Prevalence of Sexual Function and Vibrator Use Among Urogynecology Patients.

IMPORTANCE: Urogynecology patients often present with sexual dysfunction; limited information on vibrator utilization to improve sexual function in this population exists. OBJECTIVE: The aim of this study was to assess patient knowledge of and receptivity to vibrator use. STUDY DESIGN: We conducted a cross-sectional, survey-based cohort study. The survey included patient characteristics, Pelvic Floor Distress Inventory-20 (PFDI-20), Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire Short Form 12, and vibrator use questions. Our primary outcome was vibrator utilization rates comparing younger (<65) and older (≥65 years) urogynecology patients. RESULTS: Of 213 distributed, 165 (78%) surveys were analyzed. Of these, 104 participants (63%) were aged <65 years and 61 (37%) were ≥65 years. Baseline characteristics were similar between groups (all P's > 0.05). Older patients reported less vibrator utilization than younger patients (30% vs 64%, P ≤ 0.001) and were less likely to be sexually active with a partner (36% vs 62%, P = 0.002) or masturbate (23% vs 51%, P ≤ 0.001). Most patients (76%) thought physicians should discuss vibrators with patients who would like to improve their sexual function with no differences between age groups (71% vs 80%, P = 0.17). Among women receptive to vibrator use, in a multivariable analysis, patients who reported masturbation (odds ratio [OR], 13.8; 95% confidence interval [CI], 2.80-67.71), vibrator use in the past (OR, 24.4; 95% CI, 6.65-89.53), or who believed physicians should discuss vibrators in a clinical setting (OR, 11.66; 95% CI, 2.9-46.81) were more receptive to vibrator use to improve sexual function. Age did not influence receptivity. CONCLUSIONS: Vibrator utilization is greater among younger than older patients. Most urogynecologic patients think health care providers should discuss vibrator use with patients who wish to improve sexual function.

Musical enjoyment does not enhance walking speed in healthy adults during music-based auditory cueing.

BACKGROUND: Rhythmic Auditory Stimulation (RAS) involves synchronizing footsteps to music or a metronome to improve gait speed and stability in patients with neurological disorders, such as Parkinson's disease. However, responses to RAS vary across individuals, perhaps because of differences in enjoyment of the music or in musical abilities. RESEARCH QUESTION: Intuitively, musical enjoyment may influence gait responses to RAS, but enjoyment has not been systematically manipulated nor the effects empirically assessed. In addition, differences in beat perception ability are likely to influence gait responses to music, particularly when synchronizing to the beat. Therefore, we asked: how does music enjoyment alter gait, and do gait parameters differ between individuals with good versus poor beat perception ability, specifically when instructed to 'walk freely' versus 'synchronize to the beat'? METHOD: Young adults and older adults walked on a pressure sensor walkway in silence and to music that they had rated as either high or low in enjoyment, as well as a metronome. All stimuli were presented at 15 % faster than baseline cadence. Participants either walked freely to the music or synchronized to the beat. RESULTS: Music enjoyment had no significant effects on gait in either younger or older adults. Compared to baseline, younger adults walked faster (by taking longer strides) to music than the metronome, whereas older adults walked faster (by taking more steps per minute) to the metronome than music. When instructed to synchronize vs. walk freely, young adults walked faster, but older adults walked slower. Finally, regardless of instruction type, young adults with poor beat perception took shorter and slower strides to the music, whereas older adults with poor beat perception took slower strides to the music. SIGNIFICANCE: Beat perception ability, instruction type, and age affect gait more than music enjoyment does, and thus should be considered when optimizing RAS outcomes.

Vesicovaginal fistula repair at the time of colpocleisis.

INTRODUCTION AND HYPOTHESIS: The objectives of this video are to discuss the presentation, evaluation, and surgical management of a patient with a vesicovaginal fistula at the time of colpocleisis. METHOD: We present the case of an 83-year-old woman with a history of stage IV prolapse who had had a pessary device removed. Urine had been noted to be in the vaginal vault, leading to suspicion of a vesicovaginal fistula. Following evaluation, the patient decided to proceed with surgical management. The patient underwent a vesicovaginal fistula repair with concomitant colpocleisis. A cystoscopy was performed at the conclusion of the case where the bilateral ureteral stents were removed and a strong efflux was noted at both ureteral orifices. RESULTS: At the patient's 1-month follow-up, she had no complaints of prolapse or vaginal leaking. CONCLUSION: Neglect of a vaginal pessary can lead to serious complications, indicating the importance of patient education and careful follow-up. Surgical planning is a key component in effectively managing a vesicovaginal fistula with ureteral presentation in order to preserve ureteral integrity. Concomitant vesicovaginal repair and colpocleisis can be performed safely with effective cure of a vesicovaginal fistula and stage IV prolapse.

Patient injuries and malfunctions associated with robotic prostatectomy: review of the manufacturer and user facility device experience database.

Robotic prostatectomy is the most commonly performed robotic procedure in the United States. Increasing utilization of this procedure necessitates characterization of robot malfunctions and associated patient injuries. We performed a review of adverse events reported to a publicly available database. We searched the Manufacturer and User Facility Device Experience (MAUDE) database for reported adverse events (RAE) involving the intuitive surgical system. Reports involving prostatectomy from 2014 to 2019 were extracted and analyzed for data regarding death, patient injury, and device malfunction. Of 9109 reported adverse events (RAE), 602 were extracted for robotic prostatectomy over the study period. Seven were patient deaths (1.2%), 53 (8.8%) were patient injuries (Table 1), and 542 (90.0%) were malfunctions (Table 2). Malfunctions resulted in 25 aborted cases, 21 open conversions, and 25 laparoscopic conversions (71/542, 13.1%; Fig. 1). Instrument failures comprised the majority (76.4%) of malfunctions. Seven malfunctions (1.3%) resulted in patient injury. The most common device-related injury involved the monopolar curved scissors. No reported deaths were related to robot malfunction. Instrument failures comprise majority of the malfunctions of the Da Vinci robot during robot-assisted laparoscopic prostatectomy. When malfunctions do occur they are usually recoverable and rarely lead to patient injury.

Robotic Surgery for Urologic Deep Infiltrating Endometriosis: A Review and Case Presentations.

Urologic involvement is seen in 1.2-3.9% of women with endometriosis. The bladder (84%) is the most common location of urinary tract endometriosis and the retro-trigone and dome of the bladder are the most frequently affected sites. Ureteral involvement is commonly extrinsic and leads to compression and fibrosis of peri-ureteral tissue, leading to obstruction. Robotic-assisted laparoscopy provides additional advantages of 3D visualization, shorter learning curve compared to conventional laparoscopy, improved dissection in tight pelvic spaces, and facilitation of suturing techniques. In this review, we present the multidisciplinary management of four cases of deep infiltrating endometriosis of the urinary tract in a tertiary referral center of expertise and a review of the literature.

Experimental Mutations in Superoxide Dismutase 1 Provide Insight into Potential Mechanisms Involved in Aberrant Aggregation in Familial Amyotrophic Lateral Sclerosis.

Mutations in more than 80 different positions in superoxide dismutase 1 (SOD1) have been associated with amyotrophic lateral sclerosis (fALS). There is substantial evidence that a common consequence of these mutations is to induce the protein to misfold and aggregate. How these mutations perturb native structure to heighten the propensity to misfold and aggregate is unclear. In the present study, we have mutagenized Glu residues at positions 40 and 133 that are involved in stabilizing the ß-barrel structure of the native protein and a critical Zn binding domain, respectively, to examine how specific mutations may cause SOD1 misfolding and aggregation. Mutations associated with ALS as well as experimental mutations were introduced into these positions. We used an assay in which mutant SOD1 was fused to yellow fluorescent protein (SOD1:YFP) to visualize the formation of cytosolic inclusions by mutant SOD1. We then used existing structural data on SOD1, to predict how different mutations might alter local 3D conformation. Our findings reveal an association between mutant SOD1 aggregation and amino acid substitutions that are predicted to introduce steric strain, sometimes subtly, in the 3D conformation of the peptide backbone.

Loss of charge mutations in solvent exposed Lys residues of superoxide dismutase 1 do not induce inclusion formation in cultured cell models.

Mutations in superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis (fALS) induce the protein to misfold and aggregate. Missense mutations at more than 80 different amino acid positions have been associated with disease. How these mutations heighten the propensity of SOD1 to misfold and aggregate is unclear. With so many mutations, it is possible that more than one mechanism of aggregation may be involved. Of many possible mechanisms to explain heightened aggregation, one that has been suggested is that mutations that eliminate charged amino acids could diminish repulsive forces that would inhibit aberrant protein:protein interactions. Mutations at twenty-one charged residues in SOD1 have been associated with fALS, but of the 11 Lys residues in the protein, only 1 has been identified as mutated in ALS patients. Here, we examined whether loss of positively charged surface Lys residues in SOD1 would induce misfolding and formation of intracellular inclusions. We mutated four different Lys residues (K30, K36, K75, K91) in SOD1 that are not particularly well conserved, and expressed these variants as fusion proteins with yellow fluorescent protein (YFP) to assess inclusion formation. We also assessed whether these mutations induced binding to a conformation-restricted SOD1 antibody, designated C4F6, which recognizes non-natively folded protein. Although we observed some mutations to cause enhanced C4F6 binding, we did not observe that mutations that reduce charge at these positions caused the protein to form intracellular inclusions. Our findings may have implications for the low frequency of mutations at Lys residues SOD1 in ALS patients.

Molecular dynamics simulations of Hsp40 J-domain mutants identifies disruption of the critical HPD-motif as the key factor for impaired curing in vivo of the yeast prion [URE3].

Genetic screens using Saccharomyces cerevisiae have identified an array of Hsp40 (Ydj1p) J-domain mutants that are impaired in the ability to cure the yeast [URE3] prion through disrupting functional interactions with Hsp70. However, biochemical analysis of some of these Hsp40 J-domain mutants has so far failed to provide major insight into the specific functional changes in Hsp40-Hsp70 interactions. To explore the detailed structural and dynamic properties of the Hsp40 J-domain, 20 ns molecular dynamic simulations of 4 mutants (D9A, D36A, A30T, and F45S) and wild-type J-domain were performed, followed by Hsp70 docking simulations. Results demonstrated that although the Hsp70 interaction mechanism of the mutants may vary, the major structural change was targeted to the critical HPD motif of the J-domain. Our computational analysis fits well with previous yeast genetics studies regarding highlighting the importance of J-domain function in prion propagation. During the molecular dynamics simulations several important residues were identified and predicted to play an essential role in J-domain structure. Among these residues, Y26 and F45 were confirmed, using both in silico and in vivo methods, as being critical for Ydj1p function.

Human J-protein DnaJB6b Cures a Subset of Saccharomyces cerevisiae Prions and Selectively Blocks Assembly of Structurally Related Amyloids.

Human chaperone DnaJB6, an Hsp70 co-chaperone whose defects cause myopathies, protects cells from polyglutamine toxicity and prevents purified polyglutamine and Aß peptides from forming amyloid. Yeast prions [URE3] and [PSI(+)] propagate as amyloid forms of Ure2 and Sup35 proteins, respectively. Here we find DnaJB6-protected yeast cells from polyglutamine toxicity and cured yeast of both [URE3] prions and weak variants of [PSI(+)] prions but not strong [PSI(+)] prions. Weak and strong variants of [PSI(+)] differ only in the structural conformation of their amyloid cores. In line with its anti-prion effects, DnaJB6 prevented purified Sup35NM from forming amyloids at 37 °C, which produce predominantly weak [PSI(+)] variants when used to infect yeast, but not at 4 °C, which produces mostly strong [PSI(+)] variants. Thus, structurally distinct amyloids composed of the same protein were differentially sensitive to the anti-amyloid activity of DnaJB6 both in vitro and in vivo. These findings have important implications for strategies using DnaJB6 as a target for therapy in amyloid disorders.

Direct and indirect mechanisms for wild-type SOD1 to enhance the toxicity of mutant SOD1 in bigenic transgenic mice.

Co-expression of wild-type human superoxide dismutase 1 (WT-hSOD1) with ALS mutant hSOD1 accelerates disease onset relative to mice expressing only mutant protein. Here, we analyzed the effect of co-expressed WT-hSOD1 in two established mutant mouse models (L126Z and G37R), and a new model that expresses the first 102 amino acids of SOD1 with mutations at histidines 46, 48 and 63 to eliminate Cu binding (Cu-V103Z). A subset of Cu-V103Z mice developed paralysis between 500 and 730 days. Similar to mice expressing L126Z-SOD1, the spinal cords of this new model showed SOD1 immunoreactive fibrillar inclusions. Co-expression of WT-hSOD1 with Cu-V103Z SOD1 moderately accelerated the age to paralysis, similar in magnitude to WT/L126Z mice. In either combination of these bigenic mice, the severity of fibrillar inclusion pathology was diminished and unreactive to antibodies specific for the C terminus of WT protein. Co-expression of WT-hSOD1 fused to yellow fluorescent protein (WT-hSOD1:YFP) with G37R-hSOD1 produced earlier disease, and spinal cords of paralyzed bigenic mice showed YFP fluorescent inclusion-like structures. In bigenic L126Z/WT-hSOD1:YFP mice, disease was not accelerated and WT-hSOD1:YFP remained diffusely distributed. A combination of split luciferase complementation assays and affinity capture-binding assays demonstrated that soluble G37R-hSOD1 efficiently and tightly bound soluble WT-hSOD1, whereas soluble forms of the Cu-V103Z and L126Z variants demonstrated low affinity. These data indicate that WT-hSOD1 may indirectly augment the toxicity of mutant protein by competing for protective factors, but disease onset seems to be most accelerated when WT-hSOD1 interacts with mutant SOD1 and becomes misfolded.

Hsp40s specify functions of Hsp104 and Hsp90 protein chaperone machines.

Hsp100 family chaperones of microorganisms and plants cooperate with the Hsp70/Hsp40/NEF system to resolubilize and reactivate stress-denatured proteins. In yeast this machinery also promotes propagation of prions by fragmenting prion polymers. We previously showed the bacterial Hsp100 machinery cooperates with the yeast Hsp40 Ydj1 to support yeast thermotolerance and with the yeast Hsp40 Sis1 to propagate [PSI+] prions. Here we find these Hsp40s similarly directed specific activities of the yeast Hsp104-based machinery. By assessing the ability of Ydj1-Sis1 hybrid proteins to complement Ydj1 and Sis1 functions we show their C-terminal substrate-binding domains determined distinctions in these and other cellular functions of Ydj1 and Sis1. We find propagation of [URE3] prions was acutely sensitive to alterations in Sis1 activity, while that of [PIN+] prions was less sensitive than [URE3], but more sensitive than [PSI+]. These findings support the ideas that overexpressing Ydj1 cures [URE3] by competing with Sis1 for interaction with the Hsp104-based disaggregation machine, and that different prions rely differently on activity of this machinery, which can explain the various ways they respond to alterations in chaperone function.

Features of wild-type human SOD1 limit interactions with misfolded aggregates of mouse G86R Sod1.

Mutations in the gene encoding superoxide dismutase 1 (SOD1) account for about 20% of the cases of familial amyotrophic lateral sclerosis (fALS). It is well established that mutations in SOD1, associated with fALS, heighten the propensity of the protein to misfold and aggregate. Although aggregation appears to be a factor in the toxicity of mutant SOD1s, the precise nature of this toxicity has not been elucidated. A number of other studies have now firmly established that raising the levels of wild-type (WT) human SOD1 (hSOD1) proteins can in some manner augment the toxicity of mutant hSOD1 proteins. However, a recent study demonstrated that raising the levels of WT-hSOD1 did not affect disease in mice that harbor a mouse Sod1 gene (mSod1) encoding a well characterized fALS mutation (G86R). In the present study, we sought a potential explanation for the differing effects with WT-hSOD1 on the toxicity of mutant hSOD1 versus mutant mSod1. In the cell culture models used here, we observe poor interactions between WT-hSOD1 and misfolded G86R-mSod1, possibly explaining why over-expression of WT-hSOD1 does not synergize with mutant mSod1 to accelerate the course of the disease in mice.

Role of disulfide cross-linking of mutant SOD1 in the formation of inclusion-body-like structures.

BACKGROUND: Pathologic aggregates of superoxide dismutase 1 (SOD1) harboring mutations linked to familial amyotrophic lateral sclerosis (fALS) have been shown to contain aberrant intermolecular disulfide cross-links. In prior studies, we observed that intermolecular bonding was not necessary in the formation of detergent- insoluble SOD1 complexes by mutant SOD1, but we were unable to assess whether this type of bonding may be important for pathologic inclusion formation. In the present study, we visually assess the formation of large inclusions by fusing mutant SOD1 to yellow fluorescent protein (YFP). METHODOLOGY/PRINCIPAL FINDINGS: Experimental constructs possessing mutations at all cysteine residues in SOD1 (sites 6, 57, 111, and 146 to F,S,Y,R or G,S,Y,R, respectively) were shown to maintain a high propensity of inclusion formation despite the inability to form disulfide cross-links. Interestingly, although aggregates form when all cysteines were mutated, double mutants of the ALS mutation C6G with an experimental mutation C111S exhibited low aggregation propensity. CONCLUSIONS/SIGNIFICANCE: Overall, this study is an extension of previous work demonstrating that cysteine residues in mutant SOD1 play a role in modulating aggregation and that intermolecular disulfide bonds are not required to produce large intracellular inclusion-like structures.