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Victoria A Jackman,1 Krisztina Bajzak,2 Alex Rains,3 Michelle Swab,4 Michelle E Miller,2 Gabrielle S Logan,5 Diana L Gustafson6 1Faculty of Medicine, Memorial University, Newfoundland & Labrador, St. John’s Canada; 2Discipline of Obstetrics and Gynecology, Memorial University, Newfoundland & Labrador, St. John’s Canada; 3Department of Medicine, University of Chicago, Chicago, IL, USA; 4Health Sciences Library, Faculty of Medicine, Memorial University, Newfoundland & Labrador, St. John’s Canada; 5Department of Anesthesiology, Perioperative and Pain Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada; 6Division of Population Health and Applied Health Sciences, Faculty of Medicine, Memorial University, Newfoundland & Labrador, St. John’s CanadaCorrespondence: Krisztina Bajzak, Email kbajzak@yahoo.comIntroduction: Localized provoked vulvodynia (LPV) is a prevalent sexual health condition with significant negative impacts on quality of life. There is a lack of consensus regarding effective management.Methods: We used Arksey and O’Malley’s five-step method to identify, collate, and evaluate literature published between 2010 and 2023. The scoping review investigated the efficacy or effectiveness of interventions in the management of LPV. The aim of this paper is to map the literature on the efficacy or effectiveness of physical interventions.Results: The review produced 19 primary studies of physical interventions for LPV. These include acupuncture, laser therapy, physiotherapy, transcutaneous electrical nerve stimulation, low-intensity shockwave therapy, transcranial direct current stimulation, and vestibulectomy.Conclusion: Published studies that investigated a range of physical treatments for LPV showed some positive effects, except for transcranial direct-current stimulation. The remaining modalities demonstrated improved sexual pain and treatment satisfaction, when measured. Findings were mixed for non-sexual pain. There was insufficient evidence to draw conclusions regarding other outcomes. Researchers are encouraged to conduct larger, high-quality studies that sample more diverse patient populations and use patient-oriented outcomes to assess effectiveness of physical modalities.Keywords: chronic vulvar pain, vestibulodynia, dyspareunia, laser therapy, physiotherapy, physical therapy, acupuncture, vestibulectomy, low-intensity shockwave therapy, transcranial direct-current stimulation, tDCS, transcutaneous electrical nerve stimulation, TENS

Alex Rains,1 Krisztina Bajzak,2 Michelle E Miller,2 Michelle Swab,3 Gabrielle S Logan,4 Victoria A Jackman,5 Diana L Gustafson6 1Department of Medicine, University of Chicago, Chicago, IL, USA; 2Discipline of Obstetrics and Gynecology, Memorial University, St. John’s, Newfoundland & Labrador, Canada; 3Health Sciences Library, Faculty of Medicine, Memorial University, St. John’s, Newfoundland & Labrador, Canada; 4Department of Anesthesiology, Perioperative and Pain Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada; 5Faculty of Medicine, Memorial University, St. John’s, Newfoundland & Labrador, Canada; 6Division of Community Health and Humanities, Faculty of Medicine, Memorial University, St. John’s, Newfoundland & Labrador, CanadaCorrespondence: Alex Rains, Email rainsa@uchicago.eduIntroduction: Localized provoked vulvodynia (LPV) is a chronic condition characterized by pain in the vulvar vestibule, which can be provoked by pressure or touch and which is not tied to a clear underlying cause. Research into the etiology of and most appropriate treatment strategy for LPV is still limited.Methods: Using Arksey and O’Malley’s model for scoping reviews, we evaluated the research question: what is the current evidence regarding the efficacy/effectiveness of multimodal or interdisciplinary interventions for the treatment of LPV? We collated and analyzed articles from 2010 to 2023 to capture the current research landscape.Results: Our review identified 27 studies, which either compared treatments between classes (eg pharmacologic versus psychologic modalities) or described interdisciplinary treatment programs. We identify several trends in the literature. First, outcome measures are inconsistent between studies, often unvalidated, and may not adequately mirror patient concerns. Second, the absence of appropriate comparator groups in many studies restricts providers’ ability to appraise which treatments may be most efficacious. Third, selection bias and demographic homogeneity limit generalizability. Finally, we highlight the need for head-to-head trials of vestibulectomy with other treatments considered first line for vulvodynia management.Conclusion: There is insufficient evidence to suggest the superiority of one treatment modality for LPV relative to others or to recommend a particular interdisciplinary management strategy. Future research should use a head-to-head design where sham control is impossible, incorporate patient-centered outcome measures, and investigate impacts of treatment among diverse samples of LPV patients.Keywords: multidisciplinary, interdisciplinary, multimodal, chronic pain, vulvodynia, dyspareunia

The modified phytochemical derivative, 1,1-bis(3'-indolyl)-1-( p -chlorophenyl) methane (C-DIM12), has been identified as a potential therapeutic platform based on its capacity to improve disease outcomes in models of neurodegeneration and cancer. However, comprehensive safety studies investigating pathology and off-target binding have not been conducted. To address this, we administered C-DIM12 orogastrically to outbred male CD-1 mice for 7 days (50 mg/kg/day, 200 mg/kg/day, and 300 mg/kg/day) and investigated changes in hematology, clinical chemistry, and whole-body tissue pathology. We also delivered a single dose of C-DIM12 (1 mg/kg, 5 mg/kg, 25 mg/kg, 100 mg/kg, 300 mg/kg, 1,000 mg/kg) orogastrically to male and female beagle dogs and investigated hematology and clinical chemistry, as well as plasma pharmacokinetics over 48-h. Consecutive in-vitro off-target binding through inhibition was performed with 10 μM C-DIM12 against 68 targets in tandem with predictive off-target structural binding capacity. These data show that the highest dose C-DIM12 administered in each species caused modest liver pathology in mouse and dog, whereas lower doses were unremarkable. Off-target screening and predictive modeling of C-DIM12 show inhibition of serine/threonine kinases, calcium signaling, G-protein coupled receptors, extracellular matrix degradation, and vascular and transcriptional regulation pathways. Collectively, these data demonstrate that low doses of C-DIM12 do not induce pathology and are capable of modulating targets relevant to neurodegeneration and cancer., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The purpose of this study was to evaluate plasma ondansetron (OND) concentrations in a population of dogs with naturally occurring nausea after oral OND administration. Twenty-four dogs were randomly assigned to receive one of the following doses of oral OND: 0.5 mg/kg q8h, 0.5 mg/kg q12h, 1 mg/kg q8h, or 1 mg/kg q12h. Blood samples for plasma OND measurements were collected at baseline and 2, 4, and 8 h after administration of the first dose of OND. OND concentrations averaged over an 8 h time period were not significantly different between dose groups (0.5 mg/kg group: median 8.5 ng/mL [range 1-96.8 ng/mL], 1 mg/kg group: median 7.4 ng/mL [range 1-278.7 ng/mL]). The mean maximum concentrations in the 0.5 mg/kg and 1 mg/kg groups were 35.8 ± 49.0 ng/mL and 63.3 ± 121.1 ng/mL, respectively. OND concentrations were below the lower limit of quantification (LLOQ) in 50% (18/36) of samples in the 0.5 mg/kg groups and 39% (14/36) of samples in the 1 mg/kg groups. Six dogs (6/24, 25%) did not have OND detected at any time. The mean nausea scores at baseline were similar amongst all groups and decreased over time. The bioavailability of oral OND appears to be poor. Despite low plasma OND concentrations, nausea scores improved over time.

Growing resistance to current antiparasitic medications, both in livestock and in zoological species under human care, makes it imperative to evaluate available drugs on the market, such as eprinomectin. In this prospective study, five males and one female of reticulated ( Giraffa reticulata ; n = 2), Masai ( Giraffa tippelskirchii ; n = 1), Nubian ( Giraffa camelopardalis ; n = 2), and hybrid subspecies ( n = 1) of giraffe, received 1.5 mg/kg eprinomectin topically along the dorsum. Using high-performance liquid chromatography, concentrations of eprinomectin in plasma samples collected at 0, 4, 24, and 48 h, and 7, 14, 21, and 28 d were evaluated following drug administration. Complete blood cell counts and biochemistry panels were performed before ( n = 6) and after ( n = 3) eprinomectin administration. Samples for modified double centrifugal fecal flotation ( n = 6) were evaluated prior to eprinomectin administration to evaluate for endoparasites and were repeated after the study ( n = 5). Noncompartmental pharmacokinetic analysis was applied to the data. The observed maximum plasma concentration was 11.45 ng/ml and the time of observed maximum concentration was 2.67 d. The mean terminal half-life was 5.16 d. No adverse effects were observed related to eprinomectin administration and no blood work changes were observed. Parasite loads decreased ( n = 3) or did not change ( n = 2) after eprinomectin administration. The mean peak plasma concentration of eprinomectin in giraffe was similar to that achieved in cattle, despite using three times the dose.

Purpose: The Coexpression Extrapolation (COXEN) gene expression model with chemotherapy-specific scores [for methotrexate, vinblastine, adriamycin, cisplatin (ddMVAC) and gemcitabine/cisplatin (GC)] was developed to identify responders to neoadjuvant chemotherapy (NAC). We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, progression-free survival (PFS), and overall survival (OS) in patients treated in S1314., Experimental Design: A total of 237 patients were randomized between four cycles of ddMVAC (51%) and GC (49%). On the basis of Affymetrix transcriptomic data, we determined subtypes using three classifiers: TCGA (k = 5), Consensus (k = 6), and MD Anderson (MDA; k = 3) and assessed subtype association with path response to NAC and determined associations with COXEN. We also tested whether each classifier contributed additional predictive power when added to a model based on predefined stratification (strat) factors (PS 0 vs. 1; T2 vs. T3, T4a)., Results: A total of 155 patients had gene expression results, received at least three of four cycles of NAC, and had pT-N response based on radical cystectomy. TCGA three-group classifier basal-squamous (BS)/neuronal, luminal (Lum), Lum infiltrated, and GC COXEN score yielded the largest AUCs for pT0 (0.59, P = 0.28; 0.60, P = 0.18, respectively). For downstaging (