Use of the metastatic breast cancer progression (MBC-P) questionnaire to assess the value of progression-free survival for women with metastatic breast cancer.

While overall survival (OS) has historically been the primary endpoint for clinical trials in oncology, progression-free survival (PFS) has gained acceptance as a valuable surrogate endpoint. However, there are no known published reports about the value of PFS from the patient's perspective. We developed a questionnaire that included items regarding quality of life (QoL) and the importance of different treatment outcomes and presented hypothetical scenarios for which respondents were asked to indicate their preferences concerning treatments as they relate to PFS. 282 women with metastatic breast cancer (MBC), ranging in age from 21 to 80 years completed an online version of this questionnaire. The majority of women (66 %) had been diagnosed with MBC within the previous 3 years and 56 % had been told their MBC had progressed. When asked to rank five treatment characteristics from most important to least important, respondents ranked "extending PFS" as the second most important treatment outcome after OS. When presented with a hypothetical scenario of two women receiving different treatments, respondents preferred the treatment that resulted in longer PFS (16 vs. 12 months), even when OS and side effects were assumed to be equal. Specifically, when asked to consider which woman within the hypothetical scenario had better QoL, physical functioning, and emotional well-being, respondents more often chose the woman who experienced longer PFS (QoL: 40 vs. 6 %; physical functioning: 32 vs. 8 %; emotional well-being: 58 vs. 6 %) compared to the woman within the hypothetical scenario who had a shorter time of progression. Respondents rated their own QoL highest after being told their MBC was responding to treatment (mean score 76.6) versus after the initial diagnosis of breast cancer and MBC (68.5 and 60.3). These findings suggest that extending PFS is an important treatment outcome and, from a patient perspective, improves overall QoL, physical functioning, and emotional well-being

Measurement properties of the Flu-Like Symptom Index from the Hepatitis Physical Symptom Severity Diary

Purpose Chronic Hepatitis C (CHC) Virus infection is a serious health issue in the US. Standard treatment involves peginterferon alpha and ribavirin, often associated with adverse side effects including flu-like symptoms. These adverse effects are common reasons for the discontinuation of treatment and therefore represent a major obstacle in the effective treatment of CHC. Methods The Hepatitis Physical Symptom Severity Diary, a newly developed patient-reported outcome mea-sure for assessing physical symptoms in CHC patients, was recently developed. It contains four questions addressing flu-like symptoms [the Flu-Like Symptom Index (FLSI)]. Measurement properties of the FLSI in CHC patients were assessed using data from two randomized clinical trials. Results Exploratory factor analysis using data from baseline and the last visit while on treatment supported a single-factor solution for the FLSI. Internal reliability and test–retest reliability are acceptable (Cronbach’s alpha range 0.73–0.81; intraclass correlation coefficient range 0.85–0.97), and correspondence to several similar con-structs was acceptable. The FLSI score was higher among those with investigator-reported flu-like symptoms (mean = 4.1) versus those without (1.4), although not statistically significant (p = 0.12). Responsiveness of the FLSI was moderate, as measured by standardized effect sizes and response means, and the minimum important difference (MID) was estimated at 2.5–3.0 points. Conclusions While additional research should be con-ducted to evaluate validity with more closely related con-structs and to utilize anchor-based methods for estimating the MID, data suggest that the FLSI has acceptable mea-surement properties and can be an effective tool in assessing flu-like symptoms in CHC patients

The OnyCOE-t™ questionnaire: responsiveness and clinical meaningfulness of a patient-reported outcomes questionnaire for toenail onychomycosis

BACKGROUND: This research was conducted to confirm the validity and reliability and to assess the responsiveness and clinical meaningfulness of the OnyCOE-t(™), a questionnaire specifically designed to measure patient-reported outcomes (PRO) associated with toenail onychomycosis. METHODS: 504 patients with toenail onychomycosis randomized to receive 12 weeks of terbinafine 250 mg/day with or without target toenail debridement in the IRON-CLAD(® )trial completed the OnyCOE-t™ at baseline, weeks 6, 12, 24, and 48. The OnyCOE-t™ is composed of 6 multi-item scales and 1 single-item scale. These include a 7-item Toenail Symptom assessment, which comprises both Symptom Frequency and Symptom Bothersomeness scales; an 8-item Appearance Problems scale; a 7-item Physical Activities Problems scale; a 1-item Overall Problem scale; a 7-item Stigma scale; and a 3-item Treatment Satisfaction scale. In total, 33 toenail onychomycosis-specific items are included in the OnyCOE-t™. Clinical data, in particular the percent clearing of mycotic involvement in the target toenail, and OnyCOE-t™ responses were used to evaluate the questionnaire's reliability, validity, responsiveness, and the minimally clinical important difference (MCID). RESULTS: The OnyCOE-t™ was shown to be reliable and valid. Construct validity and known groups validity were acceptable. Internal consistency reliability of multi-item scales was demonstrated by Cronbach's alpha > .84. Responsiveness was good, with the Treatment Satisfaction, Symptom Frequency, Overall Problem, and Appearance Problem scales demonstrating the most responsiveness (Guyatt's statistic of 1.72, 1.31, 1.13, and 1.11, respectively). MCID was evaluated for three different clinical measures, and indicated that approximately an 8.5-point change (on a 0 to 100 scale) was clinically meaningful based on a 25% improvement in target nail clearing. CONCLUSION: The OnyCOE-t™ questionnaire is a unique, toenail-specific PRO questionnaire that can be used with confidence in future studies of toenail onychomycosis. MCID was evaluated for three different clinical measures, and indicated that approximately a 7-point change (on a 0 to 100 scale) was clinically meaningful based on a 12.5% improvement in target nail clearing

Validation of the Patient Perception of Intensity of Urgency Scale in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia

AbstractObjectiveTo assess the reliability and validity of scores derived from the Patient Perception of Intensity of Urgency Scale (PPIUS) in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).MethodsA post hoc analysis of the phase II Solifenacin and Tamsulosin in Males with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia trial (NCT00510406), a 12-week clinical trial in men with LUTS associated with BPH, assessed the measurement properties of six PPIUS-derived scores: mean score; maximum urgency score; total urgency and frequency score (TUFS; average sum of urgency scores over 3 days); and numbers of urgency episodes, urgency episodes of grade 3 or 4, and urgency incontinence episodes. Test-retest reliability, presence of floor/ceiling effects, responsiveness to change, known-group validity, and concurrent validity were assessed for each score.ResultsA total of 901 patients had at least one valid PPIUS assessment after baseline. TUFS demonstrated good test-retest reliability (intraclass correlation coefficient >0.8), discriminated between groups defined based on International Prostate Symptom Score storage score severity (known-groups validity), had high concurrent validity, and had high responsiveness to change (Guyatt’s responsiveness statistic 0.88), with an absence of floor or ceiling effects. The psychometric properties of other PPIUS-derived scores were not as consistently robust and showed either low-to-moderate responsiveness, presence of a floor or ceiling effect, or low-to-moderate test-retest reliability.ConclusionsThis study shows that the PPIUS is reliable and valid in patients with LUTS associated with BPH. TUFS provided the best combination of psychometric properties of the six scores derived from the PPIUS and appeared to be an appropriate measure of urgency and frequency

27630 Assessing signs and symptoms of hidradenitis suppurativa from the patient perspective

Background: Qualitative research was conducted to develop a patient reported outcome (PRO) measure assessing symptoms/signs of hidradenitis suppurativa (HS), the HS Symptom Diary (HSSD). Methods: Concept elicitation (CE) and combined CE/cognitive debriefing (CD) interviews were conducted with adult patients with moderate-to-severe HS from 5 dermatology practices in North America. The CE portion of the interview sought to fully understand important concepts of HS. Subjects then completed the draft HSSD, and answered questions to evaluate its content, clarity, and relevance. Revisions were made iteratively to the HSSD. The study received institutional review board approval; subjects provided written informed consent. Results: 36 subjects were interviewed [6 = CE and 30 = CE/CD, 65% female; mean age = 39]. The most commonly reported lesion locations were armpits (81%), groin (75%), or under the breasts (31%). Subjects reported pain (100%), drainage (100%), itching (100%), swelling/ inflammation (94%), odor (86%), tenderness (81%), heat (64%), and pressure (64%) related to their lesions. The most bothersome symptoms were pain (94%), drainage (50%), swelling/inflammation (42%), and itching (33%). Pain was the most difficult symptom to manage (53%). In general, respondents were able to paraphrase each item and found the content to be clear and relevant. The final HSSD, developed as a daily diary with a 24-hour recall period, contains 8 items evaluating severity of each symptom/sign using an 11-point numeric rating scale. A 7-day version was also developed. Conclusion: Content validity of the HSSD in patients with moderate-to-severe HS has been demonstrated. Its measurement properties will be assessed using data from upcoming clinical studies

A disease-specific measure of health-related quality of life for use in adults with immune thrombocytopenic purpura: Its development and validation

BACKGROUND: No validated disease-specific measures are available to assess health-related quality of life (HRQoL) in adult subjects with immune thrombocytopenic purpura (ITP). Therefore, we sought to develop and validate the ITP-Patient Assessment Questionnaire (ITP-PAQ) for adult subjects with ITP. METHODS: Information from literature reviews, focus groups with subjects, and clinicians were used to develop 50 ITP-PAQ items. Factor analyses were conducted to develop the scale structure and reduce the number of items. The final 44-item ITP-PAQ, which includes ten scales [Symptoms (S), Bother-Physical Health (B), Fatigue/Sleep (FT), Activity (A), Fear (FR), Psychological Health (PH), Work (W), Social Activity (SA), Women's Reproductive Health (RH), and Overall (QoL)], was self-administered to adult ITP subjects at baseline and 7–10 days later. Test-retest reliability, internal consistency reliability, construct and known groups validity of the final ITP-PAQ were evaluated. RESULTS: Seventy-three subjects with ITP completed the questionnaire twice. Test-retest reliability, as measured by the intra-class correlation, ranged from 0.52–0.90. Internal consistency reliability was demonstrated with Cronbach's alpha for all scales above the acceptable level of 0.70 (range: 0.71–0.92), except for RH (0.66). Construct validity, assessed by correlating ITP-PAQ scales with established measures (Short Form-36 v.1, SF-36 and Center for Epidemiologic Studies Depression Scale, CES-D), was demonstrated through moderate correlations between the ITP-PAQ SA and SF-36 Social Function scales (r = 0.67), and between ITP-PAQ PH and SF-36 Mental Health Scales (r = 0.63). Moderate to strong inter-scale correlations were reported between ITP-PAQ scales and the CES-D, except for the RH scale. Known groups validity was evaluated by comparing mean scores for groups that differed clinically. Statistically significant differences (p < 0.01) were observed when subjects were categorized by treatment status [S, FT, B, A, PH, and QoL, perceived effectiveness of ITP treatment [S], and time elapsed since ITP diagnosis [PH]. CONCLUSION: Results provide preliminary evidence of the reliability and validity of the ITP-PAQ in adult subjects with ITP. Further work should be conducted to assess the responsiveness and to estimate the minimal clinical important difference of the ITP-PAQ to more fully understand the impact of ITP and its treatments on HRQoL

\u3ci\u3eStaphylococcus aureus\u3c/i\u3e Metabolic Adaptations during the Transition from a Daptomycin Susceptibility Phenotype to a Daptomycin Nonsusceptibility Phenotype

Staphylococcus aureus is a major cause of nosocomial and community-acquired infections. The success of S. aureus as a pathogen is due in part to its many virulence determinants and resistance to antimicrobials. In particular, methicillin-resistant S. aureus has emerged as a major cause of infections and led to increased use of the antibiotics vancomycin and daptomycin, which has increased the isolation of vancomycin-intermediate S. aureus and daptomycin-nonsusceptible S. aureus strains. The most common mechanism by which S. aureus acquires intermediate resistance to antibiotics is by adapting its physiology and metabolism to permit growth in the presence of these antibiotics, a process known as adaptive resistance. To better understand the physiological and metabolic changes associated with adaptive resistance, six daptomycin-susceptible and -nonsusceptible isogenic strain pairs were examined for changes in growth, competitive fitness, and metabolic alterations. Interestingly, daptomycin nonsusceptibility coincides with a slightly delayed transition to the postexponential growth phase and alterations in metabolism. Specifically, daptomycin-nonsusceptible strains have decreased tricarboxylic acid cycle activity, which correlates with increased synthesis of pyrimidines and purines and increased carbon flow to pathways associated with wall teichoic acid and peptidoglycan biosynthesis. Importantly, these data provided an opportunity to alter the daptomycin nonsusceptibility phenotype by manipulating bacterial metabolism, a first step in developing compounds that target metabolic pathways that can be used in combination with daptomycin to reduce treatment failures

Impact of chronic Immune Thrombocytopenic Purpura (ITP) on health-related quality of life: a conceptual model starting with the patient perspective

<p>Abstract</p> <p>Background</p> <p>Immune thrombocytopenic purpura (ITP), a condition characterized by autoimmune-mediated platelet destruction and suboptimal platelet production, is associated with symptoms such as bruising, epistaxis, menorrhagia, mucosal bleeding from the gastrointestinal and urinary tracts and, rarely central nervous system bleeding. The aim of this research is to develop a conceptual model to describe the impact of ITP and its treatment on patients' health-related quality of life (HRQoL).</p> <p>Methods</p> <p>A literature search and focus groups with adult ITP patients were conducted to identify areas of HRQoL affected by ITP. Published literature was reviewed to identify key HRQoL issues and existing questionnaires used to assess HRQoL. Focus group transcripts were reviewed, and common themes were extracted by grouping conceptual categories that described the impact on HRQoL.</p> <p>Results</p> <p>The literature synthesis and themes from the focus group data suggest that decreased platelet counts, disease symptoms, and treatment side effects influence multiple domains of HRQoL for ITP patients. Key areas affected by ITP and its treatments include emotional and functional health, work life, social and leisure activities, and reproductive health.</p> <p>Conclusion</p> <p>ITP affects various areas of HRQoL. This conceptual model will help inform the evaluation of therapeutic strategies for ITP.</p

The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans

<p>Abstract</p> <p>Background</p> <p>Arachidonic acid (AA) is a long-chain omega-6 polyunsaturated fatty acid (PUFA) synthesized from the precursor dihomo-gamma-linolenic acid (DGLA) that plays a vital role in immunity and inflammation. Variants in the Fatty Acid Desaturase (<it>FADS</it>) family of genes on chromosome 11q have been shown to play a role in PUFA metabolism in populations of European and Asian ancestry; no work has been done in populations of African ancestry to date.</p> <p>Results</p> <p>In this study, we report that African Americans have significantly higher circulating levels of plasma AA (p = 1.35 × 10^-48) and lower DGLA levels (p = 9.80 × 10^-11) than European Americans. Tests for association in N = 329 individuals across 80 nucleotide polymorphisms (SNPs) in the Fatty Acid Desaturase (<it>FADS</it>) locus revealed significant association with AA, DGLA and the AA/DGLA ratio, a measure of enzymatic efficiency, in both racial groups (peak signal p = 2.85 × 10^-16in African Americans, 2.68 × 10^-23in European Americans). Ancestry-related differences were observed at an upstream marker previously associated with AA levels (rs174537), wherein, 79-82% of African Americans carry two copies of the G allele compared to only 42-45% of European Americans. Importantly, the allelic effect of the G allele, which is associated with <it>enhanced </it>conversion of DGLA to AA, on enzymatic efficiency was similar in both groups.</p> <p>Conclusions</p> <p>We conclude that the impact of <it>FADS </it>genetic variants on PUFA metabolism, specifically AA levels, is likely more pronounced in African Americans due to the larger proportion of individuals carrying the genotype associated with increased FADS1 enzymatic conversion of DGLA to AA.</p

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function