A Survey of Implementation of ABCDE Protocols.

BACKGROUND: Spontaneous awakening trials (SATs), spontaneous breathing trials (SBTs), delirium assessment/management, early mobility have been termed the ABCDE bundle. The ABCDE bundle has been proven to improve patient outcomes. However, there is often a long gap in dissemination and implementation of evidence-based medicine. OBJECTIVES: To determine the prevalent implementation of and determinants for ABCDE protocol adoption in Pennsylvania. METHODS: We developed a survey of ABCDE bundle protocols. We surveyed factors around implementation including written protocol presence, standardized assessments to guide protocols, timing of creation of protocols, and estimated adherence to protocols. We also collected data on factors that might be determinants for protocol adoption including ICU staffing models, hospital and ICU level factors. We validated the survey tool using the Michigan Health and Hospital Association Keystone ICU collaborative. We then administered the validated survey to a leader of the medical ICU or mixed medical-surgical ICU of all Pennsylvania Hospitals. Multivariable logistic and ordinal regression were used to determine associations between ICU staffing models and hospital and ICU level factors with the presence of ABCDE bundle protocols. RESULTS: In the study cohort of Pennsylvania ICUs (n = 144), we had 100 respondents (69% response). The median number of hospital beds among the respondents was 185 (IQR 111-355) with a median of 14 ICU beds (IQR 10-20). 86% reported spontaneous awakening trial protocols, 60% reported spontaneous breathing trial protocols, 43% reported delirium assessment/management protocols, and 27% reported early mobility protocols. Being a medical ICU compared to a mixed medical-surgical ICU (OR 3.48, 95% CI 1.19-10.21, P = .02) and presence of multidisciplinary rounds (OR 4.97, 95% CI 2.07-11.94, P < .001) were associated with increasing number of ABCDE bundle protocol components. CONCLUSIONS: Variable implementation of ABCDE bundle protocols was present across Pennsylvania. Team communication is important to implementation of these protocols.

Use of the vestibular and oculomotor examination for concussion in a pediatric emergency department.

BACKGROUND: Concussion guidelines recommend a vestibular and oculomotor (VOM) examination be performed for all patients with concern for concussion, however the feasibility of performing testing is unknown. We aimed to measure rates of exam performance after implementation of training and support tools in a pediatric emergency department. METHODS: We conducted a retrospective study of patients age 6 to 18 years old presenting over a 12-month period. Charts were obtained via natural language processing, where concussion was suggested as a diagnosis in the electronic health record, and then manually reviewed to record patient and provider factors. A multivariable logistic regression was performed to determine factors associated with exam performance, and a classification and regression tree (CART) analysis was performed to determine if a specific patient type was at risk for not having testing performed. RESULTS: Four hundred patients were included in the analysis. Sixty-four percent received a VOM examination (including 73% of those diagnosed with concussion). Provider type, concussion history, symptom burden, injury mechanism, and final diagnosis were all significantly associated with exam performance. CART analysis determined patients with a non-concussion diagnosis, a non-sports injury mechanism, no prior history of concussion, and two or fewer symptoms had the lowest likelihood (46%) of receiving the exam. CONCLUSION: Performing a VOM examination for concussion is feasible in the acute setting following provider education and using clinical support tools. The exam is more likely to be performed on those children with history or exam findings associated with perceived risk for ongoing symptoms.

Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial.

RATIONALE: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown. OBJECTIVES: We aimed to determine the safety and efficacy of anastrozole in PAH. METHODS: We performed a randomized, double-blind, placebo-controlled trial of anastrozole in patients with PAH who received background therapy at two centers. MEASUREMENTS AND MAIN RESULTS: A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co-primary outcomes were percent change from baseline in 17ß-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: -40%; interquartile range [IQR], -61 to -26% vs. -4%; IQR, -14 to +4%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = +26 m) compared with placebo (median change = -12 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo -2%; IQR, -7 to +1%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events. CONCLUSIONS: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small "proof-of-principle" study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH. Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).

The Effect of Skin Pigmentation on the Accuracy of Pulse Oximetry in Infants with Hypoxemia.

To compare pulse oximetry measurement bias between infants with hypoxemia with either dark skin or light skin with Masimo Radical 7 and Nellcor Oximax. There was no significant difference in systematic bias based on skin pigment for either oximeter.

Association Between Depression and Condom Use Differs by Sexual Behavior Group in Patients with HIV.

Identifying a relationship between depression and sexual risk behavior in HIV-infected patients could establish a mechanism to enhance prevention efforts. We conducted a cross-sectional analysis using data from the University of Pennsylvania Center for AIDS Research and used ordinal logistic regression to measure the association between depression and non-condom use. 716 men who have sex with men (MSM), 262 heterosexual men and 277 heterosexual women were included. The association between depression and non-condom use was strongest in heterosexual men with and without HIV-infected regular partners (OR 8.53, 95% CI 1.18-61.89 and OR 2.30, 95% CI 0.99-5.36 respectively), but absent in heterosexual women regardless of partner. Although the OR was low in MSM overall, an association was detected in MSM without HIV-infected regular partners (OR 2.44, 95% CI 1.39-4.31). In conclusion, we demonstrated an association between depression and non-condom use driven by heterosexual men and MSM without HIV-infected regular partners. Sexual risk should be addressed when intervening on depressive symptoms in these subgroups.

Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs.

The cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs) may be influenced by interactions with antiplatelet doses of aspirin. We sought to quantitate precisely the propensity of commonly consumed NSAIDs­ibuprofen, naproxen, and celecoxib­to cause a drug-drug interaction with aspirin in vivo by measuring the target engagement of aspirin directly by MS. We developed a novel assay of cyclooxygenase-1 (COX-1) acetylation in platelets isolated from volunteers who were administered aspirin and used conventional and microfluidic assays to evaluate platelet function. Although ibuprofen, naproxen, and celecoxib all had the potential to compete with the access of aspirin to the substrate binding channel of COX-1 in vitro, exposure of volunteers to a single therapeutic dose of each NSAID followed by 325 mg aspirin revealed a potent drug-drug interaction between ibuprofen and aspirin and between naproxen and aspirin but not between celecoxib and aspirin. The imprecision of estimates of aspirin consumption and the differential impact on the ability of aspirin to inactivate platelet COX-1 will confound head-to-head comparisons of distinct NSAIDs in ongoing clinical studies designed to measure their cardiovascular risk.

Is self-reported adherence associated with clinical outcomes in women treated with anticholinergic medication for overactive bladder?

AIM: To determine the association between self-reported adherence to anticholinergic medication and clinical outcomes in women with overactive bladder (OAB). METHODS: A prospective study of women with OAB treated with fesoterodine for 8 weeks. Adherence to medication was measured using the Medication Adherence Self-report Inventory (MASRI). A self reported adherence rate of ≥80% was considered adherent. The association between self-reported adherence and clinical outcomes (Global Index of Improvement, Global impression of Severity, urinary symptom and quality of life scores) was examined. We hypothesized that adherent women would have greater improvement in urinary symptoms and quality of life than non-adherent women. RESULTS: Based on the MASRI, 115 (62.5%) women were adherent and 69 (37.5%) were non-adherent to anticholinergic medication at 8weeks. Adherent women were more likely to report overall improvement in their symptoms compared to non-adherent women (84% vs. 24%, P < 0.001). Significantly more non-adherent women described their bladder symptoms as "moderate" or "severe" at 8 weeks compared to adherent women (74% vs. 44%, P = 0.03). At 8 weeks, adherent women reported significantly greater improvement (change) in urinary symptoms from baseline to 8 weeks than non-adherent women (-13.3 ± 25.8 vs. 2.5 ± 14.4, P = 0.04). Similarly, adherent women reported greater improvement in quality of life scores than non-adherent women (- 7.9 ± 24.0 vs. -1.8 ± 11.9, P = 0.003). CONCLUSION: Self-reported non-adherence, as measured by the MASRI, is associated with clinically meaningful outcomes in women with OAB. This further validates the MASRI as a clinically useful tool for measuring adherence to anticholinergic medications in women with OAB. Neurourol. Urodynam. 35:738-742, 2016. © 2015 Wiley Periodicals, Inc.

Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia.

Cancer-associated isocitrate dehydrogenase (IDH) mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of 2HG has not been established. We studied whether 2HG measurements in acute myeloid leukemia (AML) patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Sera from 223 de novo AML patients were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry. Pretreatment 2HG levels ranged from 10 to 30 000 ng/mL and were elevated in IDH-mutants (median, 3004 ng/mL), compared to wild-type IDH (median, 61 ng/mL) (P < .0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating characteristic analysis, a discriminatory level of 700 ng/mL optimally segregated patients with and without IDH mutations, and on subsequent mutational analysis of the 13 IDH wild-type samples with 2HG levels >700 ng/mL, 9 were identified to have IDH mutations. IDH-mutant patients with 2HG levels >200 at complete remission had shorter overall survival compared to 2HG ≤200 ng/mL (hazard ratio, 3.9; P = .02). We establish a firm association between IDH mutations and serum 2HG concentration in AML, and confirm that serum oncometabolite measurements provide useful diagnostic and prognostic information that can improve patient selection for IDH-targeted therapies.

Urinary incontinence and disability in community-dwelling women: a cross-sectional study.

AIMS: Disability, an individual's reduced capacity to perform physical tasks encountered in daily routine, is associated with urinary incontinence in the elderly. Our objective was to determine if urinary incontinence is associated with disability in community-dwelling women 40 years and older. METHODS: Cross-sectional study among US women ≥40 years (n = 4,458) from National Health and Nutrition Examination Surveys 2005-2010. We estimated the age-stratified weighted prevalence and factors independently associated with disability (Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), mobility, and functional limitations) in women with and without urinary incontinence while controlling for confounders of the association between disability and urinary incontinence. RESULTS: The weighted prevalence of all disabilities was higher in women with urinary incontinence than women without urinary incontinence across most decades of life with the greatest difference in the prevalence of mobility disabilities: 40-49 years (12.1% vs. 7.0%), 50-59 years (17.0% vs. 9.2%), 60-69 years (28.3% vs. 19.8%), and 70+ years (43.8% vs. 33.0%, all P < 0.05). On multivariable analysis, after controlling for the confounding effect of age, co-morbidities, and income-poverty ratio, urinary incontinence was weakly associated with disabilities. The adjusted odds ratio (95% confidence interval) of disabilities for urinary incontinence was ADL 1.96 (1.07, 3.58), IADL 1.18 (0.78, 1.78), mobility 1.26 (1.01, 1.56), and functional limitations 1.36 (1.07, 1.73). CONCLUSIONS: Urinary incontinence is weakly associated with disabilities and cannot be implicated as a cause of disability in community dwelling women.

Validation of a self-administered instrument to measure adherence to anticholinergic drugs in women with overactive bladder.

AIM: To validate a self-administered instrument, the Medication Adherence Self-Report Inventory (MASRI) for measuring adherence to anti-cholinergic medication for overactive bladder (OAB). METHODS: Prospective study in 131 women with OAB treated with fesoterodine. Adherence was measured at 8 and 12 weeks using an interviewer administered brief medication questionnaire (BMQ) that assesses barriers to adherence (criterion standard), the MASRI, and pill count. Construct, concurrent and discriminant validity of the MASRI was assessed. We hypothesized that women who were non-adherent as measured by the MASRI would be more likely to have a belief barrier than women who were adherent to medication. RESULTS: Women diagnosed as non-adherent by the MASRI were more likely to report a belief barrier to taking medication as compared to adherent women at 8 weeks (80% vs. 38%, P < 0.001) and at 12 weeks (70% vs. 40%, P = 0.003). Significant correlations were noted between adherence rates measured by the MASRI and the BMQ at 8 weeks (r = 0.87, P < 0.001) and 12 weeks (r = 0.90, P < 0.001). Moderate correlation was noted between the adherence rate as measured by the MASRI and pill count at 8 weeks (r = 0.49, P = 0.02) but not at 12 weeks (r = 0.05, P = 0.87). The MASRI correctly identified 93% and 96% of non-adherent women at 8 and 12 weeks, respectively. Sensitivity, specificity, and positive likelihood ratio of the MASRI for predicting non-adherence was 91%, 82%, and 5.1 at 8 weeks and 90%, 85% and 6.1 at 12 weeks. CONCLUSIONS: The MASRI is a valid self-administered tool for measuring adherence to anti-cholinergic medication in women with OAB.

Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.

BACKGROUND: Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. METHODS: We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. FINDINGS: 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. INTERPRETATION: Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. FUNDING: FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

Estimating the efficacy of an interstitial cystitis/painful bladder syndrome medication in a randomized trial with both non-adherence and loss to follow-up.

We are motivated by a randomized clinical trial evaluating the efficacy of amitriptyline for the treatment of interstitial cystitis and painful bladder syndrome in treatment-naïve patients. In the trial, both the non-adherence rate and the rate of loss to follow-up are fairly high. To estimate the effect of the treatment received on the outcome, we use the generalized structural mean model (GSMM), originally proposed to deal with non-adherence, to adjust for both non-adherence and loss to follow-up. In the model, loss to follow-up is handled by weighting the estimation equations for GSMM with one over the probability of not being lost to follow-up, estimated using a logistic regression model. We re-analyzed the data from the trial and found a possible benefit of amitriptyline when administered at a high-dose level.

Race and gender variation in response to evoked inflammation.

BACKGROUND: Race- and gender-variation in innate immunity may contribute to demographic differences in inflammatory and cardiometabolic disease; yet their influence on dynamic responses during inflammatory stress is poorly understood. Our objective was to examine race and gender influence on the response to experimental endotoxemia. METHODS: The Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) study was designed to investigate regulation of inflammatory and metabolic responses during low-grade endotoxemia (LPS 1 ng/kg intravenously) in healthy individuals (median age 24, IQR=7) of European (EA; n=193, 47% female) and African ancestry (AA; n=101, 59% female). RESULTS: Baseline clinical, metabolic, and inflammatory biomarkers by race and gender were consistent with epidemiological literature; pre-LPS cytokines (e.g. median (IQR) IL-6, 2.7 (2) vs.2.1 (2) pg/ml, P=0.001) were higher in AA than EA. In contrast, acute cytokine responses during endotoxemia were lower in AA than EA (e.g. median (IQR) peak IL-1RA, 30 (38) vs.43 (45) ng/ml P=0.002) as was the induction of hepatic acute-phase proteins (e.g. median (IQR) peak CRP 12.9 (9) vs.17.4 (12) mg/L P=0.005). Further, baseline levels of cytokines were only weakly correlated with peak inflammatory responses (all r(s) <0.2) both in AA and in EA. There were less pronounced and less consistent differences in the response by gender, with males having a higher AUC for CRP response compared to females (median (IQR) AUC: 185 (112) vs. 155 (118), P=0.02). CONCLUSIONS: We observed lower levels of evoked inflammation in response to endotoxin in AA compared with EA, despite similar or higher baseline levels of inflammatory markers in AA. Our data also suggest that levels of inflammatory biomarkers measured in epidemiological settings might not predict the degree of acute stress-response or risk of diseases characterized by activation of innate immunity. TRIAL REGISTRATION: FDA clinicaltrials.gov registration number NCT00953667.

Construct validity of an instrument to measure neuropathic pain in women with bladder pain syndrome.

AIMS: To determine the construct validity of an instrument to measure neuropathic pain in women with bladder pain syndrome (BPS). Our hypothesis is that neuropathic, bladder, and bowel pain represent different constructs in women with BPS. METHODS: Secondary planned analysis of a prospective cross-sectional study of 150 women with BPS. The relationship between neuropathic pain, urinary, and bowel symptoms was assessed. RESULTS: The correlation of the total neuropathic pain score with total urinary and bowel symptom scores was low to moderate (r = 0.28-0.49). The correlation of specific neuropathic pain items with bladder and bowel pain was also low to moderate (r = 0.12-0.36). Women with neuropathic pain had significantly higher scores for urinary urgency, bladder pain, abdominal pain, diarrhea, and constipation than women with non-neuropathic pain (all P < 0.0001). CONCLUSION: Somatosensory neuropathic pain and "visceral" bladder and bowel pain represent separate but related constructs in women with BPS.

Early termination of a trial of mycophenolate mofetil for treatment of interstitial cystitis/painful bladder syndrome: lessons learned.

PURPOSE: We evaluated the efficacy and tolerability of mycophenolate mofetil in patients with treatment refractory interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A total of 210 patients with interstitial cystitis/painful bladder syndrome were to be randomized into a multicenter, placebo controlled trial using a 2:1 randomization. Participants in whom at least 3 interstitial cystitis/painful bladder syndrome specific treatments had failed and who had at least moderately severe symptoms were enrolled in a 12-week treatment study. The primary study end point was the global response assessment. Secondary end points were general and disease specific symptom questionnaires, and voiding diaries. RESULTS: Only 58 subjects were randomized before a black box warning regarding mycophenolate mofetil safety was issued by the manufacturer in October 2007. The trial was halted, and interim analysis was performed and presented to an independent data and safety monitoring board. Six of the 39 subjects (15%) randomized at study cessation were considered responders for mycophenolate mofetil compared to 3 of 19 controls (16%, p=0.67). Secondary outcome measures reflected more improvement in controls. CONCLUSIONS: In a randomized, placebo controlled trial that was prematurely halted mycophenolate mofetil showed efficacy similar to that of placebo to treat symptoms of refractory interstitial cystitis/painful bladder syndrome. The results of this limited study cannot be used to confirm or refute the hypothesis that immunosuppressive therapy may be beneficial to at least a subgroup of patients with interstitial cystitis/painful bladder syndrome. Despite study termination lessons can be gleaned to inform future investigations.

Effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome.

PURPOSE: Amitriptyline is frequently used to treat patients with interstitial cystitis/painful bladder syndrome. The evidence to support this practice is derived mainly from a small, single site clinical trial and case reports. MATERIALS AND METHODS: We conducted a multicenter, randomized, double-blind, placebo controlled clinical trial of amitriptyline in subjects with interstitial cystitis/painful bladder syndrome who were naïve to therapy. Study participants in both treatment arms received a standardized education and behavioral modification program. The drug dose was increased during a 6-week period from 10 up to 75 mg once daily. The primary outcome was a patient reported global response assessment of symptom improvement evaluated after 12 weeks of treatment. RESULTS: A total of 271 subjects were randomized and 231 (85%) provided a global response assessment at 12 weeks of followup. Study participants were primarily women (83%) and white (74%), with a median age of 38 years. In an intent to treat analysis (271) the rate of response of subjects reporting moderate or marked improvement from baseline in the amitriptyline and placebo groups was 55% and 45%, respectively (p = 0.12). Of the subgroup of subjects (207) who achieved a drug dose of at least 50 mg, a significantly higher response rate was observed in the amitriptyline group (66%) compared to placebo (47%) (p = 0.01). CONCLUSIONS: When all randomized subjects were considered, amitriptyline plus an education and behavioral modification program did not significantly improve symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. However, amitriptyline may be beneficial in persons who can achieve a daily dose of 50 mg or greater, although this subgroup comparison was not specified in advance.

Treatment and Outcomes of Oropharyngeal Cancer in People with Human Immunodeficiency Virus.

HIV-positive people are at increased risk for malignancies associated with human papillomavirus (HPV) infection, including oropharyngeal squamous cell carcinoma (OPSCC). The purpose of this study was to determine whether cancer treatment disparities exist between HIV-positive and HIV-negative people with OPSCC. We conducted a retrospective cohort study comparing OPSCC treatment adequacy and treatment outcomes in HIV-positive and HIV-negative people in the post-antiretroviral therapy era. Treatment adequacy was determined by measuring two primary endpoints associated with OPSCC survival: time to therapy and total radiation dose. Treatment outcomes were assessed by measuring disease-free and overall survival. We identified a total of 37 HIV-positive and 149 HIV-negative people with OPSCC. HIV-positive people experienced a median delay of 10 days from time of OPSCC diagnosis to start of therapy compared with HIV-negative people [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.38-0.98]. Total post-radiation dose in HIV-positive people was lower than that in HIV-negative people [58.5 Gray (Gy) versus 64.4 Gy, p = .04]. HIV-positive people also experienced greater hazards for disease recurrence (HR 3.43, 95% CI 1.39-8.46) and death (HR 4.21, 95% CI 1.29-13.80) compared with HIV-negative people. In conclusion, we detected a clinically important delay in time to therapy as well as worse disease-free and overall survival in HIV-positive people with OPSCC compared with their HIV-negative counterparts. These findings are relevant to understanding how HIV-positive people are diagnosed and undergo therapy for HPV-associated malignancies and highlight the need to address cancer treatment disparities in this group.

Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models.

The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.

Muscle tenderness in men with chronic prostatitis/chronic pelvic pain syndrome: the chronic prostatitis cohort study.

PURPOSE: Myofascial pain is a possible etiology for category III chronic prostatitis/chronic pelvic pain syndrome, either secondary to infection/inflammation or as the primary cause. We documented tenderness on physical examination in a large multicenter cohort of patients with chronic pelvic pain syndrome and compared to controls. MATERIALS AND METHODS: Data were reviewed from the National Institutes of Health Chronic Prostatitis Cohort study on 384 men with chronic pelvic pain syndrome and 121 asymptomatic controls who had complete unblinded physical examination data from 7 clinical centers between October 1998 and August 2001. Tenderness in 11 sites including prostate, genitals, abdomen and pelvic floor together with prostate size and consistency was evaluated. Data were correlated with cultures and symptoms. RESULTS: Overall 51% of patients with chronic pelvic pain syndrome and 7% of controls had any tenderness. The most common site was prostate (41% chronic pelvic pain syndrome, 5% controls), followed by external and internal pelvic floor (13% and 14% chronic pelvic pain syndrome, 0 controls) and suprapubic area (9% chronic pelvic pain syndrome, 0 controls). Of patients with chronic pelvic pain syndrome 25% had 1 tender site, 11% had 2 and 6% had 3 tender sites. Tenderness did not correlate with inflammation or infection in the prostate fluid. Prostate consistency was normal in 79% of patients with chronic pelvic pain syndrome and in 95% of controls, and did not correlate with symptom severity. Patients with chronic pelvic pain syndrome with any tenderness had significantly higher Chronic Prostatitis Symptom Index scores at baseline and at 1 year (24.1 vs 21.2 and 20.2 vs 17.5, p <0.0001) compared to patients without tenderness. CONCLUSIONS: Abdominal/pelvic tenderness is present in half of the patients with chronic pelvic pain syndrome but only 7% of controls. Extraprostatic tenderness may identify a cohort of patients with a neuromuscular source of pain.

Pregnancy and interstitial cystitis/painful bladder syndrome.

Painful bladder syndrome (PBS) and interstitial cystitis (IC) often affect women of child-bearing age. This article includes information of interest to PBS/IC patients who are pregnant or contemplating pregnancy, and to the clinicians who care for them. One topic is how pregnancy affects PBS/IC symptoms, although little is known at this time. The article also describes the pregnancy risks associated with the most commonly used PBS/IC treatments. Finally, the current knowledge regarding genetic factors in IC is discussed.