Toward safer prescribing: evaluation of a prospective drug utilization review system on inappropriate prescriptions, prescribing patterns, and adverse drug events and related health expenditure in South Korea.

OBJECTIVES: This study aimed to evaluate the effect of the prospective drug utilization review (DUR) system introduced in Korea in December 2010 as a real-time method to improve patient safety, in terms of changes in prescribing practices, adverse drug events (ADEs), and ADE-related healthcare expenditure, using non-steroidal anti-inflammatory drugs (NSAIDs) and their common ADEs as a guide. STUDY DESIGN: We used an interrupted time-series study design using generalized estimating equations to evaluate changes in prescription rate and ADE-related healthcare expenditure. Cox regression analysis was used to evaluate the probability of NSAID-associated ADEs. METHODS: A total of 154,585 outpatients with musculoskeletal or connective tissue disorders, without pre-existing gastric bleeding or ulcers were included in this study. The primary outcome was the level and trend change in prescription rate, drug-drug interactions, coprescribed gastro-protective drugs, and defined daily dose (DDD) of NSAIDs. The secondary outcome was the probability of ADEs and changes in ADE-related healthcare expenditure. RESULTS: There was a significant trend change after introducing the DUR system in terms of drug-drug interactions (-3.6%) and coprescribed gastro-protective drugs (+0.6%). The mean DDD of NSAIDs increased by 0.2. The probability of ADEs decreased overall (-1.7%) and in the high-risk group (age ≥65 years; -9.6%); however, only the latter was significant. There was no significant trend or level change in ADE-related health expenditure. CONCLUSIONS: The introduction of the DUR system was associated with more efficient prescribing, including a reduction in drug-drug interactions and an increase in the use of gastro-protective drugs. The system had a positive effect on patient outcome but was not associated with reduced ADE-related costs. Further studies are needed to evaluate the long-term effects of the DUR system in Korea.

A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Serial transrectal ultrasonography for monitoring the reproductive activity of the Asiatic black bear (Ursus thibetanus ussuricus).

This study evaluated the structural changes in the reproductive tract of Asiatic black bears using serial transrectal ultrasonography. In addition, the ultrasonographic observations were compared with the results of vaginal cytology and hormonal analyses. The collection of blood for hormonal analysis, vaginal cytology and transrectal ultrasonography was performed in two bears (Bears 1 and 2) from June 2011 to August 2013 without mating and in a third bear (Bear 3) from April to December 2012, allowing natural mating. Serial ultrasonographic observations showed cyclic changes in ovarian structures (e.g. emergence of small follicles, growth and ovulation of dominant follicles and corpus luteum (CL) formation) during the reproductive cycles of the three bears. The diameter of the uterine horns remained similar throughout the reproductive cycle in Bears 1 and 2, and it remained similar from April until October, but an enlargement containing foetuses was observed in Bear 3 in December. The ultrasonographic observations were consistent with the data obtained through vaginal cytology and progesterone analysis during the reproductive cycle. An average of 4.0 (±0.4) dominant follicles was observed during the oestrous stage (May-August), during which the superficial cells accounted for >90% of the total vaginal cells. In addition, the detection of an average of 2.6 (±0.2) CL was associated with increased plasma progesterone concentrations (3.0 ± 0.4 ng/ml) between June and December (near hibernation). In conclusion, serial transrectal ultrasonography demonstrated yearly oestrous (ovulation) cycles via follicular dynamics and CL formation on ovaries, accordingly with vaginal cytology and hormonal level in the Asiatic black bear.

Ileal digestibility of amino acids in meat meal and soybean meal fed to growing pigs.

The objective of this experiment was to determine the concentration and digestibility of crude protein (CP) and amino acid (AA) in meat meal (MM), and to compare these values with the respective values in soybean meal (SBM). Six barrows (initial body weight = 66.9±3.8 kg) surgically fitted with a T-cannula at the distal ileum were allotted to a replicated 3×3 balanced Latin square design with 3 diets and 3 periods. Two experimental diets containing test ingredients as the sole source of AA were prepared to estimate the apparent ileal digestibility (AID) for CP and AA by the direct method. An N-free diet was also prepared to estimate basal endogenous losses of CP and AA. All experimental diets contained 5% chromic oxide as an indigestible index. Each period consisted of a 5-d adaptation period and a 2-d of ileal digesta collection period. Ileal digesta samples were collected from 0900 to 1700 on d 6 and 7 of each period. The concentrations of CP, Lys, Met, and Trp in MM and SBM were analyzed to be 64.1, 3.5, 1.1 and 0.6, and 45.6, 2.8, 0.8, and 0.3%, respectively. The AID of all AA except Gly in MM was less (p<0.05) than in SBM. The AID of Lys, Met, and Trp in MM was estimated to be 56.0, 71.7, and 47.1%, respectively. The SID of all AA in MM was less (p<0.05) than in SBM. The SID of Lys, Met, and Trp was 65.1, 79.2, and 78.5%, respectively. In conclusion, the CP and AA contents in MM were greater than those in SBM whereas the ileal digestibility of all AA in MM was less than in SBM.

Conversion of twice-daily tacrolimus to once-daily tacrolimus formulation in stable pediatric kidney transplant recipients: pharmacokinetics and efficacy.

The pharmacokinetics, efficacy and safety of once-daily tacrolimus formulation (Tac-OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice-daily tacrolimus formulation (Tac-BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac-OD on a 1:1 basis and maintained on a once-daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C0 concentrations (4.10 ± 1.16-3.53 ± 1.10 ng/mL, p = 0.004), and AUC0-24 (151.8 ± 41.6-129.8 ± 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac-OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac-BID can be safely converted to Tac-OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated.

Gonadotropin-releasing hormone administration to dairy cows without a corpus luteum 4 weeks after calving increases reproductive performance.

This field study investigated whether the administration of a single dose of gonadotropin-releasing hormone (GnRH) to dairy cows without a corpus luteum (CL) 4 weeks after calving can improve reproductive performance. Holstein dairy cows underwent ultrasonography to assess the presence of ovarian structures at 29.2 ± 5.2 days post-partum, and cows were divided into two main groups based on the presence (CL group, n = 230) or absence (non-CL group, n = 460) of a CL. The non-CL group was further randomly divided into two subgroups based on the administration of GnRH (non-CL GnRH group, n = 230) or no GnRH (non-CL control group, n = 230). Subsets of cows from non-CL control (n = 166) and non-CL GnRH (n = 175) groups received a second ultrasonography at 44.5 ± 5.4 days post-partum to assess CL formation. The percentage of cows with CL at the second ultrasonography was greater in the non-CL GnRH group (70.9%) than in the non-CL control group (53.0%, p = 0.0006). The hazard of the first post-partum insemination by 150 days in milk (DIM) was higher in the CL group than in the non-CL control group (hazard ratio [HR]: 1.36, p = 0.001). The probability of a pregnancy to the first insemination was higher in non-CL GnRH (odds ratio [OR]: 1.50, p = 0.04) and CL groups (OR: 1.55, p = 0.03) compared to the non-CL control group. Furthermore, the hazard of pregnancy by 210 DIM was higher in non-CL GnRH (HR: 1.30, p = 0.01) and CL (HR: 1.51, p = 0.0001) groups than in the non-CL control group. In conclusion, administration of GnRH to dairy cows without a CL 4 weeks after calving was associated with an increase in ovulation and improved reproductive performance.

Transcriptome analysis of the response of cultured murine podocytes to puromycin aminonucleoside.

AIMS: Idiopathic nephrotic syndrome is known as a disease of the renal glomerular epithelial cells (podocytes). Recent advances in podocyte biology showed that podocytopathy is the culprit of nephrotic syndrome. To obtain comprehensive information about the response of podocytes to injury, we investigated the gene expression profile of podocytes in response to puromycin aminonucleoside (PAN)-induced injury. METHODS: Differentiated mouse podocyte cell line (MPC5) cells were treated with 25 microg/ml PAN for 24, 48, or 72 h. Gene expression profiles of these cells were analyzed. Real time PCR analysis was used to confirm the findings of microarray. RESULTS: Expression levels of 23 genes (differentially expressed genes, DEGs), including laminin alpha(1) and MMP3, were significantly different between PAN-treated podocytes and untreated cells. Gene ontology of DEGs indicated that their functional categories were cell adhesion, extracellular matrix (ECM) formation, and ECM degradation. Real-time PCR and indirect immunohistochemistry of PAN-treated and untreated podocytes confirmed the differential expression of DEGs. CONCLUSION: Using unbiased global gene expression profiling, we found that podocytes respond to PAN-induced injury by down-regulating the expression of genes involved in cell adhesion and extracellular matrix.

Unicameral bone cysts: a comparison of injection of steroid and grafting with autologous bone marrow.

Open surgery is rarely justified for the initial treatment of a unicameral bone cyst, but there is some debate concerning the relative effectiveness of closed methods. This study compared the results of steroid injection with those of autologous bone marrow grafting for the treatment of unicameral bone cysts. Between 1990 and 2001, 30 patients were treated by steroid injection and 28 by grafting with autologous bone marrow. The overall success rates were 86.7% and 92.0%, respectively (p>0.05). The success rate after the initial procedure was 23.3% in the steroid group and 52.0% in those receiving autologous bone marrow (p<0.05), and the respective cumulative success rates after second injections were 63.3% and 80.0% (p>0.05). The mean number of procedures required was 2.19 (1 to 5) and 1.57 (1 to 3) (p<0.05), the mean interval to healing was 12.5 months (4 to 32) and 14.3 months (7 to 36) (p>0.05), and the rate of recurrence after the initial procedure was 41.7% and 13.3% in the steroid and in the autologous bone marrow groups, respectively (p<0.05). Although the overall rates of success of both methods were similar, the steroid group had higher recurrence after a single procedure and required more injections to achieve healing.

Objective assessment of gait in xylazine-induced ataxic horses.

BACKGROUND: There is poor agreement between observers of equine neurological gait abnormalities using the modified Mayhew grading scale. OBJECTIVES: To stimulate a dose-dependent ataxia in horses through xylazine administration and identify quantifiable relevant gait parameters. STUDY DESIGN: Balanced, randomised, 2-way crossover design. METHODS: Eight horses were assessed before and after administration of xylazine (low dose and high dose). Gait analyses performed before and after xylazine administration included: 1) kinematic data collected on an equine high-speed treadmill (flat and 10% decline) and from accelerometers placed on head and sacrum; and 2) kinetic data collected on a force plate. RESULTS: All horses developed dose-dependent ataxia. Horses developed a dose-dependent increased stride time, stride length, and time of contact (P<0.0001), and a decreased stride frequency (P<0.0002) after administration of xylazine. Although pelvic acceleration increased in the mediolateral direction (P<0.05) in horses walked on the treadmill, this movement decreased when walking over ground after administration of xylazine (P<0.05). Furthermore, centre of pressure and path length indices changed significantly in horses following administration of xylazine (P<0.05). MAIN LIMITATIONS: This study examined one breed of horse (Arabian), all of similar height and weight. Accelerometers were attached to skin, not bone; no correction was made for artefacts from skin displacement. The sedative drug effect is of certain duration, limiting the data collection period. CONCLUSIONS: Administration of xylazine induced a dose-dependent ataxia in horses and resulted in significant changes of gait parameters, pelvic accelerations, and stabilographic variables, some of which changed in a dose-dependent fashion. Some of the altered gait parameters in this model were probably a result of overall slowing down of the stride cycle secondary to the sedative effect. Continued efforts to discover and evaluate quantifiable gait parameters that are susceptible to change following development of clinical neurological disease in horses is warranted.

Closed intramedullary nailing with percutaneous cement augmentation for long bone metastases.

AIMS: The purpose of the study was to investigate whether closed intramedullary (IM) nailing with percutaneous cement augmentation is better than conventional closed nailing at relieving pain and suppressing tumours in patients with metastases of the femur and humerus. PATIENTS AND METHODS: A total of 43 patients (27 men, 16 women, mean age 63.7 years, standard deviation (sd) 12.2; 21 to 84) underwent closed IM nailing with cement augmentation for long bone metastases. A further 27 patients, who underwent conventional closed IM nailing, served as controls. Pain was assessed using a visual analogue scale (VAS) score pre-operatively (pre-operative VAS), one week post-operatively (immediate post-operative VAS), and at six weeks post-operatively (follow-up post-operative VAS). Progression of the tumour was evaluated in subgroups of patients using F-18-fludeoxyglucose (F-18-FDG) positron emission tomography (PET)/computed tomography (CT) and/or bone scintigraphy (BS), at a mean of 8.8 and 7.2 months post-operatively, respectively. RESULTS: The mean pain scores of patients who underwent closed nailing with cement augmentation were significantly lower than those of the control patients post-operatively (immediate post-operative VAS: 3.8, sd 0.9 versus 6.0, sd 0.9; follow-up post-operative VAS: 3.3, sd 2.5 versus 6.6, sd 2.2; all p < 0.001). The progression of the metastasis was suppressed in 50% (10/20) of patients who underwent closed nailing with augmentation, but in only 8% (1/13) of those in the control group. CONCLUSION: Percutaneous cement augmentation of closed IM nailing improves the relief of pain and limits the progression of the tumour in patients with metastases to the long bones. TAKE HOME MESSAGE: Percutaneous cement augmentation while performing closed IM nailing has some advantages for long bone metastases. Cite this article: Bone Joint J 2016;98-B:703-9.