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1. Biaxial Stress Relaxation of Vaginal Tissue in Pubertal Gilts

   https://doi.org/10.1115/1.4045707  

   Pack, Erica ; Dubik, Justin ; Snyder, William ; Simon, Alexander ; Clark, Sherrie ; De Vita, Raffaella ( March 2020 , Journal of Biomechanical Engineering)

   null (Ed.)

   Abstract Pelvic organ prolapse (POP) is a condition characterized by displacement of the vagina from its normal anatomical position leading to symptoms such as incontinence, physical discomfort, and poor self-image. Conservative treatment has shown limited success and surgical procedures, including the use of mesh, often lead to severe complications. To improve the current treatment methods for prolapse, the viscoelastic properties of vaginal tissue need to be characterized. We determined the biaxial stress relaxation response of vaginal tissue isolated from healthy pubertal gilts. Square specimens (n = 20) with sides aligned along the longitudinal directions (LD) and circumferential direction (CD) of the vagina were biaxially displaced up to 5 N. The specimens were then kept at the displacements corresponding to 5 N for 20 min in both the LD and CD, and the corresponding strains were measured using digital image correlation (DIC). The stresses in the LD and CD were found to decrease by 49.91 ± 5.81% and 46.22 ± 5.54% after 20 min, respectively. The strain in the LD and CD increased slightly from 0.080 ± 0.054 to 0.091 ± 0.064 and 0.050 ± 0.039 to 0.058 ± 0.047, respectively, but these changes were not significant (p > 0.01). By using the Peleg model, the initial decay rate and the asymptotic stress during stress relaxation were found to be significantly higher in the LD than in the CD (p≪0.001), suggesting higher stress relaxation in the LD. These findings may have implications for improving current surgical mesh, mechanical devices, and physical therapy used for prolapse treatment. 

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2. Antibiotics and fecundability among female pregnancy planners: a prospective cohort study

   https://doi.org/10.1093/humrep/deab173  

   Crowe, Holly Michelle ; Wesselink, Amelia Kent ; Wise, Lauren Anne ; Wang, Tanran R ; Horsburgh, Charles Robert ; Mikkelsen, Ellen Margrethe ; Hatch, Elizabeth Elliott ( July 2021 , Human Reproduction)

   Abstract STUDY QUESTION To what extent is female preconception antibiotic use associated with fecundability? SUMMARY ANSWER Preconception antibiotic use overall was not appreciably associated with fecundability. WHAT IS KNOWN ALREADY Antibiotics are commonly used by women and are generally thought to be safe for use during pregnancy. However, little is known about possible effects of antibiotic use on fecundability, the per-cycle probability of conception. Previous research on this question has been limited to occupational rather than therapeutic exposure. STUDY DESIGN, SIZE, DURATION We analyzed data from an Internet-based preconception cohort study of 9524 female pregnancy planners aged 21–45 years residing in the USA and Canada who had been attempting to conceive for six or fewer cycles at study entry. Participants enrolled between June 2013 and September 2020 and completed baseline and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever came first. The questions pertaining to antibiotic type and indication were added to the PRESTO questionnaires in March 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS We assessed antibiotic use in the previous 4 weeks at baseline and on each follow-up questionnaire. Participants provided the name of the specific antibiotic and the indication for use. Antibiotics were classified based on active ingredient (penicillins, macrolides, nitrofurantoin, nitroimidazole, cephalosporins, sulfonamides, quinolones, tetracyclines, lincosamides), and indications were classified by type of infection (respiratory, urinary tract, skin, vaginal, pelvic, and surgical). Participants reported pregnancy status on follow-up questionnaires. We used proportional probabilities regression to estimate fecundability ratios (FR), the per-cycle probability of conception comparing exposed with unexposed individuals, and 95% confidence intervals (CI), adjusting for sociodemographics, lifestyle factors, and reproductive history. MAIN RESULTS AND THE ROLE OF CHANCE Overall, women who used antibiotics in the past 4 weeks at baseline had similar fecundability to those who had not used antibiotics (FR: 0.98, 95% CI: 0.89–1.07). Sulfonamides and lincosamides were associated with slightly increased fecundability (FR: 1.39, 95% CI: 0.90–2.15, and FR: 1.58 95% CI: 0.96–2.60, respectively), while macrolides were associated with slightly reduced fecundability (FR: 0.70, 95% CI: 0.47–1.04). Analyses of the indication for antibiotic use suggest that there is likely some confounding by indication. LIMITATIONS, REASONS FOR CAUTION Findings were imprecise for some antibiotic classes and indications for use owing to small numbers of antibiotic users in these categories. There are likely heterogeneous effects of different combinations of indications and treatments, which may be obscured in the overall null results, but cannot be further elucidated in this analysis. WIDER IMPLICATIONS OF THE FINDINGS There is little evidence that use of most antibiotics is associated with reduced fecundability. Antibiotics and the infections they treat are likely associated with fecundability through differing mechanisms, resulting in their association with increased fecundability in some circumstances and decreased fecundability in others. STUDY FUNDING/COMPETING INTEREST(S) This study was supported through funds provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (R01-HD086742, R21-HD072326). L.A.W. has received in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, Fertility Friend, and Kindara for primary data collection in PRESTO. The other authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A. 

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3. Biaxial Murine Vaginal Remodeling With Reproductive Aging

   https://doi.org/10.1115/1.4054362  

   White, Shelby E. ; Kiley, Jasmine X. ; Visniauskas, Bruna ; Lindsey, Sarah H. ; Miller, Kristin S. ( June 2022 , Journal of Biomechanical Engineering)

   Abstract Higher reproductive age is associated with an increased risk of gestational diabetes, pre-eclampsia, and severe vaginal tearing during delivery. Further, menopause is associated with vaginal stiffening. However, the mechanical properties of the vagina during reproductive aging before the onset of menopause are unknown. Therefore, the first objective of this study was to quantify the biaxial mechanical properties of the nulliparous murine vagina with reproductive aging. Menopause is further associated with a decrease in elastic fiber content, which may contribute to vaginal stiffening. Hence, our second objective was to determine the effect of elastic fiber disruption on the biaxial vaginal mechanical properties. To accomplish this, vaginal samples from CD-1 mice aged 2–14 months underwent extension-inflation testing protocols (n = 64 total; n = 16/age group). Then, half of the samples were randomly allocated to undergo elastic fiber fragmentation via elastase digestion (n = 32 total; 8/age group) to evaluate the role of elastic fibers. The material stiffness increased with reproductive age in both the circumferential and axial directions within the control and elastase-treated vaginas. The vagina demonstrated anisotropic mechanical behavior, and anisotropy increased with age. In summary, vaginal remodeling with reproductive age included increased direction-dependent material stiffness, which further increased following elastic fiber disruption. Further work is needed to quantify vaginal remodeling during pregnancy and postpartum with reproductive aging to better understand how age-related vaginal remodeling may contribute to an increased risk of vaginal tearing. 

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4. Role of fibulin-5 insufficiency and prolapse progression on murine vaginal biomechanical function

   https://doi.org/10.1038/s41598-021-00351-1  

   Clark-Patterson, Gabrielle L. ; Roy, Sambit ; Desrosiers, Laurephile ; Knoepp, Leise R. ; Sen, Aritro ; Miller, Kristin S. ( December 2021 , Scientific Reports)

   Abstract The vagina plays a critical role in supporting the pelvic organs and loss of support leads to pelvic organ prolapse. It is unknown what microstructural changes influence prolapse progression nor how decreased elastic fibers contributes to vaginal remodeling and smooth muscle contractility. The objective for this study was to evaluate the effect of fibulin-5 haploinsufficiency, and deficiency with progressive prolapse on the biaxial contractile and biomechanical function of the murine vagina. Vaginas from wildtype (n = 13), haploinsufficient (n = 13), and deficient mice with grade 1 (n = 9) and grade 2 or 3 (n = 9) prolapse were explanted for biaxial contractile and biomechanical testing. Multiaxial histology (n = 3/group) evaluated elastic and collagen fiber microstructure. Western blotting quantified protein expression (n = 6/group). A one-way ANOVA or Kruskal–Wallis test evaluated statistical significance. Pearson’s or Spearman’s test determined correlations with prolapse grade. Axial contractility decreased with fibulin-5 deficiency and POP (p < 0.001), negatively correlated with prolapse grade (ρ = − 0.80; p < 0.001), and positively correlated with muscularis elastin area fraction (ρ = − 0.78; p = 0.004). Circumferential (ρ = 0.71; p < 0.001) and axial (ρ = 0.69; p < 0.001) vaginal wall stresses positively correlated with prolapse grade. These findings demonstrated that fibulin-5 deficiency and prolapse progression decreased vaginal contractility and increased vaginal wall stress. Future work is needed to better understand the processes that contribute to prolapse progression in order to guide diagnostic, preventative, and treatment strategies. 

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5. Investigation of Murine Vaginal Creep Response to Altered Mechanical Loads

   https://doi.org/10.1115/1.4052365  

   Clark-Patterson, Gabrielle L. ; McGuire, Jeffrey A. ; Desrosiers, Laurephile ; Knoepp, Leise R. ; De Vita, Raffaella ; Miller, Kristin S. ( December 2021 , Journal of Biomechanical Engineering)

   Abstract The vagina is a viscoelastic fibromuscular organ that provides support to the pelvic organs. The viscoelastic properties of the vagina are understudied but may be critical for pelvic stability. Most studies evaluate vaginal viscoelasticity under a single uniaxial load; however, the vagina is subjected to dynamic multiaxial loading in the body. It is unknown how varied multiaxial loading conditions affect vaginal viscoelastic behavior and which microstructural processes dictate the viscoelastic response. Therefore, the objective was to develop methods using extension-inflation protocols to quantify vaginal viscoelastic creep under various circumferential and axial loads. Then, the protocol was applied to quantify vaginal creep and collagen microstructure in the fibulin-5 wildtype and haploinsufficient vaginas. To evaluate pressure-dependent creep, the fibulin-5 wildtype and haploinsufficient vaginas (n = 7/genotype) were subjected to various constant pressures at the physiologic length for 100 s. For axial length-dependent creep, the vaginas (n = 7/genotype) were extended to various fixed axial lengths then subjected to the mean in vivo pressure for 100 s. Second-harmonic generation imaging was performed to quantify collagen fiber organization and undulation (n = 3/genotype). Increased pressure significantly increased creep strain in the wildtype, but not the haploinsufficient vagina. The axial length did not significantly affect the creep rate or strain in both genotypes. Collagen undulation varied through the depth of the subepithelium but not between genotypes. These findings suggest that the creep response to loading may vary with biological processes and pathologies, therefore, evaluating vaginal creep under various circumferential loads may be important to understand vaginal function. 

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