Aisling A. Clancy

Methodological Rigor in Preclinical Cardiovascular Studies: Targets to Enhance Reproducibility and Promote Research Translation

Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.

Methodological Rigor in Preclinical Cardiovascular Studies

Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.

The forgotten woman's cancer: vulvar squamous cell carcinoma (VSCC) and a targeted approach to therapy

BACKGROUND The incidence of vulvar squamous cell carcinoma (VSCC) has been on the rise since the 1990s. There has been no new treatment for advanced and recurrent disease in decades, with most women succumbing to the disease. Despite two distinct etiologies of VSCC, human papillomavirus (HPV)-associated and HPV-independent disease, there is no difference in therapeutic options. METHODS A literature review was carried out by searching EMBASE and Medline databases between January 1990 and March 2016 by pairing the keywords of vulvar carcinoma, vulva cancer, vulvar and vulva with molecular markers involved in the cell cycle, apoptosis and angiogenesis. Molecular targets of prognostic significance were identified and targeted agents of therapeutic relevance to both HPV-independent and HPV-associated VSCC were then reviewed. RESULTS Recent advances in our understanding of the molecular biology of VSCC provide insight into the future management of VSCC with molecular targeted therapies. Aberrant cell cycle activity is common in both HPV-associated and HPV-independent VSCC and is characterized by overexpression of p53, Rb and cyclin D1, supporting targeting of these protein products and their downstream pathways. Extracellular regulators of cellular activity, such as EGFR, as well as inhibitors of angiogenesis are being clinically evaluated in VSCC. HPV-independent VSCC is characterized by actionable mutations, including PI3K, CDKN2A and PTEN. In HPV-associated disease, therapeutic vaccines targeting the E6 and E7 HPV oncogenes and immune-based therapies are under investigation. CONCLUSION There has been a paucity of clinical trials in recent years in this neglected womens cancer. Directed therapy against cell cycle regulatory molecules and extracellular proteins and the inhibition of angiogenesis are of broad therapeutic relevance in VSCC. Therapeutic strategies that target actionable mutations should be explored. In HPV-associated VSCC, novel treatments that exploit the virology of HPV and/or enhance the host immune response merit further study.

Sex Bias Is Increasingly Prevalent in Preclinical Cardiovascular Research: Implications for Translational Medicine and Health Equity for Women

Ensuring that women are adequately represented in clinical trials is recognized as essential for sex equity in health. However, the use of female animal models and sex-based reporting have not been equally enforced in preclinical stages of research, which often precede and inform clinical trials. In 2014, the National Institutes of Health announced that it would require that sex be considered as a biological variable in applications for preclinical research funding,1 yet a reluctance to include female animal models in preclinical experiments persists. Inappropriately inferring experimental findings to both sexes when a single sex is studied or when sex is not specified has the potential to disadvantage women by skewing our understanding of disease processes toward male-predominant patterns and by reducing the likelihood of female-specific therapeutics advancing to the clinical realm. We therefore systematically examined all preclinical cardiovascular studies published in American Heart Association journals with archives spanning at least 10 years ( Circulation , Circulation Research , Hypertension , Stroke , and Arteriosclerosis, Thrombosis, and Vascular Biology [ ATVB ]) for evidence of sex …

Vulvar squamous cell carcinoma (VSCC) as two diseases: HPV status identifies distinct mutational profiles including oncogenic fibroblast growth factor receptor 3

Purpose: Patients with advanced or recurrent invasive vulvar squamous cell carcinoma (VSCC) have limited treatment options and a grave prognosis. Understanding the genomic landscape may facilitate the identification of new therapies and improve clinical outcomes. Experimental Design: A retrospective chart review and molecular analysis of patients with VSCC from 2000 to 2016 was performed at the Ottawa Hospital Research Institute. The presence of oncogenic human papillomavirus (HPV) was determined by nested PCR and amplified DNA was sequenced using the Ion AmpliSeq Cancer Hotspot v2 Panel. The patients were divided into two groups according to HPV status (HPV-positive versus HPV-negative) and clinical outcome correlated with mutation status using descriptive statistics. Results: In 43 VSCC patients, there was a high mutation rate in both HPV-positive (73%) and HPV-negative (90%) disease with the two subgroups expressing distinct genetic profiles. HPV-positive tumors were characterized by oncogenic mutations in PIK3CA (27%), FGFR3 (14%), and PTEN (9%), whereas HPV-negative tumors were found to have mutations in TP53 (57%), HRAS (24%), PI3KCA (19%), and CDKN2A (14%). Mutation S249C in FGFR3 occurred in 14% of HPV-positive tumors. While there were notable differences in the occurrence of TP53, HRAS, PTEN, and FGFR3 mutations according to HPV status, only the rate of TP53 mutations was statistically significant (P = 0.0004). No significant difference in prognosis was found between patients with HPV-positive and HPV-negative VSCC. Conclusions: HPV-positive VSCC is characterized by oncogenic FGFR3 mutations that helps classify this subtype as a separate disease. Inhibitors of FGFR3 merit consideration as a therapeutic strategy in this neglected cancer in women. Clin Cancer Res; 23(15); 4501–10. ©2017 AACR.

Water-Related Vaginal Injury: A Case Report and Review of the Literature

BACKGROUND Vaginal injury can result from entry of water into the vagina under high pressure. Previously reported cases describe water-jet vaginal injuries in women participating in water-related activities, including: water skiing, personal watercraft use, waterslides, water hose and fountains, with and without foreign body in situ. CASE We describe the case of a severe vaginal laceration and hemorrhage in a 44-year-old female from a high-pressure water-jet generated during a water-ski fall requiring operative repair. Timely management resulted in excellent patient outcome. CONCLUSION A literature review demonstrated that, although uncommon, watersport-related gynaecologic injuries can be life-threatening, and women who regularly engage in watersports can be counselled regarding potential preventative measures. Physicians encountering patients with these injuries should rule out intraperitoneal injury and consider benefits of antibiotics.

Predictors of sling revision after mid-urethral sling procedures: a case-control study

To identify patient characteristics and surgical factors predictive of complications requiring mid‐urethral sling (MUS) revision/removal.

Intrauterine device visualized as extrinsic bladder mass on cystoscopy

A 45-year-old gravida 3 para 3 woman was noted to have an extrinsic bladder mass impinging on the bladder urothelium on cystoscopic assessment for longstanding bladder pain syndrome. Her past surgical history was significant for one cesarean section and a hysteroscopic endometrial resection for heavy menstrual bleeding. Due to recurrence of menorrhagia 4 years after endometrial ablation, she had a levonorgestrel intrauterine system inserted in the office setting without apparent complications and with minimal discomfort. This provided excellent menstrual control for 1 year, but since she had increasing urgency, frequency, and suprapubic pain with a full bladder, cystoscopy was performed to assess for a potentially treatable etiology and for hydrodistension. An extrinsic mass appeared to be protruding from the posterior bladder wall above the level of the trigone and was increasingly prominent with bladder filling. Given her worsening pain symptoms and visualization of the mass on cystoscopy (Fig. 1a), she chose to have the intrauterine device (IUD) removed. The IUD strings were easily visualized on speculum examination and the IUD was removed in the cystoscopy suite immediately following cystoscopy, without significant discomfort or physician effort. Immediately following removal, second-look cystoscopy (Fig. 1b) showed resolution of the mass. Saline infusion sonography (Fig. 2) was performed 3 weeks after IUD removal and a myometrial niche at the level of her previous cesarean section scar was noted. The thickness of the myometrium between the endometrial cavity and the bladder at the niche was 4 mm, and this was felt to be the most likely site of IUD perforation. Two months following IUD removal, she was reassessed and reported a significant improvement in urgency, frequency and suprapubic pain. Previous reports describe contraceptive devices in the bladder which often form secondary stones and require surgical removal [1, 2]. Women often present with urinary symptoms, and proposed mechanisms of bladder perforation include device migration or primary injury at the time of insertion. In the patient reported here the IUD had likely perforated the uterus and compressed the bladder extrinsically, possibly exacerbating urinary symptoms. IUDs are commonly used for the management of menstrual abnormalities and are a popular method of contraception given their high efficacy. Moreover, insertion of levonorgestrel intrauterine system has been reported at the time of hysteroscopic endometrial ablation to provide improved control of heavy menstrual bleeding [3]. Migration of contraceptive devices has been implicated in ureteric obstruction [4] and vesicovaginal fistula [5]. Our case demonstrates the potential contribution of a mispositioned IUD to bladder pain symptoms and the value of cystoscopy for investigation of worsening bladder symptoms. Physicians should be aware of the increased risk of IUD-related complications, such as perforation, in patients with previous uterine surgery. Moreover, in women presenting with lower urinary tract symptoms that may be IUD-related, physicians should consider urinary tract imaging and/or cystoscopy to evaluate for device migration or perforation before attempted removal. * Aisling A. Clancy aclancy@toh.ca

Methodological Rigor in Preclinical Cardiovascular StudiesNovelty and Significance: Targets to Enhance Reproducibility and Promote Research Translation

Rationale: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. Objective: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. Methods and Results: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. Conclusions: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.

Necrotizing Myositis: A Severe Tension-Free Vaginal Tape-Obturator Surgical Site Infection

Surgical removal of tension-free vaginal tape-obturator mesh, with irrigation and debridement of the left adductor compartment, was completed by a urogynaecologist with the assistance of an orthopedic surgeon (Figure 2). Wound cultures demonstrated Streptococcus constellatus and mixed anaerobic flora. Symptoms resolved completely after 4 weeks of intravenous ceftriaxone and metronidazole administration, followed by 3 weeks of oral amoxicillin-clavulanate.