > G on litter size, we utilized four different genetic models assuming dominant (GG  +  GA vs. AA), recessive (GG vs. GA  +  AA), additive (GG vs. AA) and co-dominant (GG  +  AA vs. GA) model of inheritance. Data were analyzed under random-effects models based on the I 2 value. Furthermore, sensitivity analysis was carried out to validate the stability of results. The results showed that the c.963A > G polymorphism is associated with litter size when applying a dominant model (standardized mean difference (SMD) is 0.815, 95 % CI [0.170, 1.461], P  value  =  0.013) and also with an additive model (SMD  =  0.755, 95 % CI [0.111, 1.400], P  value  =  0.022). However, the effect of c.963A > G polymorphism was not significant under recessive (SMD  =  0.186, 95 % CI [ - 0.195, 4.259], P  value  =  0.339) and co-dominant (SMD  =   - 0.119, 95 % CI [ - 0.525, 0.288], P  value  =  0.568) models. Sensitivity analysis demonstrated that dropping studies with wide confidence intervals affects overall results under the assumption of an additive model. The meta-analysis results revealed that the AA genotype could be positively connected with litter size in goats.

A novel variant in the promoter region of miR-9 gene strongly affects litter size in Markhoz goats.

This study aimed to identify and evaluate the effects of single nucleotide polymorphisms (SNPs) within miR-9 and miR-27a genes and their promoters, as well as 3'UTR regions of KITLG and IGF1 genes on litter size in Markhoz goats. PCR-SSCP analysis revealed different band patterns and sequencing results confirmed four SNPs including a C/A, a A/G, a C/T and a A/G substitution located in the promoter region of miR-9 gene, 48 bp upstream of miR-9 seed region within the 3'UTR of KITLG gene, 37 bp downstream of miR-27a gene and 39 bp upstream of miR-9 seed region within the 3'UTR of IGF1 gene, respectively. The results of the least-square analyses indicated that AA genotype of miR-9 gene strongly and positively affects litter size in Markhoz goats (P < 0.01). Furthermore, the results of the logistic regression analyses confirmed that the A allele of miR-9 gene has a tremendous impact on litter size in Markhoz goats (P < 0.01). Scanning the promoter region of miR-9 gene showed that changing C allele to A may prevent HES1, HES2, NRF1 and TCFL5 transcription factors (TFs) from binding to the promoter, which can reduce the expression of miR-9 gene. Principle component analysis (PCA) showed that approximately 60% of the variation of the data set was explained by two of four SNPs. Also, the biplot from the PCA showed a strong association between litter size and C/A polymorphism of miR-9 promoter. Linkage disequilibrium analysis revealed a very slight linkage among investigated loci.

Association between c.1189G>A single nucleotide polymorphism of GDF9 gene and litter size in goats: A meta-analysis.

Litter size is one of the most important traits in goat production and breeding. The most common and presumed single nucleotide polymorphism (SNP) detected in the Growth Differentiation Factor 9 gene is c.1189G>A (rs637044681, Ensembl) which results in an altered sequence of the encoded protein. In some studies, there was no effect of this SNP on litter size, while in other studies there was an effect. In the present study there was a meta-analysis conducted by pooling results from 11 eligible published studies to investigate effects of c.1189G>A polymorphism on litter size using four different genetic models including dominant (AA + AG compared with GG), recessive (AA compared with AG + GG), additive (AA compared with GG) and co-dominant (AA + GG compared with AG). Data were analyzed using fixed and random-effect models based on the I-squared value. Results indicate the c.1189G>A polymorphism is positively associated with litter size with use of the dominant model (SMD = 0.093, 95% CI = 0.028 to 0.158, P-Value = 0.005). There, however, was no effect of the c.1189G>A polymorphism using the recessive (SMD = 0.065, 95% CI = -0.164 to 0.295, P-Value = 0.577), additive (SMD = 0.172, 95% CI = -0.169 to 0.513, P-Value = 0.324) and co-dominant (SMD = -0.083, 95% CI = -0.200 to 0.034, P-Value = 0.164) genetic models. Results from use of the sensitivity analysis indicate the GG genotype affect litter size with use of the additive model (P < 0.01). The results from this meta-analysis indicate the GG genotype is associated with litter size in goats.

WITHDRAWN:Identification of bovine uterine transcriptomic hub genes using Bayesian network algorithms.

Ahead of Print article withdrawn by publisher.

Genome-Wide Association Studies Identify Candidate Genes for Coat Color and Mohair Traits in the Iranian Markhoz Goat.

The Markhoz goat provides an opportunity to study the genetics underlying coat color and mohair traits of an Angora type goat using genome-wide association studies (GWAS). This indigenous Iranian breed is valued for its quality mohair used in ceremonial garments and has the distinction of exhibiting an array of coat colors including black, brown, and white. Here, we performed 16 GWAS for different fleece (mohair) traits and coat color in 228 Markhoz goats sampled from the Markhoz Goat Research Station in Sanandaj, Kurdistan province, located in western Iran using the Illumina Caprine 50K beadchip. The Efficient Mixed Model Linear analysis was used to identify genomic regions with potential candidate genes contributing to coat color and mohair characteristics while correcting for population structure. Significant associations to coat color were found within or near the ASIP, ITCH, AHCY, and RALY genes on chromosome 13 for black and brown coat color and the KIT and PDGFRA genes on chromosome 6 for white coat color. Individual mohair traits were analyzed for genetic association along with principal components that allowed for a broader perspective of combined traits reflecting overall mohair quality and volume. A multitude of markers demonstrated significant association to mohair traits highlighting potential candidate genes of POU1F1 on chromosome 1 for mohair quality, MREG on chromosome 2 for mohair volume, DUOX1 on chromosome 10 for yearling fleece weight, and ADGRV1 on chromosome 7 for grease percentage. Variation in allele frequencies and haplotypes were identified for coat color and differentiated common markers associated with both brown and black coat color. This demonstrates the potential for genetic markers to be used in future breeding programs to improve selection for coat color and mohair traits. Putative candidate genes, both novel and previously identified in other species or breeds, require further investigation to confirm phenotypic causality and potential epistatic relationships.

Modeling lactation curves and estimation of genetic parameters in Holstein cows using multiple-trait random regression models.

We compared the goodness of fit of three mathematical functions (including: Legendre polynomials, Lidauer-Mäntysaari function and Wilmink function) for describing the lactation curve of primiparous Iranian Holstein cows by using multiple-trait random regression models (MT-RRM). Lactational submodels provided the largest daily additive genetic (AG) and permanent environmental (PE) variance estimates at the end and at the onset of lactation, respectively, as well as low genetic correlations between peripheral test-day records. For all models, heritability estimates were highest at the end of lactation (245 to 305 days) and ranged from 0.05 to 0.26, 0.03 to 0.12 and 0.04 to 0.24 for milk, fat and protein yields, respectively. Generally, the genetic correlations between traits depend on how far apart they are or whether they are on the same day in any two traits. On average, genetic correlations between milk and fat were the lowest and those between fat and protein were intermediate, while those between milk and protein were the highest. Results from all criteria (Akaike's and Schwarz's Bayesian information criterion, and -2*logarithm of the likelihood function) suggested that a model with 2 and 5 coefficients of Legendre polynomials for AG and PE effects, respectively, was the most adequate for fitting the data.

Tiotropium effects on airway inflammatory events in the cat as an animal model for acute cigarette smoke-induced lung inflammation.

BACKGROUND: Chronic obstructive pulmonary disease is an inflammatory lung disease mainly caused by tobacco smoke inhalation. METHODS: Fifteen healthy adult male cats were categorized into 3 groups: (1) control group, (2) exposed to cigarette smoke (CS), and (3) exposed to CS treated with tiotropium. RESULTS: Increases in clinical signs and airway responsiveness in CS cats were found compared to control animals. The airway hyperresponsiveness and clinical signs were significantly attenuated by treatment with tiotropium. The CS-induced pulmonary release of interleukin-6, interleukin-8, monocyte chemotactic protein-1, and tumor necrosis factor alpha was reduced in the tiotropium group. Exposure to CS significantly increased total inflammatory cells number in bronchoalveolar lavage fluid, which was significantly attenuated by treatment with tiotropium. The number of macrophages, eosinophils and neutrophils and lymphocytes was increased after exposure to CS. Tiotropium significantly reduced the number of all these cells. Perivascular, peribronchiolar infiltration of inflammatory cells and Reid index increased in the CS group. Treatment with tiotropium significantly reduced these parameters to control level. Enhanced lipid peroxidation with concomitant reduction of antioxidants status was observed in the CS group. Tiotropium significantly reduced the serum, lung lavage, lung, and tracheal tissue lipid peroxides to near control levels. Tiotropium also decreased lung and tracheal protein leakage, and prevented the reduction of total antioxidant status in serum, lung lavage, lung and tracheal tissue of the CS group. CONCLUSION: Cigarette smoke increases airway responsiveness and inflammation in a cat model of CS induced lung inflammation. It can effectively be reduced by treatment with tiotropium.

Impact of family history of diabetes and ethnicity on -cell function in obese, glucose-tolerant individuals.

CONTEXT: The increased insulin secretion in response to reduced insulin sensitivity (SI) is heritable, but whether the genetic predisposition is restricted to members of high-risk Caucasian families is unknown. Furthermore, the relative importance of insulin resistance and defective beta-cell compensation in the increased prevalence of type 2 diabetes (T2DM) in African-American compared with Caucasian individuals is uncertain. OBJECTIVES: We tested whether obese individuals with a family history of T2DM have decreased beta-cell compensation compared with obese controls without a family history of T2DM. In addition, we compared S(I) and insulin secretion measures in African-American and Caucasian individuals. DESIGN: SI, acute insulin response to iv glucose (AIRg), maximally potentiated insulin response to arginine (AIRmax), and disposition indexes (DIs) (DI = SI * AIRg; DImax = SI * AIRmax) were compared among nondiabetic Caucasian and African-American individuals with and without a family history of diabetes. SETTING: This study was performed in an Ambulatory General Clinical Research Center. SUBJECTS: SUBJECTS were healthy, nondiabetic individuals with or without a family history of T2DM. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Comparison of SI, AIRg, AIRmax, DI, and DImax between Caucasians and African-Americans with or without a strong family history of T2DM were made. RESULTS: Obese subjects did not differ in SI, AIRg, or DI by family history of diabetes. African-Americans had 8% lower SI (P < 0.001), but 68% higher AIRg (P < 0.001) and 46% higher DI (P = 0.001) than age, gender, body mass index-matched Caucasian individuals. However, African-Americans had lower DImax compared with Caucasians. CONCLUSIONS: We found no reduction in insulin secretion in obese subjects with a family history of T2DM compared with controls, but in general, African-Americans were more insulin resistant and had lower maximal beta-cell response (DImax). The paradoxical increased DI could be explained by the reduced hepatic insulin extraction.

Retinol binding protein 4 expression in humans: relationship to insulin resistance, inflammation, and response to pioglitazone.

CONTEXT: Retinol binding protein 4 (RBP4) was recently found to be expressed and secreted by adipose tissue, and was strongly associated with insulin resistance. OBJECTIVE: The aim was to determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans. DESIGN AND PATIENTS: RBP4 mRNA levels in adipose tissue and muscle of nondiabetic human subjects with either normal or impaired glucose tolerance (IGT) were studied, along with plasma RBP4. RBP4 gene expression was also measured in adipose tissue fractions, and from visceral and sc adipose tissue (SAT) from surgical patients. SETTING: The study was conducted at University Hospital and General Clinical Research Center. INTERVENTION: Insulin sensitivity (S(I)) was measured, and fat and muscle biopsies were performed. In IGT subjects, these procedures were performed before and after treatment with metformin or pioglitazone. MAIN OUTCOME MEASURES: The relationship between RBP4 expression and obesity, S(I), adipose tissue inflammation, and intramyocellular lipid level, and response to insulin sensitizers was measured. RESULTS: RBP4 was expressed predominantly from the adipocyte fraction of SAT. Although SAT RBP4 expression and the plasma RBP4 level demonstrated no significant relationship with body mass index or S(I), there was a strong positive correlation between RBP4 mRNA and adipose inflammation (monocyte chemoattractant protein-1 and CD68), and glucose transporter 4 mRNA. Treatment of IGT subjects with pioglitazone resulted in an increase in S(I) and an increase in RBP4 gene expression in both adipose tissue and muscle, but not in plasma RBP4 level, and the in vitro treatment of cultured adipocytes with pioglitazone yielded a similar increase in RBP4 mRNA. CONCLUSIONS: RBP4 gene expression in humans is associated with inflammatory markers, but not with insulin resistance. The increase in RBP4 mRNA after pioglitazone treatment is unusual, suggesting a complex regulation of this novel adipokine.

Do visual analogue scale (VAS) derived standard gamble (SG) utilities agree with Health Utilities Index utilities? A comparison of patient and community preferences for health status in rheumatoid arthritis patients.

BACKGROUND: Assessment of Health Related Quality of Life (HRQL) has become increasingly important and various direct and indirect methods and instruments have been devised to measure it. In direct methods such as Visual Analog Scale (VAS) and Standard Gamble (SG), respondent both assesses and values health states therefore the final score reflects patient's preferences. In indirect methods such as multi-attribute health status classification systems, the patient provides the assessment of a health state and then a multi-attribute utility function is used for evaluation of the health state. Because these functions have been estimated using valuations of general population, the final score reflects community's preferences. The objective of this study is to assess the agreement between community preferences derived from the Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) systems, and patient preferences. METHODS: Visual analog scale (VAS) and HUI scores were obtained from a sample of 320 rheumatoid arthritis patients. VAS scores were adjusted for end-aversion bias and transformed to standard gamble (SG) utility scores using 8 different power conversion formulas reported in other studies. Individual level agreement between SG utilities and HUI2 and HUI3 utilities was assessed using the intraclass correlation coefficient (ICC). Group level agreement was assessed by comparing group means using the paired t-test. RESULTS: After examining all 8 different SG estimates, the ICC (95% confidence interval) between SG and HUI2 utilities ranged from 0.45 (0.36 to 0.54) to 0.55 (0.47 to 0.62). The ICC between SG and HUI3 utilities ranged from 0.45 (0.35 to 0.53) to 0.57 (0.49 to 0.64). The mean differences between SG and HUI2 utilities ranged from 0.10 (0.08 to 0.12) to 0.22 (0.20 to 0.24). The mean differences between SG and HUI3 utilities ranged from 0.18 (0.16 to 0.2) to 0.28 (0.26 to 0.3). CONCLUSION: At the individual level, patient and community preferences show moderate to strong agreement, but at the group level they have clinically important and statistically significant differences. Using different sources of preference might alter clinical and policy decisions that are based on methods that incorporate HRQL assessment. VAS-derived utility scores are not good substitutes for HUI scores.

When patients have to pay a share of drug costs: effects on frequency of physician visits, hospital admissions and filling of prescriptions.

BACKGROUND: Previous research has shown that patient cost-sharing leads to a reduction in overall health resource utilization. However, in Canada, where health care is provided free of charge except for prescription drugs, the converse may be true. We investigated the effect of prescription drug cost-sharing on overall health care utilization among elderly patients with rheumatoid arthritis. METHODS: Elderly patients (> or = 65 years) were selected from a population-based cohort with rheumatoid arthritis. Those who had paid the maximum amount of dispensing fees (200 dollars) for the calendar year (from 1997 to 2000) were included in the analysis for that year. We defined the period during which the annual maximum co-payment had not been reached as the "cost-sharing period" and the one beyond which the annual maximum co-payment had been reached as the "free period." We compared health services utilization patterns between these periods during the 4 study years, including the number of hospital admissions, the number of physician visits, the number of prescriptions filled and the number of prescriptions per physician visit. RESULTS: Overall, 2968 elderly patients reached the annual maximum cost-sharing amount at least once during the study periods. Across the 4 years, there were 0.38 more physician visits per month (p < 0.001), 0.50 fewer prescriptions filled per month (p = 0.001) and 0.52 fewer prescriptions filled per physician visit (p < 0.001) during the cost-sharing period than during the free period. Among patients who were admitted to the hospital at least once, there were 0.013 more admissions per month during the cost-sharing period than during the free period (p = 0.03). INTERPRETATION: In a predominantly publicly funded health care system, the implementation of cost-containment policies such as prescription drug cost-sharing may have the unintended effect of increasing overall health utilization among elderly patients with rheumatoid arthritis.

Are indirect utility measures reliable and responsive in rheumatoid arthritis patients?

BACKGROUND: Preference-based, generic measures are increasingly being used to measure quality of life and as sources for quality weights in the estimation of Quality Adjusted Life Years (QALYs) in rheumatoid arthritis (RA). However, among the most commonly used instruments (the Health Utilities Index 2 and 3 [HUI2 and HUI3], the EuroQoL-5D [EQ-5D], and the Short Form-6D [SF-6D], there has been little comparative research. Therefore, we examined the reliability and responsiveness of these measures and the Rheumatoid Arthritis Quality of Life (RAQoL) and the Health Assessment Questionnaire (HAQ) in a sample of RA patients. MAJOR FINDINGS: Test-retest reliability was acceptable for all of the instruments with the exception of the EQ-5D. Using two external criteria to define change (a patient transition question and categories of the patient global assessment of disease activity VAS), the RAQoL was the most responsive of the instruments. For the indirect utility instruments, the HUI3 and the SF-6D were the most responsive for measuring positive change. On average, for patients whose RA improved, the absolute change was highest for the HUI3. CONCLUSIONS: The HUI3 and the SF-6D appear to be the most responsive of the preference-based instruments in RA. However, differences in the magnitude of the absolute change scores have important implications for cost-effectiveness analyses.