Is size in the eye of the beholder? Visual estimation of penis size among transgender and cisgender people and implications for genital gender-affirming surgery and sexual medicine.

BACKGROUND: Transgender men (TM) seeking gender-affirming phalloplasty and transgender women (TW) seeking vaginoplasty and desiring insertive intercourse must consider penis size. Evidence has shown that, at least among cisgender men (CM), penile dimensions tend to be poorly estimated. In transgender patients desiring gender-affirming surgery, inaccuracy in estimation of penis dimensions may lead to unnecessary morbidity: for TW, trauma to the neovagina; for TM with excess girth, an inability to insert. Studies on the accuracy with which transgender and cisgender patients estimate penis size are limited. AIM: To assess the degree of accuracy with which CM and CW, as well as TM and TW, visually estimate the size of the human penis, including length, width, and girth. METHODS: There were 142 participants included (25 TM, 47 TW, 30 CM, and 40 CW; net mean ± SD age, 36.6 ± 11.2 years). Participants were shown these models and asked to estimate length, width, and midshaft girth by visual inspection of 6 realistic models of a penis and scrotum of varying lengths and widths. We evaluated the accuracy of the visual measurements by comparing mean perceived dimensions with the actual dimensions of each model. OUTCOMES: We used a multivariate model of all 3 bias dimensions to test for differences in average bias among gender groups (CM, CW, TM, and TW). RESULTS: TM significantly overestimated length across the longest models. TW significantly overestimated length in the longer 3 models. All groups except for TM significantly underestimated girth in at least 1 model. No groups significantly underestimated width. CM, CW, and TM significantly overestimated width in all 6 models. CLINICAL IMPLICATIONS: When transgender patients use numbers to express penis size (either in neophallus or vaginal depth based on perceived partner size), the result is likely to be larger than expected. Use of realistic penis models as a decision-making tool may help manage patient expectations and surgery decision making preoperatively and improve postoperative patient satisfaction and safety. STRENGTHS AND LIMITATIONS: To our knowledge, this is the first study to assess visual estimation in penis size in TM and CM, as well as TW and CW. The penile models in our study were shown side by side and in the flaccid state despite having dimensions more consistent with an erect penis, which may have influenced estimations across all dimensions. CONCLUSION: Men and women (cisgender and transgender) tend to significantly overestimate penis length and width.

Shallow-depth vaginoplasty: preoperative goals, postoperative satisfaction, and why shallow-depth vaginoplasty should be offered as a standard feminizing genital gender-affirming surgery option.

BACKGROUND: Shallow-depth vaginoplasty (SDV), also referred to as vaginoplasty without creation of a vaginal canal, is an understudied alternative to full-depth vaginoplasty (FDV), or vaginoplasty with creation of a vaginal canal. SDV is associated with fewer short- and long-term risks and shorter recovery, and does not require a lifelong commitment to vaginal dilation and douching. AIM: To describe a surgical technique for SDV that creates a dimpled introitus, together with clinical outcomes, decision-making prioritization, and satisfaction data. We hypothesize that SDV patients prioritize comparable appearance and sexual function to FDV over shorter-term risk factors, and experience high satisfaction. METHODS: We describe (1) a surgical technique for SDV; (2) the proportion of patients who underwent SDV vs. FDV, with SDV complication rates; and (3) the results of an anonymous, electronic questionnaire administered via Qualtrics that assessed SDV patient demographics, terminology preferences, prioritization of decision-guiding factors for choosing SDV over FDV, and postoperative satisfaction across various domains. OUTCOMES: A total of 110 patients underwent primary feminizing genital gender-affirming surgery at a single institution between April 2017 and July 2022: 35 (32%) of 110 underwent SDV and 75 (68%) underwent FDV. The 35 SDV patients were invited to answer the study questionnaire, of which 29 (83%) completed it (mean age 51.9 ± 16.7 years, mean body mass index 27.3 ± 5.3 kg/m2). RESULTS: All but one survey respondent met one or more of the following characteristics: (1) ≥40 years of age, (2) exclusively feminine-identifying sexual partners, and/or (3) significant aversion to performing long-term vaginal dilation and douching. Ranking of 8 decision-guiding factors revealed prioritization of long-term over short-term outcomes. Postoperatively, patients reported high satisfaction across all 3 domains. When asked if they had to choose between SDV and FDV over again, 86% reported that they would choose SDV. While 14% would choose FDV, all but one reported new interest in receptive vaginal intercourse due to finding masculine-identifying partners post-SDV surgery. A total of 27% of SDV patients experienced complications that required additional surgeries; 82% of complications were related to urinary spraying. CLINICAL IMPLICATIONS: SDV is a lower-risk alternative to FDV and is associated with reduced postoperative maintenance and high postoperative satisfaction. STRENGTHS AND LIMITATIONS: This study describes the clinical outcomes of the largest documented cohort of patients to undergo SDV to date. Limitations include recall bias due to the retrospective survey and use of nonvalidated questions attributed to the paucity of validated gender-affirming surgery questionnaires. CONCLUSION: SDV's appeal to a large subset of patients (32% in this study), low complication rate, high satisfaction, and low decisional regret suggests that this surgical option should be offered to all patients seeking feminizing genital gender-affirming surgery.

Procedures Never Explained in Textbooks: How to Correctly Convert a Closed-Suction Drain to a Closed-Gravity Drain, and How to Correctly Remove a Closed-Suction Drain Off Suction.

Objective: To describe a novel method to convert a closed-system suction drain to a highly efficient closed-system gravity-dependent drain and demonstrate its efficacy in an ex-vivo model. Methods: We reviewed the 5 top-selling urology and surgery text/reference books for information on drainage systems. An ex-vivo model was designed with a reservoir of fluid connected to a Jackson-Pratt bulb drain. We measured the volume of fluid drained from the reservoir into the bulb while on-suction and off-suction. This was repeated using a novel modified bulb, where the bulb's outflow stopper was replaced with a one-way valve oriented to allow release of pressure from the bulb. Results: With the bulb on-suction, drainage was maintained regardless of the height of the drain relative to the reservoir. With the bulb off-suction, closed passive gravity-dependent drainage occurred only when the drain was below the fluid reservoir; drainage ceased at minimal volumes. With addition of a one-way valve and maintenance of the bulb below the level of the reservoir, drainage proceeded to completion. Conclusion: How surgical drains work is not described in the leading urology and general surgery textbooks/reference books. Closed-system suction drains cannot be used to achieve passive gravity-dependent drainage without allowing release of displaced air from the bulb-lumen. The novel modified drain we describe affords reversible closed-system suction and passive drainage.

Penile and Scrotal Skin Measurements to Predict Final Vaginal Depth With Penile Inversion Vaginoplasty.

INTRODUCTION: No nomogram exists to predict maximum achievable neovaginal depth before penile inversion vaginoplasty (PIV) based on available penile & scrotal skin (SS). Maximal depth is important to patients and is determined by available skin and available anatomic space within the pelvis and varies with surgical technique. AIM: We endeavored to create a nomogram to predict expected postoperative vaginal depth. METHODS: Retrospective review of all patients undergoing primary PIV at a single institution from June 2017 to February 2020 (n = 60). Pre-op: Dorsal penile and midline scrotal skin length were measured. Intra-op: Tubularized scrotal skin length measured on a dilator. Immediate post-op: Final vaginal depth measured with a dilator. OUTCOMES: The amount of available penile and scrotal skin was not associated with vaginal depth. The only variable that did significantly increase depth was the use of penile + scrotal skin, as compared to penile skin alone. (P < .001) RESULTS: In patients who underwent PIV-SS, the final vaginal depth (13.3 ± 1.9 cm) was 87% of pre-op measured penile skin length (15.3 ±- 3.0 cm). In patients who underwent PIV+SS, pre-op penile skin length was 11.1 ± 4.7±cm and pre-op midline scrotal length was 22.8 ± 2.6 cm. with a final post-op vaginal canal depth of 15.2 ± 1.3 cm. In 45/46 (98%) surgeries utilizing SS grafts, SS tube length exceeded the length necessary to achieve maximal vaginal depth, and required trimming and discard. Given that in most cases there was an excess of SS, final post-op depth equaled the maximal vaginal depth that could be surgically dissected, and was not limited by the amount of available skin. CLINICAL IMPLICATIONS: Our findings suggest that for most patients it should not be necessary to include additional tissue sources (eg, peritoneum) to create a vaginal canal during primary vaginoplasty. STRENGTHS AND LIMITATIONS: Any penile skin that was discarded due to poor quality (eg, tight phimosis, poor viability) was not measured and accounted for. This likely resulted in a slight overestimation of the contribution of the penile skin to the final vaginal depth, but did not change the overall finding that final depth was not limited by available skin. CONCLUSION: SS grafts, when harvested and tubularized using optimized technique, supplied an excess of skin necessary to line a vaginal canal space of maximal achievable depth. We found that additional tissue sources can, instead, be reserved for future salvage surgery if it becomes necessary to augment depth. Smith SM, Yuan N, Stelmar J, et al. Penile and Scrotal Skin Measurements to Predict Final Vaginal Depth With Penile Inversion Vaginoplasty. Sex Med 2022;10:100569.

A Proposed Inventory to Assess Changes in Orgasm Function of Transgender Patients Following Gender Affirming Treatments: Pilot Study.

INTRODUCTION: While providers generally counsel patients about possible effects of gender affirming treatments, such as gender affirming hormone therapy (GAHT) and gender affirming surgery (GAS), on sexual function - the effects of these treatments on orgasm function and quality are not well understood. AIM: To develop a gender transition orgasm quality inventory based on orgasm function domains transgender patients communicated were important to them. METHODS: We conducted a series of interviews in which we asked transgender patients to describe which factors related to orgasm (ie, orgasm quality and orgasm-related sexual function) were most important to them. This work generated a list of 6 domains which we incorporated into a survey instrument. The 6 domains that our work generated are: (1) Lead-time to reach orgasm, (2) Duration of orgasm, (3) Body location of orgasm sensation; (4) Description of orgasm as either a single or multiple-peak event, (5) Duration of postorgasm refractory period, and (6) Overall satisfaction with orgasm quality. Using this new questionnaire, we queried potential changes in orgasm function before and after commencing GAHT (minimum 1 year) among 130 consecutive transgender women (TW) and 33 transgender men (TM) as a pilot study. RESULTS: Within groups by gender, TW and TM cohorts reported similar responses to our inventory before starting GAHT. After commencing GAHT, TW reported notable changes in orgasm function: increase in lead-time necessary to reach orgasm, orgasm duration, and overall orgasm satisfaction; and decrease in post-orgasm refractory period. Similarly, TM reported an increase in duration of orgasm and increased overall satisfaction with orgasm quality; and a decrease in post-orgasm refractory period. Over half of the TW reported experiencing orgasms in new/additional body locations. Additionally, prior to commencing GAHT, the majority of TM and TW patients reported their orgasms as a short, single-peak event but following GAHT these same patients reported longer and protracted multiple-peak orgasms. CONCLUSION: We have developed a novel questionnaire with the purpose of assessing patient self-reported changes in orgasm function following gender affirming treatments. Findings from our pilot study shows that GAHT has the potential to positively improve sexual function and orgasm quality for transgender patients undergoing gender transition. We encourage future studies to utilize our novel questionnaire to assess potential changes in orgasm function related to various gender affirming procedures. Zaliznyak M, Lauzon M, Stelmar J, et al. A Proposed Inventory to Assess Changes in Orgasm Function of Transgender Patients Following Gender Affirming Treatments: Pilot Study. Sex Med 2022;10:100510.

'Modified Phallourethroplasty' as a Surgical Alternative to Phalloplasty With Urethral Lengthening: Technique, How We Present This Option to Patients, and Clinical Outcomes.

BACKGROUND: Most complications after masculinizing genital gender-affirming surgery (gGAS) are associated with urethral lengthening (+UL). While many transmasculine patients desire +UL for standing urination, not all patients prioritize this benefit over the significantly increased risk of complications. Currently, phalloplasty without UL (-UL) appears to be seldom offered, and previous -UL techniques create genital anatomy that is visibly different from the anatomy created by phallourethroplasty+UL (P+UL). AIM: To describe a novel surgical technique to create a normal-appearing phallus tip, scrotum, and perineal urethral opening that avoids urethral complications associated with +UL. METHODS: We describe our surgical technique and approach to patient counseling. We report patient satisfaction outcomes from the first cohort of patients to undergo this 'modified phallourethroplasty' (-UL) approach to date. OUTCOMES: Among patients who elected phalloplasty over metoidioplasty, 13/40 (32.5%) patients elected P-UL. Prior to 1/2020, before we standardized how we presented this option to patients, 17.4% elected this option. Of the patients that elected P-UL, 8 have completed first-stage and 7 have completed second-stage surgeries. RESULTS: All patients that have undergone P-UL have expressed satisfaction with body image and urinary function. Among patients asked to rank which of 14 preoperative factors were most important (1 = most important, 14 = least important), having a normal-appearing phallus (mean rank 4.14) and minimizing complications (mean rank 8.14) were ranked more highly than ability to urinate in a standing position (mean rank 9.14). When asked what factors most influenced their choice to have -UL (ranked from 1 to 9), elimination of risks was rated the most important (mean rank 2.71) and expected decrease in risk of needing revision surgery was rated the second most important (mean rank 3.57). CLINICAL IMPLICATIONS: The significant reduction in +UL-related complications decrease morbidity, urgent revision surgeries, and cost to our healthcare system. STRENGTHS AND LIMITATIONS: Strengths include a novel technique that provides a surgical alternative to P+UL that eliminates the majority of phalloplasty related postoperative complications. Limitations include the small number of patients who have completed first and second stage surgery, and short follow up time. CONCLUSION: It is important to understand what factors drive individual patients' choices. Patients considering masculinizing gGAS should be offered both +UL and -UL options. The costs and benefits of each option should be presented objectively and in the context of each patient's unique priorities and needs. Smith SM, Yuan N, Lee G, et al. 'Modified Phallourethroplasty' as a Surgical Alternative to Phalloplasty With Urethral Lengthening: Technique, How We Present This Option to Patients, and Clinical Outcomes. Sex Med 2022;10:100495.

Use of Voice Recordings in the Consultation of Patients Seeking Genital Gender-Affirming Surgery: An Opportunity for Broader Application Throughout Surgery?

Introduction: It has been demonstrated that patient memory for medical information is often poor and inaccurate. The use of audio recordings for patient consultation has been described; however, to our knowledge this is the first reported use of audio recordings in consultation for gender-affirming surgery. Our aim was to determine whether, and specifically how, audio recording the consultation of patients presenting for genital gender-affirming surgery would be of benefit to patients. Materials and Methods: We began to offer all new patients the opportunity to have their consultations recorded. At the end of the consultation the recording was uploaded to a USB, which was given to the patient to keep. We then surveyed all patients who had received a copy of their recorded consultation to query the utility of having access to an audio recording of their consultation. Results: 71/72 (98.6%) patients who were given the option to have their consultation recorded chose to do so. 50/71 (70%) of patients who had their consultation recorded responded to our survey. Patients reported that having access to a voice recording of their consultation was beneficial and was viewed overwhelmingly positively. Conclusions: Routine audio recording of patient consultations is highly beneficial to patients, with little cost to providers, and should be considered as a valuable addition to the new patient consultation. This approach may have applications in broader clinical contexts where patients face numerous, complex, and nuanced management options. The study would benefit from continued application and a larger (multi-center, international) sample.

Frailty as predictor of complications in patients undergoing percutaneous nephrolithotomy (PCNL).

INTRODUCTION & OBJECTIVE: Surgical complications are difficult to predict, despite existing tools. Frailty phenotype has shown promise estimating postoperative risk among the elderly. We evaluate the use of frailty as a predictive tool on patients undergoing percutaneous renal surgery. METHODS: Frailty was prospectively analyzed using the Hopkins Frailty Index, consisting of 5 components yielding an additive score: patients categorized not frail, intermediate, or severely frail. Primary outcomes were complications during admission and 30-day complication rate. Secondary outcomes included overall hospital length of stay (LOS) and discharge location. RESULTS: A total of 100 patients recruited, of whom five excluded as they did not need the procedure. A total of 95 patients analyzed; 69, 10, and 16 patients were not frail, intermediate, and severely frail, respectively. There were no differences in blood loss, number of dilations, presence of a staghorn calculus, laterality, or location of dilation. Severely frail patients were likely to be older and have a higher American Society of Anesthesiologists score and Charlson comorbidity index. Patients of intermediate or severe frailty were more likely to exhibit postoperative fevers, bacteremia, sepsis, and require ICU admissions (P < 0.05). Frail patients had a longer LOS (P < 0.001) and tended to require skilled assistance when discharge (p < 0.0001). CONCLUSIONS: Frailty assessment appears useful stratifying those at risk of extended hospitalization, septic complications, and need for assistance following percutaneous renal surgery. Risks of sepsis, bacteremia, and post-operative hemorrhage may be higher in frail individuals. Preoperative assessment of frailty phenotype may give insight into treatment decisions and represent a modifiable marker allowing future trials exploring the concept of "prehabilitation".

Outcomes and Complications After Intervention for Postradiation Prostatic Urethral Stenosis.

OBJECTIVE: To study and report on treatment outcomes after surgical intervention for postradiation prostatic urethral stenosis. METHODS: A retrospective chart review was performed, identifying all patients treated at our institution from July 2014-June 2018 with the ICD-10 code N42.89 for prostatic urethral stenosis. RESULTS: Twenty-two patients were identified with the diagnosis of prostatic urethral stenosis. Patients who had less than 3 months of follow up or etiologies other than postradiation were excluded from analysis. 16 patients were included in the final analysis with an average follow up of 2.6 years (range 3 months to 6.8 years). Average age was 74 years (range 63-84). The average number of interventions performed before referral to a reconstructive urologist was 2.2 (range 0-6). Following referral, an additional 1.2 procedures were performed. Transurethral resection of prostate was the most common intervention, performed in 11 patients; urethroplasty was performed in 2 and the remainder underwent endoscopic incision or dilation. None of the urethroplasty patients required any further intervention for recurrent stenosis. Five patients became severely incontinent and required placement of an artificial urinary sphincter. CONCLUSION: Prostatic urethral stenosis is a rare complication occurring after radiotherapy for prostate cancer. Endoscopic management can be successful in stabilizing patients, while urethroplasty can be feasibly performed in patients with short prostatic apical strictures.

A Comparison of the Assay Sensitivity of Average and Worst Pain Intensity in Pharmacologic Trials: An ACTTION Systematic Review and Meta-Analysis.

Identifying methods to improve assay sensitivity in randomized clinical trials (RCTs) may facilitate the discovery of efficacious pain treatments. RCTs evaluating pain treatments typically use average pain intensity (API) or worst pain intensity (WPI) as the primary efficacy outcome. However, little evidence is available comparing the assay sensitivity of these 2 measures. In this systematic review and meta-analysis, we comprehensively reviewed all low back pain, osteoarthritis pain, fibromyalgia, diabetic peripheral neuropathy pain, and postherpetic neuralgia RCTs that used a parallel group design. Eligibility required: 1) primary RCT report published between 1980 and 2016, 2) comparing 1 or more active, efficacious pharmacologic pain treatment(s) with placebo, and 3) providing data on the standardized effect size (SES) for API as well as WPI for all treatment arms. Twenty-seven active versus placebo comparisons were identified in 23 eligible articles. Using a random-effects meta-analysis, API SES and WPI SES did not differ significantly (difference = -.021, 95% confidence interval = -.047 to .004, P = .12). The findings indicate that, depending on the objectives of the study, either API or WPI could be used as a primary outcome measure in clinical trials for the chronic pain conditions included in this analysis. PERSPECTIVE: Understanding the comparative assay sensitivity of API and WPI may advance pain treatment research. A meta-analysis of trials of efficacious pharmacologic treatments in 5 pain conditions did not show a statistically significant difference between the assay sensitivity of API and WPI.

Research Design Characteristics of Published Pharmacologic Randomized Clinical Trials for Irritable Bowel Syndrome and Chronic Pelvic Pain Conditions: An ACTTION Systematic Review.

Chronic pain conditions occurring in the lower abdomen and pelvis are common, often challenging to manage, and can negatively affect health-related quality of life. Methodological challenges in designing randomized clinical trials (RCTs) for these conditions likely contributes to the limited number of available treatments. The goal of this systematic review of RCTs of pharmacologic treatments for irritable bowel syndrome and 3 common chronic pelvic pain conditions are to: 1) summarize the primary end points and entry criteria, and 2) evaluate the clarity of reporting of important methodological details. In total, 127 RCTs were included in the analysis. The most common inclusion criteria were a minimum pain duration (81%), fulfilling an established diagnostic criteria (61%), and reporting a minimum pain intensity (42%). Primary end points were identified for only 57% of trials. These end points, summarized in this article, were highly variable. The results of this systematic review can be used to inform future research to optimize the entry criteria and outcome measures for pain conditions occurring in the lower abdomen and pelvis, to increase transparency in reporting to allow for proper interpretation of RCT results for clinical and policy applications, and to facilitate the aggregation of data in meta-analyses. PERSPECTIVE: This article summarizes entry criteria and outcome measures and the clarity of reporting of these important design features in RCTs of irritable bowel syndrome and 3 common chronic pelvic pain conditions. These results can be used to improve design of future trials of these largely unaddressed pain conditions.

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations.

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials. PERSPECTIVE: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability.

Reporting of Design Features and Analysis Details in Randomized Clinical Trials of Procedural Treatments for Cancer Pain: An ACTTION Systematic Review.

BACKGROUND AND OBJECTIVES: The objective of this study was to assess the reporting of randomized clinical trials investigating procedural treatments (eg, nerve blocks, targeted drug delivery) for cancer pain, with a focus on aspects that are particularly challenging in these trials. METHODS: This article presents results from a systematic review of reporting of randomized clinical trials of procedural interventions for cancer pain. Articles were identified by searching PubMed from 1966 to June 2014. Data related to quality of reporting are presented for early (1985-2004) and late periods (2005-2014). RESULTS: A total of 35 published trials were included. Approximately two-thirds of the articles clearly indicated the level of blinding. Only 26% reported a primary outcome measure. Less than half explicitly reported the number of patients who completed the trial, and only 1 reported a method that was used to accommodate missing data. Almost one-third of articles included a responder analysis, all of which specified the definition of a responder. CONCLUSIONS: The goal of highlighting these deficiencies in reporting is to promote transparent reporting of details affecting the completion and interpretation of procedural cancer pain trials so that their quality can be more easily evaluated.

Participant Preferences for Pharmacologic Chronic Pain Treatment Trial Characteristics: An ACTTION Adaptive Choice-Based Conjoint Study.

Barriers to clinical trial recruitment can delay study completion, potentially resulting in increased costs and an unrepresentative sample. In the current study of 150 participants with chronic pain, we used a computerized adaptive choice-based conjoint survey that included 8 characteristics that may affect enrollment in pharmacologic pain treatment trials (ie, treatment allocation, frequency of pain ratings, treatment administration method, current medications, number of study visits, availability of evening and weekend visits, invasiveness of laboratory procedures, payment). These data were analyzed using Sawtooth Software ver. 8.4.8 (Sawtooth Software, Inc, Orem, UT), which identifies the characteristics that dominate participants' decisions across multiple sets of potential trials. Three characteristics had the largest relative importance in participants' trial preferences: 1) invasiveness of required laboratory procedures (ie, 22%), with no procedures or blood tests preferred over ice-water sensory testing or skin biopsy; 2) ability to continue current pain medications (21%); and 3) payment for study participation (21%), with higher payment preferred. The fourth most important characteristic was number of study visits (13%), with participants preferring fewer in-person visits and more phone contacts. Understanding the preferences of potential participants is an important step toward enhancing enrollment in pain treatment trials. PERSPECTIVE: This article presents the preferences of individuals with chronic pain conditions regarding modifiable pain treatment trial characteristics (eg, number of study visits, payment, treatment allocation). These findings may help to improve enrollment into analgesic clinical trials and in turn accelerate the development of new pain treatments.

Sustained correction of FVII deficiency in dogs using AAV-mediated expression of zymogen FVII.

Factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder treated by infusion of fresh-frozen plasma, plasma-derived FVII concentrates and low-dose recombinant activated FVII. Clinical data suggest that a mild elevation of plasma FVII levels (>10% normal) results in improved hemostasis. Research dogs with a G96E missense FVII mutation (FVII-G96E) have <1% FVII activity. By western blot, we show that they have undetectable plasmatic antigen, thus representing the most prevalent type of human FVII deficiency (low antigen/activity). In these dogs, we determine the feasibility of a gene therapy approach using liver-directed, adeno-associated viral (AAV) serotype 8 vector delivery of a canine FVII (cFVII) zymogen transgene. FVII-G96E dogs received escalating AAV doses (2E11 to 4.95E13 vector genomes [vg] per kg). Clinically therapeutic expression (15% normal) was attained with as low as 6E11 vg/kg of AAV and has been stable for >1 year (ongoing) without antibody formation to the cFVII transgene. Sustained and supraphysiological expression of 770% normal was observed using 4.95E13 vg/kg of AAV (2.6 years, ongoing). No evidence of pathological activation of coagulation or detrimental animal physiology was observed as platelet counts, d-dimer, fibrinogen levels, and serum chemistries remained normal in all dogs (cumulative 6.4 years). We observed a transient and noninhibitory immunoglobulin G class 2 response against cFVII only in the dog receiving the highest AAV dose. In conclusion, in the only large-animal model representing the majority of FVII mutation types, our data are first to demonstrate the feasibility, safety, and long-term duration of AAV-mediated correction of FVII deficiency.

Reporting of intention-to-treat analyses in recent analgesic clinical trials: ACTTION systematic review and recommendations.

The intention-to-treat (ITT) principle states that all subjects in a randomized clinical trial (RCT) should be analyzed in the group to which they were assigned, regardless of compliance with assigned treatment. Analyses performed according to the ITT principle preserve the benefits of randomization and are recommended by regulators and statisticians for analyses of RCTs. The objective of this study was to determine the frequency with which publications of analgesic RCTs in 3 major pain journals report an ITT analysis and the percentage of the author-declared ITT analyses that include all randomized subjects and thereby fulfill the most common interpretation of the ITT principle. RCTs investigating noninvasive, pharmacologic and interventional (eg, nerve blocks, implantable pumps, spinal cord stimulators, surgery) treatments for pain, published between January 2006 and June 2013 (n=173), were included. None of the trials using experimental pain models reported an ITT analysis; 47% of trials investigating clinical pain conditions reported an ITT analysis, and 5% reported a modified ITT analysis. Of the analyses reported as ITT, 67% reported reasons for excluding subjects from the analysis, and 18% of those listing reasons for exclusion did not do so in the Methods section. Such mislabeling can make it difficult to identify traditional ITT analyses for inclusion in meta-analyses. We hope that deficiencies in reporting identified in this study will encourage authors, reviewers, and editors to promote more consistent use of the term "intention to treat" for more accurate reporting of RCT-based evidence for pain treatments.

NF-κB affects proliferation and invasiveness of breast cancer cells by regulating CD44 expression.

NF-κB plays an important role in cancer initiation and progression. CD44, a cell surface glycoprotein, is involved in many cellular processes including cell adhesion, migration and proliferation. However, whether and how the two molecules interact in breast cancer is not clear. In recent years, the up-regulation of CD44 has served as a marker for tumor initiating cells in breast cancer and other cancer types. Despite the important role of CD44 in cellular processes and cancer, the mechanism underlying CD44 up-regulation in cancers remains poorly understood. Previously, we have identified a novel cis-element, CR1, located upstream of the CD44 promoter. We demonstrated that NF-κB and AP-1 are key trans-acting factors that interact with CR1. Here, we further analyzed the role of NF-κB in regulating CD44 expression in triple negative breast cancer cells, MDA-MB-231 and SUM159. Inhibition of NF-κB by Bay-11-7082 resulted in a reduction in CD44 expression. CD44 repression via NF-κB inhibition consequently decreased proliferation and invasiveness of breast cancer cells. These findings provide not only new insight into the molecular mechanism underlying CD44 regulation but also potential therapeutic targets that may help eliminate chemo- and radiation-resistant cancer cells.

RReACT goes global: perils and pitfalls of constructing a global open-access database of registered analgesic clinical trials and trial results.

Eliminating publication bias requires ensuring public awareness of studies and access to results. Clinical trial registries provide basic trial information, but access to unbiased trial results is inadequate. Nearly all studies of trial registration and results reporting have been limited to the ClinicalTrials.gov registry. We analyzed trial registration, registry functionality, cross-registry harmonization, and results reporting on all 15 primary registries in the World Health Organization International Clinical Trials Registry Platform (ICTRP) for postherpetic neuralgia, painful diabetic neuropathy, and fibromyalgia. A total of 447 unique trials were identified, with 86 trials listed on more than one registry. A comprehensive search algorithm was used to find trial results in the peer-reviewed literature and the grey literature. Creating a global database of registered trials and trial results proved surprisingly difficult for several reasons: (1) ICTRP does not reliably identify trials listed on multiple registries, manual searches are necessary; (2) Searching ICTRP yields different results than searching individual registries; (3) Outcome measure descriptions for multiply registered trials vary between registries; (4) Registry-publication pairings are often inaccurate or incomplete; (5) Grey literature results are not permanent. Overall, only 46% of all trials had results available. Trials registered on ClinicalTrials.gov were significantly more likely to have results (52% vs. 18%, P<0.001), partly due to the ability to post results directly to the registry. In addition to the simple remedy of including trial registration numbers on all meeting abstracts and peer-reviewed papers, specific strategies are offered to facilitate identifying multiply registered studies and ensuring accurate pairing of results and publications.

Discrepancies between registered and published primary outcome specifications in analgesic trials: ACTTION systematic review and recommendations.

The National Institutes of Health released the trial registry ClinicalTrials.gov in 2000 to increase public reporting and clinical trial transparency. This systematic review examined whether registered primary outcome specifications (POS; ie, definitions, timing, and analytic plans) in analgesic treatment trials correspond with published POS. Trials with accompanying publications (n = 87) were selected from the Repository of Registered Analgesic Clinical Trials (RReACT) database of all postherpetic neuralgia, diabetic peripheral neuropathy, and fibromyalgia clinical trials registered at ClinicalTrials.gov as of December 1, 2011. POS never matched precisely; discrepancies occurred in 79% of the registry-publication pairs (21% failed to register or publish primary outcomes [PO]). These percentages did not differ significantly between industry and non-industry-sponsored trials. Thirty percent of the trials contained unambiguous POS discrepancies (eg, omitting a registered PO from the publication, "demoting" a registered PO to a published secondary outcome), with a statistically significantly higher percentage of non-industry-sponsored than industry-sponsored trials containing unambiguous POS discrepancies. POS discrepancies due to ambiguous reporting included vaguely worded PO registration; or failing to report the timing of PO assessment, statistical analysis used for the PO, or method to address missing PO data. At best, POS discrepancies may be attributable to insufficient registry requirements, carelessness (eg, failing to report PO assessment timing), or difficulty uploading registry information. At worst, discrepancies could indicate investigator impropriety (eg, registering imprecise PO ["pain"], then publishing whichever pain assessment produced statistically significant results). Improvements in PO registration, as well as journal policies requiring consistency between registered and published PO descriptions, are needed.

Cell specific CD44 expression in breast cancer requires the interaction of AP-1 and NFκB with a novel cis-element.

Breast cancers contain a heterogeneous population of cells with a small percentage that possess properties similar to those found in stem cells. One of the widely accepted markers of breast cancer stem cells (BCSCs) is the cell surface marker CD44. As a glycoprotein, CD44 is involved in many cellular processes including cell adhesion, migration and proliferation, making it pro-oncogenic by nature. CD44 expression is highly up-regulated in BCSCs, and has been implicated in tumorigenesis and metastasis. However, the genetic mechanism that leads to a high level of CD44 expression in breast cancer cells and BCSCs is not well understood. Here, we identify a novel cis-element of the CD44 directs gene expression in breast cancer cells in a cell type specific manner. We have further identified key trans-acting factor binding sites and nuclear factors AP-1 and NFκB that are involved in the regulation of cell-specific CD44 expression. These findings provide new insight into the complex regulatory mechanism of CD44 expression, which may help identify more effective therapeutic targets against the breast cancer stem cells and metastatic tumors.