Dysregulated inflammatory response to urogynecologic meshes in women with diabetes and its implications.

BACKGROUND: Diabetes is an independent risk factor for mesh complications in women undergoing mesh-augmented surgical repairs of stress urinary incontinence and/or pelvic organ prolapse. The underlying mechanism remains unclear. OBJECTIVE: This study aimed to define the diabetes-associated alterations in the host inflammatory response to mesh and correlate them with perioperative glucose management. STUDY DESIGN: Deidentified demographics and medical records of patients who underwent mesh removal and participated in a mesh biorepository study were reviewed (n=200). In patients with diagnosed diabetes (n=25), blood glucose management before initial mesh implantation and before and after mesh removal was assessed by blood glucose and hemoglobin A1c levels. Age- and body mass index-matched tissue samples excised from patients with and without diabetes were examined. Transcriptomic profiles of immune cell markers, immune mediators, key inflammatory regulators, cell senescence, and epigenetic enzymes were determined by multiplex transcriptomic assays (NanoString). Ratios of apoptotic cells to CD68+ macrophages were examined with immunofluorescence. Protein profiles of 12 molecules involved in apoptotic cell clearance were examined with a multiplex protein assay (Luminex). RESULTS: Demographic and clinical characteristics, including duration between mesh implantation and removal, reason for removal, and type of mesh, etc., were comparable between patients with and without diabetes, except for 11.6% higher body mass index in the former (P=.005). In patients with diabetes, suboptimal management of blood glucose following mesh implantation was observed, with 59% of the patients having loosely or poorly controlled glucose before and after the mesh removal. Ongoing chronic inflammatory response was observed in the excised mesh-tissue complexes in both groups, whereas markers for M2 macrophages (Mrc1 [mannose receptor C-type 1]) and helper T cells (Cd4 [CD4 molecule]) were increasingly expressed in the diabetic vs nondiabetic group (P=.023 and .047, respectively). Furthermore, the gene expressions of proinflammatory Ccl24 (C-C motif chemokine ligand 24) and Ccl13 (C-C motif chemokine ligand 13) were upregulated by 1.5- and 1.8-fold (P=.035 and .027, respectively), whereas that of Il1a (interleukin 1 alpha) was paradoxically downregulated by 2.2-fold (P=.037) in the diabetic vs nondiabetic group. Interestingly, strong positive correlations were found between the expression of Ccl13, Setdb2 (SET domain bifurcated histone lysine methyltransferase 2), and M2 macrophage markers, and between the expression of Il1a, Fosl1 (activator protein-1 transcription factor subunit), and dendritic cell markers, suggesting the involvement of macrophages and dendritic cells in the diabetes-dysregulated proinflammatory response. Supportively, apoptotic cell clearance, which is an important function of macrophages, appeared to be impaired in the diabetic group, with a significantly increased protein level of CALR (calreticulin), an "eat-me" signal on the surface of apoptotic cells (P=.031), along with an increase of AXL (AXL receptor tyrosine kinase) (P=.030), which mediates apoptotic cell clearance. CONCLUSION: Diabetes was associated with altered long-term inflammatory response in complicated mesh implantation, particularly involving innate immune cell dysfunction. Suboptimal blood glycemic control following mesh implantation may contribute to this immune dysregulation, necessitating further mechanistic studies.

A soft elastomer alternative to polypropylene for pelvic organ prolapse repair: a preliminary study.

INTRODUCTION AND HYPOTHESIS: We compared the impact of a mesh manufactured from the soft elastomer polydimethylsiloxane (PDMS) to that of a widely used lightweight polypropylene (PP) mesh. To achieve a similar overall device stiffness between meshes, the PDMS mesh was made with more material and therefore was heavier and less porous. We hypothesized that the soft polymer PDMS mesh, despite having more material, would have a similar impact on the vagina as the PP mesh. METHODS: PDMS and PP meshes were implanted onto the vaginas of 20 rabbits via colpopexy. Ten rabbits served as sham. At 12 weeks, mesh-vagina complexes were explanted and assessed for contractile function, histomorphology, total collagen, and glycosaminoglycan content. Outcome measures were compared using one-way ANOVA and Kruskal-Wallis testing with appropriate post-hoc testing. RESULTS: Relative to sham, vaginal contractility was reduced following the implantation of PP (p = 0.035) but not the softer PDMS (p = 0.495). PP had an overall greater negative impact on total collagen and glycosaminoglycan content, decreasing by 53% (p < 0.001) and 54% (p < 0.001) compared to reductions of 35% (p = 0.004 and p < 0.001) with PDMS. However, there were no significant differences in the contractility, collagen fiber thickness, total collagen, and glycosaminoglycan content between the two meshes. CONCLUSIONS: Despite having a substantially higher weight, PDMS had a similar impact on the vagina compared to a low-weight PP mesh, implicating soft polymers as potential alternatives to PP. The notion that heavyweight meshes are associated with a worse host response is not applicable when comparing across materials.

It's all about who you know: Memory retention of a rat's cagemates during infancy negatively predicts adulthood hippocampal FGF2.

Recent research has demonstrated that individual differences in infant fear memory positively predict adulthood anxiety-like behavior and conditioned fear expression. However, the physiological mechanisms underlying this relationship and the effect of environmental (e.g., social) influences on the stability of this relationship have not been explored. In the present study, we examined whether individual differences in infant fear memory predict levels of endogenous fibroblast growth factor-2 (FGF2; a biomarker of fear/anxiety) in adulthood, and whether the mean memory retention of a rat's cagemates predicts conditioned fear expression and FGF2 in adulthood. We conditioned infant rats to associate a white noise with shock, and tested their memory of the association 1 week later. They were then weaned and randomly assigned to cage/cagemates. In adulthood, rats received weak context conditioning (i.e., a single shock) and were tested for fear of the context the following day. Rats were then euthanized and their brains extracted to measure levels of hippocampal FGF2 protein. Across 2 experiments, an individual rat's fear memory during infancy positively predicted their own fear expression in adulthood, but the mean memory retention of their cagemates did not predict fear expression. In contrast, the mean memory retention of a rat's cagemates during infancy negatively predicted hippocampal FGF2 protein in adulthood, but an individual rat's memory retention did not predict their own levels of FGF2. These data support the idea that variations in the fearfulness of a rat's cagemates predict individual differences on physiological measures in adulthood.

Comparison of 2 single incision slings on the vagina in an ovine model.

BACKGROUND: Stress urinary incontinence carries a significant healthcare burden for women worldwide. Single incision slings are minimally invasive mesh devices designed to treat stress urinary incontinence. For prolapse repair, meshes with higher porosity and lower structural stiffness have been associated with improved outcomes. OBJECTIVE: In this study, we compared the higher stiffness, lower porosity Altis sling with the lower stiffness, higher porosity Solyx sling in an ovine model. We hypothesized that SIS-B would have a negative impact on the host response. STUDY DESIGN: A total of Altis and Solyx single incision slings were implanted suburethrally into sheep according to the manufacturer's instructions on minimal tension. The mesh-urethral-vaginal complex and adjacent ungrafted vagina (no mesh control) were harvested en bloc at 3 months. Masson's trichrome and picrosirius red staining of 6 µm thin sections was performed to measure interfiber distance and tissue integration. Smooth muscle contractility to a 120 mM KCl stimulus was performed in an organ bath to measure myofiber-driven contractions. Standard biochemical assays were used to quantify glycosaminoglycan, total collagen, and elastin content, and collagen subtypes. Bending stiffness was performed in response to a uniaxial force to define susceptibility to folding/buckling. Statistical analysis was performed using Mann-Whitney, Gabriel's pairwise post hoc, Wilcoxon matched-pairs, and chi-square tests. RESULTS: The animals had similar ages (3-5 years), parity (multiparous), and weights (45-72 kg). Trichrome cross sections showed that the Altis sling buckled in a "C" or "S" shape in most samples (8 of 11), whereas buckling after Solyx sling implantation was observed in only a single sample (1 of 13; P=.004). Tissue integration, as measured by the presence of collagen or smooth muscle between the mesh fibers on trichrome 4× imaging, was increased in samples implanted with the Solyx sling compared with the Altis sling (P<.05). Total collagen content decreased significantly with both products when compared with the ungrafted vagina consistent with stress shielding. There was no difference in the 2 groups with regard to glycosaminoglycan or elastin content. The Altis sling mesh tissue complex demonstrated significantly higher amounts of both collagen types I and III than the Solyx sling-implanted tissue and the ungrafted control. Smooth muscle contractility in response to 120 mM KCl was decreased after implantation of both slings compared with the sham (P=.011 and P<.01), with no difference between mesh types (P=.099). Bending stiffness in the Altis sling was more than 4 times lower than in the Solyx, indicating an increased propensity to buckle (0.0186 vs 0.0883). CONCLUSION: The structurally stiffer Altis sling had decreased tissue integration and increased propensity to buckle after implantation. Increased collagen types I and III after the implantation of this device suggests that these changes may be associated with a fibrotic response. In contrast, the Solyx sling largely maintained a flat configuration and had improved tissue integration. The deformation of the Altis sling is not an intended effect and is likely caused by its lower bending stiffness. Both meshes induced a decrease in collagen content and smooth muscle contractility similar to previous findings for prolapse meshes and consistent with stress shielding. The long-term impact of buckling warrants further investigation.

New Zealand white rabbit: a novel model for prolapse mesh implantation via a lumbar colpopexy.

INTRODUCTION AND HYPOTHESIS: New Zealand white rabbits are an inexpensive large-animal model. This study explored the rabbit as a model for mesh-augmented colpopexy using the intra-abdominal vagina. We hypothesized that polypropylene mesh would negatively impact rabbit vaginal smooth muscle (VSM) morphology and contractile function, similar to the nonhuman primate (NHP)-the established model for prolapse mesh evaluation. METHODS: Restorelle was implanted onto the vagina of ten rabbits via lumbar colpopexy after a hysterectomy. Ten rabbits served as sham. Twelve weeks post-implantation, the vagina was excised and VSM morphology and vaginal contractility were assessed. Outcome measures were compared using independent samples t and Mann-Whitney U tests with a Bonferroni correction, where appropriate. Results from the rabbits were compared with published NHP data. RESULTS: Animals had similar age, parity and BMI. VSM was 18% thinner after Restorelle implantation, P = 0.027. Vaginal contractility was 43% decreased in response to 120 mM KCl (P = 0.003), similar to the 46% reduction observed in the NHP vagina implanted with Restorelle (P = 0.027). Three meshes wrinkled in vivo, resulting in dramatic thinning of the underlying vagina in the area of the mesh causing a mesh exposure. CONCLUSIONS: Polypropylene mesh negatively impacts VSM morphology and vaginal contractility in the rabbit, similar to the NHP, suggesting that the rabbit may serve as an alternative large-animal model. The vaginal thinning and appearance of a mesh exposure in the area of a mesh wrinkle suggest the rabbit may also serve as a model for understanding the pathophysiology of mesh exposure.

Barriers and facilitators to optimising inpatient bladder management after spinal cord injury.

STUDY DESIGN: Qualitative survey. OBJECTIVES: Examine clinicians' perspectives on adherence to published evidence-based guidelines and clinician-perceived barriers, and facilitators to optimising inpatient bladder management within one Spinal Cord Injury (SCI) service. SETTING: Surgical Hospital (acute care) and SCI Unit (sub-acute, rehabilitation) in Western Australia (WA). METHODS: Clinicians reviewed an 'Evidence Matrix' summarising published clinical practice guidelines and recommendations for SCI bladder management. Focus groups examined the extent to which current practice adhered to recommendations and identified perceived barriers and facilitators to optimal management. Data were analysed thematically using a deductive approach. RESULTS: Current management closely mirrors published recommendations. Key facilitators included long-standing prioritisation of rapid progression from urethral indwelling (IDC) to a 6 hourly intermittent catheterisation (IC) protocol; regular competency audits of catheterisation technique; and a Spinal Urology Clinical Nurse Consultant (CNC) position. Barriers included limited resources/staffing; restricted access to Neuro-urology consultation; inter-disciplinary communication gaps; and delays in determining and implementing long-term bladder management. CONCLUSIONS: Inpatient SCI bladder care in WA closely emulates published evidence, although adherence at other sites may reveal different practices. Bladder management was found to have been facilitated by a strong culture of practice led by Neuro-urologists, informed by evidence and embraced by Senior Clinicians. Further reduction in duration of initial IDC, provision of early and ongoing Neuro-urology consultations as part of standard care, increased interdisciplinary communication and dedicated SCI Urology theatre lists would further optimise management.

Early urinary tract infection after spinal cord injury: a retrospective inpatient cohort study.

STUDY DESIGN: Retrospective audit. OBJECTIVES: Examine factors associated with urinary tract infection (UTI), UTI incidence and impact on hospital length of stay (LOS) in new, inpatient adult traumatic spinal cord injury (SCI). SETTING: Western Australian Hospitals managing SCI patients. METHODS: Data on UTIs, bladder management and LOS were obtained from hospital databases and medical records over 26 months. Adherence to staff-administered intermittent catheterisation (staff-IC) was determined from fluid balance charts. RESULTS: Across the cohort (n = 70) UTI rate was 1.1 starts/100 days; UTI by multi-resistant organisms 0.1/100 days. Having ≥1 UTIs compared with none and longer duration of initial urethral indwelling catheterisation (IDC) were associated with longer LOS (p-values < 0.001). For patients with ≥1 UTIs (n = 43/70), longer duration of initial IDC was associated with shorter time to first UTI (1 standard deviation longer [SD, 45.0 days], hazard ratio (HR): 0.7, 95% confidence interval [CI] 0.5-1.0, p-value 0.044). In turn, shorter time to first UTI was associated with higher UTI rate (1 SD shorter [30.7 days], rate ratio (RR): 1.32, 95%CI 1.0-1.7, p-value 0.039). During staff-IC periods (n = 38/70), protocols were followed (85.7% ≤ 6 h apart, 96.1% < 8 h), but 26% of IC volumes exceeded 500 mL; occasional volumes > 800 mL and interruptions requiring temporary IDC were associated with higher UTI rates the following week (odds ratios (ORs): 1.6, 95%CI 1.1-2.3, p-value 0.009; and 3.9, 95%CI 2.6-5.9, p-value < 0.001 respectively). CONCLUSIONS: Reducing initial IDC duration and limiting staff-IC volumes could be investigated to possibly reduce inpatient UTIs and LOS. SPONSORSHIP: None.

Individual differences in fear extinction and anxiety-like behavior.

There is growing appreciation for the substantial individual differences in the acquisition and inhibition of aversive associations, and the insights this might give into identifying individuals particularly vulnerable to stress and psychopathology. We examined whether animals that differed in rate of extinction (i.e., Fast versus Slow) were different in their response to an acute stress in adulthood or following a chronic stress that occurred either early or later in life. We found that Slow Extinguishers had significantly poorer extinction retention than Fast Extinguishers, but an acute stressor did not differentially affect anxiety-like behavior in the two groups. Further, while exposure to chronic stress in adulthood did not impact on the extinction phenotypes or anxiety-like behavior, exposure to chronic stress early in life affected both extinction retention and anxiety-like behavior. These findings have implications for the development of a more nuanced approach to identifying those most at risk of anxiety disorders.

Evaluating a Trauma-Informed Care Training Program for Mental Health Clinicians.

The aim of this study was to evaluate the interRAI Trauma-Informed Care (TIC) training program based on evidence-informed Collaborative Action Plans. Focus groups and the Attitude Related Trauma-Informed Care (ARTIC) questionnaire addressed clinicians' and mental health professionals' attitudes toward the application of TIC with their child and youth clients. An explanatory sequential design was conducted. In total, 105 clinicians and mental health professionals who participated in a 4-hour, in-person or virtual TIC training, two comprehensive seminars, and 28 trauma-informed training web-based modules completed the ARTIC questionnaire. Researchers conducted seven focus groups with clinicians/participants (N = 23) to discuss the views and effectiveness of the interRAI TIC educational training modules. To quantitatively measure the change of attitudes towards TIC, descriptive statistical analysis was completed using the means and standard deviation of the ARTIC scores at the initial time point, the follow-up time point, and the difference between scores at both time points. Paired sample t-tests were conducted on both the overall score and each of the subscales in each of the three samples (total sample, online subsample, and hybrid subsample). A thematic analysis was conducted to generate qualitative findings from the focus groups. Findings from the quantitative and qualitative analyses suggest that the interRAI TIC training provided clinicians with an improved sense of knowledge and ability to apply trauma-informed care planning with their clients.

How Do Employees in the Disability and Family and Domestic Violence Sectors Respond to Disclosures of Violence From Women With Disability?

Women with disability experience higher rates of family and domestic violence (FDV) compared to the rest of the population. There is limited research into how workers in FDV and disability organizations respond to violence against women with disability. Using a case study vignette of a woman with disability disclosing FDV, this phenomenological study explored how 10 employees across the disability and FDV sectors respond to disclosures of abuse, the barriers that influenced their response, and suggested ways to improve their practices. The study found that responses were often insufficient to meet the needs of women with disability.

Vaginal host response to polycarbonate urethane, an alternative material for the repair of pelvic organ prolapse.

Complications following surgical repair of pelvic organ prolapse (POP) with polypropylene mesh (PPM) are common. Recent data attributes complications, in part, to stiffness mismatches between the vagina and PPM. We developed a 3D printed elastomeric membrane (EM) from a softer polymer, polycarbonate urethane (PCU). EMs were manufactured with more material given the low inherent material strength of PCU. We hypothesized that the EMs would be associated with an improved host response as compared to PPM. A secondary goal was to optimize the material distribution (fiber width and device thickness) within EMs, in regards to the host response. EM constructs (2 × 1 cm2) with varied polymer stiffness, fiber width, and device thickness were implanted onto the vagina of New Zealand white rabbits for 12 weeks and compared to similarly sized PPMs. Sham implanted animals served as controls. Mixed effects generalized linear models were used to compare the effect of construct type accounting for differences in independent variables. EMs had an overall superior host response compared to PPM as evidenced by preservation of vaginal smooth muscle morphology (p-values<0.01), decreased total cellular response to construct fibers (p-values<0.001), and a reduced percent of macrophages (p-values<0.02) independent of how the material was distributed. Both PPM and EMs negatively impacted vaginal contractility and glycosaminoglycan (GAG) content relative to Sham (all p-values<0.001) with EMs having less of an impact on GAGs (p-values<0.003). The results suggest that softer PCU EMs made with more material are well tolerated by the vagina and comprises a future material for POP repair devices. STATEMENT OF SIGNIFICANCE: Prolapse is a debilitating condition in which loss of support to the vagina causes it and the organs supported by it to descend from their normal position in the pelvis. Surgical solutions to rebuild support involves the use of polypropylene mesh which is orders of magnitude stiffer than the vagina. This mismatch results in complications including exposure of the mesh into the vagina and pain. To provide an innovative solution for women, we have developed an elastomeric membrane from a soft polymer that matches the stiffness of the vagina. Here, we show in a rabbit animal model that this device incorporates better into the vagina and is associated with an overall improved host response as compared to polypropylene mesh.

Towards a culture of care for ethical review: connections and frictions in institutional and individual practices of social research ethics.

As researchers, institution-wide regulatory and organisational cultures guide our work. Over the past two decades, University Research Ethics Committees have been formally established across social science disciplines. However, the functioning of these committees has not been without critique. It is often argued that established ethical procedures informed by the medical sciences do not fit well with the more iterative epistemologies and unpredictable practices of doing social fieldwork. In this paper, I contribute to these discussions by considering what a further framework, a 'culture of care', might offer to university research ethics. A culture of care has evolved in contexts like the National Health Service (NHS) and animal research, and makes central claims around support, openness, collaboration and relationships. Bringing this to research ethics, I explore experiences of care through moments of friction in doing fieldwork with people living with Motor Neurone Disease. Identifying gaps between the institutional, personal and relational, I tentatively suggest some key features that a culture of care for research ethics might seek to develop. These discussions are also timely. Wider conversations emerging around reimagining research cultures in higher education provide an opportune moment to consider what a reimagined research ethics might look like and offer too.

Intravesical hyaluronic acid with chondroitin sulphate to prevent urinary tract infection after spinal cord injury.

CONTEXT/OBJECTIVE: Prevention of urinary tract infection (UTI) after spinal cord injury is an important goal. Intravesical hyaluronic acid with chondroitin sulphate (HA+CS) has been effective in preventing UTI in other settings. We aimed to demonstrate safety and feasibility of a standard treatment course of 7 intravesical HA+CS instillations over 12 weeks, in patients with acute (Arm A) and chronic (Arm B) spinal cord injury (SCI). DESIGN: Follow-up of adverse events, quality of life bladder management difficulty (BMD) and bladder complication (BC) T-scores at baseline (Arm B only), 12 and 24 weeks, and symptomatic urinary tract infection (UTI). RESULTS: Of 33 and 14 individuals screened, 2 and 8 participants were recruited to the study for Arm A and Arm B respectively. Of the 10 participants, 8 completed all 7 instillations. HA+CS commonly caused cloudy urine with urinary sediment which was mild and short-lived. In Arm B, a mean reduction in BMD and BC T-scores was observed from baseline (57.3 and 54.4 respectively), of 6.8 and 4.3 at 12 weeks and 1.6 and 2.8 at 24 weeks, respectively. Four participants with a history of frequent UTI in the prior 12 months did not have UTI in the 24 weeks of the study. CONCLUSIONS: HA+CS was well tolerated. Recruitment was more difficult in early acute SCI; participants with chronic SCI were highly motivated to reduce UTI and manage self-administration without difficulty. Larger case-control or randomized controlled trials in patients with neurogenic bladder from SCI are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03945110.

Mesh deformation: A mechanism underlying polypropylene prolapse mesh complications in vivo.

Polypropylene meshes used in pelvic organ prolapse (POP) repair are hampered by complications. Most POP meshes are highly unstable after tensioning ex vivo, as evidenced by marked deformations (pore collapse and wrinkling) that result in altered structural properties and material burden. By intentionally introducing collapsed pores and wrinkles into a mesh that normally has open pores and remains relatively flat after implantation, we reproduce mesh complications in vivo. To do this, meshes were implanted onto the vagina of rhesus macaques in nondeformed (flat) vs deformed (pore collapse +/- wrinkles) configurations and placed on tension. Twelve weeks later, animals with deformed meshes had two complications, (1) mesh exposure through the vaginal epithelium, and (2) myofibroblast proliferation with fibrosis - a mechanism of pain. The overarching response to deformed mesh was vaginal thinning associated with accelerated apoptosis, reduced collagen content, increased proteolysis, deterioration of mechanical integrity, and loss of contractile function consistent with stress shielding - a precursor to mesh exposure. Regional differences were observed, however, with some areas demonstrating myofibroblast proliferation and matrix deposition. Variable mechanical cues imposed by deformed meshes likely induce these two disparate responses. Utilizing meshes associated with uniform stresses on the vagina by remaining flat with open pores after tensioning is critical to improving outcomes. STATEMENT OF SIGNIFICANCE: Pain and exposure are the two most reported complications associated with the use of polypropylene mesh in urogynecologic procedures. Most meshes have unstable geometries as evidenced by pore collapse and wrinkling after tensioning ex vivo, recapitulating what is observed in meshes excised from women with complications in vivo. We demonstrate that collapsed pores and wrinkling result in two distinct responses (1) mesh exposure associated with tissue degradation and atrophy and (2) myofibroblast proliferation and matrix deposition consistent with fibrosis, a tissue response associated with pain. In conclusion, mesh deformation leads to areas of tissue degradation and myofibroblast proliferation, the likely mechanisms of mesh exposure and pain, respectively. These data corroborate that mesh implantation in a flat configuration with open pores is a critical factor for reducing complications in mesh-augmented surgeries.

Characterization of vaginal immune response to a polypropylene mesh: Diabetic vs. normoglycemic conditions.

OBJECTIVE: Urogynecology meshes, typically manufactured from polypropylene, are widely used in the surgical treatment of stress urinary incontinence and pelvic organ prolapse. However, mesh-associated complications such as mesh exposure can develop in women undergoing mesh implantation, for which diabetes is an independent risk factor. We aimed to define the impact of diabetes on the vaginal immune response to mesh by comparing diabetic vs. normoglycemic conditions longitudinally in a rat sacrocolpopexy model. METHODS: Diabetes (blood glucose ≥ 300 mg/dL) was induced in middle-aged female Wistar rats with streptozotocin (STZ). A polypropylene mesh was implanted on the vagina via modified sacrocolpopexy following bilateral ovariectomy and supracervical hysterectomy for 3-, 7-, and 42-days. Sham-operated controls underwent the same procedures without mesh. Mesh-associated inflammation, immune cell populations and cytokine/chemokine profiles were examined in the excised vaginal tissues. RESULTS: Diabetes was reliably induced starting on the 3rd day following STZ injection. Under both normoglycemic and diabetic conditions, mesh caused a prolonged inflammatory response in the vagina with increased proinflammatory chemokines MCP-1 and MIP-1α as compared to Sham. Major differences between the two conditions were found at the later stage (42 days post-surgery), including an increased inflammation with larger foreign body granuloma and more giant cells at the mesh-tissue interface, increased fraction of macrophages in the immune cell population, and higher proinflammatory chemokine IP-10 in the diabetic group. CONCLUSION: Polypropylene mesh implanted on the vagina induces prolonged inflammation at the mesh-tissue interface. Diabetes increases the mesh-associated inflammation in the long term, which is related to a dysregulated macrophage response. STATEMENT OF SIGNIFICANCE: This study investigated the mechanism underlying the increased risk in women with diabetes for developing mesh complications such as mesh exposure. The significance includes: (1) it is the first study investigating vaginal host response to a prosthesis under the influence of diabetes; (2) the longitudinal study design elucidated the dynamic changes of vaginal immune response to mesh from very early to late stages; (3) our findings may inform future mechanistic studies and studies investigating preventive/therapeutic strategies to improve the outcomes of women with diabetes receiving vaginal implants.

Towards a feminist philosophy of engagements in health-related research.

Engagement with publics, patients, and stakeholders is an important part of the health research environment today,and different modalities of 'engaged' health research have proliferated in recent years. Yet, th ere is no consensus on what, exactly, 'engaging' means, what it should look like, and what the aims, justifications, or motivations for it should be. In this paper, we set out what we see as important, outstanding challenges around the practice and theory of engaging and consider the tensions and possibilities that the diverse landscape of engaging evokes. We examine the roots, present modalities and institutional frameworks that have been erected around engaging, including how they shape and delimit how engagements are framed, enacted, and justified. We inspect the related issue of knowledge production within and through engagements, addressing whether engagements can, or should, be framed as knowledge producing activities. We then unpack the question of how engagements are or could be valued and evaluated, emphasising the plural ways in which 'value' can be conceptualised and generated. We conclude by calling for a philosophy of engagements that can capture the diversity of related practices, concepts and justifications around engagements, and account for the plurality of knowledges and value that engagements engender, while remaining flexible and attentive to the structural conditions under which engagements occur. Such philosophy should be a feminist one, informed by feminist epistemological and methodological approaches to equitable modes of research participation, knowledge production, and valuing. Especially, translating feminist tools of reflexivity and positionalityinto the sphere of engagements can enable a synergy of empirical, epistemic and normative considerations in developing accounts of engaging in both theory and praxis. Modestly, here, we hope to carve out the starting points for this work.

Mesh induced fibrosis: The protective role of T regulatory cells.

Polypropylene mesh is widely used in urogynecologic surgery, but complications rates (pain and exposure) approach 10%. Emerging evidence implicates the adaptive immune system in regulating the foreign body response to mesh, particularly regulatory T cells (Tregs), which modify macrophage differentiation and down-regulate CD8+ effector T cells. We hypothesize that Tregs protect against a profibrotic response, a likely mechanism of pain complications. Here, thin sections of mesh-tissue complexes removed for the primary complaint of pain (N = 14) or exposure (N = 15) were labeled for CD8, CD4 (Th), and FoxP3 (Tregs) via immunofluorescence. The same sections were analyzed for localized collagen deposition via a customized semi-quantitative assessment (0.25 mm2 grid) after trichrome staining. TGF-ß1 concentrations were determined by enzyme-linked immunosorbent assay. Fewer Treg and CD4+ cells were found in fibrotic areas versus non-fibrotic areas (503 and 550/cm2 fewer, respectively, both P < 0.001). TGF-ß1 was higher in mesh samples compared to autologous control biopsies. TGF-ß 1 inversely correlated with age, r -0.636(p = 0.008). No differences were found in T cell subgroups or fibrotic indices between pain and exposure groups. A moderate inverse relationship was found between TGF-ß1 and Tregs (r -0.402, P = 0.009). Tregs were present up to 12 years after mesh implantation, challenging the assumption that the adaptive immune response to a foreign body is transient. In conclusion, the inverse relationship between fibrosis and Tregs, and TGF-ß1 and Tregs points to a protective role of these cells. Similar immunologic responses in patients with pain and exposure suggest these complications exist along a spectrum. STATEMENT OF SIGNIFICANCE: The use of polypropylene mesh has been associated with improved outcomes in urogynecologic surgery, but is associated with significant complications, including pain and exposure through the vaginal epithelium. The host immune response features a prolonged inflammatory reaction containing innate immune cells and T lymphocytes clustered in capsules around the mesh fibers. This study uncovers the inverse relationship between T regulatory cells and the extent of fibrosis around the mesh, suggesting an anti-fibrotic effect. In addition, concentrations of T regulatory and T effector cells and levels of fibrosis connect these two most common complications into one mechanistic pathway. These new insights into the immune response to implanted mesh are an important step in understanding the causes of these surgical complications.

A precision medicine approach to pharmacological adjuncts to extinction: a call to broaden research.

There is a pressing need to improve treatments for anxiety. Although exposure-based therapy is currently the gold-standard treatment, many people either do not respond to this therapy or experience a relapse of symptoms after treatment has ceased. In recent years, there have been many novel pharmacological agents identified in preclinical research that have potential as adjuncts for exposure therapy, yet very few of these are regularly integrated into clinical practice. Unfortunately, the robust effects observed in the laboratory animal often do not translate to a clinical population. In this review, we discuss how age, sex, genetics, stress, medications, diet, alcohol, and the microbiome can vary across a clinical population and yet are rarely considered in drug development. While not an exhaustive list, we have focused on these factors because they have been shown to influence an individual's vulnerability to anxiety and alter the neurotransmitter systems often targeted by pharmacological adjuncts to therapy. We argue that for potential adjuncts to be successfully translated from the lab to the clinic empirical research must be broadened to consider how individual difference factors will influence drug efficacy.

Effects of d-cycloserine on individual differences in relapse of fear.

The major weakness of psychological and pharmacological interventions for anxiety disorders is that the fear often returns. We examined whether DCS, which has attracted considerable attention as a potential pharmacological adjunct to therapy, reduces relapse, and whether individual differences in the rate of extinction modulates its effectiveness in reducing relapse. Experimentally-naïve adult male rats received pairings of a white noise CS with a shock US, extinction to a criterion immediately followed by an injection of DCS or Saline, and then were tested for relapse of fear (renewal, spontaneous recovery, or reinstatement; in four separate experiments). The number of blocks to reach criteria in extinction was used to classify animals as "Fast" or "Slow" Extinguishers. We consistently found that while DCS reduced relapse in Fast Extinguishers, it had minimal effects on relapse in Slow Extinguishers. Importantly, the differences in the effect of DCS on Fast and Slow Extinguishers was not due to Fast Extinguishers being less susceptible to relapse as animals in both groups exhibited similar amounts of relapse when injected with saline. Relapse, of all three types tested, was consistently reduced by DCS, but only in the Fast Extinguishers. Such findings contribute to a growing literature identifying factors that could influence the efficacy of pharmacological adjuncts to exposure therapy. These results have important implications for the development of personalized treatment approaches, which recognize, and are tailored to, individual differences.