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1.  Subsets of airway myeloid-derived regulatory cells distinguish mild asthma from COPD 
Subsets of myeloid-derived regulatory cells (MDRC), phenotypically similar to myeloid-derived suppressor cells found in cancer, have recently been appreciated as critical regulators of airway inflammation in mouse models of asthma.
We test the hypothesis that subsets of airway MDRC contribute differentially to the inflammatory milieu in human asthma and chronic obstructive pulmonary disease (COPD).
We used BAL to identify and characterize human airway MDRC from 10 normal, 9 mild asthmatic and 8 COPD subjects, none treated with inhaled or systemic corticosteroids. We defined subsets of airway MDRC by flow cytometry, the molecular mediators they produce and their abilities to regulate proliferation of polyclonally activated autologous T-lymphocytes.
We found substantial differences in the functional potential of MDRC subsets in normal, asthmatic and COPD subjects, with these differences regulated by the nitrosative and oxidative free radicals and cytokines they produced. Nitric oxide-producing MDRC suppressed and superoxide-producing MDRC enhanced proliferation of polyclonally activated autologous CD4 T-cells. HLA-DR+CD11+CD11c+CD163− superoxide-producing MDRC, which stimulated proliferation of autologous T-cells, comprised a high fraction of MDRC in airways of subjects with mild asthma or COPD, but not normals. CD11b+CD14+CD16−HLA-DR− nitric oxide-producing MDRC, which suppressed T-cell proliferation, were present in high numbers in airways of subjects with mild asthma, but not subjects with COPD or normals.
Subsets of airway MDRC conclusively discriminate mild asthmatics, subjects with COPD and normal subjects from each other. The distinctive activities of these MDRC in asthma and COPD may provide novel targets for new therapeutics in these common disorders.
PMCID: PMC4323991  PMID: 25420684
myeloid cell; macrophage; nitric oxide; superoxide; T-regulatory cell
2.  Impact of a Hospice Emergency Kit for Veterans and Their Caregivers: A Prospective Cohort Study 
Journal of Palliative Medicine  2014;17(8):931-938.
Background: Although hospice emergency kits (HEKs) are provided by many home hospice agencies, little is known about their use, side effects, and perceived impact.
Objective: To evaluate HEK medication utilization, side effects, and impact as perceived by home hospice patients and their caregivers.
Methods: We conducted a prospective longitudinal cohort study. Participants included 43 veterans and their family/caregivers referred to community home hospices with a Veterans Affairs (VA)-provided HEK. Measurements included patient/family reports based on weekly telephone interviews, electronic medical record (EMR) review, and after-death caregiver interviews.
Results: The HEK was used by 27 of 43 patients/caregivers (62.8%). In 11 cases, they reported using the kit on more than one occasion. The most commonly used medications were morphine concentrate (30.2% of patients), lorazepam (20.9%), and levofloxacin (16.3%). In 15 cases (34.9%), the family thought the HEK may have helped the patient stay at home. Nineteen of the 43 patients made at least one visit to the emergency department (ED) and 22 were hospitalized. Most admissions through the ED were due to uncontrolled pain and/or gastrointestinal problems, such as nausea or bowel obstruction. In after-death interviews, opinions of the HEK were uniformly positive. Respondents described the HEK's usefulness and felt supported and empowered by its presence in the home. Minor side effects were reported in four cases.
Conclusions: Findings provide promising evidence that HEKs are a feasible and well-tolerated method for achieving timely relief of emergent symptoms in home hospice patients and possibly avoiding unwanted ED visits and hospitalizations.
PMCID: PMC4118704  PMID: 24927070
3.  Effect of Self-Referral on Bone Mineral Density Testing and Osteoporosis Treatment 
Medical care  2014;52(8):743-750.
Despite national guidelines recommending bone mineral density screening with dual-energy xray absorptiometry (DXA) in women ≥65 years old, many women do not receive initial screening.
To determine the effectiveness of health system and patient-level interventions designed to increase appropriate DXA testing and osteoporosis treatment through (1) an invitation to self-refer for DXA (self-referral), (2) self-referral plus patient educational materials, and (3) usual care (UC, physician referral).
Research Design
Parallel, group-randomized, controlled trials performed at Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Georgia (KPG).
Women ≥ 65 years old without a DXA in past 5 years.
DXA completion rates 90 days after intervention mailing and osteoporosis medication receipt 180 days after initial intervention mailing.
From >12,000 eligible women, those randomized to self-referral were significantly more likely to receive a DXA than UC (13.0 – 24.1% self-referral vs. 4.9 – 5.9% UC, p < 0.05). DXA rates did not significantly increase with patient educational materials. Osteoporosis was detected in a greater proportion of self-referral women compared to UC (p < 0.001). The number needed to receive an invitation to result in a DXA in KPNW and KPG regions was approximately 5 and 12, respectively. New osteoporosis prescription rates were low (0.8 – 3.4%) but significantly greater among self-referral versus UC in KPNW.
DXA rates significantly improved with a mailed invitation to schedule a scan without physician referral. Providing women the opportunity to self-refer may be an effective, low-cost strategy to increase access for recommended osteoporosis screening.
PMCID: PMC4101066  PMID: 24984211
osteoporosis; screening; DXA; randomized controlled trial
4.  Racial and ethnic differences in older adults with knee osteoarthritis 
Knee osteoarthritis (OA) contributes significantly to disability in older individuals and racial/ethnic minorities are disproportionately affected. The present study aimed to characterize differences in clinical and experimental pain including pain inhibition among older African-Americans (AAs) and non-Hispanic whites (NHWs) with knee OA.
AAs and NHWs with knee OA (n=267) completed clinical and functional pain assessments including quantitative sensory testing (QST). We hypothesized that 1) AAs would display lower pain tolerance and higher heat, mechanical and cold pain ratings compared to NHWs; 2) AAs would display greater temporal summation compared to NHWs; 3) AAs would display reduced pain inhibition compared to NHWs; 4) AAs would demonstrate greater clinical pain and poorer function relative to NHWs; and 5) QST would significantly predict clinical pain within each race/ethnicity.
AAs displayed increased pain sensitivity, temporal summation and reduced pain inhibition than NHWs. AAs reported greater clinical pain and poorer function than NHWs. Race/ethnic differences in clinical pain became non-significant when controlling for education and income, whereas differences in QST remained highly significant. Although pain inhibition predicted clinical pain in both groups, different QST measures were additionally predictive of clinical pain within groups.
Our study establishes race/ethnic differences in experimental and clinical pain and function in older individuals with knee OA. Our findings that different QST measures were associated with clinical pain within race/ethnic groups while reduced pain inhibition was important in all participants warrants further study evaluating common and group-specific pathophysiological mechanisms contributing to clinical pain in OA.
PMCID: PMC4077911  PMID: 24729357
5.  Dietary carbohydrate, glycemic index, glycemic load, and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort 
Cancer causes & control : CCC  2011;22(7):995-1002.
To evaluate the associations between dietary carbohydrate, glycemic index (GI), glycemic load (GL), and incident prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.
Between September 1993 and September 2000, 38,343 men were randomized to the screening arm of the trial at one of 10 PLCO centers. A food frequency questionnaire administered at baseline assessed usual dietary intake over the preceding 12 months. Prostate cancer was ascertained by medical follow-up of suspicious screening results and annual mailed questionnaires and confirmed with medical records. Cox proportional hazards regression was used to model the associations of carbohydrate, GI, and GL with prostate cancer risk.
During follow-up (median = 9.2 years), 2,436 incident prostate cancers were identified among 30,482 eligible participants. Overall, there were no associations of baseline carbohydrate, GI, or GL with incident prostate cancer in minimally or fully adjusted models. There were no associations when the 228 advanced and 2,208 non-advanced cancers were analyzed separately.
Dietary carbohydrate, GI, and GL were not associated with incident prostate cancer in PLCO. The narrow range of GI in this cohort may have limited our ability to detect associations, an issue that future studies should address.
PMCID: PMC4470253  PMID: 21553078
Prostatic neoplasms; Dietary carbohydrates; Glycemic index
6.  Intervention to Improve Care at Life’s End in Inpatient Settings: The BEACON Trial 
Widespread implementation of palliative care treatment plans could reduce suffering in the last days of life by adopting best practices of traditionally home-based hospice care in inpatient settings.
To evaluate the effectiveness of a multi-modal intervention strategy to improve processes of end-of-life care in inpatient settings.
Implementation trial with an intervention staggered across hospitals using a multiple-baseline, stepped wedge design.
Six Veterans Affairs Medical Centers (VAMCs).
Staff training was targeted to all hospital providers and focused on identifying actively dying patients and implementing best practices from home-based hospice care, supported with an electronic order set and paper-based educational tools.
Main Measures
Several processes of care were identified as quality endpoints for end-of-life care (last 7 days) and abstracted from electronic medical records of veterans who died before or after intervention (n = 6,066). Primary endpoints were proportion with an order for opioid pain medication at time of death, do-not-resuscitate order, location of death, nasogastric tube, intravenous line infusing, and physical restraints. Secondary endpoints were administration of opioids, order/administration of antipsychotics, benzodiazepines, and scopolamine (for death rattle); sublingual administration; advance directives; palliative care consultations; and pastoral care services. Generalized estimating equations were conducted adjusting for longitudinal trends.
Key Results
Significant intervention effects were observed for orders for opioid pain medication (OR: 1.39), antipsychotic medications (OR: 1.98), benzodiazepines (OR: 1.39), death rattle medications (OR: 2.77), sublingual administration (OR: 4.12), nasogastric tubes (OR: 0.71), and advance directives (OR: 1.47). Intervention effects were not significant for location of death, do-not-resuscitate orders, intravenous lines, or restraints.
This broadly targeted intervention strategy led to modest but statistically significant changes in several processes of care, indicating its potential for widespread dissemination to improve end-of-life care for thousands of patients who die each year in inpatient settings.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2724-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4026508  PMID: 24449032
palliative care; end-of-life care; palliative medicine; hospice; inpatient
7.  Macronutrients, Diet Quality, and Frailty in Older Men 
Frailty, a phenotype of multisystem impairment and expanding vulnerability, is associated with higher risk of adverse health outcomes not entirely explained by advancing age. We investigated associations of macronutrients, dietary fiber, and overall diet quality with frailty status in older community-dwelling men.
Participants were 5,925 men aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study at six U.S. centers. Diet was assessed at baseline with a food frequency questionnaire. We assessed frailty status (robust, intermediate, or frail) at baseline and at a second clinic visit (a mean of 4.6 years later) using a slightly modified Cardiovascular Health Study frailty index. We used multinomial logistic regression to assess associations between macronutrient intake, dietary fiber, and the Diet Quality Index Revised with frailty status at baseline and at the second clinic visit.
At baseline, 2,748 (46.4%) participants were robust, 2,681 (45.2%) were intermediate, and 496 (8.4%) were frail. Carbohydrate, fat, protein, and dietary fiber showed no consistent associations with frailty status. Overall diet quality exhibited fairly consistent associations with frailty status. The Diet Quality Index Revised was inversely associated with frail status relative to robust status at the baseline visit (odds ratio for Q5 vs Q1 = 0.44, 95% confidence interval: 0.30, 0.63; p for trend < .0001) and at the second clinic visit (odds ratio for Q5 vs Q1 = 0.18, 95% confidence interval: 0.03, 0.97; p for trend = .0180).
Overall diet quality was inversely associated with prevalent and future frailty status in this cohort of older men.
PMCID: PMC4022097  PMID: 24304504
Frailty; Nutrition; Epidemiology.
8.  Moving towards multiple site outcomes in spinal cord injury pain clinical trials: An issue of clustered observations in trial design and analysis 
Pain remains a problem for many with spinal cord injury (SCI), and there is a need for sound, randomized clinical trials examining the efficacy of existing and novel therapeutics. SCI-related pain is complex, as more than one type of pain is often experienced. The purpose of this report is to (i) demonstrate how to design and power calculation of a clinical trial of SCI pain using multiple pain sites per individual; (ii) discuss consequences of failing to adjust for this; and (iii) provide intraclass correlation (ICC) estimates for common pain outcome measures that may be used to power future clinical trials in SCI pain.
Using an existing dataset from a past SCI pain clinical trial, the ICC was calculated for common pain outcome measures to illustrate appropriate corrections for powering, analyzing and interpreting results from multiple pain sites per individual. The problem associated with not accounting for multiple pain sites per individual and the effect on the Type I error rate is also shown.
Results and Discussion
Not accounting for the ICC can lead to (1) incorrect power estimates in the design of a trial, and (2) an inflated Type I error rate with a higher likelihood of misinterpretation of outcomes.
Powering for future SCI pain trials and statistical analysis of trial outcomes may be substantially compromised if methods do not account for the intra-individual associations between pain sites, ultimately affecting study interpretations and evidence-based practice. We present ICC estimates based on SCI pain data for purposes of estimating power for future trials.
PMCID: PMC4064577  PMID: 24621021
Spinal cord injury; Pain; Clinical trials; RCT; Intraclass correlation coefficient; ICC
9.  FcγRIIIa SNPs and haplotypes affect human IgG binding and association with lupus nephritis in African Americans 
To investigate whether the FcγRIIIa-66R/H/L polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66R/H/L and FcγRIIIa-176F/V as well as copy number variation (CNV) confer risk for development of SLE and lupus nephritis.
FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG binding assays. FCGR3A SNP and CNV genotypes were determined by Pyrosequencing methodology in a cohort of 1728 SLE patients and 2404 healthy controls.
The FcγRIIIa-66L/H/R (rs10127939) polymorphism influences ligand binding capacity in the context of the FcγRIIIa-176V (rs396991) allele. The low binding FcγRIIIa-176F allele was associated with SLE nephritis (p = 0.0609) in African Americans but not in European Americans (p > 0.10). Nephritis among African American SLE subjects was associated with FcγRIIIa low binding haplotypes containing the 66R/H/L and 176F variants (p = 0.03) and with low binding genotype combinations (p = 0.002). No association was observed in European American SLE patients. The distribution of FCGR3A CNV was not significantly different between controls and SLE patients with or without nephritis.
FcγRIIIa-66R/H/L influences ligand binding. The low binding haplotypes formed by 66R/H/L and 176F confer enhanced risk for lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or SLE nephritis in either African Americans or European Americans.
PMCID: PMC4069204  PMID: 24782186
10.  Comparing denominator degrees of freedom approximations for the generalized linear mixed model in analyzing binary outcome in small sample cluster-randomized trials 
Small number of clusters and large variation of cluster sizes commonly exist in cluster-randomized trials (CRTs) and are often the critical factors affecting the validity and efficiency of statistical analyses. F tests are commonly used in the generalized linear mixed model (GLMM) to test intervention effects in CRTs. The most challenging issue for the approximate Wald F test is the estimation of the denominator degrees of freedom (DDF). Some DDF approximation methods have been proposed, but their small sample performances in analysing binary outcomes in CRTs with few heterogeneous clusters are not well studied.
The small sample performances of five DDF approximations for the F test are compared and contrasted under CRT frameworks with simulations. Specifically, we illustrate how the intraclass correlation (ICC), sample size, and the variation of cluster sizes affect the type I error and statistical power when different DDF approximation methods in GLMM are used to test intervention effect in CRTs with binary outcomes. The results are also illustrated using a real CRT dataset.
Our simulation results suggest that the Between-Within method maintains the nominal type I error rates even when the total number of clusters is as low as 10 and is robust to the variation of the cluster sizes. The Residual and Containment methods have inflated type I error rates when the cluster number is small (<30) and the inflation becomes more severe with increased variation in cluster sizes. In contrast, the Satterthwaite and Kenward-Roger methods can provide tests with very conservative type I error rates when the total cluster number is small (<30) and the conservativeness becomes more severe as variation in cluster sizes increases. Our simulations also suggest that the Between-Within method is statistically more powerful than the Satterthwaite or Kenward-Roger method in analysing CRTs with heterogeneous cluster sizes, especially when the cluster number is small.
We conclude that the Between-Within denominator degrees of freedom approximation method for F tests should be recommended when the GLMM is used in analysing CRTs with binary outcomes and few heterogeneous clusters, due to its type I error properties and relatively higher power.
PMCID: PMC4458010  PMID: 25899170
Wald F test; Type I error; Power
11.  Age and race effects on pain sensitivity and modulation among middle-aged and older adults 
This study tested the effects of aging and race on responses to noxious stimuli using a wide range of stimulus modalities. The participants were 53 non-Hispanic Blacks and 138 non-Hispanic White adults, ages 45 to 76. The participants completed a single 3-hour sensory testing session where responses to thermal, mechanical, and cold stimuli were assessed. The results suggest that there are selected age differences, with the older group less sensitive to warm and painful heat stimuli than middle-aged participants, particularly at the knee. This site effect supports the hypothesis that the greatest decrement in pain sensitivity associated with aging occurs in the lower extremities. In addition, there were several instances where age and race effects were compounded, resulting in greater race differences in pain sensitivity among the older participants. Overall, the data suggest that previously reported race differences in pain sensitivity emerged in our older samples, and this study contributes new findings in that these differences may increase with age in non-Hispanic Blacks for temporal summation and both heat and cold immersion tolerance. We have added to the aging and pain literature by reporting several small to moderate differences in responses to heat stimuli between middle and older age adults.
PMCID: PMC4005289  PMID: 24239561
aging; race; threshold; temporal summation; conditioned pain modulation
12.  Intra-abdominal Pressure Changes Associated with Lifting: Implications for Postoperative Activity Restrictions 
To describe the effect of lifting maneuver and quantity of weight lifted on the generation of intra-abdominal pressure.
Study Design
Forty-one women undergoing urodynamic evaluation performed four lifting maneuvers, each while lifting 0, 2.5, 5, 10, and 15 kg. The lifting maneuvers were routine activities including squatting with and without assistance, lifting from a counter and receiving weight. Pressure was recorded with a rectal microtip catheter. Each lift was performed twice and the average pressure change was analyzed.
Controlling for potential confounding variables, repeated-measures ANOVA revealed a significant interaction between lift weight and lift maneuver (p= <0.001). Squatting was associated with generation of higher intra-abdominal pressure than lifting from a counter or receiving weights into outstretched arms (p= <0.001). Lifting ≥2.5 kg resulted in significant changes in intra-abdominal pressure regardless of lift maneuver (p= <0.001).
Both lifting maneuver and quantity of weight should be considered when counseling patients regarding postoperative lifting.
PMCID: PMC4329922  PMID: 18068145
Intra-abdominal pressure; weight lifting; postoperative instructions; pelvic floor surgery
13.  Simple regression for correcting ΔCt bias in RT-qPCR low-density array data normalization 
BMC Genomics  2015;16(1):82.
Reverse transcription quantitative PCR (RT-qPCR) is considered the gold standard for quantifying relative gene expression. Normalization of RT-qPCR data is commonly achieved by subtracting the Ct values of the internal reference genes from the Ct values of the target genes to obtain ΔCt. ΔCt values are then used to derive ΔΔCt when compared to a control group or to conduct further statistical analysis.
We examined two rheumatoid arthritis RT-qPCR low density array datasets and found that this normalization method introduces substantial bias due to differences in PCR amplification efficiency among genes. This bias results in undesirable correlations between target genes and reference genes, which affect the estimation of fold changes and the tests for differentially expressed genes. Similar biases were also found in multiple public mRNA and miRNA RT-qPCR array datasets we analysed. We propose to regress the Ct values of the target genes onto those of the reference genes to obtain regression coefficients, which are then used to adjust the reference gene Ct values before calculating ΔCt.
The per-gene regression method effectively removes the ΔCt bias. This method can be applied to both low density RT-qPCR arrays and individual RT-qPCR assays.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1274-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4335788  PMID: 25888492
RT-PCR; Normalization; ΔCt; Housekeeping genes; Regression
14.  Prevalence and Trends of Symptomatic Pelvic Floor Disorders in U.S. Women 
Obstetrics and gynecology  2014;123(1):141-148.
To estimate the prevalence and trends of these pelvic floor disorders in U.S. women from 2005–2010.
We utilized the National Health and Nutritional Examination Survey (NHANES) from 2005–2006, 2007–2008, and 2009–2010. A total of 7,924 non-pregnant women (aged 20 years or older) were categorized as having: urinary incontinence – moderate to severe (3 or higher on a validated urinary incontinence (UI) severity index, range 0–12); fecal incontinence – at least monthly (solid, liquid, or mucus stool); and pelvic organ prolapse – seeing or feeling a bulge. Potential risk factors included age, race and ethnicity, parity, education, poverty income ratio, body mass index (BMI) (<25, 25–29, ≥30 kg/m2), co-morbidity count, and reproductive factors. Using appropriate sampling weights, weighted chi square analysis and multivariable logistic regression models with odds ratios (OR) and 95% confidence intervals (95% CI) were reported.
The weighted prevalence rate of one or more pelvic floor disorder was 25.0% (95% CI 23.6, 26.3), including 17.1% (95% CI 15.8, 18.4) of women with moderate-to-severe urinary incontinence, 9.4% (95% CI 8.6, 10.2) with fecal incontinence, and 2.9% (95% CI 2.5, 3.4) with prolapse. From 2005 to 2010, no significant differences were found in the prevalence rates of any individual disorder or for all disorders combined (p>0.05). After adjusting for potential confounders, higher BMI, greater parity, and hysterectomy were associated with higher odds of one or more pelvic floor disorder.
Although rates of pelvic floor disorders did not change from 2005–2010, these condition remain common with one quarter of adult U.S. women reporting at least one disorder.
PMCID: PMC3970401  PMID: 24463674
15.  Risk Factors Associated with Reoperation for Bleeding following Liver Transplantation 
HPB Surgery  2014;2014:816246.
Introduction. This study's objective was to identify risk factors associated with reoperation for bleeding following liver transplantation (LTx). Methods. A retrospective study was performed at a single institution between 2001 and 2012. Operative reports were used to identify patients who underwent reoperation for bleeding within 2 weeks following LTx (operations for nonbleeding etiologies were excluded). Results. Reoperation for bleeding was observed in 101/928 (10.8%) of LTx patients. The following characteristics were associated with reoperation on multivariable analysis: recipient MELD score (OR 1.06/MELD unit, 95% CI 1.03, 1.09), number of platelets transfused (OR 0.73/platelet unit, 95% CI 0.58, 0.91), and aminocaproic acid utilization (OR 0.46, 95% CI 0.27, 0.80). LTx patients who underwent reoperation for bleeding had a longer ICU stay (5 days ± 7 versus 2 days ± 3, P < 0.001) and hospitalization (18 days ± 9 versus 10 days ± 18, P < 0.001). The risk of death increased in patients who underwent reoperation for bleeding (HR 1.89, 95% CI 1.26, 2.85). Conclusion. Reoperation for bleeding following LTx was associated with increased resource utilization and recipient mortality. A lower threshold for intraoperative platelet transfusion and antifibrinolytics, especially in patients with high lab-MELD score, may decrease the incidence of reoperation for bleeding following LTx.
PMCID: PMC4258335  PMID: 25505820
16.  Psychological Profiles and Pain Characteristics of Older Adults With Knee Osteoarthritis 
Arthritis care & research  2013;65(11):1786-1794.
To identify psychological profiles in persons with knee osteoarthritis (OA) and to determine the relationship between these profiles and specific pain and sensory characteristics, including temporal summation and conditioned pain modulation.
Individuals with knee OA (n = 194) completed psychological, health, and sensory assessments. Hierarchical cluster analysis was used to derive psychological profiles that were compared across several clinical pain/disability and experimental pain responses.
Cluster 1 had high optimism with low negative affect, pain vigilance, anger, and depression, along with the lowest self-reported pain/disability and the lowest sensitivity to mechanical, pressure, and thermal pain (P < 0.01 for all). Cluster 2 had low positive affect with high somatic reactivity, while cluster 3 showed high pain vigilance with low optimism. Clusters 2 and 3 had intermediate levels of self-reported pain/disability and cluster 3 experienced central sensitization to mechanical stimuli. Participants in cluster 3 also displayed significant pain facilitation (P < 0.05). Cluster 4 exhibited the highest pain vigilance, reactivity, negative affect, anger, and depression. These individuals experienced the highest self-reported pain/disability, including widespread pain (P < 0.001 for all). Cluster 4 was most sensitive to mechanical, pressure, and thermal stimuli, and showed significant central sensitization to mechanical and thermal stimuli (P < 0.001 for all).
Our findings demonstrate the existence of homogeneous psychological profiles displaying unique sets of clinical and somatosensory characteristics. Multidisciplinary treatment approaches consistent with the biopsychosocial model of pain should provide significant advantages if targeted to profiles such as those in our OA sample.
PMCID: PMC3922880  PMID: 23861288
17.  Multiple Lupus Associated ITGAM Variants Alter Mac-1 Function on Neutrophils 
Arthritis and rheumatism  2013;65(11):2907-2916.
Multiple studies have demonstrated that single-nucleotide polymorphisms (SNPs) in the ITGAM locus (including the non-synonymous SNPs rs1143679, rs1143678, rs1143683) are associated with SLE. ITGAM encodes the protein CD11b, a subunit of the β2 integrin Mac-1. The purpose of this study was to determine the effects of ITGAM genetic variation on the biological functions of neutrophil Mac-1.
Neutrophils from ITGAM genotyped and sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil ITGAM variants was probed with complement coated erythrocytes, serum treated zymosan, heat treated zymosan and IgG coated erythrocytes. The adhesion capacity of ITGAM variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor α-stimulated endothelial cells was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry.
Mac-1–mediated neutrophil phagocytosis, determined in cultures with 2 different complement-coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of ITGAM. This reduction in phagocytosis was related to variation at either rs1143679 (in the β-propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf-1 regions). Phagocytosis mediated by Fcγ receptors was also significantly reduced in donors with variant ITGAM alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant ITGAM alleles. These functional alterations were not attributable to differences in total receptor expression or activation.
The nonsynonymous ITGAM variants rs1143679 and rs1143678/rs113683 contribute to altered Mac-1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE.
PMCID: PMC3969028  PMID: 23918739
18.  Application of the OMERACT filter to measures of core outcome domains in recent clinical studies of acute gout 
The Journal of rheumatology  2014;41(3):574-580.
To determine the extent to which instruments that measure core outcome domains in acute gout fulfil the OMERACT filter requirements of truth, discrimination and feasibility.
Patient-level data from four randomised controlled trials of agents designed to treat acute gout and one observational study of acute gout were analysed. For each available measure construct validity, test-retest reliability, within-group change using effect size, between-group change using the Kruskall-Wallis statistic and repeated measures generalised estimating equations were assessed. Floor and ceiling effects were also assessed and MCID was estimated. These analyses were presented to participants at OMERACT 11 to help inform voting for possible endorsement.
There was evidence for construct validity and discriminative ability for 3 measures of pain (0 to 4 Likert, 0 to 10 numeric rating scale, 0 to 100 mm visual analogue scale). Likewise, there appears to be sufficient evidence for a 4-point Likert scale to possess construct validity and discriminative ability for physician assessment of joint swelling and joint tenderness. There was some evidence for construct validity and within-group discriminative ability for the Health Assessment Questionnaire as a measure of activity limitations, but not for discrimination between groups allocated to different treatment.
There is sufficient evidence to support measures of pain (using Likert, numeric rating scale or visual analogue scales), joint tenderness and swelling (using Likert scale) as fulfilling the requirements of the OMERACT filter. Further research on a measure of activity limitations in acute gout clinical trials is required.
PMCID: PMC4212978  PMID: 24429178
gout; outcome measures; psychometrics
19.  Experimental pain sensitivity differs as a function of clinical pain severity in symptomatic knee osteoarthritis 
Pain in knee osteoarthritis (OA) has historically been attributed to peripheral pathophysiology; however, the poor correspondence between objective measures of disease severity and clinical symptoms suggests that non-local factors, such as altered central processing of painful stimuli, also contribute to clinical pain in knee OA. Consistent with this notion, recent evidence demonstrates that patients with knee OA exhibit increased sensitivity to painful stimuli at body sites unaffected by clinical pain.
In order to further investigate the contribution of altered pain processing to knee OA pain, the current study tested the hypothesis that symptomatic knee OA is associated with enhanced sensitivity to experimental pain stimuli at the knee and at remote body sites unaffected by clinical pain. We further anticipated that pain sensitivity would differ as a function of the OA symptom severity. Older adults with and without symptomatic knee OA completed a series of experimental pain assessments. A median split of the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) was used to stratify participants into low vs. high OA symptom severity.
Compared to controls and the low symptom group, individuals in the high symptom group were more sensitive to suprathreshold heat stimuli, blunt pressure, punctuate mechanical, and cold stimuli. Individuals in the low symptomatic OA group subgroup exhibited experimental pain responses similar to the pain-free group on most measures. No group differences in endogenous pain inhibition emerged.
These findings suggest that altered central processing of pain is particularly characteristic of individuals with moderate to severe symptomatic knee OA.
PMCID: PMC3831366  PMID: 23973137
WOMAC; knee osteoarthritis; experimental pain; severity
20.  Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial 
The pharmacogenomics journal  2013;14(1):48-53.
Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 TEAR Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P <0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.
PMCID: PMC3701736  PMID: 23545897
Methotrexate; rheumatoid arthritis; pharmacogenetics
21.  Temporal summation of pain as a prospective predictor of clinical pain severity in adults aged 45 years and above with knee osteoarthritis: ethnic differences 
Psychosomatic medicine  2014;76(4):302-310.
Enhanced pain facilitation is reportedly an important contributor to the clinical pain experiences of individuals with knee osteoarthritis (OA). Ethnic differences in the prevalence and severity of knee OA in addition to associated pain are also well documented. Temporal summation (TS) of pain is a widely applicable quantitative sensory testing method that invokes neural mechanisms related to pain facilitatory processes. This study tested whether TS of pain, an index of pain facilitation, differentially predicts the clinical pain experiences of African Americans and non-Hispanic Whites with symptomatic knee OA.
A total of 225 study participants underwent assessment of TS of mechanical and heat pain stimuli applied to their most symptomatic knee and their ipsilateral hand (mechanical) or forearm (heat). Using telephone-based surveys, participants subsequently reported their average and worst clinical pain severity across four consecutive weeks following assessment of TS.
In predicting future clinical pain, ethnicity interacted with TS of mechanical pain (but not heat pain), such that TS of mechanical pain at the knee significantly predicted greater clinical ratings of average (b = .02, p = .016) and worst (b = .02, p = .044) clinical pain for non-Hispanic Whites but not African Americans (p’s > .30).
These results reveal the importance of considering ethnicity when examining pain facilitation and the clinical pain of individuals with symptomatic knee OA. The results of this study are discussed in terms of ethnic differences in the predictors of clinical pain experiences among African Americans and non-Hispanic Whites with knee OA.
PMCID: PMC4066647  PMID: 24804882
Pain; Knee Osteoarthritis (OA); Ethnicity; Pain Facilitation; Temporal Summation (TS)
22.  Allelic Dependent Expression of an Activating Fc receptor on B cells Enhances Humoral Immune Responses 
Science translational medicine  2013;5(216):216ra175.
B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.
PMCID: PMC3982386  PMID: 24353158
23.  Resource Utilization Associated with Procurement of Transplantable Organs from Donors that do not meet OPTN Eligible Death Criteria 
Transplantation  2014;97(10):1043-1048.
The strategy of evaluating every donation opportunity warrants an investigation into the financial feasibility of this practice. The purpose of this investigation is to measure resource utilization required for procurement of transplantable organs in an organ procurement organization (OPO).
Donors were stratified into those that met OPTN-defined eligible death criteria (ED Donors, n=589) and those that did not (NED Donors, n=703). Variable direct costs and time utilization by OPO staff for organ procurement were measured and amortized per organ transplanted using permutation methods and statistical bootstrapping/resampling approaches.
More organs per donor were procured (3.66 ± 1.2 vs. 2.34 ± 0.8, p<0.0001) and transplanted (3.51 ± 1.2 vs. 2.08 ± 0.8, p<0.0001) in ED donors compared to NED donors. The variable direct costs were significantly lower in NED donors ($29,879.4 ± 11590.1 vs. $19,019.6 ± 7599.60, p<0.0001). In contrast, the amortized variable direct costs per organ transplanted were significantly higher in the NED donors ($8,414.5 ± 138.29 vs. $9,272.04 ± 344.56, p<0.0001). ED donors where thoracic organ procurement occurred were 67% more expensive than in abdominal-only organ procurement. The total time allocated per donor was significantly shorter in NED donors (91.2 ± 44.9 hours vs. 86.8 ± 78.6, p=0.01). In contrast, the amortized time per organ transplanted was significantly longer in the NED donors (23.1 ± 0.8 hours vs. 36.9 ± 3.2, p<0.001).
The variable direct costs and time allocated per organ transplanted is significantly higher in donors that do not meet the eligible death criteria.
PMCID: PMC4024080  PMID: 24503760
Eligible Death Donor; Non-Eligible Death Donor; Organ Procurement; Deceased Donor Organs; Variable Direct Cost; Resource Allocation
24.  Comparison of the Disease Activity Score using Erythrocyte Sedimentation Rate and C-reactive Protein in African-Americans with Rheumatoid Arthritis 
The Journal of rheumatology  2013;40(11):1812-1822.
The Disease Activity Score based on 28 joints (DAS28) has been increasingly used in clinical practice and research studies of rheumatoid arthritis (RA). Studies have reported discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in RA patients. However such comparison is lacking in African-Americans with RA.
This analysis included participants from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry which enrolls self-declared African-Americans with RA. Using tender and swollen joint counts separate ESR-based and CRP-based DAS28 scores (DAS28-ESR3 and DAS28-CRP3) were calculated, as were DAS28-ESR4 and DAS28-CRP4, which included the patient’s assessment of disease activity. The scores were compared using paired t-test, simple agreement and kappa, correlation coefficient and Bland-Altman plots.
Of the 233 included participants, 85% were women, mean age at enrollment was 52.6 years, and median disease duration at enrollment was 21 months. Mean DAS28-ESR3 was significantly higher than DAS28-CRP3 (4.8 vs. 3.9; p<0.001). Similarly, mean DAS28-ESR4 was significantly higher than DAS28-CRP4 (4.7 vs. 3.9; p<0.001). ESR-based DAS28 remained higher than CRP-based DAS28 even when stratified by age, sex, and disease duration. Overall agreement was not high between DAS28-ESR3 and DAS28-CRP3 (50%) or between DAS28-ESR4 and DAS28-CRP4 (59%). DAS28-CRP3 underestimated disease activity in 47% of the participants relative to DAS28-ESR3 and DAS28-CRP4 in 40% of the participants relative to DAS28-ESR4.
There was significant discordance between the ESR-based and CRP-based DAS28 which could impact clinical treatment decisions in African-Americans with RA.
PMCID: PMC3987124  PMID: 23950187
DAS28; Rheumatoid Arthritis; African-Americans
25.  Complementary and Alternative Medicine Use in African Americans With Rheumatoid Arthritis 
Arthritis care & research  2014;66(2):180-189.
Racial/ethnic differences with regard to complementary and alternative medicine (CAM) use have been reported in the US. However, specific details of CAM use by African Americans with rheumatoid arthritis (RA) are lacking.
Data were collected from African Americans with RA enrolled in a multicenter registry regarding the use of CAM, including food supplements, topical applications, activities, and alternative care providers. Factors associated with CAM use by sex and disease duration were assessed using t-test, Wilcoxon’s rank sum test, chi-square test, and logistic regression analyses.
Of the 855 participants, 85% were women and mean age at enrollment was 54 years. Overall, ever using any of the CAM treatments, activities, and providers was 95%, 98%, and 51%, respectively (median of 3 for number of treatments, median of 5 for activities, and median of 1 for providers). Those with longer disease duration (>2 years) were significantly more likely (odds ratio >2.0, P < 0.05) to use raisins soaked in vodka/gin, to take fish oils, or to drink alcoholic beverages for RA treatment than those with early disease. As compared to men, women were significantly (P < 0.05) more likely to pray/attend church, write in a journal, and use biofeedback, but were less likely to smoke tobacco or topically apply household oils for treatment of RA.
CAM use was highly prevalent in this cohort, even in individuals with early disease. Health care providers need to be aware of CAM use as some treatments may potentially have interactions with conventional medicines. This could be important within this cohort of African Americans, where racial disparities are known to affect access to conventional care.
PMCID: PMC3977347  PMID: 23983105

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