Association of Longitudinal Changes in Symptoms and Urinary Biomarkers in Patients with Urological Chronic Pelvic Pain Syndrome: A MAPP Research Network Study.

PURPOSE: We analyzed a series of novel noninvasive urinary biomarkers for their ability to objectively monitor the longitudinal clinical status of patients with urological chronic pelvic pain syndrome. MATERIALS AND METHODS: Baseline, 6 and 12-month urine samples were collected (216) and used to quantify vascular endothelial growth factor, vascular endothelial growth factor (VEGF) receptor 1 (R1), neutrophil gelatinase associated lipocalin (NGAL), matrix metalloproteinase-2, matrix metalloproteinase (MMP)-9, and MMP-9/NGAL complex by enzyme-linked immunosorbent assays. Patient symptom changes were classified as improved, stable or worse using a functional clustering algorithm. Proportional odds models were used to evaluate the association between symptom change and urinary biomarkers. RESULTS: Across all sampled participants, longitudinal decreases in normalized VEGF concentration (pg/µg) were associated with pain severity improvement, and decreases in MMP-9, NGAL and VEGF-R1 concentration (pg/ml) as well as NGAL normalized concentration were associated with improved urinary symptoms. Longitudinal decreases in normalized VEGF-R1 were associated with pain improvement in patients with moderate widespreadness, no bladder symptoms and no painful filling. Lower baseline normalized VEGF-R1 concentration was associated with pain improvement in patients with pelvic pain only. Higher baseline MMP-9/NGAL levels were associated with pain and urinary improvement across all participants. Moreover, longitudinal increases in MMP-2 concentration was associated with improved pain in men and patients with painful filling. CONCLUSIONS: Our results suggest these urinary biomarkers may be useful in monitoring urological chronic pelvic pain syndrome symptom changes with respect to both urinary severity and pain severity. With further testing, they may represent objective biological measures of urological chronic pelvic pain syndrome progression and/or resolution while also providing insight into the pathophysiology of urological chronic pelvic pain syndrome.

Clinical and Psychosocial Predictors of Urological Chronic Pelvic Pain Symptom Change in 1 Year: A Prospective Study from the MAPP Research Network.

PURPOSE: We examined baseline clinical and psychosocial characteristics that predict 12-month symptom change in men and women with urological chronic pelvic pain syndromes. MATERIALS AND METHODS: A total of 221 female and 176 male patients with urological chronic pelvic pain syndromes were recruited from 6 academic medical centers in the United States and evaluated at baseline with a comprehensive battery of symptom, psychosocial and illness-impact measures. Based on biweekly symptom reports, a functional clustering procedure classified participant outcome as worse, stable or improved on pain and urinary symptom severity. Cumulative logistic modeling was used to examine individual predictors associated with symptom change as well as multiple predictor combinations and interactions. RESULTS: About 60% of participants had stable symptoms with smaller numbers (13% to 22%) showing clear symptom worsening or improvement. For pain and urinary outcomes the extent of widespread pain, amount of nonurological symptoms and poorer overall health were predictive of worsening outcomes. Anxiety, depression and general mental health were not significant predictors of outcomes but pain catastrophizing and self-reported stress were associated with pain outcome. Prediction models did not differ between men and women and for the most part they were independent of symptom duration and age. CONCLUSIONS: These results demonstrate for the first time in a large multisite prospective study that presence of widespread pain, nonurological symptoms and poorer general health are risk factors for poorer pain and urinary outcomes in men and women. The results point to the importance of broad based assessment for urological chronic pelvic pain syndromes and future studies of the mechanisms that underlie these findings.

Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

OBJECTIVE: To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies. METHODS: Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF-R1) and NGAL were assayed and quantitated using mono-specific enzyme-linked immunosorbent assays for each protein. Log-transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/µg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t-test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver-operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression. RESULTS: Significantly higher normalized concentrations (pg/µg) of VEGF, VEGF-R1 and MMP-9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP-9 and MMP-9/NGAL complex, and urinary severity was significantly positively associated with MMP-9, MMP-9/NGAL complex and VEGF-R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP-9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP-2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF-R1. CONCLUSION: Altered levels of MMP-9, MMP-9/NGAL complex and VEGF-R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP-9 and VEGF-R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.

Relationship between chronic nonurological associated somatic syndromes and symptom severity in urological chronic pelvic pain syndromes: baseline evaluation of the MAPP study.

PURPOSE: We used MAPP data to identify participants with urological chronic pelvic pain syndromes only or a chronic functional nonurological associated somatic syndrome in addition to urological chronic pelvic pain syndromes. We characterized these 2 subgroups and explored them using 3 criteria, including 1) MAPP eligibility criteria, 2) self-reported medical history or 3) RICE criteria. MATERIALS AND METHODS: Self-reported cross-sectional data were collected on men and women with urological chronic pelvic pain syndromes, including predominant symptoms, symptom duration and severity, nonurological associated somatic syndrome symptoms and psychosocial factors. RESULTS: Of 424 participants with urological chronic pelvic pain syndromes 162 (38%) had a nonurological associated somatic syndrome, including irritable bowel syndrome in 93 (22%), fibromyalgia in 15 (4%), chronic fatigue syndrome in 13 (3%) and multiple syndromes in 41 (10%). Of 233 females 103 (44%) had a nonurological associated somatic syndrome compared to 59 of 191 males (31%) (p = 0.006). Participants with a nonurological associated somatic syndrome had more severe urological symptoms and more frequent depression and anxiety. Of 424 participants 228 (54%) met RICE criteria. Of 228 RICE positive participants 108 (47%) had a nonurological associated somatic syndrome compared to 54 of 203 RICE negative patients (28%) with a nonurological associated somatic syndrome (p < 0.001). CONCLUSIONS: Nonurological associated somatic syndromes represent important clinical characteristics of urological chronic pelvic pain syndromes. Participants with a nonurological associated somatic syndrome have more severe symptoms, longer duration and higher rates of depression and anxiety. RICE positive patients are more likely to have a nonurological associated somatic syndrome and more severe symptoms. Because nonurological associated somatic syndromes are more common in women, future studies must account for this potential confounding factor in urological chronic pelvic pain syndromes.

On the Efficacy and Mediation of a One-on-One HIV Risk-Reduction Intervention for African American Men Who Have Sex with Men: A Randomized Controlled Trial.

We examined the efficacy and mediation of Being Responsible for Ourselves (BRO), an HIV/STI risk-reduction intervention for African American men who have sex with men (MSM), the population with the highest HIV-diagnosis rate in the US. We randomized African American MSM to one of two interventions: BRO HIV/STI risk-reduction, targeting condom use; or attention-matched control, targeting physical activity and healthy diet. The interventions were based on social cognitive theory, the reasoned-action approach, and qualitative research. Men reporting anal intercourse with other men in the past 90 days were eligible and completed pre-intervention, immediately post-intervention, and 6 and 12 months post-intervention surveys. Of 595 participants, 503 (85 %) completed the 12-month follow-up. Generalized-estimating-equations analysis indicated that, compared with the attention-matched control intervention, the BRO intervention did not increase consistent condom use averaged over the 6- and 12-month follow-ups, which was the primary outcome. Although BRO did not affect the proportion of condom-protected intercourse acts, unprotected sexual intercourse, multiple partners, or insertive anal intercourse, it did reduce receptive anal intercourse compared with the control, a behavior linked to incident HIV infection. Mediation analysis using the product-of-coefficients approach revealed that although BRO increased seven of nine theoretical constructs it was designed to affect, it increased only one of three theoretical constructs that predicted consistent condom use: condom-use impulse-control self-efficacy. Thus, BRO indirectly increased consistent condom use through condom-use impulse-control self-efficacy. In conclusion, although BRO increased several theoretical constructs, most of those constructs did not predict consistent condom use; hence, the intervention did not increase it. Theoretical constructs that interventions should target to increase African American MSM's condom use are discussed.

Novel Adjuvant S-540956 Targets Lymph Nodes and Reduces Genital Recurrences and Vaginal Shedding of HSV-2 DNA When Administered with HSV-2 Glycoprotein D as a Therapeutic Vaccine in Guinea Pigs.

Herpes simplex virus type 2 (HSV-2) is a leading cause of genital ulcer disease and a major risk factor for acquisition and transmission of HIV. Frequent recurrent genital lesions and concerns about transmitting infection to intimate partners affect the quality of life of infected individuals. Therapeutic vaccines are urgently needed to reduce the frequency of genital lesions and transmission. S-540956 is a novel vaccine adjuvant that contains CpG oligonucleotide ODN2006 annealed to its complementary sequence and conjugated to a lipid that targets the adjuvant to lymph nodes. Our primary goal was to compare S-540956 administered with HSV-2 glycoprotein D (gD2) with no treatment in a guinea pig model of recurrent genital herpes (studies 1 and 2). Our secondary goals were to compare S-540956 with oligonucleotide ODN2006 (study1) or glucopyranosyl lipid A in a stable oil-in-water nano-emulsion (GLA-SE) (study 2). gD2/S-540956 reduced the number of days with recurrent genital lesions by 56%, vaginal shedding of HSV-2 DNA by 49%, and both combined by 54% compared to PBS, and was more efficacious than the two other adjuvants. Our results indicate that S-540956 has great potential as an adjuvant for a therapeutic vaccine for genital herpes, and merits further evaluation with the addition of potent T cell immunogens.

Augmented generalized estimating equations for improving efficiency and validity of estimation in cluster randomized trials by leveraging cluster-level and individual-level covariates.

Recent methodological advances in covariate adjustment in randomized clinical trials have used semiparametric theory to improve efficiency of inferences by incorporating baseline covariates; these methods have focused on independent outcomes. We modify one of these approaches, augmentation of standard estimators, for use within cluster randomized trials in which treatments are assigned to groups of individuals, thereby inducing correlation. We demonstrate the potential for imbalance correction and efficiency improvement through consideration of both cluster-level covariates and individual-level covariates. To improve small-sample estimation, we consider several variance adjustments. We evaluate this approach for continuous and binary outcomes through simulation and apply it to data from a cluster randomized trial of a community behavioral intervention related to HIV prevention in Tanzania.

Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities.

OBJECTIVE: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities. STUDY DESIGN: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities. RESULTS: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1). CONCLUSION: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis.

Symptom Duration in Patients With Urologic Chronic Pelvic Pain Syndrome is not Associated With Pain Severity, Nonurologic Syndromes and Mental Health Symptoms: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Network Study.

OBJECTIVE: To evaluate if patients with urologic chronic pelvic pain syndromes (UCPPS) with longer duration of symptoms experience more severe pain and urologic symptoms, higher rates of chronic overlapping pain conditions (COPC) and psychosocial comorbidities than those with a more recent onset of the condition. We evaluated cross-sectional associations between UCPPS symptom duration and (1) symptom severity, (2) presence of COPC, and (3) mental health comorbidities. METHODS: We analyzed baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain. Symptom severity, COPC, and mental health comorbidities were compared between patients with symptom duration of < 2 vs ≥ 2 years. Symptom severity was assessed by the Genitourinary Pain Index, the Interstitial Cystitis Symptom and Problem Index, and Likert scales for pelvic pain, urgency, and frequency. Depression and anxiety were evaluated with the Hospital Anxiety and Depression Scale and stress with the Perceived Stress Scale. RESULTS: Males (but not females) with UCPPS symptom duration ≥2 years had more severe symptoms than those with <2 years. Participants with short (<2 years) and longer (≥2 years) symptom duration were as likely to experience COPC. CONCLUSION: Longer UCPPS symptom duration was associated with more severe symptoms only in limited patient subpopulations. Symptom duration was not associated with risk for COPC or mental health comorbidities. Females with longer UCPPS duration had decreased distress, but the association was largely attributable to age.

Resting-state functional connectivity predicts longitudinal pain symptom change in urologic chronic pelvic pain syndrome: a MAPP network study.

Chronic pain symptoms often change over time, even in individuals who have had symptoms for years. Studying biological factors that predict trends in symptom change in chronic pain may uncover novel pathophysiological mechanisms and potential therapeutic targets. In this study, we investigated whether brain functional connectivity measures obtained from resting-state functional magnetic resonance imaging at baseline can predict longitudinal symptom change (3, 6, and 12 months after scan) in urologic chronic pelvic pain syndrome. We studied 52 individuals with urologic chronic pelvic pain syndrome (34 women, 18 men) who had baseline neuroimaging followed by symptom tracking every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We found that brain functional connectivity can make a significant prediction of short-term (3 month) pain reduction with 73.1% accuracy (69.2% sensitivity and 75.0% precision). In addition, we found that the brain regions with greatest contribution to the classification were preferentially aligned with the left frontoparietal network. Resting-state functional magnetic resonance imaging measures seemed to be less informative about 6- or 12-month symptom change. Our study provides the first evidence that future trends in symptom change in patients in a state of chronic pain may be linked to functional connectivity within specific brain networks.

Widespread Psychosocial Difficulties in Men and Women With Urologic Chronic Pelvic Pain Syndromes: Case-control Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network.

OBJECTIVE: To determine the extent, severity, and sex differences of psychosocial deficits in men and women with urologic chronic pelvic pain syndromes (UCPPS), which in the past have been considered separate bladder (interstitial cystitis-painful bladder syndrome) and prostate (chronic prostatitis-chronic pelvic pain syndrome) disorders. Evaluations of men and women separately suggest UCPPS is associated with increased anxiety and depression. However, studies directly testing deficits in broader psychosocial domains such as cognitive processes, intimate relationships, and trauma history, or tests of sex differences in the pattern of difficulties associated with UCPPS have not been performed. METHODS: A total of 233 female and 191 male UCPPS patients and 235 female and 182 male healthy controls (HCs) were recruited from 6 academic medical centers in the United States and evaluated with a comprehensive battery of symptom, psychosocial, and illness impact measures. Primary comparisons of interest were between UCPPS patients and HCs and between men and women with UCPPS. RESULTS: In addition to greater negative effect, male and female UCPPS patients show higher levels of current and lifetime stress, poorer illness coping, increased self-report of cognitive deficits, and more widespread pain symptoms compared with sex- and education-matched HCs. Similar problems were found in male and female UCPPS patients although female UCPPS patients showed increased self-report of childhood adversity and more widespread symptoms of pain and discomfort. CONCLUSION: Given the significance of psychosocial variables in prognosis and treatment of chronic pain conditions, the results add substantially to our understanding of the breath of difficulties associated with UCPPS and point to important areas for clinical assessment.

Mindfulness-based stress reduction compared with cognitive behavioral therapy for the treatment of insomnia comorbid with cancer: a randomized, partially blinded, noninferiority trial.

PURPOSE: Our study examined whether mindfulness-based stress reduction (MBSR) is noninferior to cognitive behavioral therapy for insomnia (CBT-I) for the treatment of insomnia in patients with cancer. PATIENTS AND METHODS: This was a randomized, partially blinded, noninferiority trial involving patients with cancer with insomnia recruited from a tertiary cancer center in Calgary, Alberta, Canada, from September 2008 to March 2011. Assessments were conducted at baseline, after the program, and after 3 months of follow-up. The noninferiority margin was 4 points measured by the Insomnia Severity Index. Sleep diaries and actigraphy measured sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency. Secondary outcomes included sleep quality, sleep beliefs, mood, and stress. RESULTS: Of 327 patients screened, 111 were randomly assigned (CBT-I, n = 47; MBSR, n = 64). MBSR was inferior to CBT-I for improving insomnia severity immediately after the program (P = .35), but MBSR demonstrated noninferiority at follow-up (P = .02). Sleep diary-measured SOL was reduced by 22 minutes in the CBT-I group and by 14 minutes in the MBSR group at follow-up. Similar reductions in WASO were observed for both groups. TST increased by 0.60 hours for CBT-I and 0.75 hours for MBSR. CBT-I improved sleep quality (P < .001) and dysfunctional sleep beliefs (P < .001), whereas both groups experienced reduced stress (P < .001) and mood disturbance (P < .001). CONCLUSION: Although MBSR produced a clinically significant change in sleep and psychological outcomes, CBT-I was associated with rapid and durable improvement and remains the best choice for the nonpharmacologic treatment of insomnia.

FLEXIBLE COVARIATE-ADJUSTED EXACT TESTS OF RANDOMIZED TREATMENT EFFECTS WITH APPLICATION TO A TRIAL OF HIV EDUCATION.

The primary goal of randomized trials is to compare the effects of different interventions on some outcome of interest. In addition to the treatment assignment and outcome, data on baseline covariates, such as demographic characteristics or biomarker measurements, are typically collected. Incorporating such auxiliary co-variates in the analysis of randomized trials can increase power, but questions remain about how to preserve type I error when incorporating such covariates in a flexible way, particularly when the number of randomized units is small. Using the Young Citizens study, a cluster randomized trial of an educational intervention to promote HIV awareness, we compare several methods to evaluate intervention effects when baseline covariates are incorporated adaptively. To ascertain the validity of the methods shown in small samples, extensive simulation studies were conducted. We demonstrate that randomization inference preserves type I error under model selection while tests based on asymptotic theory may yield invalid results. We also demonstrate that covariate adjustment generally increases power, except at extremely small sample sizes using liberal selection procedures. Although shown within the context of HIV prevention research, our conclusions have important implications for maximizing efficiency and robustness in randomized trials with small samples across disciplines.