Publications by authors named "Susan Reed"

165 Publications

Evaluation of systemic estrogen for preventing urinary tract infections in postmenopausal women.

Menopause 2021 May 10. Epub 2021 May 10.

Medical School, University of Washington School of Medicine, Seattle, WA Department of Global Health, University of Washington School of Medicine, Seattle, WA Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA Department of Obstetrics and Gynecology, University of Texas Southwestern, Dallas, TX.

Importance: Current guidelines for postmenopausal recurrent urinary tract infection (rUTI) prevention recommend the use of vaginal topical estrogen products but not systemic estrogens. Studies show that vaginal estrogen decreases the risk of rUTI, but evidence against use of systemic estrogen is less convincing.

Objective: We performed a comprehensive literature review to evaluate the effect of systemic estrogen on UTI occurrence among postmenopausal women.

Evidence Review: MEDLINE (PubMed), EMBASE, and CINAHL were searched for manuscripts published in English between January 1990 and July 2020. The search terms were "urinary tract infection" and "estrogen." Inclusion criteria were studies of postmenopausal women who received systemic estrogen therapy (any regimen) that reported UTI frequency during any follow-up period. Case studies, commentaries, and reviews were excluded. A priori specifications of seven study criteria were set representing the ideal study for assessing efficacy of systemic estrogen for rUTI prevention and were used to evaluate each included study.

Findings: Searches identified 281 results, and after deduplication and review, 8 studies met inclusion criteria: 4 randomized controlled trials, 1 secondary analysis of a randomized controlled trial, 1 prospective cohort study, 1 case-control study, and 1 cross-sectional study. Of the eight included studies, only two enrolled postmenopausal women with a rUTI diagnosis, four had sufficient sample size to detect a clinically meaningful difference between systemic estrogen versus placebo, two used dosage regimens anticipated to achieve a therapeutic effect, and three assessed UTI rates for an adequate duration of 6 months or more (the standard minimum duration of time needed to make a diagnosis of rUTI). Overall, none of the studies met all predefined criteria for the ideal study to assess the efficacy of systemic estrogen for rUTI prevention.

Conclusions And Relevance: UTIs will continue to be a significant cause of morbidity and hospitalizations in postmenopausal women unless more research is done to better understand the role of estrogen on UTI rates. The evidence arguing use (or abandonment) of systemic estrogen for the prevention of rUTI is based on few studies with substantial methodologic limitations; there is significant room for improvement.
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http://dx.doi.org/10.1097/GME.0000000000001769DOI Listing
May 2021

Association between postmenopausal vulvovaginal discomfort, vaginal microbiota, and mucosal inflammation.

Am J Obstet Gynecol 2021 Mar 4. Epub 2021 Mar 4.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: Half of all postmenopausal women report symptoms of vulvar, vaginal, or urinary discomfort with substantial impact on sexual function and quality of life; underlying mechanisms leading to symptoms are poorly understood.

Objective: To examine the possibility that the vaginal microbiota and/or mucosal immune response contributes to the severity of bothersome vaginal symptoms, we conducted a substudy of samples from a randomized trial of vaginal treatment for genitourinary syndrome of menopause to compare these features between women whose symptoms improved and women whose symptoms did not improve.

Study Design: This is a secondary analysis of samples collected in a 12-week randomized trial of treatment with vaginal estradiol or moisturizer vs placebo for moderate-severe postmenopausal symptoms of vaginal discomfort. We randomly selected 20 women in each arm with ≥2-point decrease in most bothersome symptom severity (responders) and 20 matched controls with ≤1-point decrease (nonresponders). At 0, 4, and 12 weeks, we characterized vaginal microbiota (16S ribosomal RNA gene sequencing), vaginal fluid metabolites (broad-based metabolomic profiling), vaginal fluid-soluble immune markers (Meso Scale Discovery), pH, and vaginal maturation index. We compared responders with nonresponders at baseline and across all visits using linear mixed models to evaluate associations with microbiota, metabolites, and immune markers, incorporating visit and participant-specific random effects while controlling for treatment arm.

Results: Here, the mean age of women was 61 years (n=120), and most women (92%) were white. At enrollment, no significant differences were observed between responders and nonresponders in age, most bothersome symptom type or severity, microbiota composition or diversity, Lactobacillus dominance, metabolome, or immune markers. There was a significant decrease in diversity of the vaginal microbiota in both responders and nonresponders (P<.001) over 12 weeks. Although this change did not differ by responder status, diversity was associated with treatment arm: more women in the estradiol arm (63%) had Lactobacillus-dominant, lower diversity bacterial communities than women in the moisturizer (35%) or dual placebo (23%) arms (P=.001) at 12 weeks. The metabolome, vaginal maturation index, and measured immune markers were not associated with responder status over the 12 weeks but varied by treatment arm.

Conclusion: Postmenopausal vaginal symptom severity was not significantly associated with vaginal microbiota or mucosal inflammatory markers in this small study. Women receiving vaginal estradiol experienced greater abundance of lactobacilli and lower vaginal pH at end of treatment.
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http://dx.doi.org/10.1016/j.ajog.2021.02.034DOI Listing
March 2021

Mapping a Pandemic: SARS-CoV-2 Seropositivity in the United States.

medRxiv 2021 Jan 31. Epub 2021 Jan 31.

Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates. To address this, we analyzed seropositivity in US adults who have not previously been diagnosed with COVID-19. Individuals with characteristics that reflect the US population (n = 11,382) and who had not previously been diagnosed with COVID-19 were selected by quota sampling from 241,424 volunteers (ClinicalTrials.gov NCT04334954 ). Enrolled participants provided medical, geographic, demographic, and socioeconomic information and 9,028 blood samples. The majority (88.7%) of samples were collected between May 10th and July 31st, 2020. Samples were analyzed via ELISA for anti-Spike and anti-RBD antibodies. Estimation of seroprevalence was performed by using a weighted analysis to reflect the US population. We detected an undiagnosed seropositivity rate of 4.6% (95% CI: 2.6 - 6.5%). There was distinct regional variability, with heightened seropositivity in locations of early outbreaks. Subgroup analysis demonstrated that the highest estimated undiagnosed seropositivity within groups was detected in younger participants (ages 18-45, 5.9%), females (5.5%), Black/African American (14.2%), Hispanic (6.1%), and Urban residents (5.3%), and lower undiagnosed seropositivity in those with chronic diseases. During the first wave of infection over the spring/summer of 2020 an estimate of 4.6% of adults had a prior undiagnosed SARS-CoV-2 infection. These data indicate that there were 4.8 (95% CI: 2.8-6.8) undiagnosed cases for every diagnosed case of COVID-19 during this same time period in the United States, and an estimated 16.8 million undiagnosed cases by mid-July 2020.
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http://dx.doi.org/10.1101/2021.01.27.21250570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852277PMC
January 2021

Design of the Association of Uterine Perforation and Expulsion of Intrauterine Device study: a multisite retrospective cohort study.

Am J Obstet Gynecol 2021 Jun 15;224(6):599.e1-599.e18. Epub 2021 Jan 15.

Bayer AG, Berlin, Germany.

Background: Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, a European prospective observational study that enrolled 61,448 participants (2006-2012), found that women breastfeeding at the time of device insertion or with the device inserted at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration-mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device-related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion.

Objective: We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up.

Study Design: APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights.

Results: The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74-177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m, and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record.

Conclusion: Combining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.
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http://dx.doi.org/10.1016/j.ajog.2021.01.003DOI Listing
June 2021

Comparison of the vaginal microbiota in postmenopausal Black and White women.

J Infect Dis 2020 Dec 23. Epub 2020 Dec 23.

Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA.

Objective: We compared vaginal microbial communities in postmenopausal Black and White women.

Methods: Shotgun sequencing of vaginal swabs from postmenopausal women self-identified as Black or White was compared using MiRKAT.

Results: Vaginal community dominance by Lactobacillus crispatus or L. gasseri was more common in 44 postmenopausal Black women (n = 12, 27%) than among 44 matched White women (N = 2, 5%; p = 0.01). No individual taxa were significantly more abundant in either group.

Conclusions: We identified small overall differences in vaginal microbial communities of Black and White postmenopausal women. L. crispatus dominance was more common in Black women.
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http://dx.doi.org/10.1093/infdis/jiaa780DOI Listing
December 2020

Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model.

Clin Infect Dis 2020 Nov 19. Epub 2020 Nov 19.

LID Clinical Studies Unit, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: It is imperative to identify new targets for improved vaccines and therapeutics against influenza and one such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein.

Methods: We conducted a randomized, double-blind, Phase II placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. A single 50mg/kg dose of CR6261 was infused 24 hours after challenge and the primary efficacy outcome was area under the curve of viral RNA detection over time.

Results: Ninety-one healthy volunteers were randomized and underwent influenza challenge; 49 received CR6261 and 42 placebo. CR6261 had no statistically significant effect on AUC (AUC 48.56 log (copies/mL) x days, IQR 202 vs. AUC 25.53 log (copies/mL) x days, IQR 155), P=0.315), and no clinically significant effect on influenza disease measures including number of symptoms, duration of symptoms, or FLU-PRO scores. Preexisting anti-NA antibody titers were most predictive of reduced influenza disease. CR6261 reached a mean peak serum concentration of 1x10 6 ng/ml 15 minutes after infusion, and a mean peak of 5.97x10 2 ng/ml in the nasal mucosa 2-3 days after infusion.

Conclusions: The results of this study suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may be limited in efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multi-faceted strategy rather than as a standalone therapeutic.
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http://dx.doi.org/10.1093/cid/ciaa1725DOI Listing
November 2020

Bacterial Communities Associated With Abnormal Nugent Score in Postmenopausal Versus Premenopausal Women.

J Infect Dis 2021 Jun;223(12):2048-2052

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

The Nugent score is the reference standard for bacterial vaginosis (BV) diagnosis but has not been validated in postmenopausal women. We compared relative abundances from 16S ribosomal RNA gene sequencing of vaginal microbiota with Nugent score in cohorts of premenopausal (n = 220) and postmenopausal (n = 144) women. In premenopausal women, 33 taxa were significantly correlated with Nugent score, including the classic BV-associated taxa Gardnerella, Atopobium, Sneathia, Megasphaera, and Prevotella. In postmenopausal women, 11 taxa were significantly associated with Nugent score, including Prevotella but no other BV-associated genera. High Nugent scores should not be used to infer BV in postmenopausal women.
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http://dx.doi.org/10.1093/infdis/jiaa675DOI Listing
June 2021

Safety Aspects of a Randomized Clinical Trial of Maternal and Infant Vitamin D Supplementation by Feeding Type Through 7 Months Postpartum.

Breastfeed Med 2020 12 11;15(12):765-775. Epub 2020 Sep 11.

Division of Neonatology, Department of Pediatrics, Shawn Jenkins Children's Hospital, Medical University of South Carolina, Charleston, South Carolina, USA.

The safety of higher dose vitamin D (vitD) supplementation in women who change from exclusive or full breastfeeding to combination feeding or who continue supplementation after cessation of breastfeeding is unknown. Compare vitD supplementation safety of 6,400 to 400 IU/day and 2,400 IU/day using specific laboratory parameters in postpartum women and their infants through 7 months postpartum by feeding type. In this randomized controlled trial, mothers (exclusively breastfeeding or formula-feeding) were randomized at 4-6 weeks' postpartum to 400, 2,400, or 6,400 IU vitD (cholecalciferol)/day for 6 months. Breastfeeding infants in 400 IU group received oral 400 IU vitD/day; infants in 2,400 and 6,400 IU groups received placebo. Maternal safety parameters (serum vitD, 25-hydroxy-vitamin D [25(OH)D; calcidiol], calcium, phosphorus, intact PTH; urinary calcium/creatinine ratios; and feeding type/changes) were measured monthly; infant parameters were measured at months 1, 4, and 7. Sufficiency was defined as 25(OH)D >50 nmol/L. Feeding type was defined as exclusive/full, combination, or formula-feeding. Data were analyzed using SAS 9.4. Four hundred nineteen mother-infant pairs were randomized into the three treatment groups and followed: 346 breastfeeding and 73 formula-feeding pairs. A dose of 6400 IU/day safely and significantly increased maternal vitD and 25(OH)D from baseline in all mothers regardless of feeding type ( < 0.0001) and was superior to the 400 and 2,400 IU groups in achieving vitD sufficiency with no other differences in safety parameters by treatment or feeding type. Infants in the 2,400 IU group were more likely vitD-deficient than the other groups; otherwise, there were no infant safety parameter differences. While 6,400 IU/day was more effective than 400 or 2,400 IU/day in achieving maternal vitD sufficiency in all feeding groups, the groups did not differ on other safety parameters. Similarly, infant safety parameters did not differ by treatment group or feeding status. Clinical Trial Registration: FDA IND Number: 66,346; ClinicalTrials.gov Number: NCT00412074.
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http://dx.doi.org/10.1089/bfm.2020.0056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757584PMC
December 2020

Effects of pharmacologic and nonpharmacologic interventions on menopause-related quality of life: a pooled analysis of individual participant data from four MsFLASH trials.

Menopause 2020 10;27(10):1126-1136

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Objective: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network conducted three randomized clinical trials (RCTs) testing six interventions treating vasomotor symptoms (VMS), and also collected menopause-related quality of life (QOL) measures. A fourth RCT assessed an intervention for insomnia symptoms among women with VMS. We describe these seven interventions' effects on menopause-related QOL relative to control in women with VMS.

Methods: We pooled individual-level data from 1,005 peri- and postmenopausal women with 14 or more VMS/week across the four RCTs. Interventions included escitalopram 10 to 20 mg/d; yoga/aerobic exercise; 1.8 g/d omega-3-fatty acids; oral 17-beta-estradiol 0.5 mg/d; venlafaxine XR 75 mg/d; and cognitive behavioral therapy for insomnia (CBT-I). Outcomes measures were the Menopause-specific Quality of Life scale and its subscales.

Results: Significant improvements in total Menopause-specific Quality of Life from baseline were observed with estradiol, escitalopram, CBT-I, and yoga, with mean decreases of 0.3 to 0.5 points relative to control. The largest improvement in the vasomotor subscale was observed with estradiol (-1.2 points), with more modest but significant effects seen with escitalopram, yoga, and CBT-I. Significant improvements in the psychosocial subscale were observed for escitalopram, venlafaxine, and CBT-I. For the physical subscale, the greatest improvement was observed for CBT-I and exercise, whereas for the sexual subscale, the greatest improvement was observed for CBT-I, with yoga and estradiol demonstrating smaller effects.

Conclusions: These results suggest that for menopause-related QOL, women have a variety of treatment strategies to choose from and can select an approach based on most bothersome symptoms and individual preferences.
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http://dx.doi.org/10.1097/GME.0000000000001597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034544PMC
October 2020

To the Editor.

Menopause 2020 07;27(7):836-837

Public Health Sciences Fred Hutchinson Cancer Research Center Seattle, WA.

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http://dx.doi.org/10.1097/GME.0000000000001606DOI Listing
July 2020

Pre-existing immunity to influenza virus hemagglutinin stalk might drive selection for antibody-escape mutant viruses in a human challenge model.

Nat Med 2020 08 29;26(8):1240-1246. Epub 2020 Jun 29.

Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

The conserved region of influenza hemagglutinin (HA) stalk (or stem) has gained attention as a potent target for universal influenza vaccines. Although the HA stalk region is relatively well conserved, the evolutionarily dynamic nature of influenza viruses raises concerns about the possible emergence of viruses carrying stalk escape mutation(s) under sufficient immune pressure. Here we show that immune pressure on the HA stalk can lead to expansion of escape mutant viruses in study participants challenged with a 2009 H1N1 pandemic influenza virus inoculum containing an A388V polymorphism in the HA stalk (45% wild type and 55% mutant). High level of stalk antibody titers was associated with the selection of the mutant virus both in humans and in vitro. Although the mutant virus showed slightly decreased replication in mice, it was not observed in cell culture, ferrets or human challenge participants. The A388V mutation conferred resistance to some of the potent HA stalk broadly neutralizing monoclonal antibodies (bNAbs). Co-culture of wild-type and mutant viruses in the presence of either a bNAb or human serum resulted in rapid expansion of the mutant. These data shed light on a potential obstacle for the success of HA-stalk-targeting universal influenza vaccines-viral escape from vaccine-induced stalk immunity.
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http://dx.doi.org/10.1038/s41591-020-0937-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450362PMC
August 2020

Safety and immunogenicity of a mosquito saliva peptide-based vaccine: a randomised, placebo-controlled, double-blind, phase 1 trial.

Lancet 2020 06 11;395(10242):1998-2007. Epub 2020 Jun 11.

LID Clinical Studies Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: In animal models, immunity to mosquito salivary proteins protects animals against mosquito-borne disease. These findings provide a rationale to vaccinate against mosquito saliva instead of the pathogen itself. To our knowledge, no vector salivary protein-based vaccine has been tested for safety and immunogenicity in humans. We aimed to assess the safety and immunogenicity of Anopheles gambiae saliva vaccine (AGS-v), a peptide-based vaccine derived from four A gambiae salivary proteins, in humans.

Methods: In this randomised, placebo-controlled, double-blind, phase 1 trial, participants were enrolled at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Participants were eligible if they were healthy adults, aged 18-50 years with no history of severe allergic reactions to mosquito bites. Participants were randomly assigned (1:1:1), using block randomisation and a computer-generated randomisation sequence, to treatment with either 200 nmol of AGS-v vaccine alone, 200 nmol of AGS-v with adjuvant (Montanide ISA 51), or sterile water as placebo. Participants and clinicians were masked to treatment assignment. Participants were given a subcutaneous injection of their allocated treatment at day 0 and day 21, followed by exposure to feeding by an uninfected Aedes aegypti mosquito at day 42 to assess subsequent risk to mosquito bites in a controlled setting. The primary endpoints were safety and immunogenicity at day 42 after the first immunisation. Participants who were given at least one dose of assigned treatment were assessed for the primary endpoints and analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03055000, and is closed for accrual.

Findings: Between Feb 15 and Sept 10, 2017, we enrolled and randomly assigned 49 healthy adult participants to the adjuvanted vaccine (n=17), vaccine alone (n=16), or placebo group (n=16). Five participants did not complete the two-injection regimen with mosquito feeding at day 42, but were included in the safety analyses. No systemic safety concerns were identified; however, one participant in the adjuvanted vaccine group developed a grade 3 erythematous rash at the injection site. Pain, swelling, erythema, and itching were the most commonly reported local symptoms and were significantly increased in the adjuvanted vaccine group compared with both other treatment groups (nine [53%] of 17 participants in the adjuvanted vaccine group, two [13%] of 16 in the vaccine only group, and one [6%] of 16 in the placebo group; p=0·004). By day 42, participants who were given the adjuvanted vaccine had a significant increase in vaccine-specific total IgG antibodies compared with at baseline than did participants who were give vaccine only (absolute difference of log-fold change of 0·64 [95% CI 0·39 to 0·89]; p=0·0002) and who were given placebo (0·62 [0·34 to 0·91]; p=0·0001). We saw a significant increase in IFN-γ production by peripheral blood mononuclear cells at day 42 in the adjuvanted vaccine group compared with in the placebo group (absolute difference of log ratio of vaccine peptide-stimulated vs negative control 0·17 [95% CI 0·061 to 0·27]; p=0·009) but we saw no difference between the IFN-γ production in the vaccine only group compared with the placebo group (0·022 [-0·072 to 0·116]; p=0·63).

Interpretation: AGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease.

Funding: Office of the Director and the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, and National Institutes of Health.
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http://dx.doi.org/10.1016/S0140-6736(20)31048-5DOI Listing
June 2020

Lights on MsFLASH: a review of contributions.

Menopause 2020 04;27(4):473-484

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Objective: The Menopause Strategies: Finding Lasting Answers for Symptoms and Health clinical trials network was funded by the National Institutes of Health to find new ways to alleviate the most common, bothersome menopausal symptoms by designing and conducting multiple concurrent clinical intervention studies, accommodating a wide scope of populations and intervention strategies.

Methods: Trials were conducted in Boston, Indianapolis, Minneapolis, Oakland, Philadelphia, and Seattle, with the Data Coordinating Center in Seattle, and were designed with standardized eligibility criteria and endpoints. Primary outcomes focused on vasomotor symptoms, sleep quality and insomnia symptoms, and vaginal symptoms. Secondary outcomes included quality of life, sexual function, and mood.

Results: We completed five randomized clinical trials and three ancillary studies, testing nine interventions in over 1,300 women and collecting nearly 16,000 bio-specimens. Escitalopram, venlafaxine hydrochloride extended release, and low-dose estradiol diminished hot flashes by approximately 50% as compared with a 30% decrease by placebo. No benefits on vasomotor symptoms were observed with yoga or exercise compared with usual activity, nor with omega-3 supplementation compared with placebo. Cognitive behavioral therapy for insomnia reduced self-reported insomnia symptoms and improved overall sleep quality compared with menopause education control. We did not find significant benefit from a vaginal estradiol tablet or a vaginal moisturizer compared with placebo tablet and gel in diminishing the severity of vaginal symptoms.

Conclusions: The MsFLASH trials contributed substantially to our understanding of bothersome menopausal symptom treatment. It is important that clinicians counseling women about available treatment options consider all therapies-both nonhormonal and hormonal.
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http://dx.doi.org/10.1097/GME.0000000000001461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009305PMC
April 2020

Patient-centered change in the day-to-day impact of postmenopausal vaginal symptoms: results from a multicenter randomized trial.

Am J Obstet Gynecol 2020 07 15;223(1):99.e1-99.e9. Epub 2020 Jan 15.

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: Vulvovaginal symptoms, which include dryness, irritation, and pain with intercourse, are common among postmenopausal women and are associated with impaired sexual functioning and quality of life. Previous assessment of treatment strategies for these symptoms has been limited by a lack of sensitive patient-centered outcome measures that assess symptom impact on functional and quality-of-life domains.

Objective: We aimed to (1) examine change in the impact of postmenopausal vulvovaginal symptoms on multiple aspects of well-being and functioning in relation to vaginal estradiol and moisturizer treatment and (2) guide meaningful interpretation of scores on a structured-item questionnaire measure of condition-specific impact.

Study Design: Data were drawn from postmenopausal women who were enrolled in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health Vaginal Health Trial (a 12-week, double-blind, placebo-controlled randomized trial of treatment for vulvovaginal symptoms) who were assigned to vaginal 10-μg estradiol tablet plus placebo gel (n=98), vaginal moisturizer plus placebo tablet (n=97), or dual placebo (n=94). At baseline and 12-week follow up, participants completed the Day-to-Day Impact of Vaginal Aging questionnaire to assess the impact of vaginal symptoms on 4 domains (activities of daily living, emotional well-being, sexual functioning, and body image), each on a 0-4 point scale. Day-to-Day Impact of Vaginal Aging sensitivity to change was assessed by the examination of the associations between change in Day-to-Day Impact of Vaginal Aging domain scores and vulvovaginal symptom severity from baseline to 12 weeks with analysis of covariance. Within-woman and between-group minimal clinically important improvement was assessed with the use of an anchor-based approach that relates change in Day-to-Day Impact of Vaginal Aging domain scores with self-reported benefit from treatment.

Results: Participants in all treatment arms (n=289) demonstrated reduced impact of vulvovaginal symptoms on all domains of well-being and functioning as assessed by Day-to-Day Impact of Vaginal Aging at 12-week follow up, with no significant differences in improvement between women who were assigned to either estradiol tablet or vaginal moisturizer compared with placebo. For all Day-to-Day Impact of Vaginal Aging domains, mean impact scores were reduced when participants reported symptom improvement (-0.3 to -0.8 point change in Day-to-Day Impact of Vaginal Aging scores for <2-point symptom severity change vs -0.4 to -1.6 point change in Day-to-Day Impact of Vaginal Aging scores for 2+ point symptom severity change; all P<.001). Minimal clinically important change in Day-to-Day Impact of Vaginal Aging domain scale scores, which are anchored to self-reported meaningful benefit from treatment at 12 weeks, ranged from -0.4 to -1.3 (within-woman) and -0.2 to -0.7 (between-group). Observed change and minimal clinically important difference were largest for the sexual functioning domain.

Conclusion: The impact of vulvovaginal symptoms on day-to-day activities, sexual function, emotional well-being, and body image may be improved with low-dose vaginal estradiol, moisturizer, or topical placebo. The Day-to-Day Impact of Vaginal Aging questionnaire demonstrates sensitivity to change with treatment of vulvovaginal symptoms, particularly Day-to-Day Impact of Vaginal Aging scales that focus on symptom impact on sexual functioning and body image. Minimal clinically important improvement in the impact of vulvovaginal symptoms as measured by the Day-to-Day Impact of Vaginal Aging can be defined with the use of these measures.
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http://dx.doi.org/10.1016/j.ajog.2019.12.270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321858PMC
July 2020

Adenomyosis incidence, prevalence and treatment: United States population-based study 2006-2015.

Am J Obstet Gynecol 2020 07 15;223(1):94.e1-94.e10. Epub 2020 Jan 15.

Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, Washington. Electronic address:

Background: Adenomyosis symptoms are disabling. Population-based data on incidence and prevalence of adenomyosis are lacking that could guide future evidence-based treatments and clinical management.

Objective: To evaluate the incidence, 10-year secular trends, and prevalence of adenomyosis diagnoses and to describe symptoms and treatment patterns in a large U.S. cohort.

Study Design: We performed a retrospective population-based cohort study of women aged 16-60 years in 2006-2015, enrolled in Kaiser Permanente Washington, a mixed-model health insurance and care delivery system. Adenomyosis diagnoses identified by ICD codes from the International Classification of Diseases 9th and 10th editions and potential covariates were extracted from computerized databases. Women with prior hysterectomy, and for incidence estimates women with prior adenomyosis diagnoses, were excluded. Linear trends in incidence rates over the 10-year study period were evaluated using Poisson regression. Rates and trend tests were examined for all women adjusting for age using direct standardization to the 2015 study population, by age groups, and by race/ethnicity. Chart reviews were performed to validate diagnostic accuracy of ICD codes in identifying adenomyosis incidence. Symptoms and treatment patterns at diagnosis and in the following 5 years were assessed.

Results: A total of 333,693 women contributed 1,185,855 woman-years (2006-2015) for incidence calculations. Associated symptom-related codes (menorrhagia or abnormal uterine bleeding, dysmenorrhea or pelvic pain, dyspareunia, and infertility) were observed in 90.8%; 18.0% had co-occurrent endometriosis codes and 47.6% had co-occurrent uterine fibroid codes. The overall adenomyosis incidence was 1.03% or 28.9 per 10,000 woman-years, with a high of 30.6 in 2007 and a low of 24.4 in 2014. Overall age-adjusted estimated incidence rates declined during the 10-year study interval (linear trend P < .05). Incidence was highest for women aged 41-45 years (69.1 per 10,000 woman-years in 2008) and was higher for black (highest 44.6 per 10,000 woman-years in 2011) vs white women (highest 27.9 per 10,000 woman-years in 2010). Overall prevalence in 2015 was 0.8% and was highest among women aged 41-45 years (1.5%). Among the 624 potential adenomyosis cases identified by diagnostic codes in 2012-2015 and with sufficient information in the medical record to determine true case status, 490 were confirmed as incident cases, yielding a 78.5% (95% confidence interval, 75.1%, 81.7%) positive predictive value of adenomyosis ICD-9/ICD-10 codes for identifying an incident adenomyosis case. Health care burden was substantial: 82.0% of women had hysterectomies, nearly 70% had imaging studies suggestive of adenomyosis, and 37.6% used chronic pain medications.

Conclusion: Adenomyosis burden to the individual and the health care system is high. Incidence rates are disproportionately high among black women. These findings are of concern, as currently available long-term medical therapies remain limited beyond hysterectomy. Our data and methodologies are novel and could serve as a foundation to guide clinicians and health care systems to develop clinical management plans and track outcomes for women with adenomyosis.
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http://dx.doi.org/10.1016/j.ajog.2020.01.016DOI Listing
July 2020

Convergent-Divergent Validity and Correlates of the Day-to-Day Impact of Vaginal Aging Domain Scales in the MsFLASH Vaginal Health Trial.

J Sex Med 2020 01 4;17(1):117-125. Epub 2019 Dec 4.

School of Medicine, University of California San Francisco, San Francisco, CA.

Introduction: Clinical research and management of postmenopausal vaginal symptoms have been limited by the lack of validated measures for assessing symptom impact.

Aim: To evaluate convergent-divergent validity of the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire among postmenopausal women with moderate-to-severe vulvovaginal symptoms and identify demographic and clinical factors associated with greater symptom impact.

Methods: We examined baseline data from postmenopausal women with moderate-to-severe vulvovaginal itching, pain, irritation, dryness, or pain with intercourse in a randomized trial of vaginal estradiol, moisturizer, or placebo. In addition to completing the DIVA questionnaire, participants rated the severity of their most bothersome vulvovaginal symptom, underwent assessment of vaginal pH and epithelial cytology, and completed other self-report measures including the Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), and Patient Health Questionnaire-8 for depression (PHQ-8).

Main Outcome Measure: The main outcome measures were the unadjusted correlations and multivariable-adjusted associations with 4 DIVA domain scales designed to assess symptom impact on day-to-day activities, sexual functioning, emotional well-being, and body image/self-concept on a scale of 0 to 4.

Results: Among 301 women, we detected moderately strong correlations between the DIVA emotional well-being scale and PHQ-8 scores (Pearson correlation coefficient [r] = 0.39) and strong correlations between the DIVA sexual functioning scale and FSFI and FSDS scores (r > 0.50). No significant correlations were detected between any DIVA scales and vaginal pH or epithelial cytology. In adjusted linear-regression analyses, greater vulvovaginal symptom severity was associated with worse DIVA scores for emotional well-being, sexual functioning, and self-concept/body image (average 0.3- to 0.5-point higher DIVA score for each 1-point difference in vulvovaginal symptom severity). Depression symptoms were associated with worse DIVA scores for activities of daily living and emotional well-being (0.2- to 0.4-point higher DIVA score for each 5- point worsening of PHQ-8 score). Women reporting recent sexual activity had lower symptom impact on sexual functioning and self-concept/body image domains (-0.3- to -0.4-point lower DIVA score with weekly sexual activity).

Clinical Implications: Findings suggest that the impact of postmenopausal vaginal symptoms on functioning and well-being is greater in women with co-morbid depression symptoms and less frequent sexual activity, independent of symptom severity.

Strengths & Limitations: Strengths include the multicenter sample and wide array of measures. Results may not generalize to women with mild symptoms.

Conclusion: Our results support the construct validity of the DIVA questionnaire for clinical practice and research and indicate that depression and lower frequency of sexual activity are markers of greater impact of postmenopausal vaginal symptoms on multiple dimensions of functioning and quality of life. Hunter MM, Guthrie KA, Larson JC, et al. Convergent-Divergent Validity and Correlates of the Day-to-Day Impact of Vaginal Aging Domain Scales in the MsFLASH Vaginal Health Trial. J Sex Med 2020;17:117-125.
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http://dx.doi.org/10.1016/j.jsxm.2019.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956841PMC
January 2020

Toward Preventing Enamel Hypoplasia: Modeling Maternal and Neonatal Biomarkers of Human Calcium Homeostasis.

Caries Res 2020 30;54(1):55-67. Epub 2019 Oct 30.

Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA.

Aim: The aim of this study was to assess biomarkers of calcium homeostasis and tooth development, in mothers during pregnancy and their children at birth, for enamel hypoplasia (EH) in the primary maxillary central incisor teeth.

Methods: Bayesian methodology was used for secondary data analyses from a randomized, controlled trial of prenatal vitamin D3 supplementation in healthy mothers (N = 350) and a follow-up study of a subset of the children. The biomarkers were serum calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), total circulating 25-dihydroxyvitamin D (25(OH)D), and 1,25-dihydroxyvitamin D (1,25(OH)2D). The maternal biomarkers were assayed monthly during pregnancy, and the child's biomarkers were derived from cord blood. Digital images of the child's 2 teeth were scored for EH using Enamel Defects Index criteria for each of the incisal, middle, and cervical regions for an EH extent score.

Results: The child EH prevalence was 41% (60/145), with most defects present in the incisal and middle tooth regions. Cord blood iPTH and 1,25(OH)2D levels were significantly associated with EH extent after controlling for maternal factors. For every 1 pg/mL increase in cord blood iPTH, the EH extent decreased by approximately 6%. For every 10 pg/mL increase in cord blood 1,25(OH)2D, the EH extent increased by almost 30% (holding all other terms constant and adjusting for subject-level heterogeneity). The relationship between maternal 25(OH)D and maternal mean iPTH varied significantly by EH extent.

Conclusion: The results suggest possible modifiable relationships of maternal and neonatal factors of calcium homeostasis during pregnancy and at birth for EH, contributing to the frontier of knowledge regarding sound tooth development for dental caries prevention.
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http://dx.doi.org/10.1159/000502793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299520PMC
November 2020

Identification and validation of uterine perforation, intrauterine device expulsion, and breastfeeding in four health care systems with electronic health records.

Clin Epidemiol 2019 23;11:635-643. Epub 2019 Jul 23.

Bayer OY , Espoo, Finland.

Objective: To validate algorithms identifying uterine perforations and intrauterine device (IUD) expulsions and to ascertain availability of breastfeeding status at the time of IUD insertion.

Study Design And Setting: Four health care systems with electronic health records (EHRs) participated: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI). The study included women ≤50 years of age with an IUD insertion. Site-specific algorithms using structured and unstructured data were developed and a sample validated by EHR review. Positive predictive values (PPVs) of the algorithms were calculated. Breastfeeding status was assessed in a random sample of 125 women at each research site with IUD placement within 52 weeks postpartum.

Results: The study population included 282,028 women with 325,582 IUD insertions. The PPVs for uterine perforation were KPNC 77%, KPSC 81%, KPWA 82%, and RI 47%; PPVs for IUD expulsion were KPNC 77%, KPSC 87%, KPWA 68%, and RI 37%. Across all research sites, breastfeeding status at the time of IUD insertion was determined for 94% of those sampled.

Conclusions: Algorithms with a high PPV for uterine perforation and IUD expulsion were developed at 3 of the 4 research sites. Breastfeeding status at the time of IUD insertion could be determined at all research sites. Our findings suggest that a study to evaluate the associations of breastfeeding and postpartum IUD insertions with risk of uterine perforation and IUD expulsion can be successfully conducted retrospectively; however, automated application of algorithms must be supplemented with chart review for some outcomes at one research site due to low PPV.
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http://dx.doi.org/10.2147/CLEP.S201044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662160PMC
July 2019

Facebook advertising for recruitment of midlife women with bothersome vaginal symptoms: A pilot study.

Clin Trials 2019 10 6;16(5):476-480. Epub 2019 May 6.

Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.

Background: The MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) Network recruited into five randomized clinical trials (n = 100-350) through mass mailings. The fifth trial tested two interventions for postmenopausal vulvovaginal symptoms (itching, pain, irritation, dryness, or pain with sex) and thus required a high level of sensitivity to privacy concerns. For this trial, in addition to mass mailings we pilot tested a social media recruitment approach. We aimed to evaluate the feasibility of recruiting healthy midlife women with bothersome vulvovaginal symptoms to participate in the Vaginal Health Trial through Facebook advertising.

Methods: As part of a larger advertising campaign that enrolled 302 postmenopausal women for the 12-week randomized, double-blind, placebo-controlled Vaginal Health Trial from April 2016 to February 2017, Facebook advertising was used to recruit 25 participants. The target population for recruitment by mailings and by Facebook ads included women aged 50-70 years and living within 20 miles of study sites in Minneapolis, MN and Seattle, WA. Design of recruitment letters and Facebook advertisements was informed by focus group feedback. Facebook ads were displayed in the "newsfeed" of targeted users and included a link to the study website. Response rates and costs are described for both online ads and mailing.

Results: Facebook ads ran in Minneapolis for 28 days and in Seattle for 15 days, with ads posted and removed from the site as needed based on clinic flow and a set budget limit. Our estimated Facebook advertising reach was over 200,000 women; 461 women responded and 25 were enrolled at a cost of US$14,813. The response rate per estimated reach was 0.22%; costs were US$32 per response and US$593 per randomized participant. The social media recruitment results varied by site, showing greater effectiveness in Seattle than in Minneapolis. We mailed 277,000 recruitment letters; 2166 women responded and 277 were randomized at a cost of US$98,682. The response rate per letter sent was 0.78%; costs were US$46 per response and US$356 per randomized participant. Results varied little across sites.

Conclusion: Recruitment to a clinical trial testing interventions for postmenopausal vaginal symptoms is feasible through social media advertising. Variability in observed effectiveness and costs may reflect the small sample sizes and limited budget of the pilot recruitment study.
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http://dx.doi.org/10.1177/1740774519846862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742530PMC
October 2019

Sexual frequency and pain in a randomized clinical trial of vaginal estradiol tablets, moisturizer, and placebo in postmenopausal women.

Menopause 2019 08;26(8):816-822

Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.

Objective: To evaluate the efficacy of two common interventions for bothersome postmenopausal vaginal symptoms on improving sexual frequency and pain.

Methods: This is a post-hoc analysis of data from a 12-week double-blind placebo-controlled trial that randomized postmenopausal women (ages 45-70 years) with moderate-severe genitourinary discomfort to vaginal 10 μg estradiol tablet plus placebo gel (n = 102), placebo tablet plus vaginal moisturizer (n = 100), or dual placebo (n = 100). Outcomes were proportion of sexually active women at 12 weeks, frequency of sexual activity, and pain severity with sexual activity (0-3 scale). Consistent with the original study design, comparisons were made between each active arm and the dual placebo arm.

Results: Most women enrolled in the trial, 294/302 (97%), had sufficient data to be included in this analysis. Mean age of participants was 61 years, most were white (88%), college educated (66%), and most reported sexual activity in the month before enrollment (81%). After 12 weeks of treatment, a similar proportion of women in the vaginal estrogen and dual placebo groups reported sexual activity in the past week (50% and 40%; P = 0.10) and the past month (78% and 84%, P = 0.52). Mean (standard deviation) pain with sexual activity scores at 12 weeks were similar between vaginal estrogen (1.0 [1.0]) and placebo (0.9 [0.9], P = 0.52] groups. The proportion sexually active at 12 weeks (35%) and mean (standard deviation) pain severity in the vaginal moisturizer group (1.1 [0.9]) did not differ from placebo (P = 0.36).

Conclusions: Compared to placebo, neither low-dose vaginal estradiol nor vaginal moisturizer treatment over 12 weeks resulted in significantly greater increases in the proportions of women reporting sexual activity or improvement in pain scores with sexual activity.

Trial Registration: Clinical trials.gov: NCT02516202.
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http://dx.doi.org/10.1097/GME.0000000000001341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663586PMC
August 2019

Identification of Incident Uterine Fibroids Using Electronic Medical Record Data.

EGEMS (Wash DC) 2019 Mar 29;7(1). Epub 2019 Mar 29.

Kaiser Permanente Washington, US.

Introduction: Uterine fibroids are the most common benign tumors of the uterus and are associated with considerable morbidity. Diagnosis codes have been used to identify fibroid cases, but their accuracy, especially for incident cases, is uncertain.

Methods: We performed medical record review on a random sample of 617 women who received a fibroid diagnosis during 2012-2014 to assess diagnostic accuracy for incident fibroids. We developed 2 algorithms aimed at improving incident case-finding using classification and regression tree analysis that incorporated additional electronic health care data on demographics, symptoms, treatment, imaging, health care utilization, comorbidities and medication. Algorithm performance was assessed using medical record as gold standard.

Results: Medical record review confirmed 482 fibroid cases as incident, resulting a 78 percent positive predictive value (PPV) for incident cases based on diagnosis codes alone. Incorporating additional electronic data, the first algorithm classified 395 women with a pelvic ultrasound on diagnosis date but none before as incident cases. Of these, 344 were correctly classified, yielding an 87 percent PPV, 71 percent sensitivity, and 62 percent specificity. A second algorithm built on the first algorithm and further classified women based on a fibroid diagnosis code of 218.9 in 2 years after incident diagnosis and lower body mass index; yielded 93 percent PPV, 53 percent sensitivity, and 85 percent specificity.

Conclusions: Compared to diagnosis codes alone, our algorithms using fibroid diagnosis codes and additional electronic data improved identification of incident cases with higher PPV, and high sensitivity or specificity to meet different aims of future studies seeking to identify incident fibroids from electronic data.
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http://dx.doi.org/10.5334/egems.264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450248PMC
March 2019

Influenza A Reinfection in Sequential Human Challenge: Implications for Protective Immunity and "Universal" Vaccine Development.

Clin Infect Dis 2020 02;70(5):748-753

Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, Bethesda, Maryland.

Background: Identification of correlates of protection against human influenza A virus infection is important in development of broadly protective ("universal") influenza vaccines. Certain assumptions underlie current vaccine developmental strategies, including that infection with a particular influenza A virus should offer long-term or lifelong protection against that strain, preventing reinfection. In this study we report observations made when 7 volunteers participated in sequential influenza challenge studies where they were challenged intranasally using the identical influenza A(H1N1)pdm09 virus approximately 1 year apart. We evaluate and describe the outcomes of these 7 rechallenge participants and discuss what these results may suggest about correlates of protection and development of more broadly protective influenza vaccines.

Methods: Seven participants were enrolled in 2 viral challenge studies at 7.5- to 18.5-month intervals. Both challenge studies used the identical lot of influenza A (H1N1)pdm09 virus administered intranasally. We evaluated pre- and postchallenge hemagglutination inhibition, neuraminidase inhibition, and stalk antibody titers; peripheral blood leukocyte host gene expression response profiles; daily viral detection via nasal wash; and clinical signs and symptoms.

Results: At least 3 of 7 participants demonstrated confirmed laboratory evidence of sequential infection, with 5 of 7 demonstrating clinical evidence.

Conclusions: The data presented in this report demonstrate that sequential infection with the identical influenza A virus can occur and suggest it may not be rare. These data raise questions about immune memory responses in an acute superficial respiratory mucosal infection and their implications in development of broadly protective influenza vaccines. Further investigation of these observations is warranted.

Clinical Trials Registration: NCT01646138; NCT01971255.
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http://dx.doi.org/10.1093/cid/ciz281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319262PMC
February 2020

A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model.

Clin Infect Dis 2019 11;69(12):2082-2090

LID Clinical Studies Unit, Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

Background: The development of vaccines and therapeutics has relied on healthy volunteer influenza challenge studies. A validated human infection model with wild-type A(H1N1)pdm09 was reported previously. Our objective was to characterize a wild-type influenza A/Bethesda/MM1/H3N2 challenge virus in healthy volunteers.

Methods: Participants received a single dose of a cell-based, reverse-genetics, Good Manufacturing Practices-produced wild-type influenza A(H3N2)2011 virus intranasally and were isolated at the National Institutes of Health Clinical Center for ≥9 days. Dose escalation was performed from 104 to 107 TCID50 (50% tissue culture infectious dose). Viral shedding and clinical disease were evaluated daily.

Results: Of 37 participants challenged, 16 (43%) had viral shedding and 27 (73%) developed symptoms, with 12 (32%) participants experiencing mild to moderate influenza disease (MMID), defined as shedding and symptoms. Only participants receiving 106 and 107 TCID50 experienced MMID at 44% and 40%, respectively. Symptom severity peaked on day 3, whereas most viral shedding occurred 1-2 days after challenge. Only 10 (29%) participants had a ≥4-fold rise in hemagglutination inhibition antibody titer after challenge.

Conclusions: The A/Bethesda/MM1/H3N2 challenge virus safely induced MMID in healthy volunteers, but caused less MMID than the A(H1N1)pdm09 challenge virus even at the highest dose. There was less detection of shedding though the incidence of symptoms was similar to A(H1N1)pdm09. Fewer serum anti-hemagglutinin (HA) antibody responses with less MMID indicate that preexisting immunity factors other than anti-HA antibody may limit shedding in healthy volunteers. This A/Bethesda/MM1/H3N2 challenge virus can be utilized in future studies to further explore pathogenesis and immunity and to evaluate vaccine candidates.

Clinical Trials Registration: NCT02594189.
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http://dx.doi.org/10.1093/cid/ciz141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880340PMC
November 2019

A US population-based study of uterine fibroid diagnosis incidence, trends, and prevalence: 2005 through 2014.

Am J Obstet Gynecol 2018 12 3;219(6):591.e1-591.e8. Epub 2018 Oct 3.

Obstetrics and Gynecology, School of Medicine, University of Washington, Seattle, WA. Electronic address:

Background: Despite considerable public health burden, uterine fibroid population-based incidence estimates are few. Secular trends over time are even more limited.

Objective: We sought to evaluate the incidence, 10-year secular trends, and prevalence of uterine fibroid diagnoses and describe the proportion of symptomatic women.

Study Design: We performed a retrospective population-based cohort study of women, aged 18-65 years, enrolled 2005 through 2014 in Kaiser Permanente Washington. Uterine fibroid diagnoses identified by International Classification of Diseases, Ninth Revision codes and potential covariates were extracted from computerized databases. Women with prior hysterectomy and, for incidence estimates, women with prior fibroid diagnoses were excluded. Linear trends in incidence rates over the 10-year study period were evaluated using Poisson regression models. Rates and trend tests were examined for all women, by age groups, and by race/ethnicity.

Results: Associated International Classification of Diseases, Ninth Revision symptom-related codes were observed in 90% of incident cases. Incidence rates for fibroid diagnoses were highest for the age group 45-49 years, 240.3 per 10,000 woman-years in 2014, and for black women across all years. Overall age-adjusted estimated incidence rates declined during the 10-year study interval, from 139.4 per 10,000 woman-years in 2005 to 101.4 in 2014 (P value trend .0008). Overall prevalence in 2014 was 9.6%, and was highest among women aged 50-54 years (15.9%). Black women had higher prevalence (18.5%) than other racial/ethnic groups.

Conclusion: We found a decreasing trend of new uterine fibroid diagnoses among predominantly symptomatic women ages 18-65 years in a recent 10-year interval. This finding was due, perhaps in part, to secular trends of decreasing hysterectomies. Nonetheless, uterine fibroids remain a common health burden, with a prevalence of nearly 10%. Rates are disproportionately high and occur at younger ages for black women, and possibly for other non-white racial/ethnic groups. These findings are of concern, as current available long-term medical therapies remain limited.
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http://dx.doi.org/10.1016/j.ajog.2018.09.039DOI Listing
December 2018

Parenting and perinatal depression: meeting women's needs.

J Psychosom Obstet Gynaecol 2019 12 15;40(4):274-282. Epub 2018 Aug 15.

Department of Obstetrics and Gynecology, University of Washington , Seattle , WA , USA.

Symptoms of depression during pregnancy and the postpartum period can negatively impact parenting. It is important to understand the parenting experiences of women with depression, and what parenting support they need. This is a mixed methods analysis of data (demographic data, depression outcomes, patient survey results, and transcripts of patient and care manager focus groups) from an open treatment trial of the feasibility of delivering perinatal depression treatment using collaborative care in a rural obstetric setting. Patients who attended focus groups did not differ significantly from those who did not. Qualitative analysis of focus groups revealed the following themes: Maternal mood and parenting difficulties are interrelated; Access to depression treatment is complicated by expectations for the perinatal period and by factors related to parenting; Women want parenting support in the context of treatment for perinatal depression. Women receiving perinatal depression treatment experience unique parenting challenges and desire parenting support. Healthcare providers caring for these women should be mindful of their patients' parenting needs. Future research should explore ways to integrate parenting interventions with depression treatments. Mother-infant interaction is a key determinant of optimal infant development and integrating parenting support with perinatal depression treatments can have significant public health impact.
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http://dx.doi.org/10.1080/0167482X.2018.1490723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377349PMC
December 2019

Time to advocate for better science, and better treatments for women.

Menopause 2018 10;25(10):1065-1068

Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA Department of Obstetrics and Gynecology, University of Washington, Seattle, WA Fred Hutchinson Cancer Research Center, Seattle, WA.

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http://dx.doi.org/10.1097/GME.0000000000001175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136944PMC
October 2018

Good Clinical Practice in Diagnosis of Vulvovaginal Symptoms-Reply.

JAMA Intern Med 2018 08;178(8):1136-1137

Fred Hutchinson Cancer Research Center, Seattle, Washington.

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http://dx.doi.org/10.1001/jamainternmed.2018.2856DOI Listing
August 2018

Effects of vaginal estradiol tablets and moisturizer on menopause-specific quality of life and mood in healthy postmenopausal women with vaginal symptoms: a randomized clinical trial.

Menopause 2018 10;25(10):1086-1093

Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, CA.

Objective: Compare the effects of a vaginal estradiol tablet and a vaginal moisturizer, each to placebo, on menopause-related quality of life and mood in postmenopausal women with moderate-severe vulvovaginal symptoms.

Methods: A total of 302 postmenopausal women enrolled in a 12-week, double-blind, placebo-controlled randomized trial were assigned to vaginal 10 μg estradiol tablet plus placebo gel (n = 102), vaginal moisturizer plus placebo tablet (n = 100), or dual placebo (n = 100). We measured change from randomization to 12 weeks in total score of the Menopause-Specific Quality of Life (MENQOL) questionnaire. We also evaluated the four MENQOL domains, depressive symptoms as measured by the Patient Health Questionnaire 8, and anxiety symptoms as measured by the Generalized Anxiety Disorder (GAD-7) questionnaire.

Results: Treatment with vaginal estradiol resulted in significantly greater improvement in total MENQOL scores compared to dual placebo (mean difference between arms -0.3 at 12 weeks (95% confidence interval [CI] -0.5, 0.0; P = 0.01). A statistically significant group mean difference favoring vaginal estradiol was observed for the MENQOL sexual function domain (-0.4 at 12 weeks; 95% CI -1.0, 0.1; P = 0.005), but not for any of the other domains. Treatment with vaginal moisturizer did not provide greater improvement compared to placebo in total MENQOL scores (mean difference 0.2 at 12 weeks; 95% CI -0.1, 0.4; P = 0.38) or in any of the MENQOL domains. Neither treatment group showed improvement compared with placebo in the Patient Health Questionnaire 8 or Generalized Anxiety Disorder Questionnaire .

Conclusions: Treatment with low-dose vaginal estradiol, but not vaginal moisturizer, modestly improved menopause-related quality of life and sexual function domain scores in postmenopausal women with moderate-severe vulvovaginal symptoms.
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http://dx.doi.org/10.1097/GME.0000000000001131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136971PMC
October 2018

Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial.

JAMA Intern Med 2018 05;178(5):681-690

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Importance: Nearly half of postmenopausal women report bothersome vulvovaginal symptoms, but few data support the efficacy of 2 commonly recommended treatments.

Objective: To compare the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptoms.

Design, Setting, And Participants: This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration.

Interventions: Vaginal 10-μg estradiol tablet (daily for 2 weeks, then twice weekly) plus placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs dual placebo (n = 100).

Main Outcomes And Measures: The main outcome was decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks. Additional measures included a composite vaginal symptom score, Female Sexual Function Index (FSFI) score (2-36), modified Female Sexual Distress Score-Revised item 1, treatment satisfaction and meaningful benefit, Vaginal Maturation Index, and vaginal pH.

Results: The 302 women had a mean (SD) age of 61 (4) years and were primarily white (267 [88%]), college educated (200 [66%]), and sexually active (245 [81%]). Most women (294 [97%]) provided data for the primary analysis. The most commonly reported MBS was pain with vaginal penetration (182 [60%]), followed by vulvovaginal dryness (63 [21%]). Mean baseline MBS severity was similar between treatment groups: estradiol, 2.4 (95% CI, 2.3 to 2.6); moisturizer, 2.5 (95% CI, 2.3 to 2.6); placebo, 2.5 (95% CI, 2.4 to 2.6). All treatment groups had similar mean reductions in MBS severity over 12 weeks: estradiol, -1.4 (95% CI, -1.6 to -1.2); moisturizer, -1.2 (95% CI, -1.4 to -1.0); and placebo, -1.3 (95% CI, -1.5 to -1.1). No significant differences were seen between estradiol (P = .25) or moisturizer (P = .31) compared with placebo. Mean total FSFI improvement was similar between estradiol (5.4; 95% CI, 4.0 to 6.9) and placebo (4.5; 95% CI, 2.8 to 6.1) (P = .64), and between moisturizer (3.1; 95% CI, 1.7 to 4.5) and placebo (P = .17).

Conclusions And Relevance: Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms.

Trial Registration: clinicaltrials.gov Identifier: NCT02516202.
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http://dx.doi.org/10.1001/jamainternmed.2018.0116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885275PMC
May 2018

Text messaging to support a perinatal collaborative care model for depression: A multi-methods inquiry.

Gen Hosp Psychiatry 2018 May - Jun;52:14-20. Epub 2018 Jan 31.

Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, United States; Department of Global Health, University of Washington, Seattle, WA, United States.

Objective: Mental health care integrated into obstetric settings improves access to perinatal depression treatments. Digital interactions such as text messaging between patient and provider can further improve access. We describe the use of text messaging within a perinatal Collaborative Care (CC) program, and explore the association of text messaging content with perinatal depression outcomes.

Methods: We analyzed data from an open treatment trial of perinatal CC in a rural obstetric clinic. Twenty five women with Patient Health Questionnaire-9 score of ≥10 enrolled in CC, and used text messaging to communicate with their Care Manager(CM). We used surveys and focus groups to assessacceptability of text messaging with surveys and focus groups. We calculated the number of text messages exchanged, and analyzed content to understand usage patterns. We explored association between text messaging content and depression outcomes.

Results: CMs initiated 85.4% messages, and patients responded to 86.9% messages. CMs used text messaging for appointment reminders, and patients used it to obtain obstetric and parenting information. CMs had concerns about the likelihood of boundary violations. Patients appreciated the asynchronous nature of text messaging.

Conclusion: Text messaging is feasible and acceptable within a perinatal CC program. We need further research into the effectiveness of text messaging content, and response protocols.
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http://dx.doi.org/10.1016/j.genhosppsych.2018.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936469PMC
October 2018