Potential role of physical labor and cultural views of menstruation in high incidence of pelvic organ prolapse in Nepalese women: a comparative study across the menstrual cycle.

Introduction: Pelvic organ prolapse (POP) is a significant health concern for young Nepali women, with potential risk factors including pelvic floor trauma from vaginal delivery and heavy lifting. The prevalence of symptomatic POP (SPOP) among nulliparous women in Nepal is 6%, while the general population of Nepali women aged 15-49 years reports a prevalence of 7%. Surprisingly, the average age of SPOP onset in Nepal is 27 years, challenging the assumption that postmenopausal age and vaginal delivery are the sole risk factors. This study aims to investigate the influence of increased intra-abdominal pressure (IAP) during lifting tasks on pelvic organ descent in Nepali women across different menstrual cycle stages. Methods: The study included 22 asymptomatic Nepali women aged 18-30 years who regularly engage in heavy lifting. Intra-abdominal pressure was measured intra-vaginally during typical and simulated lifting tasks, which encompassed various scenarios such as ballistic lifting, ramped lifting, and pre-contraction of pelvic floor muscles, as well as coughing, Valsalva maneuver, and pelvic floor contractions. Pelvic floor displacement was recorded using transperineal ultrasound during menstruation, ovulation, and the mid-luteal phase. Results: Results indicated that pelvic floor displacement was greater during menstruation than ovulation when performing a simulated ballistic lifting task (6.0 ± 1.6 mm vs. 5.1 ± 1.5 mm, p = 0.03, d = 0.6). However, there was no significant difference in pelvic floor displacement during lifting when the pelvic muscles were pre-contracted. Conclusion: These findings suggest that lifting heavy loads during menstruation may increase the risk of stretching and injuring pelvic floor supportive tissues, potentially contributing to SPOP in young Nepali women. Pre-contracting pelvic floor muscles during lifting tasks may offer a protective effect. Understanding these factors could aid in developing targeted preventive measures and raising awareness about the impact of heavy lifting on pelvic floor health among Nepali women.

A comparison of the binding sites of antibodies and single-domain antibodies.

Antibodies are the largest class of biotherapeutics. However, in recent years, single-domain antibodies have gained traction due to their smaller size and comparable binding affinity. Antibodies (Abs) and single-domain antibodies (sdAbs) differ in the structures of their binding sites: most significantly, single-domain antibodies lack a light chain and so have just three CDR loops. Given this inherent structural difference, it is important to understand whether Abs and sdAbs are distinguishable in how they engage a binding partner and thus, whether they are suited to different types of epitopes. In this study, we use non-redundant sequence and structural datasets to compare the paratopes, epitopes and antigen interactions of Abs and sdAbs. We demonstrate that even though sdAbs have smaller paratopes, they target epitopes of equal size to those targeted by Abs. To achieve this, the paratopes of sdAbs contribute more interactions per residue than the paratopes of Abs. Additionally, we find that conserved framework residues are of increased importance in the paratopes of sdAbs, suggesting that they include non-specific interactions to achieve comparable affinity. Furthermore, the epitopes of sdAbs are only marginally less accessible than those of Abs: we posit that this may be explained by differences in the orientation and compaction of sdAb and Ab CDR-H3 loops. Overall, our results have important implications for the engineering and humanization of sdAbs, as well as the selection of the best modality for targeting a particular epitope.

Pelvic floor muscle length changes with breathing in males: A preliminary report.

The study aimed to identify whether pelvic floor muscles modulate length with breathing, and if any length changes induced by breathing relate to abdominal cavity displacement and intra-abdominal pressure. To investigate these relationships, displacement of pelvic landmarks that related to pelvic floor muscle length using transperineal ultrasound imaging, breath volume, intra-abdominal pressure, abdominal and ribcage displacement, and abdominal and anal sphincter muscle electromyography were measured during quiet breathing and breathing with increased dead-space in ten healthy men. Pelvic floor muscle landmark displacement modulated with ribcage motion during breathing. This relationship was stronger for: i) motion of the urethrovesical junction (puborectalis muscle length change) than the mid-urethra landmark (striated urethral sphincter muscle length change), and ii) dead-space breathing in standing than dead-space breathing in supine or quiet breathing in standing. In most (but not all) participants, the urethrovesical junction descended during inspiration and elevated during expiration. Striated urethral sphincter length changes during the respiratory cycle was independent of intra-abdominal pressure. In summary, breathing involves pelvic floor muscle length changes and is consistent with the role of these muscles during respiration to aid maintenance of continence, lung ventilation and/or provision of support to the abdominal cavity. Clinicians who train pelvic floor muscles need to be aware that length change of pelvic floor muscles is expected with breathing.

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism.

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.

Evidence for increased tone or overactivity of pelvic floor muscles in pelvic health conditions: a systematic review.

OBJECTIVE: Pelvic floor muscle tone, which includes active and passive components, is argued to be increased in many pelvic health conditions, including those involving pain. This study systematically reviewed evidence for increased pelvic floor muscle tone in pelvic health conditions. DATA SOURCES: Electronic databases (PubMed, CINAHL, and Embase) were searched up to May 31, 2021. The search strategy included variants of pelvic and/or floor, muscle, and tone using keywords and Medical Subject Headings (MeSH) terms. STUDY ELIGIBILITY CRITERIA: Studies were included if they investigated increased tone of the pelvic floor muscle and reported measures of active or mechanical properties of the pelvic floor muscle in humans with any pelvic health condition, including pain, bowel, urogenital, or sexual dysfunctions. Studies of any design were included, except systematic and narrative reviews. Reference lists of studies, reviews, and book chapters were searched for additional studies. METHODS: Data were extracted using a standardized form, including measurement tool and outcome measure. Risk of bias was analyzed using a modified ROBINS-I (Risk of Bias In Non-randomized Studies - of Interventions) tool, and a score was allocated to determine whether the study provided "convincing" interpretation (comparison with condition-free control group, valid measure, no application issues). RESULTS: In total, 151 studies were included, reporting 8 different tools (electromyography, dynamometry, manometry, digital palpation, defecography, ultrasound, magnetic resonance imaging, other). The most common pelvic health condition was pelvic pain (n=16 conditions), followed by bowel and urogenital conditions. Most studies (57%) were cross-sectional. A healthy control group was infrequently included for comparison (27%). Unvalidated methods or methods applied in a manner that precluded convincing interpretation were common (94%). Of the 15 measurement tools that provided convincing evidence, 10 demonstrated greater tone in a pelvic health condition (all pain) compared with controls, and 5 showed no difference. CONCLUSION: Despite the large literature, few studies provide convincing evidence for increased tone/overactivity of pelvic floor muscles in pelvic health conditions. Interpretation is hampered by design and measurement issues. Terminology was often inaccurate. Few studies investigate male, transgender, and pediatric groups.

Targeting CD74 in B-cell non-Hodgkin lymphoma with the antibody-drug conjugate STRO-001.

Overexpression of CD74, a type II transmembrane glycoprotein involved in MHC class II antigen presentation, has been reported in many B-cell non-Hodgkin lymphomas (NHLs) and in multiple myeloma (MM). STRO-001 is a site-specific, predominantly single-species antibody-drug conjugate (ADC) that targets CD74 and has demonstrated efficacy in xenograft models of MM and tolerability in non-human primates. Here we report results of preclinical studies designed to elucidate the potential role of STRO-001 in B-cell NHL. STRO-001 displayed nanomolar and sub-nanomolar cytotoxicity in 88% (15/17) of cancer cell lines tested. STRO-001 showed potent cytotoxicity on proliferating B cells while limited cytotoxicity was observed on naïve human B cells. A linear dose-response relationship was demonstrated in vivo for DLBCL models SU-DHL-6 and U2932. Tumor regression was induced at doses less than 5 mg/kg, while maximal activity with complete cures were observed starting at 10 mg/kg. In MCL Mino and Jeko-1 xenografts, STRO-001 starting at 3 mg/kg significantly prolonged survival or induced tumor regression, respectively, leading to tumor eradication in both models. In summary, high CD74 expression levels in tumors, nanomolar cellular potency, and significant anti-tumor in DLBCL and MCL xenograft models support the ongoing clinical study of STRO-001 in patients with B-cell NHL.

Discovery of STRO-002, a Novel Homogeneous ADC Targeting Folate Receptor Alpha, for the Treatment of Ovarian and Endometrial Cancers.

STRO-002 is a novel homogeneous folate receptor alpha (FolRα) targeting antibody-drug conjugate (ADC) currently being investigated in the clinic as a treatment for ovarian and endometrial cancers. Here, we describe the discovery, optimization, and antitumor properties of STRO-002. STRO-002 was generated by conjugation of a novel cleavable 3-aminophenyl hemiasterlin linker-warhead (SC239) to the nonnatural amino acid para-azidomethyl-L-phenylalanine incorporated at specific positions within a high affinity anti-FolRα antibody using Sutro's XpressCF+, which resulted in a homogeneous ADC with a drug-antibody ratio (DAR) of 4. STRO-002 binds to FolRα with high affinity, internalizes rapidly into target positive cells, and releases the tubulin-targeting cytotoxin 3-aminophenyl hemiasterlin (SC209). SC209 has reduced potential for drug efflux via P-glycoprotein 1 drug pump compared with other tubulin-targeting payloads. While STRO-002 lacks nonspecific cytotoxicity toward FolRα-negative cell lines, bystander killing of target negative cells was observed when cocultured with target positive cells. STRO-002 is stable in circulation with no change in DAR for up to 21 days and has a half-life of 6.4 days in mice. A single dose of STRO-002 induced significant tumor growth inhibition in FolRα-expressing xenograft models and patient-derived xenograft models. In addition, combination treatment with carboplatin or Avastin further increased STRO-002 efficacy in xenograft models. The potent and specific preclinical efficacy of STRO-002 supports clinical development of STRO-002 for treating patients with FolRα-expressing cancers, including ovarian, endometrial, and non-small cell lung cancer. Phase I dose escalation for STRO-002 is in progress in ovarian cancer and endometrial cancer patients (NCT03748186 and NCT05200364).

The relationship between pre- and postprostatectomy measures of pelvic floor muscle function and development of early incontinence after surgery.

AIMS: The aim of this study is to investigate (i) whether pelvic floor muscle (PFM) shortening can be enhanced by provision of training focused on striated urethral sphincter (SUS) with feedback before prostatectomy, (ii) whether PFM shortening during voluntary efforts and coughing before and after prostatectomy differs between men who do and do not report symptoms of urinary incontinence 1 month after prostatectomy, and (iii) the relationship between severity of incontinence after prostatectomy and features of pelvic floor function (muscle shortening) and urethral length before and after prostatectomy. METHODS: Sixty men referred for preoperative PFM training before radical prostatectomy participated. The International Continence Society Male Short Form questionnaire was used to quantify continence status. Transperineal ultrasound (US) imaging was used to record pelvic displacements related to activation of striated urethral sphincter, bulbocavernosus (BC) and puborectalis muscles during cough, "natural" voluntary contraction following pamphlet instruction, and trained voluntary contraction after formal physiotherapist instruction including US feedback. RESULTS: Pelvic floor displacements following training differed between continent and incontinent men; continent participants demonstrated increased SUS shortening after training (compared with "natural"), but no difference was observed between trained and "natural" contractions for incontinent participants. Motion at ano-rectal junction during cough was reduced following surgery, but voluntary and involuntary activation of SUS or BC was not consistently affected by surgery. CONCLUSIONS: Participants' capacity to improve function of the SUS with training appears related to postprostatectomy continence outcome.

Validation of shear wave elastography as a noninvasive measure of pelvic floor muscle stiffness.

OBJECTIVES: To investigate the validity of shear wave elastography (SWE) as a measure of stiffness of the puborectalis muscle by examining: (1) the relationship between puborectalis muscle stiffness and pelvic floor muscle (PFM) activation at different intensities; and (2) the relationship between puborectalis stiffness and pelvic floor morphometry during contractions at different intensities. METHODS: Fifteen healthy asymptomatic women performed 6-s isometric PFM contractions at different intensities (0, 10%, 20%, 30%, 50%, 75%, and 100% of maximal voluntary contraction) guided by intravaginal electromyography (EMG). Stiffness of the puborectalis muscle was measured using SWE by calculating the average shear modulus in regions of interest that contained puborectalis muscle fibers parallel to the transducer. Pelvic floor morphometry was assessed in the mid-sagittal plane using transperineal B-mode ultrasound imaging. Shear modulus, EMG (root mean square amplitude) and pelvic floor morphometry parameters were normalized to the value recorded during maximal voluntary contraction. To assess the relationship between stiffness and pelvic floor activation/morphometry, coefficient of determination (r2 ) was calculated for each participant and a group average was computed. RESULTS: Shear modulus and EMG were highly correlated (average r2 ; left 0.90 ± 0.08, right 0.87 ± 0.15). Shear modulus also strongly correlated with bladder neck position (x-axis horizontal coordinates relative to the pubic symphysis), anorectal rectal angle and position, levator plate angle, and antero-posterior diameter of the levator hiatus (average r2 : range 0.62-0.78). CONCLUSIONS: These findings support the validity of SWE to assess puborectalis muscle stiffness in females. Stiffness measures were strongly associated with PFM EMG and pelvic floor morphometry and may be used to indirectly assess the level of activation of the puborectalis muscle without the use of more invasive techniques. By overcoming limitations of current assessment tools, this promising noninvasive and real-time technique could enable important breakthrough in the pathophysiology and management of pelvic floor disorders.

The influence of prostatectomy and body position on location and displacement of pelvic landmarks with pelvic floor muscle contraction.

AIMS: To compare pelvic floor muscle (PFM) anatomy and function (i) between pre- and post-prostatectomy in standing, and (ii) between sitting and standing postprostatectomy. METHODS: Thirty-two men scheduled to undergo a prostatectomy volunteered to participate. Transperineal ultrasound imaging was used to visualize five anatomical pelvic landmarks that have been validated to reflex anatomy and activity of PFMs (pubic symphysis, anorectal junction [ARJ], mid-urethra [MU], bulb of penis [BP], and urethrovesical junction [UVJ]). Both before and after prostatectomy, participants performed three submaximal PFM contractions in sitting and/or standing positions while ultrasound data were recorded. RESULTS: Postprostatectomy the UVJ location was more caudal and dorsal, the ARJ (puborectalis) vector was longer, the BP was more ventral than preprostatectomy, and these landmarks moved less ventrally with contraction. After prostatectomy, the MU, BP, and ARJ were more ventral in standing than sitting. The UVJ was more caudal and elevated more with contraction in standing than sitting after prostatectomy. CONCLUSION: These data demonstrate differences in the anatomy and mechanics of PFMs post- versus pre-prostatectomy, and between sitting and standing positions postprostatectomy. Findings are consistent with surgical changes to the bladder and urethral anatomy. Reduced passive support for the urethra and bladder are likely to may contribute to differences between standing and sitting postprostatectomy.

The repeatability of measurements of male pelvic floor anatomy and function made from transperineal ultrasound images of healthy men and those before and after prostatectomy.

AIMS: To investigate the inter- and intratester repeatability of measurement of the location and displacement of five pelvic landmarks related to pelvic floor muscles with transperineal ultrasound (TPUS) imaging recorded from healthy men and men before and after prostatectomy. METHODS: TPUS images were selected from four different participant groups: healthy men, men awaiting prostatectomy, men 2 weeks after prostatectomy, and men 12 months after prostatectomy. On two separate occasions, two assessors with different levels of experience performed analysis of location and displacement of five pelvic landmarks in images made at rest and during voluntary contraction. A two-way mixed effects, single measurement, absolute agreement intraclass correlation coefficient (ICC) was used to investigate the repeatability. RESULTS: Intertester reliability of all locations at rest for all groups was excellent (ICCs > 0.8) except for the craniocaudal coordinate of the ventral urethrovesical junction for men 2 weeks postprostatectomy and the anorectal junction for men with a cancerous prostate. Intertester reliability of the measurement of landmark displacement was acceptable (>0.5) for the dorsoventral axis of motion but not for the craniocaudal axis of motion for all landmarks across all groups. The more experienced assessor was consistently more repeatable. More deeply placed landmarks were more often excluded from analysis and had poorer reliability. CONCLUSIONS: Analysis of TPUS images across clinical groups is repeatable for both location and displacement of pelvic landmarks related to pelvic floor muscles when measures are made twice. Analysis experience, landmark depth and optimization of ultrasound settings appear to be important factors in reliability.

Novel insight into pressurization of the male and female urethra through application of a multi-channel fibre-optic pressure transducer: Proof of concept and validation.

PURPOSE: To confirm feasibility of recording pressure along the length of the urethra using a multi-sensor fibre-optic pressure catheter; to identify the spatial and temporal features of changes in pressure along the urethra at sites related to specific striated pelvic floor muscles; and to investigate the relationship between urethral pressures and activation of individual pelvic floor muscles estimated from ultrasound imaging. MATERIALS AND METHODS: Proof-of-concept study including one male (47 years old) and one female (33 years old). A multi-sensor fibre optic pressure catheter (10 mm sensor separation) was inserted into the urethra. Pressure data were recorded simultaneously with trans-perineal ultrasound imaging measures of pelvic floor muscle activity during sub-maximal and maximal voluntary contractions and evoked coughs. RESULTS: Pressure changes along the urethra were recorded in all tasks in both participants. Face validity of interpretation of pressure measures with respect to individual muscles was supported by correlation with ultrasound-measured displacements induced by the relevant muscles. Onset of pressure increase occurred in a distal to proximal sequence in the urethra of the male but not the female during voluntary contraction. Peak urethral pressures varied in location, timing and amplitude between tasks. Evoked cough induced in the greatest urethral pressure increase across all tasks for both participants. CONCLUSIONS: The high spatial resolution pressure catheter provide viable and valid recordings of urethral pressure in a male and female. Data provide preliminary evidence of sex differences in spatial and temporal distribution of urethral pressure changes.

Influence of body position on dynamics of the pelvic floor measured with transperineal ultrasound imaging in men.

AIMS: This paper aims to evaluate the feasibility of transperineal ultrasound imaging (TPUS) for visualizing the motion of pelvic landmarks associated with striated pelvic floor muscle contraction in men in standing; to compare the locations of pelvic landmarks between sitting and standing; and to compare the effects of different body positions on measures of pelvic floor muscle contraction. METHODS: Thirty-five men awaiting prostatectomy volunteered to participate. Participants performed three repetitions of submaximal pelvic floor contraction in sitting and again in standing. Movement of pelvic landmarks with contraction was recorded using an ultrasound imaging transducer placed on the perineum. RESULTS: The feasibility of TPUS in men in standing was demonstrated through the visualization of three out of four pelvic landmarks in more than 95% of images in the standing position. Analysis of pelvic landmarks and their respective relationships with muscle shortening demonstrated that the anorectal junction and urethrovesical junction were lower and the estimated length of puborectalis was shorter in standing than sitting. The mid-urethra (striated urethral sphincter) and anorectal junction (puborectalis) landmark displaced further cranially in standing than sitting. CONCLUSIONS: TPUS can be used to visualize three pelvic landmarks in men with cancerous prostates. Puborectalis is shorter at rest in standing than sitting, and elevation of the mid-urethra and the anorectal junction is more in standing than sitting. Together these findings indicate that feedback for pelvic floor muscle training is possible in both positions, but the position needs to be standardized for a comparative assessment.

Comparison of dynamic features of pelvic floor muscle contraction between men with and without incontinence after prostatectomy and men with no history of prostate cancer.

AIM: To compare features of pelvic floor muscle function between men with and without incontinence after prostatectomy and men with no history of prostate cancer. METHODS: The study included men with incontinence postprostatectomy (PPI; n = 20), continent men postprostatectomy (PPC; n = 23) and a control group (CC; n = 20). Transperineal ultrasound imaging recorded motion associated with contraction of the striated urethral sphincter (SUS), puborectalis (PR) and bulbocavernosus (BC) muscles during maximal voluntary contraction (MVC), submaximal efforts, evoked coughing and bearing down. Anatomical landmark displacements were compared between groups and receiver operating characteristics were calculated to determine the threshold displacements that best differentiated PPI and PPC. RESULTS: PPC demonstrated greater SUS, PR, and BC displacement than PPI during MVC (All: P < .01). During cough, PPC had less bladder neck descent (PR lengthening), and greater BC shortening (P = .003) than both PPI and CC. PPC also achieved greater SUS displacement (P = .025) than PPI during cough. The best discrimination between PPI and PPC was achieved when men exceeded threshold displacement for both SUS (≥4.1 mm) and PR (≥2.4 mm) during MVC. The urethral length was not different between PPC and PPI. CONCLUSIONS: Men who were continent postprostatectomy achieved greater shortening of the SUS, PR, and BC muscles than incontinent men during voluntary contractions and demonstrated better PR and BC function than control participants during coughing. The capacity to shorten the SUS ≥4.1 mm and the PR ≥2.4 mm best distinguished between PPI and PPC and might be a useful clinical target for conservative treatment programs.

Reconsideration of pelvic floor muscle training to prevent and treat incontinence after radical prostatectomy.

Urinary incontinence is common after radical prostatectomy. Pelvic floor muscle training provides a plausible solution. Although early trials provided promising results, systematic reviews have questioned the efficacy of this intervention. A major consideration is that most clinical trials in men have applied principles developed for pelvic floor muscle training for stress urinary incontinence in women, despite differences in anatomy between sexes and differences in the mechanisms for continence/incontinence. Literature regarding continence control in men has been conflicting and often based on erroneous anatomy. New understanding of continence mechanisms in men, including the complex contribution of multiple layers of striated pelvic floor muscles, and detailed consideration of the impact of radical prostatectomy on continence anatomy and physiology, have provided foundations for a new approach to pelvic floor muscle training to prevent and treat incontinence after prostatectomy. An approach to training can be designed to target the pathophysiology of incontinence. This approach relies on principles of motor learning and exercise physiology, in a manner that is tailored to the individual patient. The aims of this review are to consider new understanding of continence control in men, the mechanisms for incontinence after radical prostatectomy, and to review the characteristics of a pelvic floor muscle training program designed to specifically target recovery of continence after prostatectomy.

Efficacy of a personalised pelvic floor muscle training programme on urinary incontinence after radical prostatectomy (MaTchUP): protocol for a randomised controlled trial.

INTRODUCTION: Prostate cancer is the most common cancer in men. Prostatectomy is the most common treatment. Morbidity from prostatectomy is high-80% of men experience urinary incontinence which negatively impacts the quality of life. Postsurgical pelvic floor muscle training is commonly prescribed but recent systematic reviews found no evidence of efficacy. We propose a new treatment that commences preoperatively and targets functional training of specific pelvic floor muscles that contribute to urinary continence. Assessment and biofeedback using transperineal ultrasound imaging assists in training. This will be compared against conventional training (maximal pelvic floor muscle contraction assessed by digital rectal examination) and no training. Embedded physiological studies will allow the investigation of moderation and mediation of the treatment effect on the outcomes. METHODS AND ANALYSIS: This randomised clinical trial will include 363 men scheduled to undergo radical prostatectomy for prostate cancer. Participants will be randomised into urethral training, conventional training and no training groups. Clinical data will be collected at baseline (1-2 weeks presurgery) and postsurgery after catheter removal, weekly to 3 months (primary endpoint) and monthly to 12 months. Outcomes include 24-hour pad weight test (primary), incontinence, quality of life and cost-effectiveness data. Neuromuscular control measures of pelvic floor muscles will be measured at baseline, postsurgery, 6 weeks, 3 and 12 months. Study assessors and statisticians will be blinded to the group allocation. ETHICS AND DISSEMINATION: This study is registered with the Australian New Zealand Clinical Trials Registry and has ethical approval from the university and host hospital ethics committees. Trial outcomes will be shared via national/international conference presentations and peer-reviewed journal publications. TRIAL REGISTRATION NUMBER: ACTRN12617000788370; Pre-results.

Neuromotor control during stair ambulation in individuals with patellofemoral osteoarthritis compared to asymptomatic controls.

BACKGROUND: Patellofemoral OA is characterized by PF pain during activities that load a flexed knee. Stair stepping ability is frequently impaired, yet little is known of the muscular recruitment strategies utilized during this task. Altered recruitment strategies may provide targets for clinical interventions. We aimed to determine if people with PFOA ascend and descend stairs with different muscular recruitment strategies compared to similar aged healthy individuals. METHODS: Twenty-two people with PFOA and 20 controls were recruited. Electromyographic recordings from gluteus maximus and medius, medial and lateral hamstrings, vastus medialis and lateralis, medial and lateral gastrocnemius and soleus were acquired during stair ascent and descent. Force plate data was acquired to determine timing of foot placements and characterize dynamic stability. RESULTS: Seventeen people with PFOA (59 ±â€¯10 years, 73 ±â€¯13 kg, 167 ±â€¯9 cm) and 15 controls (57 ±â€¯10 years, 73 ±â€¯16 kg, 171 ±â€¯11 cm) had complete data. People with PFOA demonstrated: longer vastii activation duration during descent (lateralis: p = 0.01; medialis: p = 0.02); earlier onset of vastus lateralis for ascent (p < 0.01) and descent (p = 0.04); earlier onset of soleus in descent (p = 0.04); and shorter duration of GMax during ascent (p = 0.05). Peak Fz timing (time between the start of the anticipatory postural adjustment and the end of the stepping task) was ∼70ms later during stair descent in PFOA compared to controls (p = 0.01). SIGNIFICANCE: People with PFOA utilize muscular activation strategies consistent with minimizing knee pain during stair ambulation. Clinical interventions aimed at gluteal and quadriceps activation may be warranted in PFOA.

Task-specific differences in respiration-related activation of deep and superficial pelvic floor muscles.

The female pelvic floor muscles (PFM) are arranged in distinct superficial and deep layers that function to support the pelvic/abdominal organs and maintain continence, but with some potential differences in function. Although general recordings of PFM activity show amplitude modulation in conjunction with fluctuation in intra-abdominal pressure such as that associated with respiration, it is unclear whether the activities of the two PFM layers modulate in a similar manner. This study aimed to investigate the activation of the deep and superficial PFM during a range of respiratory tasks in different postures. Twelve women without pelvic floor dysfunction participated. A custom-built surface electromyography (EMG) electrode was used to record the activation of the superficial and deep PFM during quiet breathing, breathing with increased dead space, coughing, and maximal and submaximal inspiratory and expiratory efforts. As breathing demand increased, the deep PFM layer EMG had greater coherence with respiratory airflow at the frequency of respiration than the superficial PFM (P = 0.038). During cough, the superficial PFM activated earlier than the deep PFM in the sitting position (P = 0.043). In contrast, during maximal and submaximal inspiratory and expiratory efforts, the superficial PFM EMG was greater than that for the deep PFM (P = 0.011). These data show that both layers of PFM are activated during both inspiration and expiration, but with a bias to greater activation in expiratory tasks/phases. Activation of the deep and superficial PFM layers differed in most of the respiratory tasks, but there was no consistent bias to one muscle layer. NEW & NOTEWORTHY Although pelvic floor muscles are generally considered as a single entity, deep and superficial layers have different anatomies and biomechanics. Here we show task-specific differences in recruitment between layers during respiratory tasks in women. The deep layer was more tightly modulated with respiration than the superficial layer, but activation of the superficial layer was greater during maximal/submaximal occluded respiratory efforts and earlier during cough. These data highlight tightly coordinated recruitment of discrete pelvic floor muscles for respiration.

Activity of Deep and Superficial Pelvic Floor Muscles in Women in Response to Different Verbal Instructions: A Preliminary Investigation Using a Novel Electromyography Electrode.

INTRODUCTION: Verbal instructions are used clinically to encourage activation of the pelvic floor muscles (PFM). Whether separate layers of PFM activate differently in response to instructions remains unknown. AIM: To test the hypotheses that (i) instructions that aimed to bias activity of a specific muscle layer would increase activation of the targeted layer to a greater extent than the other layer, (ii) activity of individual PFM layers would differ between instructions, and (iii) PFM activity would be symmetrical for all instructions. METHOD: PFM electromyography (EMG) was recorded using custom-designed surface electrodes in 12 women without PFM dysfunction. The electrode included 4 pairs of recording surfaces orientated to measure EMG from deep and superficial PFM on each side. 3 submaximal contractions were performed for 5 seconds in response to 7 verbal instructions. Root-mean-squared EMG amplitude was calculated for 1 second during the period when participants most closely matched the target activation level. A repeated-measures anova was used to test whether PFM EMG differed between instructions and between regions. The EMG increase of individual muscles relative to that of the reference muscle [deep/right PFM] was compared to no change with t-tests for single samples. MAIN OUTCOME MEASURE: PFM EMG amplitude. RESULTS: Superficial PFM EMG was greater than deep PFM for all instructions (P = .039). 2 instructions induced the greatest amplitude of EMG for the superficial PFM: "squeeze the muscles around the vaginal opening as if to purse lips of your mouth" and "draw the clitoris in a posterior direction" (P = .036). Asymmetry was found in the deeper PFM in 3 instructions designed to bias the superficial PFM. STRENGTH & LIMITATIONS: This preliminary study recorded activation of deep and superficial PFM layers in females with a custom-designed novel electrode. Some cross-talk of recording between muscle layers is possible but unlikely to impact the major findings. CONCLUSION: Verbal instructions used to teach PFM contractions can influence their pattern of activity. This study provides preliminary evidence that, in a selection of verbal instructions, the superficial PFM activates more than the deep PFM, and that the deep PFM can have asymmetrical activation. Aljuraifani R, Stafford RE, Hall LM, et al. Activity of Deep and Superficial Pelvic Floor Muscles in Women in Response to Different Verbal Instructions: A Preliminary Investigation Using a Novel Electromyography Electrode J Sex Med 2019;16:673-679.

Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001.

STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM.