Overactive Bladder
Conditions
Keywords
Overactive Bladder, OAB, Urinary Tract Infection, UTI, Microbiome, Bacteria, Solifenacin, 16S rRNA sequence
Brief summary
No one really knows what causes overactive bladder syndrome (OAB). Urinary tract infection (UTI)causes similar symptoms to OAB with the difference being the presence of bacteria, as evidenced by routine microbiology cultures. Recent work by the group on the genitourinary microbiome (GUM) has shown that female urine, even in the absence of culture evidence of bacteria does have evidence of bacterial DNA. Bacterial 16S rRNA can be isolated from urine and sequenced to identify bacterial species present in urine. From this the investigators can hypothesize that urinary bacteria contribute to urinary symptoms and that there is a difference in the bacterial communities in the urine of women who respond to Solifenacin, a drug used to treat OAB, versus those that do not.
Detailed description
This is a prospective study with two groups: Women who have accepted a clinical recommendation for OAB treatment with solifenacin and a comparator (control) group of women unaffected by OAB. All women will have a baseline urine assessment with bacterial genome sequencing. Solifenacin treated patients will also have urine assessments with bacterial genomic sequencing at 4 and 12 weeks on treatment.
Interventions
DRUGSolifenacin
5 mg for 4 weeks with option to increase to 10 mg for an additional 8 weeks
Sponsors
Astellas Pharma US, Inc.
Loyola University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 89 Years
Healthy volunteers
Yes
Inclusion criteria
Controls: Women without bother from urinary symptoms will be screened for potential study participation using the pelvic floor distress inventory (PFDI). Women with negative urinary responses will be further screened for participation using the following eligibility criteria: * no anticholinergic medications for bladder conditions, * no antibiotic exposure in the past 4 weeks for any reason, * no immunologic deficiency, * no pelvic malignancy or pelvic radiation, and * Untreated symptomatic POP \> POP-Q Stage II. OAB cohort: Women with bother from overactive bladder symptoms will be screened for potential study participation using the pelvic floor distress inventory (PFDI). Women with positive urinary responses for urge predominant symptoms will be further screened for participation using the following eligibility criteria: * willing to take Solifenacin as treatment for OAB, * no neurological disease known to affect the lower urinary tract, * no current UTI (based on urine dipstick) or recurrent UTI, * no antibiotic exposure in the past 4 weeks for any reason, * no immunologic deficiency, * no pelvic malignancy or pelvic radiation, * untreated symptomatic POP \> POP-Q Stage II, * no contraindications to receiving Solifenacin.
Exclusion criteria
* Women who are of child-bearing potential who are pregnant, nursing, intending to become pregnant during the study or not practicing a reliable form of contraception are also excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bacterial Genomic Sequencing | 12 weeks | Participants were classified into Low Biomass, Lactobacillus, Gardnerella, Diverse, and Other urotypes based on the bacterial DNA at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Overactive Bladder Questionnaire (OABQ) | End of study (Week 12) | The Overactive Bladder Questionnaire (OAB-q) was developed to assess symptom bother and the impact of overactive bladder (OAB) on health-related quality of life (HRQL). The instrument comprises 33 items. Response options for the symptom frequency and HRQL items are presented as 6-point Likert scales ranging from 'none of the time' to 'all of the time' for symptom frequency (and 'not at all' to 'a very great deal' for symptom bother). From these 33 items, six sub-scales are assessed separately: (1) OAB symptom severity, (2) Coping with OAB symptoms, (3) Concern for OAB symptoms, (4) Sleep as a function of OAB symptoms, (5) Social functioning as a consequence of OAB symptoms, and (6) Health related quality of life (HRQL) as a function of OAB symptoms. Each sub-scale score ranges from 0 to 100 (where higher scores indicate more severe OAB symptoms and lower scores indicate minimal symptom severity). |
| Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | 12 weeks | The PFDI comprises 46 items on a 4-point symptom severity scale ranging from 1 = Not at all to 4 = Quite a bit. From these items, 13 separate sub-scales are reported: (1) Obstructive discomfort, (2) Irritation, (3) Stress resulting from urinal distress, (4) A general sub-scale for pelvic organ prolapse distress, (5) An anterior sub-scale for pelvic organ prolapse distress, (6) A posterior sub-scale for pelvic organ prolapse distress, (7) An obstructive sub-scale for colorectal anal distress, (8) Incontinence, (9) Pain, and (10) A rectal prolapse sub-scale for colorectal anal distress. For each of these sub-scales, scores from from 0 to 100 (where higher scores indicate greater symptom severity). There are three additional sub-scales: (11) The urinary distress inventory, (12) The pelvic organ distress inventory, and (13) The colorectal distress inventory. Each of these ranges from 0 to 400 (with higher scores indicating greater symptom severity). |
Countries
United States
Participant flow
Recruitment details
Recruitment began on July 16th, 2012 and ended on May 22nd, 2014 (i.e., 22.2 months). Participants were recruited during their outpatient appointments to the Urogynecology Clinic at Loyola University Medical Center (Maywood, IL) by a member of the research team.
Pre-assignment details
This was a 12-week open label study with no randomization scheme. Following diagnosis, patients were administered 5 mg daily solifenacin. At the 4-week visit, if a participant's symptoms were adequately controlled (response), she continued at dose for the study duration. If a participant reported no improvement, the dose was increased to 10 mg.
Participants by arm
| Arm | Count |
|---|---|
| Urinary Urge Incontinence Seventy-four (n = 74) women received 5mg daily solifenacin (with an option to increase to 10mg daily solifenacin at 4 weeks) for the treatment of urinary urge incontinence (UUI). | 74 |
| Non-Urinary Urge Incontinence Sixty (n = 60) women without UUI were evaluated at baseline only (week 0) in order to serve as a control cohort. These women never received study therapy (i.e., 5-10mg daily solifenacin). | 60 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 0 |
Baseline characteristics
| Characteristic | Total | Non-Urinary Urge Incontinence | Urinary Urge Incontinence |
|---|---|---|---|
| Age, Continuous | 56.04 years STANDARD_DEVIATION 14.34 | 49 years STANDARD_DEVIATION 14.7 | 61.5 years STANDARD_DEVIATION 11.5 |
| Body Mass Index | 30.59 kg/m2 STANDARD_DEVIATION 7.61 | 27.9 kg/m2 STANDARD_DEVIATION 5.5 | 32.7 kg/m2 STANDARD_DEVIATION 8.4 |
| Coronary Artery Disease No | 124 participants | 59 participants | 65 participants |
| Coronary Artery Disease Yes | 10 participants | 1 participants | 9 participants |
| Diabetes No | 125 participants | 58 participants | 67 participants |
| Diabetes Yes | 9 participants | 2 participants | 7 participants |
| Estrogen Status Negative | 39 participants | 32 participants | 7 participants |
| Estrogen Status Positive | 91 participants | 26 participants | 65 participants |
| Estrogen Status Unknown | 4 participants | 2 participants | 2 participants |
| Hypertension No | 97 participants | 49 participants | 48 participants |
| Hypertension Yes | 37 participants | 11 participants | 26 participants |
| Marital Status Divorced | 15 participants | 6 participants | 9 participants |
| Marital Status Married | 75 participants | 37 participants | 38 participants |
| Marital Status Separated | 4 participants | 1 participants | 3 participants |
| Marital Status Single | 25 participants | 15 participants | 10 participants |
| Marital Status Widowed | 15 participants | 1 participants | 14 participants |
| Prior Treatment for OAB No prior treatment | 97 participants | 60 participants | 37 participants |
| Prior Treatment for OAB Prior Treatment | 37 participants | 0 participants | 37 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Black | 25 participants | 12 participants | 13 participants |
| Race/Ethnicity, Customized Hispanic | 9 participants | 4 participants | 5 participants |
| Race/Ethnicity, Customized White | 99 participants | 43 participants | 56 participants |
| Region of Enrollment United States | 134 participants | 60 participants | 74 participants |
| Sequencing Urotypes at Baseline Diverse urotype | 12 participants | 4 participants | 8 participants |
| Sequencing Urotypes at Baseline Gardnerella urotype | 12 participants | 4 participants | 8 participants |
| Sequencing Urotypes at Baseline Lactobacillus urotype | 31 participants | 16 participants | 15 participants |
| Sequencing Urotypes at Baseline Low biomass | 71 participants | 34 participants | 37 participants |
| Sequencing Urotypes at Baseline Other urotypes | 8 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 134 Participants | 60 Participants | 74 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking Non-Smoker | 124 participants | 56 participants | 68 participants |
| Smoking Smoker | 10 participants | 4 participants | 6 participants |
| Vaginal Parity | 2.00 Births | 2.00 Births | 2.00 Births |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 74 | 0 / 0 |
| serious Total, serious adverse events | 0 / 74 | 0 / 0 |
Outcome results
Primary
Bacterial Genomic Sequencing
Participants were classified into Low Biomass, Lactobacillus, Gardnerella, Diverse, and Other urotypes based on the bacterial DNA at baseline.
Time frame: 12 weeks
Population: This was a completer analysis comprising participants who completed 12 weeks of treatment (n = 50).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Urinary Urge Incontinence | Bacterial Genomic Sequencing | Lactobacillus urotype | 11 participants |
| Urinary Urge Incontinence | Bacterial Genomic Sequencing | Low biomass | 25 participants |
| Urinary Urge Incontinence | Bacterial Genomic Sequencing | Diverse urotype | 3 participants |
| Urinary Urge Incontinence | Bacterial Genomic Sequencing | Gardnerella urotype | 6 participants |
| Urinary Urge Incontinence | Bacterial Genomic Sequencing | Other urotypes | 3 participants |
Secondary
Assessment of Overactive Bladder Questionnaire (OABQ)
The Overactive Bladder Questionnaire (OAB-q) was developed to assess symptom bother and the impact of overactive bladder (OAB) on health-related quality of life (HRQL). The instrument comprises 33 items. Response options for the symptom frequency and HRQL items are presented as 6-point Likert scales ranging from 'none of the time' to 'all of the time' for symptom frequency (and 'not at all' to 'a very great deal' for symptom bother). From these 33 items, six sub-scales are assessed separately: (1) OAB symptom severity, (2) Coping with OAB symptoms, (3) Concern for OAB symptoms, (4) Sleep as a function of OAB symptoms, (5) Social functioning as a consequence of OAB symptoms, and (6) Health related quality of life (HRQL) as a function of OAB symptoms. Each sub-scale score ranges from 0 to 100 (where higher scores indicate more severe OAB symptoms and lower scores indicate minimal symptom severity).
Time frame: End of study (Week 12)
Population: Participants who received solifenacin were asked to complete the OABQ at 12 weeks in order to assess overactive bladder symptoms.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Urinary Urge Incontinence | Assessment of Overactive Bladder Questionnaire (OABQ) | Symptom Severity Score | 17.50 units on a scale |
| Urinary Urge Incontinence | Assessment of Overactive Bladder Questionnaire (OABQ) | Coping Score | 92.50 units on a scale |
| Urinary Urge Incontinence | Assessment of Overactive Bladder Questionnaire (OABQ) | Concern Score | 97.14 units on a scale |
| Urinary Urge Incontinence | Assessment of Overactive Bladder Questionnaire (OABQ) | Sleep Score | 92.00 units on a scale |
| Urinary Urge Incontinence | Assessment of Overactive Bladder Questionnaire (OABQ) | Social Score | 100.00 units on a scale |
| Urinary Urge Incontinence | Assessment of Overactive Bladder Questionnaire (OABQ) | Health Related Quality of Life (HRQL) | 92.80 units on a scale |
| Solifenacin Non-Responder | Assessment of Overactive Bladder Questionnaire (OABQ) | Social Score | 96.00 units on a scale |
| Solifenacin Non-Responder | Assessment of Overactive Bladder Questionnaire (OABQ) | Symptom Severity Score | 37.50 units on a scale |
| Solifenacin Non-Responder | Assessment of Overactive Bladder Questionnaire (OABQ) | Sleep Score | 84.00 units on a scale |
| Solifenacin Non-Responder | Assessment of Overactive Bladder Questionnaire (OABQ) | Coping Score | 80.00 units on a scale |
| Solifenacin Non-Responder | Assessment of Overactive Bladder Questionnaire (OABQ) | Health Related Quality of Life (HRQL) | 76.00 units on a scale |
| Solifenacin Non-Responder | Assessment of Overactive Bladder Questionnaire (OABQ) | Concern Score | 82.86 units on a scale |
Comparison: For symptom-severity score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size and non-normal distributions of symptom severity scores. The null hypothesis is that there is no difference between the two groups in symptom severity, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) symptom severity than the other group.p-value: 0.052Wilcoxon (Mann-Whitney)
Comparison: For coping score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size, non-normal distributions, and outliers of coping scores. The null hypothesis is that there is no difference between the two groups in coping, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) coping than the other group.p-value: 0.04Wilcoxon (Mann-Whitney)
Comparison: For the concern score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size, non-normal distributions, and outlier of the concern scores. The null hypothesis is that there is no difference between the two groups in their concern, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) concern than the other group.p-value: 0.03Wilcoxon (Mann-Whitney)
Comparison: For the sleep score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size, non-normal distributions, and outliers of sleep scores. The null hypothesis is that there is no difference between the two groups in sleep scores, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) sleep scores than the other group.p-value: 0.37Wilcoxon (Mann-Whitney)
Comparison: For social score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size, non-normal distributions, and outliers of social scores. The null hypothesis is that there is no difference between the two groups in social scores, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) social scores than the other group.p-value: 0.04Wilcoxon (Mann-Whitney)
Comparison: For the overall health related quality of life (HRQL) score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size, non-normal distributions, and outliers of HRQL scores. The null hypothesis is that there is no difference between the two groups in health related quality of life, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) health realted quality of life than the other group.p-value: 0.04Wilcoxon (Mann-Whitney)
Secondary
Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire
The PFDI comprises 46 items on a 4-point symptom severity scale ranging from 1 = Not at all to 4 = Quite a bit. From these items, 13 separate sub-scales are reported: (1) Obstructive discomfort, (2) Irritation, (3) Stress resulting from urinal distress, (4) A general sub-scale for pelvic organ prolapse distress, (5) An anterior sub-scale for pelvic organ prolapse distress, (6) A posterior sub-scale for pelvic organ prolapse distress, (7) An obstructive sub-scale for colorectal anal distress, (8) Incontinence, (9) Pain, and (10) A rectal prolapse sub-scale for colorectal anal distress. For each of these sub-scales, scores from from 0 to 100 (where higher scores indicate greater symptom severity). There are three additional sub-scales: (11) The urinary distress inventory, (12) The pelvic organ distress inventory, and (13) The colorectal distress inventory. Each of these ranges from 0 to 400 (with higher scores indicating greater symptom severity).
Time frame: 12 weeks
Population: Participants who received solifenacin were asked to complete the PFDI questionnaire at 12 weeks in order to assess certain bowel, bladder, and pelvic symptoms.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Stress Score | 8.33 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Pelvic Organ Prolapse Distress Inventory Score | 20.83 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | General Score | 7.14 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Obstructive Score | 0 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Irritative Score | 12.50 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Pain Irritation Score | 10.71 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Anterior Score | 8.33 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Rectal Prolapse | 0 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Urinary Distress Inventory Score | 40.19 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Colo-Rectal-Anal Distress Inventory Score | 17.86 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Posterior Score | 0 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Incontinence Score | 0 units on a scale |
| Urinary Urge Incontinence | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Obstructive Discomfort Score | 5.77 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Incontinence Score | 10.00 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Obstructive Discomfort Score | 7.69 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Irritative Score | 32.50 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Stress Score | 16.67 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Urinary Distress Inventory Score | 60.26 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | General Score | 14.29 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Anterior Score | 8.33 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Posterior Score | 16.67 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Pelvic Organ Prolapse Distress Inventory Score | 47.62 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Obstructive Score | 16.67 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Pain Irritation Score | 10.71 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Rectal Prolapse | 0 units on a scale |
| Solifenacin Non-Responder | Assessment of Pelvic Floor Disease Inventory (PFDI) Questionnaire | Colo-Rectal-Anal Distress Inventory Score | 42.86 units on a scale |
Comparison: For the obstructive discomfort score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in obstructive discomfort, and and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) obstructive discomfort than the other group.p-value: 0.46Wilcoxon (Mann-Whitney)
Comparison: For the irritative score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in irritation, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) irritation than the other group.p-value: 0.07Wilcoxon (Mann-Whitney)
Comparison: For the stress score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in stress, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) stress than the other group.p-value: 0.11Wilcoxon (Mann-Whitney)
Comparison: For the urinary distress inventory score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in urinary distress, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) urinary distress than the other group.p-value: 0.09Wilcoxon (Mann-Whitney)
Comparison: For the general score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in general pelvic floor disease severity, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) general pelvic floor disease severity than the other group.p-value: 0.09Wilcoxon (Mann-Whitney)
Comparison: For the anterior score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in anterior pelvic floor disease severity, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) anterior pelvic floor disease severity than the other group.p-value: 0.82Wilcoxon (Mann-Whitney)
Comparison: For the posterior score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in posterior pelvic floor disease severity, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) posterior pelvic floor disease severity than the other group.p-value: 0.06Wilcoxon (Mann-Whitney)
Comparison: For the pelvic organ prolapse distress score, the non-parametric Mann-Whitney test was used to compare the responder and non-responder groups due to low sample size in the non-responder group (n = 13). The null hypothesis is that there is no difference between the two groups in pelvic organ prolapse distress, and the two-sided alternative hypothesis is that one of the two groups has higher (or lower) pelvic organ prolapse distress than the other group.p-value: 0.07Wilcoxon (Mann-Whitney)