Drug-related problems associated with direct oral anticoagulants: an observational cross-sectional study of medical record review by pharmacists in a large teaching hospital.

Background: Prescribing DOACs presents with challenges in the elderly and patients with renal and hepatic impairment. To mitigate safety risks, pharmacists have a role in detection, prevention, and resolution of DOAC-associated drug-related problems (DRPs). Objectives: To identify the types of DOAC-associated DRPs in patients on DOAC therapy and factors that predispose patients to DOAC-associated DRPs. Methods: An observational cross-sectional study was conducted in SGH from January 1, 2017, to May 31, 2019, on patients prescribed with a DOAC (rivaroxaban, dabigatran, and apixaban). Data were electronically extracted for patient demographics, clinical characteristics, and details of DOAC-related DRPs identified by pharmacists. Matching of DRP group to non-DRP group at a ratio of 1:2 based on gender, race, and DOAC was performed. The DRP group included patients with detected DRPs while non-DRP group included patients without them. Descriptive analysis was used to summarize patient characteristics and types of DOAC-associated DRPs. In the matched population, conditional logistic regression was used to calculate unadjusted (UOR) and adjusted odds (AOR) ratio to detect association of DOAC-associated DRPs with age, renal function, ≥2 comorbidities, and DOAC indication (atrial fibrillation [AF] vs venous thromboembolism). Results: A total of 8432 patients prescribed DOACs were analyzed, which consisted of 827 (9.8%) and 7602 (90.2%) patients with DRPs and no DRPs, respectively. The top DOAC-associated DRP was inappropriate drug regimen (n = 487, 60.1%). After matching, 2403 patients were analyzed, consisting of 801 patients from DRP group and 1602 from non-DRP group. Factors associated with DOAC-associated DRPs were statistically significant for renal function at creatinine clearance (CrCl) of >30 to 50 mL/min/1.73 m2 (AOR: 1.42; 95% CI: 1.14-1.76; P = .002), 15 to 30 mL/min/1.73 m2 (OR: 1.94; 95% CI: 1.42-2.66; P < .001), and <15 mL/min/1.73m2 (OR: 2.35; 95% CI: 1.13-4.88; P = .022), respectively, compared with a CrCl of >50 mL/min/1.73 m2 and DOAC indication for AF (AOR: 1.84; 95% CI: 1.47-2.30; P < .001) compared with venous thromboembolism. Conclusion: Inappropriate drug regimen was the most common DOAC-associated DRP. Impaired renal function and patients with AF increased the likelihood of DOAC-associated DRPs.

Integrated analysis of next generation sequencing minimal residual disease (MRD) and PET scan in transplant eligible myeloma patients.

Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS-MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10-6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD had poor agreement, with high rates of PET-CT negativity in MRD-positive patients. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the ability to measure deeper and sustainable responses distinguishes patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.

Human leukocyte antigen class-I variation is associated with atopic dermatitis: A case-control study.

Atopic dermatitis (AD) is a common immune-medicated skin disease. Previous studies have explored the relationship between Human Leukocyte Antigen (HLA) allelic variation and AD with conflicting results. The aim was to examine HLA Class I genetic variation, specifically peptide binding groove variation, and associations with AD. A case-control study was designed to evaluate HLA class I allelic variation and binding pocket polymorphisms, using next generation sequencing on 464 subjects with AD and 388 without AD. Logistic regression was used to evaluate associations with AD by estimating odds ratios (95% confidence intervals). Significant associations were noted with susceptibility to AD (B*53:01) and protection from AD (A*01:01, A*02:01, B*07:02 and C*07:02). Evaluation of polymorphic residues in Class I binding pockets revealed six amino acid residues conferring protection against AD: A9F (HLA-A, position 9, phenylalanine) [pocket B/C], A97I [pocket C/E], A152V [pocket E], A156R [pocket D/E], B163E [pocket A] and C116S [pocket F]. These findings demonstrate that specific HLA class I components are associated with susceptibility or protection from AD. Individual amino acid residues are relevant to protection from AD and set the foundation for evaluating potential HLA Class I molecules in complex with peptides/antigens that may initiate or interfere with T-cell responses.

The association between newborn screening analytes as measured on a second screen and childhood autism in a Texas Medicaid population.

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case-control study examined data on 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Subjects were linked to their 2007-2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain.

The association between newborn screening analytes and childhood autism in a Texas Medicaid population, 2010-2012.

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. It is commonly diagnosed at 3 or 4 years of age. We explored whether there was an association of any analytes measured by newborn screening tests with a later diagnosis of ASD. A database was compiled of 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Two controls (without any ASD diagnosis) were matched to each case by infant sex and birth year/month. All study subjects were linked to their 2007-2009 birth and newborn screening laboratory records, including values for 36 analytes or analyte ratios. We examined the association of analytes/ratios with a later diagnosis of ASD. Among 3,258 cases and 6,838 controls, seven analytes (e.g., 17-hydroxyprogesterone, acylcarnitines) were associated with a later ASD diagnosis. In this exploratory study, an ASD diagnosis was associated with 7 of 36 newborn screening analytes/ratios. These findings should be replicated in other population-based datasets.

Determining performance characteristics of an NGS-based HLA typing method for clinical applications.

This study presents performance specifications of an in-house developed human leukocyte antigen (HLA) typing assay using next-generation sequencing (NGS) on the Illumina MiSeq platform. A total of 253 samples, previously characterized for HLA-A, -B, -C, -DRB1 and -DQB1 were included in this study, which were typed at high-resolution using a combination of Sanger sequencing, sequence-specific primer (SSP) and sequence-specific oligonucleotide probe (SSOP) technologies and recorded at the two-field level. Samples were selected with alleles that cover a high percentage of HLA specificities in each of five different race/ethnic groups: European, African-American, Asian Pacific Islander, Hispanic and Native American. Sequencing data were analyzed by two software programs, Omixon's target and GenDx's NGSengine. A number of metrics including allele balance, sensitivity, specificity, precision, accuracy and remaining ambiguity were assessed. Data analyzed by the two software systems are shown independently. The majority of alleles were identical in the exonic sequences (third field) with both programs for HLA-A, -B, -C and -DQB1 in 97.7% of allele determinations. Among the remaining discrepant genotype calls at least one of the analysis programs agreed with the reference typing. Upon additional manual analysis 100% of the 2530 alleles were concordant with the reference HLA genotypes; the remaining ambiguities did not exceed 0.8%. The results demonstrate the feasibility and significant benefit of HLA typing by NGS as this technology is highly accurate, eliminates virtually all ambiguities, provides complete sequencing information for the length of the HLA gene and forms the basis for utilizing a single methodology for HLA typing in the immunogenetics labs.

Towards allele-level human leucocyte antigens genotyping - assessing two next-generation sequencing platforms: Ion Torrent Personal Genome Machine and Illumina MiSeq.

Human leucocyte antigens (HLA) typing has been a challenge due to extreme polymorphism of the HLA genes and limitations of the current technologies and protocols used for their characterization. Recently, next-generation sequencing techniques have been shown to be a well-suited technology for the complete characterization of the HLA genes. However, a comprehensive assessment of the different platforms for HLA typing, describing the limitations and advantages of each of them, has not been presented. We have compared the Ion Torrent Personal Genome Machine (PGM) and Illumina MiSeq, currently the two most frequently used platforms for diagnostic applications, for a number of metrics including total output, quality score per position across the reads and error rates after alignment which can all affect the accuracy of HLA genotyping. For this purpose, we have used one homozygous and three heterozygous well-characterized samples, at HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1. The total output of bases produced by the MiSeq was higher, and they have higher quality scores and a lower overall error rate than the PGM. The MiSeq also has a higher fidelity when sequencing through homopolymer regions up to 9 bp in length. The need to set phase between distant polymorphic sites was more readily achieved with MiSeq using paired-end sequencing of fragments that are longer than those obtained with PGM. Additionally, we have assessed the workflows of the different platforms for complexity of sample preparation, sequencer operation and turnaround time. The effects of data quality and quantity can impact the genotyping results; having an adequate amount of good quality data to analyse will be imperative for confident HLA genotyping. The overall turnaround time can be very comparable between the two platforms; however, the complexity of sample preparation is higher with PGM, while the actual sequencing time is longer with MiSeq.

Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.

Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.

Interpretation of the DermaLab Combo® pigmentation and vascularity measurements in burn scar assessment: an exploratory analysis.

BACKGROUND: The DermaLab Combo® measures pigmentation and vascularity of a burn scar more reliably than the modified Vancouver Scar Scale (mVSS). This study aims to examine how the DermaLab Combo® continuous measurements of pigmentation and vascularity of burns scars relate to the mVSS, a standard clinical scar assessment method; and secondly, to obtain evidence to support the concurrent validity of DermaLab Combo® measurements for pigmentation and vascularity. METHOD: Scar assessments were performed on an index burn scar of 100 subjects using two methods: the mVSS (two raters) and the DermaLab Combo® device (one rater). Using the DermaLab Combo®, measurements of pigmentation and vascularity for the index scar and an adjacent normal skin site were obtained. Indices were generated to represent the scar pigmentation (melanin index, MI%) and scar vascularity (erythema index, EI%) relative to the patient's matched normal skin. Exploratory univariate and bivariate analyses were conducted and the concordance of classification by mVSS score using DermaLab® cut-off values was assessed. RESULTS: For pigmentation, the results suggest a 80% classification concordance for the DermaLab Combo® MI% values into mVSS pigmentation categories (hypopigmentation, normal pigmentation and hyperpigmentation) using two predictors (MI% and EI%) and visually fitted discriminant axis cut-offs. Due to the high degree of overlap of EI% values between the vascularity categories, meaningful classification of EI% values using the mVSS was not possible. CONCLUSION: Quantifying percentage changes in melanin and erythema relative to matched normal skin improved understanding of the DermaLab Combo® pigmentation and vascularity measurements. The DermaLab Combo® pigmentation MI% values were able to be classified into pigmentation categories of the mVSS, and pigmentation classification concordance was further improved with consideration of the scar's DermaLab Combo® vascularity EI% values. The DermaLab Combo® is an objective tool; however, while the measurement provides continuous numerical data that may be useful for identifying change over time in clinical scar monitoring of pigmentation and vascularity, further work will be useful to understand the DermaLab Combo® measurements to optimise the interpretation of these data.

Identification and characterization of a novel HLA-B hybrid allele, B*08:132 with Next Generation Sequencing.

The new allele is a hybrid between B*08:01:01 and B*42:01:01.

Housing breeding mice in three different IVC systems: maternal performance and pup development.

A proper cage environment is essential for the welfare of laboratory mice, especially for females during the energy demanding lactation period and for pups during early development and growth. The most common housing system for laboratory mice is individually ventilated cages (IVCs) of which there are different layouts and ventilation strategies available on the market. The present study investigates the impact of cage environment in three different IVC types, on the maternal performance of females, and pup development and growth in C57BL/6NCrl and Crl:NMRI Foxn1 nu mice. The results show differences in in-cage climate, female body weight, pup growth, feed and water consumption, and nest quality between cage types. There was a distinct effect of genotype in these differences, with the main effects found in NMRI NU mice. The results indicate that IVC systems might need to be managed differently for mice of different types and/or different physiological status. Many of the differences seen between cage systems could be drawn to the physical construction of the cage, such as location of feed hopper and location of air inlet and outlet. In conclusion, IVC in-cage climate affects the maternal performance of female mice and pup growth, but with differences between the two strains tested.

Effect of aerial insecticide spraying on West Nile virus disease--north-central Texas, 2012.

During 2012, four north-central Texas counties experienced high West Nile virus (WNV) disease incidence. Aerial insecticide spraying was conducted in two counties. To evaluate the effect of spraying on WNV disease, we calculated incidence rate ratios (IRRs) in treated and untreated areas by comparing incidence before and after spraying; for unsprayed areas, before and after periods were defined by using dates from a corresponding sprayed area. In treated areas, WNV neuroinvasive disease incidence before and after spraying was 7.31/100,000 persons and 0.28/100,000 persons, respectively; the IRR was 26.42 (95% confidence interval [CI]: 12.42-56.20). In untreated areas, the before and after incidence was 4.80/100,000 persons and 0.45/100,000 persons, respectively; the IRR was 10.57 (95% CI: 6.11-18.28). The ratio of IRRs was 2.50 (95% CI: 0.98-6.35). Disease incidence decreased in both areas, but the relative change was greater in aerial-sprayed areas.

Reliability of scar assessments performed with an integrated skin testing device - the DermaLab Combo(®).

BACKGROUND: The DermaLab Combo(®) is a device with potential to make objective measurements of key scar components - pigmentation, vascularity, pliability and thickness. This study assessed the inter-rater and test-retest reliability of these measurements. METHOD: Three raters performed scar assessments on thirty patients with burn scars using the DermaLab Combo(®). Measurements of pigmentation, vascularity, pliability and thickness were made and intra-class correlation coefficients (ICC) were derived for inter-rater and test-retest reliability. RESULTS: Inter-rater reliability was found to be "excellent" in the 'best' and 'worst' areas of the index scar and normal skin for pigmentation (ICC: 0.94-0.98) and thickness (ICC: 0.86-0.96). Test-retest reliability was also "excellent" for pigmentation (ICC: 0.87-0.89) and thickness (ICC: 0.92-0.97) in all areas. Vascularity showed "good" to "excellent" inter-rater reliability (ICC: 0.66-0.84) in all areas however test-retest reliability was "low" (ICC: 0.29-0.42). Test-retest reliability was "excellent" for pliability (ICC: 0.76-0.91). Technical limitations were encountered making measurements in some scars for thickness, and in particular, pliability. CONCLUSION: The DermaLab Combo(®) measured pigmentation, thickness and pliability with "excellent" reliability. If future studies provide protocols to improve test-retest reliability of vascularity measurements and obtain pliability measurements more successfully, the DermaLab Combo(®) will be valuable device for scar assessment.

Age-related injury and compensation claim rates in heavy industry.

BACKGROUND: Although ageing workers face specific health and safety concerns, conflicting evidence exists regarding the effects of age on workplace injury rates and workers' compensation claims. AIMS: To examine injury and workers' compensation claim rates by age and injury type in an aluminium smelter over a 9-year period. METHODS: Routinely collected data for workplace injuries and workers' compensation claims were retrieved for the period from 1997 to 2005. RESULTS: The study included a total of 709 workers who experienced 2281 at-work injuries and submitted 446 claims. In 1997, 16% of employees were aged 50 or over; by 2005 that proportion had more than doubled to 35%. Injury and claim rates in all age groups did not change significantly during this period. Workers younger than 30 years of age had the highest injury rates, with differences most significant for injuries other than sprains and strains. Claim rates were not significantly different across age groups. CONCLUSIONS: These findings do not provide evidence to support the notion that older workers sustain more injuries and are more likely to claim compensation for their injuries. Our findings demonstrate that in this workplace, older workers were able to maintain their ability to work safely. This contrasts with the finding that younger workers had the highest injury and claim rates. While adapting to the needs of an ageing workforce, employers should not lose sight of the need to nurture a strong culture of working safely among their youngest workers.

Analysis of postoperative pain in robotic versus traditional laparoscopic hysterectomy.

The aim of this study was to assess postoperative pain and narcotic use in the first 23 h following robotic versus traditional laparoscopic hysterectomy for benign pathology. The study design was that of a retrospective case-control study of robotic (first 100 consecutive) versus traditional (last 100 consecutive) total laparoscopic hysterectomy cases at an obstetrics and gynecology multi-institutional community practice. Patient characteristics were equivalent in both groups (age, p = 0.364; body mass index, p = 0.326; uterine weight, p = 0.565), except for a higher number of Caucasians in the traditional laparoscopic group (p = 0.017). Compared to patients who underwent robotic laparoscopic hysterectomy, those who underwent the traditional procedure had higher visual analog scale pain scores (3.1 ± 1.5 vs. 4.6 ± 2.4, respectively; p < 0.001) and used more narcotics (27.5 vs. 35.4 mg hydrocodone, respectively; p < 0.05). Factors that could potentially increase pain (more procedures, more ports, total incision size, and longer operative time) were significantly higher in the robotic group, but only surgical approach, amount of narcotic, and age correlated with pain levels when evaluated with regression analysis. Complication rates were equivalent between groups. In conclusion, patients who underwent robotic assisted laparoscopic hysterectomy had statistically decreased postoperative pain scores and narcotic use than those who underwent the traditional laparoscopic approach, even when the robotic cases involved more procedures and ports and were associated with longer operative time.

Design of a medication reconciliation application: facilitating clinician-focused decision making with data from multiple sources.

BACKGROUND: Medication reconciliation is an essential, but resource-intensive process without a "gold standard" to measure medication adherence. Medication reconciliation applications that focus on facilitating clinicians' decision-making are needed. Since no single available source of medication information is adequate, combining data sources may improve usefulness and outcomes. OBJECTIVES: We aimed to design a medication reconciliation application that could incorporate multiple data sources and convey information about patients' adherence to prescribed medications. We discuss design decisions integral to developing medication reconciliation applications for the electronic health record. The discussion is relevant for health IT developers, clinical providers, administrators, policy makers, and patients. Three hypotheses drove our design of this application: 1) Medication information comes from a variety of sources, each having benefits and limitations; 2) improvements in patient safety can result from reducing the cognitive burden and time required to identify medication changes; 3) a well-designed user interface can facilitate clinicians' understanding and clinical decision making. METHODS: Relying on evidence about interface design and medication reconciliation, an application for the electronic health record at an academic medical center in the U.S. was designed. Multiple decisions that considered the availability, value, and display of the medication data are explored: Information from different sources; interval changes in medications; the sorting of information; and the user interface. RESULTS: THE PROTOTYPE MEDICATION RECONCILIATION APPLICATION DESIGN REFLECTS THE VISUAL ORGANIZATION, CATEGORIZATION, MODALITY OF INTERACTIONS, AND PRESENTATION OF MEDICATION INFORMATION FROM THREE DATA SOURCES: patient, electronic health record, and pharmacy. CONCLUSIONS: A new medication reconciliation user interface displays information from multiple sources, indicates discrepancies among sources, displays information about adherence, and sorts the medication list in a useful display for clinical decision making. Gathering, verifying, and updating medication data are resource-intensive processes. The outcomes of integrating, interpreting, and presenting medication information from multiple sources remain to be studied.

In the media: Burns as a method of assault.

AIM: The aims of this study were to determine whether a change occurred in the pattern of assault burn injury cases hospitalised to the adult state burns unit, Western Australia, from 2004 to mid-year of 2012, and to compare patient and burn characteristics of adult assault burns with those admitted for unintentional burns. METHODS: Study data were obtained from the Royal Perth Hospital (RPH) Burns Minimum Dataset (BMDS). Aggregated data of unintentional burn admissions during the same period were provided by the BMDS data manager to enable comparisons with assault burn patients. RESULTS: Assault burn admissions during 2004-2012 accounted for approximately 1% of all adult burn hospitalisations. All assault victims were burned by either thermal or scald agents. A high rate of intubation (24%) and ICU admission (1 in 3 cases) was observed in the fire assault group. The six assault cases undergoing intubation were severe burns, median TBSA 50%, most commonly affecting the face, head and torso, half of these cases had inhalational injuries and also required escharotomies. Comparison of admissions by calendar period showed no statistically significant differences in demographic, burn cause or TBSA%. However, statistically significant differences were found for pre-morbid psychiatric history (15% vs. 58%, p=0.025) and concomitant fractures or dislocations (46% vs. 2%), p=0.011). CONCLUSIONS: While the proportion of assault burn admissions per total burn admissions steadily increased from 0.4% in 2009 to 1.5% in mid-2012, this proportion did not exceed that peak level observed of 2.1% for 2004.