Does Dry Eye Disease Severity Impact Efficacy of Varenicline Solution Nasal Spray on Sign and Symptom Treatment Outcomes?

SIGNIFICANCE: There is a clinical necessity for dry eye disease treatments that perform across a broad range of presenting patient severities. Varenicline solution nasal spray (VNS), a unique cholinergic agonist ocular surface-sparing nasal spray therapy, demonstrated significant improvement in both signs and symptoms of dry eye disease in subjects with mild, moderate, and severe symptoms as the clinical studies enrolled a more real-world patient population. PURPOSE: This study evaluated efficacy outcomes for VNS in patients with mild-moderate and severe dry eye disease. METHODS: An analysis of integrated data from two randomized clinical trials, ONSET-1 (NCT03636061) and ONSET-2 (NCT04036292) (vehicle control [VC], n = 294; VNS 0.03 mg, n = 308), was performed. Adults 22 years or older with dry eye disease, Ocular Surface Disease Index score of ≥23, corneal fluorescein staining score of ≥2 in ≥1 regions/≥4 all regions, and Schirmer Test Score (STS) of ≤10 mm (no restrictions on Eye Dryness Score [EDS]) were included in this study. Efficacy was evaluated using analysis of covariance among pre-specified subgroups of mild-moderate and severe baseline disease severity defined by STS (≤5 vs. >5) and EDS (<60 vs. ≥60). Consistency of effect was evaluated by interaction tests. RESULTS: No treatment-subgroup interactions were observed for all end points ( P > .05). The odds of achieving a ≥10-mm improvement in STS for VNS versus VC for patients with baseline STS ≤5 and >5 were 3.4(95% confidence interval, 2.0 to 5.6) and 2.3(1.3 to 4.0) and for EDS of <60 and ≥60 were 3.4(1.9 to 6.1) and 2.5(1.5 to 4.0). Least-squares mean treatment/VC differences in change from baseline in EDS for patients with baseline STS ≤5 or >5 were -7.4(95% confidence interval, -12.5 to -2.4) and -2.8(-8.7 to 3.1); EDS of <60 and ≥60 were -2.9(-8.3 to 2.5) and -8.1(-13.6 to -2.6). CONCLUSIONS: Compared with VC, VNS improved tear production and patient-reported symptoms in patients with dry eye disease, demonstrating consistency of effect regardless of initial presenting severity.

Serologic Response to Helicobacter pylori Proteins Associated With Risk of Colorectal Cancer Among Diverse Populations in the United States.

BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States. METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of seropositivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression. RESULTS: Overall, 40% of controls and 41% of cases were H pylori-seropositive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific seropositivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P = .008) and specifically among African Americans (P = .007). CONCLUSIONS: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk, particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

Performance of multiplex serology in discriminating active vs past Helicobacter pylori infection in a primarily African American population in the southeastern United States.

PURPOSE: To feasibly analyze associations of Helicobacter pylori (H. pylori) with disease in large cohort studies, assays are needed to assess H. pylori prevalence in existing biospecimens. However, serology has traditionally been unable to distinguish active from past infection. We sought to determine the sensitivity of seropositivity to H. pylori proteins to detect active infection. METHODS: We measured antibody responses to 13 H. pylori proteins using multiplex serology in serum samples of a training (n = 78) and validation set (n = 49) collected concurrently from patients undergoing urea breath test (UBT). To determine sensitivity of seropositivity to H. pylori proteins for active infection, a cutoff was applied to achieve 90% specificity. Antibody levels were retested in a subset of participants (n = 16) 6 months after baseline. RESULTS: With a specificity of 91%, seropositivity to H. pylori proteins VacA, GroEl, HcpC, and HP1564 ascertained active infection from 100% to 75% sensitivity. Positivity to a combination of these proteins (≥2 out of the 4) resulted in specificity of 90% and sensitivity of 100%. The validation set replicated results from the training set. Among those participants with successful H. pylori eradication after baseline, antibody levels decreased significantly for VacA, HcpC, and HP1564 when assessed 6 months later. CONCLUSION: Utilizing the cutoffs for seropositivity established through comparison with UBT, seropositivity to ≥2 of the H. pylori proteins VacA, GroEl, HcpC, and HP1564 determines active H. pylori infection at high specificity and sensitivity and may approximate the prevalence of active H. pylori infection in large cohorts.

Chemokine Receptor 7 Is Essential for Coxiella burnetii Whole-Cell Vaccine-Induced Cellular Immunity but Dispensable for Vaccine-Mediated Protective Immunity.

BACKGROUND: Protective immunity against Coxiella burnetii infection is conferred by vaccination with virulent (PI-WCV), but not avirulent (PII-WCV) whole-cell inactivated bacterium. The only well-characterized antigenic difference between virulent and avirulent C. burnetii is they have smooth and rough lipopolysaccharide (LPS), respectively. METHODS: Mice were vaccinated with PI-WCV and PII-WCV. Humoral and cellular responses were evaluated using protein chip microarrays and ELISpots, respectively. Dendritic cell (DC) maturation after stimulation with PI-WVC and PII-WVC was evaluated using flow cytometry. Vaccine-challenge studies were performed to validate the importance of the receptor CCR7. RESULTS: Other than specific antibody response to PI-LPS, similar antibody profiles were observed but IgG titers were significantly higher after vaccination with PI-WCV. Furthermore, higher frequency of antigen-specific CD4+ T cells was detected in mice immunized with PI-WCV. PI-WCV-stimulated DCs displayed significantly higher levels of CCR7 and migratory ability to secondary lymphoid organs. Challenge-protection studies in wild-type and CCR7-deficient mice confirmed that CCR7 is critical for PI-WCV-induced cellular immunity. CONCLUSIONS: PI-WVC stimulates protective immunity to C. burnetii in mice through stimulation of migratory behavior in DCs for protective cellular immunity. Additionally, the humoral immune response to LPS is an important component of protective immunity.

The carry-over effects of school gardens on fruit and vegetable availability at home: A randomized controlled trial with low-income elementary schools.

This group-randomized controlled trial examines the effects of a school garden intervention on availability of fruits and vegetables (FV) in elementary school children's homes. Within each region, low income U.S. schools in Arkansas, Iowa, New York, and Washington State were randomly assigned to intervention group (n = 24) or waitlist control group (n = 22). Children were in grades 2, 4, and 5 at baseline (n = 2768). The garden intervention consisted of both raised-bed garden kits and a series of grade-appropriate lessons. FV availability at home was measured with a modified version of the GEMS FJV Availability Questionnaire. The instrument was administered at baseline (Fall 2011) and throughout the intervention (Spring 2012, Fall 2012, Spring 2013). Analyses were completed using general linear mixed models. The garden intervention led to an overall increase in availability of low-fat vegetables at home. Among younger children (2nd grade at baseline), the garden intervention led to greater home availability of vegetables, especially, low-fat vegetables. Moreover, for the younger group, garden intervention fidelity (GIF) or robustness predicted home availability of fruit, vegetables, and low-fat vegetables. School gardens have potential to affect FV availability in the home environment.

The Association of Diabetes and Obesity With Prostate Cancer Progression: HCaP-NC.

BACKGROUND: The role of race in modifying the association among diabetes, obesity, and prostate cancer (CaP) progression is not well studied. We evaluated diabetes and obesity in association with time to CaP progression in White Americans (Whites) and Black Americans (Blacks). METHODS: Our study sample consisted of 363 White and 284 Black research participants from the Health Care Access and CaP Treatment in North Carolina (HCaP-NC) cohort. The association between self-reported diabetes or obesity and CaP progression (mean follow-up time approximately 5 years) was assessed using Cox proportional hazards modeling, with adjustment for potential confounders. Stratum-specific hazard ratio (HR) estimates for Whites and Blacks were evaluated. RESULTS: Self-reported diabetes was not associated with CaP progression in the cohort as a whole (HR: 0.86, 95%CI: 0.54, 1.35), or among racially defined groups (Whites, HR: 1.03, 95%CI: 0.50, 2.13 or Blacks, HR: 0.77, 95%CI: 0.43, 1.39). Obesity was positively associated with CaP progression among Whites, in models including (HR: 1.79, 95%CI: 1.08, 2.97), and excluding (HR: 1.80, 95%CI: 1.09, 2.96) diabetes as a covariate. No association was observed between obesity and CaP progression in Blacks or the cohort as whole. CONCLUSIONS: Self-reported diabetes was not associated with CaP progression In HCaP-NC. Obesity was associated with CaP progression only among White research participants. Prostate 77:878-887, 2017. © 2017 Wiley Periodicals, Inc.

Endocrine therapy and urogenital outcomes among women with a breast cancer diagnosis.

PURPOSE: Endocrine therapy for breast cancer can exacerbate menopausal symptoms. The association between endocrine therapy and common pelvic floor disorders including urinary incontinence has rarely been evaluated. We examined urogenital and sexual side effects among women with a breast cancer diagnosis, comparing endocrine therapy users to nonusers. METHODS: Urogenital and sexual symptoms were self-reported during the enrollment interview within the University of North Carolina Cancer Survivorship Cohort. Tumor characteristics and endocrine therapy use were collected from medical and prescription records. We calculated multivariable prevalence ratios (PR) and 95 % confidence intervals (CI) for the association of endocrine therapy (versus no endocrine therapy) and urinary incontinence, overall and by therapy type (tamoxifen or aromatase inhibitors). PROMIS Sexual Function and Satisfaction domain scores were compared across endocrine therapy groups. RESULTS: Among the 548 women with a breast cancer diagnosis, 49 % received endocrine therapy. Overall, 18 % of women reported urinary incontinence symptoms. We observed no association between urinary incontinence and endocrine therapy use overall (PR = 0.97; 95 % CI 0.67, 1.43), tamoxifen (PR = 1.20; 95 % CI 0.74, 1.96), or aromatase inhibitors (PR = 0.89; 95 % CI 0.55, 1.42), compared to no use. Approximately 55 % of women were sexually active. Sexual function scores did not vary according to endocrine therapy use, although urinary incontinence was associated with lower satisfaction scores (p = 0.05). CONCLUSIONS: Our findings demonstrate a high prevalence of urinary incontinence after breast cancer diagnosis similar to the overall prevalence in older U.S. women, and this did not vary strongly according to use of endocrine therapy.

The association of diabetes and obesity with prostate cancer aggressiveness among Black Americans and White Americans in a population-based study.

PURPOSE: Few studies have investigated the role of race in the association of diabetes and obesity with prostate cancer aggressiveness. Here we evaluate the independent association between diabetes and obesity with prostate cancer aggressiveness in White Americans and Black Americans. METHODS: Our cross-sectional, case-only study consisted of 1,058 White Americans and 991 Black Americans from the North Carolina-Louisiana Prostate Cancer (PCaP) project. Diabetes status was determined by self-report. Obesity was determined using body mass index and calculated based on anthropometric measurements. High aggressive prostate cancer was defined as Gleason sum ≥8, or prostate-specific antigen >20 ng/ml, or Gleason sum = 7 and clinical stage cT3-cT4. The association between diabetes and obesity with high aggressive prostate cancer at diagnosis was evaluated using multivariable logistic regression and adjusted for potential confounders. RESULTS: Diabetes was not associated with high aggressive prostate cancer in the overall sample (OR 1.04; 95% CI 0.79, 1.37), White Americans (OR 1.00; 95% CI 0.65, 1.57) or Black Americans (OR 1.07; 95% CI 0.75, 1.53). Obesity, independent of diabetes, was positively associated with high aggressive prostate cancer in White Americans (OR 1.98; 95% CI 1.14, 3.43), but not in the overall sample (OR 1.37; 95% CI 0.99, 1.92) or Black Americans (OR 1.09; 95% CI 0.71, 1.67). CONCLUSIONS: Diabetes was not associated with prostate cancer aggressiveness, overall, or in either race group. Obesity, independent of diabetes, was associated with high aggressive prostate cancer only in White Americans.

Trends in the use of postprostatectomy therapies for patients with prostate cancer: a surveillance, epidemiology, and end results Medicare analysis.

BACKGROUND: For patients with adverse pathologic factors (positive surgical margins, extracapsular extension, or seminal vesicle invasion) on prostatectomy pathology, the use and timing of postsurgical treatments are controversial. The goal of the current study was to examine patterns of care in patients with a pathologic indication for postprostatectomy radiotherapy (RT) using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. METHODS: A total of 3460 men treated with radical prostatectomy for localized prostate cancer between 2000 and 2006 with at least 1 adverse pathologic factor and at least 3 years of claims data after surgery were included. Medicare claims through December 31, 2009 were examined. Rates of postprostatectomy hormonal therapy, RT, or both were examined. Logistic regression analysis examined potential factors associated with the receipt and timing of RT. RESULTS: Within 3 years after surgery, 1076 patients (31%) received some form of further therapy, including 850 (25%) who received RT. Receipt of RT was < 35% in all subgroups including every year of study. Fewer than one-half of patients who received RT (43%) did so within 6 months of surgery. On multivariate analysis, pathologic T classification and tumor grade were associated with receipt of RT within 6 months or 3 years of surgery, as were younger age, geographic region, and population density. CONCLUSIONS: Rates of postprostatectomy RT remain low and the timing of RT has not appreciably changed since the publication of the randomized trials supporting the use of adjuvant RT. The use of hormone therapy is almost as common as RT, despite a relative lack of evidence supporting its use in this setting.

Racial differences in time from prostate cancer diagnosis to treatment initiation: a population-based study.

BACKGROUND: Timely delivery of care has been identified by the Institute of Medicine as an indicator for quality health care, and treatment delay is a potentially modifiable obstacle that can contribute to the disparities among African American (AA) and Caucasian patients in prostate cancer recurrence and mortality. Using the Surveillance, Epidemiologic and End Results (SEER)-Medicare linked database, we compared time from diagnosis to treatment in AA and Caucasian prostate cancer patients. METHODS: A total of 2506 AA and 21,454 Caucasian patients diagnosed with localized prostate cancer from 2004 through 2007 and treated within 12 months were included. Linear regression was used to assess potential differences in time to treatment between AA and Caucasian patients, after adjusting for sociodemographic and clinical covariates. RESULTS: Time from diagnosis to definitive (prostatectomy and radiation) treatment was longer for AA patients in all risk groups, and most pronounced in high-risk cancer (96 versus 105 days, P < .001). On multivariate analysis, racial differences to any and definitive treatment persisted (ß = 7.3 and 7.6, respectively, for AA patients). Delay to definitive treatment was longer in high-risk (versus low-risk) disease and in more recent years. CONCLUSIONS: AA patients with prostate cancer experienced longer time from diagnosis to treatment than Caucasian patients with prostate cancer. AA patients appear to experience disparities across all aspects of this disease process, and together these factors in receipt of care plausibly contribute to the observed differences in rates of recurrence and mortality among AA and Caucasian patients with prostate cancer.

Profiling the humoral immune response of acute and chronic Q fever by protein microarray.

Antigen profiling using comprehensive protein microarrays is a powerful tool for characterizing the humoral immune response to infectious pathogens. Coxiella burnetii is a CDC category B bioterrorist infectious agent with worldwide distribution. In order to assess the antibody repertoire of acute and chronic Q fever patients we have constructed a protein microarray containing 93% of the proteome of Coxiella burnetii, the causative agent of Q fever. Here we report the profile of the IgG and IgM seroreactivity in 25 acute Q fever patients in longitudinal samples. We found that both early and late time points of infection have a very consistent repertoire of IgM and IgG response, with a limited number of proteins undergoing increasing or decreasing seroreactivity. We also probed a large collection of acute and chronic Q fever patient samples and identified serological markers that can differentiate between the two disease states. In this comparative analysis we confirmed the identity of numerous IgG biomarkers of acute infection, identified novel IgG biomarkers for acute and chronic infections, and profiled for the first time the IgM antibody repertoire for both acute and chronic Q fever. Using these results we were able to devise a test that can distinguish acute from chronic Q fever. These results also provide a unique perspective on isotype switch and demonstrate the utility of protein microarrays for simultaneously examining the dynamic humoral immune response against thousands of proteins from a large number of patients. The results presented here identify novel seroreactive antigens for the development of recombinant protein-based diagnostics and subunit vaccines, and provide insight into the development of the antibody response.

Matching-adjusted indirect comparison of phase 3 clinical trial outcomes of OC-01 (varenicline solution) nasal spray and lifitegrast 5% ophthalmic solution for the treatment of dry eye disease.

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a methodology for cross-study comparisons after adjusting for baseline characteristic imbalances. It is a comparative analytical approach used across therapeutic areas absent head-to-head trial outcomes. OBJECTIVE: To compare the efficacy of OC-01 (varenicline solution) 0.03 mg nasal spray (OC-01 VNS) to lifitegrast 5% ophthalmic solution on tear production and patient-reported eye dryness in patients with dry eye disease (DED) using data from phase 3 clinical trials via MAIC analysis. METHODS: Individual patient data (IPD) from the phase 3 registrational trial of OC-01 VNS and aggregate data from 2 phase 3 trials of lifitegrast in the publicly available XIIDRA New Drug Application were used. Using unanchored MAIC methods, IPD were weighted on clinically relevant baseline variables (age, race, sex, baseline Schirmer's test score [STS], and Eye Dryness Score [EDS]) to produce weighted OC-01 VNS datasets matched to the same lifitegrast datasets' variables. Least-squares (LS) mean change from baseline (CFB) in STS for OC-01 VNS was calculated using the identical analysis of covariance model and covariates used to calculate the same values for lifitegrast in the XIIDRA New Drug Application and was then compared. LS mean EDS (based on a 100- point Visual Analogue Scale) was compared via analysis of covariance in the weighted OC-01 VNS and lifitegrast datasets. OC-01 VNS at 2 and 4 weeks compared to lifitegrast data at 2 and 6 weeks. RESULTS: Data from 511 subjects (n = 260 treated; 251 vehicle control [VC]) in the OC-01 VNS phase 3 trial, 588 (n = 293 treated, 295 VC) in the lifitegrast phase 3 OPUS-1 trial, and 718 (n = 358 treated, 360 VC) in the lifitegrast phase 3 OPUS-2 trial were analyzed. The LS mean STS CFB for OC-01 VNS at 2 and 4 weeks was significantly greater than that for lifitegrast at 2 and 6 weeks in OPUS-1 and OPUS-2 (P < 0.0001 for all comparisons). The LS mean EDS CFB for OC-01 VNS at 2 and 4 weeks was significantly greater than that for lifitegrast at 2 and 6 weeks in OPUS-1 (P < 0.0001 for both comparisons) and at 4 weeks vs lifitegrast at 6 weeks in OPUS-2 (P < 0.0001). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produced significantly greater improvement in mean STS and comparable or greater improvement in EDS compared with lifitegrast in phase 3 trials. These findings suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with lifitegrast for the treatment of DED within the conditions of the analysis methodology. DISCLOSURES D White is a consultant for Oyster Point Pharma, Inc. L Hendrix, M Macsai, and A Gibson are employees and shareholders for Oyster Point Pharma, Inc. L Sun was an employee of COEUS, Clinical Research at the time of study conduct and received funding from Oyster Point Pharma, Inc. I Tam is an employee of COEUS, Clinical Research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc was involved in the study design, data collection, data analysis, and preparation of the manuscript and is the manufacturer/licensee of OC-01 (varenicline solution) nasal spray. Oyster Point Pharma, Inc., sponsored the phase 3 OC-01 (varenicline solution) clinical study from which analysis data were obtained.

Safety, adherence and discontinuation in varenicline solution nasal spray clinical trials for dry eye disease.

Aim: Herein, we report safety outcomes for varenicline solution nasal spray (VNS) within the context of clinical trial discontinuation, contrasting those with discontinuation outcomes from topical cyclosporine and lifitegrast clinical trials. Materials & methods: 1061 subjects were randomized across three clinical trials to receive either VNS 0.06 mg, VNS 0.03 mg, VNS 0.006 mg or vehicle control. Subjects who discontinued from treatment were noted and assigned to their appropriate categories. Results: Despite treatment emergent adverse events, 93.5% of subjects receiving VNS completed the treatment period. By comparison, only 80% of subjects in the integrated clinical trials for cyclosporine ophthalmic emulsion and 91% of subjects in the integrated trials for lifitegrast ophthalmic solution completed the full treatment period, respectively. Conclusion: In clinical trials, VNS demonstrated improvements in dry eye disease signs and symptoms, was well-tolerated, and had an overall completion rate >93%. Conventional dry eye treatments (e.g., cyclosporine and lifitegrast) noted considerably higher discontinuation rates in their clinical trials.

Does Menopausal Status Affect Dry Eye Disease Treatment Outcomes with OC-01 (Varenicline Solution) Nasal Spray? A Post Hoc Analysis of ONSET-1 and ONSET-2 Clinical Trials.

INTRODUCTION: This study sought to compare the efficacy of OC-01 (varenicline solution) nasal spray for treatment of dry eye disease (DED) in postmenopausal women (PM+) versus women who were not postmenopausal (PM-). METHODS: This was a post hoc subgroup analysis of data integrated from two prior randomized controlled clinical trials, ONSET-1 and ONSET-2. Women randomized to treatment with OC-01 (varenicline solution) nasal spray 0.03 mg or vehicle control (VC) whose self-reported menopausal status (PM+ versus PM-) was known were included. Outcomes included the treatment difference (the OC-01 [varenicline solution] nasal spray change from baseline [CFB] minus VC CFB) in Schirmer test score (STS, mm) with anesthesia and the eye dryness score (EDS) measured on a 100-mm visual analog scale (0 = no discomfort, 100 = maximal discomfort). Least-squares mean treatment differences were derived from analysis of covariance (ANCOVA) models. RESULTS: Overall, 449 female participants in the ONSET-1 and ONSET-2 trials randomized to the OC-01 (varenicline solution) nasal spray 0.03 mg or VC groups were included in this analysis. The treatment-menopausal status interaction terms in the STS and EDS ANCOVA and logistic regression models were not statistically significant (p > 0.05), indicating consistency of treatment effect between the PM- and PM+ groups. The treatment difference in STS was similar in the PM- and PM+ groups (6.7 and 5.5 mm, respectively). The treatment difference in EDS was similar in the PM- and PM+ groups (- 5.5 and - 4.1, respectively). CONCLUSIONS: OC-01 (varenicline solution) nasal spray demonstrated similar efficacy in promoting natural tear production and improving symptoms in both PM- and PM+ groups. As menopausal-related hormonal changes may be associated with more severe DED, these results may support OC-01 (varenicline solution) nasal spray as an effective treatment for DED in women regardless of presenting menopausal status. TRIAL REGISTRATION: Post hoc subgroup analysis of data integrated from ONSET-1 (ClinicalTrials.gov identifier NCT03636061) and ONSET-2 (ClinicalTrials.gov identifier NCT04036292).

OC-01 (Varenicline Solution) Nasal Spray for the Treatment of Dry Eye Disease Signs and Symptoms in Subjects with Autoimmune Disease: Integrated Data from ONSET-1 and ONSET-2.

Purpose: We evaluate the treatment effect of OC-01 (varenicline solution) nasal spray (VNS) in dry eye disease (DED) subjects from two randomized trials who self-reported autoimmune disease (AID). Patients and Methods: Post hoc subgroup analysis of subjects reporting a history of AID from the integrated OC-01 VNS 0.03 or 0.06 mg and vehicle control (VC) treatment groups of the ONSET-1 and ONSET-2 trials. Mean change in Schirmer test with anesthesia score (STS, mm) and Eye Dryness Score (EDS) from baseline to 28 days was compared between OC-01 VNS and VC groups. Consistency of treatment effect in subjects with and without AID was evaluated using treatment-subgroup interaction terms in ANCOVA models for mean changes from baseline STS and EDS, and in a logistic regression model for proportion achieving ≥10 mm STS improvement. Results: Of the 891 participants, 31 reported comorbid AID. In all models, the treatment-subgroup interaction terms were not significant (p>0.05), indicating consistency of therapeutic effect of OC-01 VNS in subjects with and without AID. In subjects with AID, the treatment difference for STS was 11.8 mm and -9.3 for EDS and difference for proportion of subjects with ≥10 mm STS improvement was 61.1%. The most common adverse event was sneeze (82-84%), graded as mild by 98% of subjects. Conclusion: OC-01 VNS demonstrated consistency in improving both tear production and patient-reported symptoms in subjects with AID, consistent with pivotal ONSET-1 and 2 trial results. Further investigation is warranted, and results may further support use of OC-01 VNS for DED in AID patients.

The effects of school gardens on fruit and vegetable consumption at school: A randomized controlled trial with low-income elementary schools in four U.S. states.

This randomized controlled trial examines the effects of a school garden intervention on children's fruit and vegetable (FV) consumption at school over two years. We randomly assigned schools to the intervention group that received gardens and related curriculum (n = 24) or to the waitlist control group that received gardens and curriculum at the conclusion of the study (n = 22). Children in second, fourth, and fifth grade at baseline (n = 2767) in low-income schools (n = 46) in four U.S. States (Arkansas, Iowa, New York, and Washington) participated. The intervention comprised gardens for each classroom; a curriculum focused on nutrition, plant science, and horticulture, including activities and FV tasting sessions; resources for the school that addressed topics such as soil contamination and food safety; an implementation guide focused on issues related to planning, planting, and maintaining the garden through the year, engaging volunteers, summer gardening, building community capacity, and sustaining the gardening program. FV consumption was measured by photographing lunches before and after children ate, for 2-3 days, at baseline and at each of 3 subsequent periods of data collection during the intervention. FV consumption was calculated using Digital Food Image Analysis. Among children in the intervention, fruit consumption and low-fat vegetable consumption increased from pre-garden baseline to post-garden more than among control group children. Garden intervention fidelity (GIF) also predicted changes in dietary intake, with more robust interventions showing a stronger effect than weaker interventions. GIF-lessons was a particularly potent predictor of change in dietary intake. School gardens modestly increase children's FV consumption at school.

Impact of distance to a urologist on early diagnosis of prostate cancer among black and white patients.

PURPOSE: We examined whether an increased distance to a urologist is associated with a delayed diagnosis of prostate cancer among black and white patients, as manifested by higher risk disease at diagnosis. MATERIALS AND METHODS: North Carolina Central Cancer Registry data were linked to Medicare claims for patients with incident prostate cancer diagnosed in 2004 to 2005. Straight-line distances were calculated from the patient home to the nearest urologist. Race stratified multivariate ordinal logistic regression was used to examine the association between distance to a urologist and prostate cancer risk group (low, intermediate, high or very high/metastasis) at diagnosis for black and white patients while accounting for age, comorbidity, marital status and diagnosis year. An overall model was then used to examine the distance × race interaction effect. RESULTS: Included in analysis were 1,720 white and 531 black men. In the overall cohort the high risk cancer rate increased monotonically with distance to a urologist, including 40% for 0 to 10, 45% for 11 to 20 and 57% for greater than 20 miles. Correspondingly the low risk cancer rate decreased with longer distance. On race stratified multivariate analysis longer distance was associated with higher risk prostate cancer for white and black patients (p = 0.04 and <0.01, respectively) but the effect was larger in the latter group. The distance × race interaction term was significant in the overall model (p = 0.03). CONCLUSIONS: Longer distance to a urologist may disproportionally impact black patients. Decreasing modifiable barriers to health care access, such as distance to care, may decrease racial disparities in prostate cancer.

Improvement of gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients.

As many as 50% of liver transplant patients suffer gastrointestinal (GI) disturbances post-transplant. Conversion from mycophenolate mofetil (MMF) to mycophenolate sodium (EC-MPS) alleviates GI symptom burden in renal transplant recipients. We employed a validated patient and physician-reported assessment to evaluate the impact of conversion to EC-MPS in liver transplant patients. This is a prospective, longitudinal, single-center, open-label pilot study. Thirty-one MMF-treated liver transplant patients with GI symptoms were converted to equimolar EC-MPS. Gastrointestinal Symptom Rating Scale (GSRS), GI Quality of Life, SF-12v2 and physician-reported assessments were used to evaluate GI symptom burden and severity. A significant improvement in overall GSRS score was noted from baseline (2.57; 95% CI 2.12-3.10) to one month (1.90; 1.68-2.12; p = 0.0007) and three months (1.82; 1.60-2.04; p = 0.0002) post-conversion with significant reductions in all subgroups except Reflux. The overall Gastrointestinal Quality of Life Index (GIQLI) score also showed significant increase in health-related quality of life between one month (90.89; 84.04-97.75) and three months (100.04; 94.57-105.51; p = 0.0009), with all subgroups except social functioning (p = 0.0861) and medical treatment (p = 0.3156) demonstrating significant improvements. This pilot study demonstrates improvement in GI symptom burden when converting from equimolar doses of MMF to EC-MPS. This benefit persisted for three months without evidence of rejection.

Antigenic analysis for vaccines and diagnostics.

Coxiella burnetii infection is frequently unrecognized or misdiagnosed, as symptoms generally mimic an influenza-like illness. However, the disease (Q fever) may result in chronic infection, usually manifesting as potentially fatal endocarditis. The development of a chronic fatigue-like sequela may also occur. Infected ruminants are the major reservoir for infection in humans, primarily through exposure to birth products or aerosols that transmit the bacterium over wide regions. A vaccine against C. burnetii infection has been in use in Australia for abattoir and agricultural workers for many years. The possibility of adverse reactions in those with previous exposure to the agent has prevented its use elsewhere. Subunit vaccines, utilizing chemical extraction of components thought to cause adverse reactions, are in development, but none are yet licensed. Others have sought to combine immunogenic peptides with or without selected lipopolysaccharide components to produce a vaccine without the possibility of adverse reactions. Selected immunogenic proteins have been shown to induce both humoral and cellular immune responses. Although current diagnosis of infection relies on serological testing, the presentation of specific antibody occurs 7-15 days following the onset of symptoms, delaying treatment that may result in prolonged morbidity. PCR detection of DNA to specific C. burnetii antigens in the blood is possible early in infection, but PCR may become negative when PII IgG antibodies appear. PCR is useful for early diagnosis when Q fever is suspected, as in large epidemics, and shortens the delay in the identification of Q fever endocarditis. Others have combined PCR with ELISA or other methods to increase the ability to detect infection at any stage. The search for new diagnostic reagents and vaccines has utilized new methods for discovery of immunoreactive proteins. DNA analysis of the heterogeneity of C. burnetii isolates has led to a greater understanding of the diversity of isolates and a means to determine whether there is a correlation between strain and disease severity. 2-D SDS PAGE of immunogenic proteins reactive with human or animal infection sera and mass spectrometric analysis of specific secreted or outer membrane proteins have identified candidate antigens. Microarrays have allowed the analysis of peptide libraries of open reading frames to evaluate the immunogenicity of complete genomes.

Matching-adjusted indirect comparison of phase 3 clinical trial outcomes: OC-01 (varenicline solution) nasal spray and cyclosporine a 0.05% ophthalmic emulsion for the treatment of dry eye disease.

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical method that derives indirect comparisons between treatments when head-to-head studies have not been performed. OBJECTIVE: To compare the efficacy of OC-01 varenicline nasal spray (OC-01 VNS) 0.03 mg to cyclosporine A (CsA) 0.05% ophthalmic emulsion on tear production in patients with dry eye disease based on data from the respective phase 3 clinical trials using the MAIC technique. METHODS: Individual patient data were drawn from the phase 3 registry trial of OC-01 VNS; aggregate data were drawn from 2 phase 3 trials of CsA in the publicly available New Drug Application for CsA 0.05% ophthalmic emulsion (RESTASIS). Using unanchored MAIC methods, the individual patient data were weighted based on 4 clinically relevant baseline variables (age, race, sex, and baseline Schirmer test score [STS]) to produce a weighted OC-01 VNS dataset matched to the key demographics of the CsA dataset. Least-squares mean change from baseline in STS for OC-01 VNS was calculated using the identical analysis of variance model used to calculate the same value for CsA in the RESTASIS New Drug Application, which were then compared. Proportions of subjects with improvement of 10 mm or more from baseline in STS were compared in the weighted OC-01 VNS and CsA dataset. Time points available for comparisons were CsA trials at 3 and 6 months and OC-01 data at 2 and 4 weeks. RESULTS: Data from 511 subjects in the OC-01 VNS phase 3 trial and 585 in the CsA phase 3 trials were analyzed. The least-squares mean STS change from baseline for OC-01 VNS at 2 and 4 weeks was significantly higher than that for CsA at 3 and 6 months (P < 0.0001 for all comparisons). Mean STS improvements were approximately 6-7 mm for OC-01 VNS and approximately 1 mm for CsA. The proportion of subjects with improvement of 10 mm or more from baseline in STS was significantly higher for OC-01 VNS (50.2%) than CsA (11.7 and 17.1% in the 2 CsA studies; P < 0.0001 for both comparisons). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produces significantly greater improvement in mean STS and results in significantly greater numbers of patients with substantial improvement in STS (percentage ≥ 10 mm) compared with CsA. Together, absent more robust data from head-to-head trials, findings may suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with CsA for the treatment of dry eye disease within conditions of the analysis methodology. DISCLOSURES: Dr Visco was a consultant for Novartis, Allergan, and Oyster Point, Inc. Ms Hendrix and Drs Macsai and Gibson are employees and shareholders for Oyster Point Pharma, Inc. Drs Sun and Tam participated in clinical research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc sponsored the Phase 3 OC-01 (varenicine solution) clinical study from which analysis data are obtained.