X-ray structure of the metastable SEPT14-SEPT7 coiled coil reveals a hendecad region crucial for heterodimerization.

Septins are membrane-associated, GTP-binding proteins that are present in most eukaryotes. They polymerize to play important roles as scaffolds and/or diffusion barriers as part of the cytoskeleton. α-Helical coiled-coil domains are believed to contribute to septin assembly, and those observed in both human SEPT6 and SEPT8 form antiparallel homodimers. These are not compatible with their parallel heterodimeric organization expected from the current model for protofilament assembly, but they could explain the interfilament cross-bridges observed by microscopy. Here, the first structure of a heterodimeric septin coiled coil is presented, that between SEPT14 and SEPT7; the former is a SEPT6/SEPT8 homolog. This new structure is parallel, with two long helices that are axially shifted by a full helical turn with reference to their sequence alignment. The structure also has unusual knobs-into-holes packing of side chains. Both standard seven-residue (heptad) and the less common 11-residue (hendecad) repeats are present, creating two distinct regions with opposite supercoiling, which gives rise to an overall straight coiled coil. Part of the hendecad region is required for heterodimerization and therefore may be crucial for selective septin recognition. These unconventional sequences and structural features produce a metastable heterocomplex that nonetheless has enough specificity to promote correct protofilament assembly. For instance, the lack of supercoiling may facilitate unzipping and transitioning to the antiparallel homodimeric state.

Structure and Function of the α-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase.

Mupirocin is a clinically important antibiotic produced by a trans-AT Type I polyketide synthase (PKS) in Pseudomonas fluorescens. The major bioactive metabolite, pseudomonic acid A (PA-A), is assembled on a tetrasubstituted tetrahydropyran (THP) core incorporating a 6-hydroxy group proposed to be introduced by α-hydroxylation of the thioester of the acyl carrier protein (ACP) bound polyketide chain. Herein, we describe an in vitro approach combining purified enzyme components, chemical synthesis, isotopic labelling, mass spectrometry and NMR in conjunction with in vivo studies leading to the first characterisation of the α-hydroxylation bimodule of the mupirocin biosynthetic pathway. These studies reveal the precise timing of hydroxylation by MupA, substrate specificity and the ACP dependency of the enzyme components that comprise this α-hydroxylation bimodule. Furthermore, using purified enzyme, it is shown that the MmpA KS0 shows relaxed substrate specificity, suggesting precise spatiotemporal control of in trans MupA recruitment in the context of the PKS. Finally, the detection of multiple intermodular MupA/ACP interactions suggests these bimodules may integrate MupA into their assembly.

Structure and Function of the α-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase.

Mupirocin is a clinically important antibiotic produced by a trans-AT Type I polyketide synthase (PKS) in Pseudomonas fluorescens. The major bioactive metabolite, pseudomonic acid A (PA-A), is assembled on a tetrasubstituted tetrahydropyran (THP) core incorporating a 6-hydroxy group proposed to be introduced by α-hydroxylation of the thioester of the acyl carrier protein (ACP) bound polyketide chain. Herein, we describe an in vitro approach combining purified enzyme components, chemical synthesis, isotopic labelling, mass spectrometry and NMR in conjunction with in vivo studies leading to the first characterisation of the α-hydroxylation bimodule of the mupirocin biosynthetic pathway. These studies reveal the precise timing of hydroxylation by MupA, substrate specificity and the ACP dependency of the enzyme components that comprise this α-hydroxylation bimodule. Furthermore, using purified enzyme, it is shown that the MmpA KS0 shows relaxed substrate specificity, suggesting precise spatiotemporal control of in trans MupA recruitment in the context of the PKS. Finally, the detection of multiple intermodular MupA/ACP interactions suggests these bimodules may integrate MupA into their assembly.

Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin.

Mupirocin is a clinically important antibiotic produced by Pseudomonas fluorescens NCIMB 10586 that is assembled by a complex trans-AT polyketide synthase. The polyketide fragment, monic acid, is esterified by a 9-hydroxynonanoic acid (9HN) side chain which is essential for biological activity. The ester side chain assembly is initialised from a 3-hydroxypropionate (3HP) starter unit attached to the acyl carrier protein (ACP) MacpD, but the fate of this species is unknown. Herein we report the application of NMR spectroscopy, mass spectrometry, chemical probes and in vitro assays to establish the remaining steps of 9HN biosynthesis. These investigations reveal a complex interplay between a novel iterative or "stuttering" KS-AT didomain (MmpF), the multidomain module MmpB and multiple ACPs. This work has important implications for understanding the late-stage biosynthetic steps of mupirocin and will be important for future engineering of related trans-AT biosynthetic pathways (e.g. thiomarinol).

Photovoice exploration of physical activity norms and values among rural and remote pulmonary rehabilitation participants in British Columbia, Canada.

PURPOSE: Individuals with chronic obstructive pulmonary disease (COPD) engage in less physical activity compared to the general population, which can lead to worsened symptoms. In pulmonary rehabilitation (PR) programs, participants learn strategies to complete activities more easily. For such strategies to be effective, however, PR clinicians must understand their clients' activity values and practices within their geocultural contexts. In this qualitative study, our aim was to explore physical activity norms and values among people with COPD living in remote and rural locations, using Photovoice methodology. MATERIALS AND METHODS: We recruited 12 participants from rural PR sites in British Columbia, Canada. During two distinct seasons (winter and summer), participants photographed meaningful activities then completed semi-structured interviews. We analyzed transcripts using a three-step hermeneutic method, which revealed three themes. RESULTS: Participants discussed feeling conflicted regarding their COPD symptoms and physical activity, as difficulties in activity engagement cause stress, but remaining active also fosters a sense of purpose and well-being. Meanwhile, participants' activities are inextricably linked to their rural, remote, and seasonal environment. CONCLUSIONS: Our study provides insight into how people with COPD resiliently engage in activities in a rural environment with distinct weather variations. Findings highlight the importance of considering individual factors when recommending activities in PR programs.Implications for rehabilitationAlthough people with chronic lung disease often encounter difficulty and stress in completing their daily activities, they both recognize the importance of and derive great personal meaning from remaining active.The unique social, geographical, physical, and climatic environments of rural and remote dwelling people with chronic lung disease can both enable and challenge their activity engagement.Pulmonary rehabilitation (PR) programs and clinicians must situate their activity recommendations within the geographic contexts of their clients - which can vary across the seasons.Support for participants' mental health is a vital aspect of PR.

How is resilience conceptualized and operationalized in occupational therapy and occupational science literature? Protocol for a scoping review / Como a resiliência é conceituada e operacionalizada na literatura de ciência ocupacional e terapia ocupacional? Protocolo para uma revisão de escopo

Abstract Introduction Resilience is a commonly discussed term describing the ability to overcome, adapt to, or cope with stressful/disruptive events. Although researchers and practitioners define resilience in diverse ways - e.g., psychological or disaster resilience - the concept fundamentally encompasses perseverance through adversity. As experts in the interplay between individuals, environments, and occupations, occupational therapists and occupational scientists have great potential to understand and enable resilience, with some similar concepts appearing in occupational theories (e.g., occupational adaptation). However, there are no published reviews of resilience in the occupation-focused literature. Objective We will explore how resilience is conceptualized and operationalized in the occupational therapy and occupational science research literature. Method Guided by the Joanna Briggs Institute scoping review methodology, we will search library databases and other sources for relevant records. Two team members will screen records for inclusion, with discrepancies settled by a third person. We will include English-language literature (including research papers, editorials, dissertations, etc.) published since 1990 which 1) contains the word root 'resilien*' and 2) is occupation focused, according to our criteria (occupational therapist/occupational scientist co-authors or research participants; and/or published in occupation-focused periodical). We will report key information of included literature, such as methodology and resilience theories discussed. Results Our study is ongoing at the time of publication; this manuscript reports its protocol without results. Conclusion Findings will be useful for clinicians and researchers looking for occupational conceptualizations of resilience. From a social justice perspective, our review may highlight evidence that occupational engagement can foster resilience among marginalized communities.

Resumo Introdução Resiliência é um termo que descreve a habilidade de superar, adaptar ou lidar com eventos estressantes ou perturbadores. Embora pesquisadores e profissionais definam resiliência de diversas maneiras - como resiliência psicológica ou a desastres - o conceito fundamentalmente engloba perseverança no enfrentamento de adversidades. Como especialistas na interação entre indivíduos, comunidades, ambientes e ocupações, terapeutas ocupacionais e cientistas ocupacionais têm potencial para compreender e propiciar a resiliência, com alguns conceitos semelhantes (como adaptação ocupacional). Entretanto, não há nenhuma revisão publicada sobre resiliência na área. Objetivo Explorar como a resiliência é conceituada e operacionalizada na literatura científica de terapia ocupacional e ciência ocupacional. Método Guiados pela metodologia para revisões de escopo proposta pelo Instituto Joanna Briggs, buscou-se por documentos em bases de dados científicas e outras fontes. Dois membros da equipe revisaram documentos para inclusão e as discrepâncias foram resolvidas por uma terceira pessoa. Utilizou-se literatura em inglês (artigos de pesquisa, editoriais, dissertações etc.) publicada desde 1990 que: (1) contenha 'resilien*' e (2) seja focada na ocupação, desde que: terapeutas ocupacionais ou cientistas ocupacionais fossem coautores ou participantes da pesquisa; e/ou publicada em periódico focado em terapia ocupacional/ciência ocupacional. Foram reportadas as principais informações dos documentos incluídos, como a metodologia e as teorias de resiliência. Resultados Este estudo está em andamento; foca-se aqui no protocolo de pesquisa, sem resultados. Conclusão As discussões serão úteis para profissionais na prática clínica e pesquisadores buscando por uma conceituação ocupacional de resiliência. De uma perspectiva de justiça social, essa revisão pode destacar evidências de que o engajamento com ocupações pode promover resiliência entre comunidades marginalizadas.

Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin.

Mupirocin is a clinically important antibiotic produced by Pseudomonas fluorescens NCIMB 10586 that is assembled by a complex trans-AT polyketide synthase. The polyketide fragment, monic acid, is esterified by a 9-hydroxynonanoic acid (9HN) side chain which is essential for biological activity. The ester side chain assembly is initialised from a 3-hydroxypropionate (3HP) starter unit attached to the acyl carrier protein (ACP) MacpD, but the fate of this species is unknown. Herein we report the application of NMR spectroscopy, mass spectrometry, chemical probes and in vitro assays to establish the remaining steps of 9HN biosynthesis. These investigations reveal a complex interplay between a novel iterative or "stuttering" KS-AT didomain (MmpF), the multidomain module MmpB and multiple ACPs. This work has important implications for understanding the late-stage biosynthetic steps of mupirocin and will be important for future engineering of related trans-AT biosynthetic pathways (e.g. thiomarinol).

Is Female Wellness Affected When Men Blame Them for Erectile Dysfunction?

INTRODUCTION: Several studies have investigated the association between erectile dysfunction (ED), its treatment, and female sexual dysfunction, but the impact of males blaming their female partners for their ED remains unknown. AIMS: To investigate whether women who are blamed by their male partners for their ED experience worse overall sexual function and satisfaction. METHODS: We performed a global, cross-sectional web-based survey to investigate female perceptions of ED. We distributed the 30-item survey via email, Reddit, Amazon Mechanical Turk, and Facebook. Women 18 years of age or older were eligible to participate and answered questions based on a 5-point Likert scale. Women were grouped by ages 18-29, 30-39, and 40 and older. MAIN OUTCOME MEASURES: The survey collected data that included general demographics and questions regarding experiencing male blame for ED and its relationship with each subject's sexual health and wellness. RESULTS: A total of 13,617 females participated in the survey. Of the women surveyed, 79% have experienced their partner losing their erection during sexual activity and approximately 1 out of 7 women (14.7%) had experienced being blamed by their partner for loss of their erection. Women who were blamed for their partner's ED were more likely to end the sexual encounter, were less sexually satisfied, and were more likely to end relationships due to their partner's ED. CONCLUSION: Approximately 1 out of 7 women have experienced male blame for their partner's ED which is associated with negative impacts on female mental health, sexual satisfaction and the success of the overall partnership. Because of its widespread impact on female wellness, male blame should be considered during evaluation of female sexual history and men must be educated on the significant impact their reactions during intimacy have on their female partners and their relationships as a whole. Dubin JM, Wyant WA, Balaji NC, et al. Is Female Wellness Affected When Men Blame Them for Erectile Dysfunction?. Sex Med 2021;9:100352.

Solution Structure and Conformational Dynamics of a Doublet Acyl Carrier Protein from Prodigiosin Biosynthesis.

The acyl carrier protein (ACP) is an indispensable component of both fatty acid and polyketide synthases and is primarily responsible for delivering acyl intermediates to enzymatic partners. At present, increasing numbers of multidomain ACPs have been discovered with roles in molecular recognition of trans-acting enzymatic partners as well as increasing metabolic flux. Further structural information is required to provide insight into their function, yet to date, the only high-resolution structure of this class to be determined is that of the doublet ACP (two continuous ACP domains) from mupirocin synthase. Here we report the solution nuclear magnetic resonance (NMR) structure of the doublet ACP domains from PigH (PigH ACP1-ACP2), which is an enzyme that catalyzes the formation of the bipyrrolic intermediate of prodigiosin, a potent anticancer compound with a variety of biological activities. The PigH ACP1-ACP2 structure shows each ACP domain consists of three conserved helices connected by a linker that is partially restricted by interactions with the ACP1 domain. Analysis of the holo (4'-phosphopantetheine, 4'-PP) form of PigH ACP1-ACP2 by NMR revealed conformational exchange found predominantly in the ACP2 domain reflecting the inherent plasticity of this ACP. Furthermore, ensemble models obtained from SAXS data reveal two distinct conformers, bent and extended, of both apo (unmodified) and holo PigH ACP1-ACP2 mediated by the central linker. The bent conformer appears to be a result of linker-ACP1 interactions detected by NMR and might be important for intradomain communication during the biosynthesis. These results provide new insights into the behavior of the interdomain linker of multiple ACP domains that may modulate protein-protein interactions. This is likely to become an increasingly important consideration for metabolic engineering in prodigiosin and other related biosynthetic pathways.

SAXS reveals highly flexible interdomain linkers of tandem acyl carrier protein-thioesterase domains from a fungal nonreducing polyketide synthase.

Menisporopsin A is a fungal bioactive macrocyclic polylactone, the biosynthesis of which requires only reducing (R) and nonreducing (NR) polyketide synthases (PKSs) to guide a series of esterification and cyclolactonization reactions. There is no structural information pertaining to these PKSs. Here, we report the solution characterization of singlet and doublet acyl carrier protein (ACP2 and ACP1 -ACP2 )-thioesterase (TE) domains from NR-PKS involved in menisporopsin A biosynthesis. Small-angle X-ray scattering (SAXS) studies in combination with homology modelling reveal that these polypeptides adopt a distinctive beads-on-a-string configuration, characterized by the presence of highly flexible interdomain linkers. These models provide a platform for studying domain organization and interdomain interactions in fungal NR-PKSs, which may be of value in directing the design of functionally optimized polyketide scaffolds.

Structure of the Human Cation-Independent Mannose 6-Phosphate/IGF2 Receptor Domains 7-11 Uncovers the Mannose 6-Phosphate Binding Site of Domain 9.

The cation-independent mannose 6-phosphate (M6P)/Insulin-like growth factor-2 receptor (CI-MPR/IGF2R) is an ∼300 kDa transmembrane protein responsible for trafficking M6P-tagged lysosomal hydrolases and internalizing IGF2. The extracellular region of the CI-MPR has 15 homologous domains, including M6P-binding domains (D) 3, 5, 9, and 15 and IGF2-binding domain 11. We have focused on solving the first structures of human D7-10 within two multi-domain constructs, D9-10 and D7-11, and provide the first high-resolution description of the high-affinity M6P-binding D9. Moreover, D9 stabilizes a well-defined hub formed by D7-11 whereby two penta-domains intertwine to form a dimeric helical-type coil via an N-glycan bridge on D9. Remarkably the D7-11 structure matches an IGF2-bound state of the receptor, suggesting this may be an intrinsically stable conformation at neutral pH. Interdomain clusters of histidine and proline residues may impart receptor rigidity and play a role in structural transitions at low pH.

A Priming Cassette Generates Hydroxylated Acyl Starter Units in Mupirocin and Thiomarinol Biosynthesis.

Mupirocin, a commercially available antibiotic produced by Pseudomonas fluorescens NCIMB 10586, and thiomarinol, isolated from the marine bacterium Pseudoalteromonas sp. SANK 73390, both consist of a polyketide-derived monic acid homologue esterified with either 9-hydroxynonanoic acid (mupirocin, 9HN) or 8-hydroxyoctanoic acid (thiomarinol, 8HO). The mechanisms of formation of these deceptively simple 9HN and 8HO fatty acid moieties in mup and tml, respectively, remain unresolved. To define starter unit generation, the purified mupirocin proteins MupQ, MupS, and MacpD and their thiomarinol equivalents (TmlQ, TmlS and TacpD) have been expressed and shown to convert malonyl coenzyme A (CoA) and succinyl CoA to 3-hydroxypropionoyl (3-HP) or 4-hydroxybutyryl (4-HB) fatty acid starter units, respectively, via the MupQ/TmlQ catalyzed generation of an unusual bis-CoA/acyl carrier protein (ACP) thioester, followed by MupS/TmlS catalyzed reduction. Mix and match experiments show MupQ/TmlQ to be highly selective for the correct CoA. MacpD/TacpD were interchangeable but alternate trans-acting ACPs from the mupirocin pathway (MacpA/TacpA) or a heterologous ACP (BatA) were nonfunctional. MupS and TmlS selectivity was more varied, and these reductases differed in their substrate and ACP selectivity. The solution structure of MacpD determined by NMR revealed a C-terminal extension with partial helical character that has been shown to be important for maintaining high titers of mupirocin. We generated a truncated MacpD construct, MacpD_T, which lacks this C-terminal extension but retains an ability to generate 3-HP with MupS and MupQ, suggesting further downstream roles in protein-protein interactions for this region of the ACP.

Attachment, Parenting, and Obesogenic Behavior: A Dyadic Perspective.

Pediatric obesity is a growing health concern afflicting the United States. The treatment for pediatric obesity, as a health epidemic, costs billions of dollars to our nation, leaving providers and researchers searching for effective and sustainable ways to better manage the biological, psychological, and social health of individuals and families. While many assessments and interventions continue to emerge, researchers have predominately focused on intra-individual concerns among white non-Hispanic populations. This quantitative study was grounded in a relational theory (attachment theory), with a dyadic and primarily Hispanic sample. Evidence from our study supported that child attachment predicted child obesogenic behavior and that this relationship was mediated by child self-regulation. Children with insecure attachments had more obesogenic behaviors and lower self-regulation of eating than those with secure attachments. Family therapists should be on the frontlines of relational research and clinical interventions that interface with biopsychosocial health across diverse cultures and families.

Evaluation of Indicators of Female Sexual Dysfunction in Adult Entertainers.

INTRODUCTION: Female sexual dysfunction (FSD) incorporates a wide range of sexual issues within the female population; however, it has not been evaluated among female adult entertainers. AIM: To evaluate the prevalence of FSD in women working in the adult entertainment industry. METHODS: A 53-question online survey was distributed to female adult entertainers via e-mail through collaboration with the Free Speech Coalition, the North American Trade Association of the Adult Industry. Surveys were sent by the Free Speech Coalition to those within the Performer Availability Screening Services database who met the criteria of having biological vaginas and having experience as adult entertainers. The surveys were answered anonymously. Statistical analysis was performed with Stata/IC 15.1. MAIN OUTCOME MEASURES: The survey acquired baseline characteristics, use of contraceptives, sexual activity, work vs home sexual satisfaction, and orgasm, in addition to evaluation of female sexual function using the Female Sexual Function Index survey, with a total score <26.55 indicative of FSD. RESULTS: Of the 147 respondents, 96 (65%) met inclusion criteria of adequately completing the survey, having a biological vagina, and working in the adult entertainment industry. The mean age was 34.1 ± 10.3 years (range 20-66). The average Female Sexual Function Index score was 28.7 ± 5.6, and 24.0% (23 of 96) of entertainers had scores indicative of FSD. Overall, women found their personal sex lives more satisfying when compared with their professional sex lives (3.99 ± 1.40 vs 3.08 ± 1.52, P < .01). When comparing women with FSD to those without FSD, women with FSD had less sexual satisfaction at home (2.8 ± 1.7 vs 4.4 ± 1.0, P < .01), fewer overall sexual events (7.0 ± 6.7 FSD vs 12.9 ± 10.0 non-FSD, P < .01), and fewer satisfying sexual events overall (3.3 ± 4.2 vs 10.7 ± 8.7, P < .01). CLINICAL IMPLICATIONS: FSD is prevalent among all women, including those within the adult entertainment industry, and must be addressed during patient interactions. STRENGTH & LIMITATION: This is the first study to evaluate the novel group of female adult entertainers. Despite this novel population, the study size is rather small and is susceptible to response bias. CONCLUSION: FSD appeared to be less prevalent among female adult entertainers than rates commonly quoted for the general population and was more often seen in the women with less satisfying personal sex lives. Dubin JM, Greer AB, Valentine C, et al. Evaluation of Indicators of Female Sexual Dysfunction in Adult Entertainers. J Sex Med 2019;16:621-623.

The molecular basis of protein toxin HicA-dependent binding of the protein antitoxin HicB to DNA.

Toxin-antitoxin (TA) systems are present in many bacteria and play important roles in bacterial growth, physiology, and pathogenicity. Those that are best studied are the type II TA systems, in which both toxins and antitoxins are proteins. The HicAB system is one of the prototypic TA systems, found in many bacterial species. Complex interactions between the protein toxin (HicA), the protein antitoxin (HicB), and the DNA upstream of the encoding genes regulate the activity of this system, but few structural details are available about how HicA destabilizes the HicB-DNA complex. Here, we determined the X-ray structures of HicB and the HicAB complex to 1.8 and 2.5 Å resolution, respectively, and characterized their DNA interactions. This revealed that HicB forms a tetramer and HicA and HicB form a heterooctameric complex that involves structural reorganization of the C-terminal (DNA-binding) region of HicB. Our observations indicated that HicA has a profound impact on binding of HicB to DNA sequences upstream of hicAB in a stoichiometric-dependent way. At low ratios of HicA:HicB, there was no effect on DNA binding, but at higher ratios, the affinity for DNA declined cooperatively, driving dissociation of the HicA:HicB:DNA complex. These results reveal the structural mechanisms by which HicA de-represses the HicB-DNA complex.

Biopsychosocial Management of Female Sexual Dysfunction: A Pilot Study of Patient Perceptions From 2 Multi-Disciplinary Clinics.

BACKGROUND: Sexual dysfunction is often complex and biopsychosocial. Traditional sexual health care management involves individual providers not in a multi-disciplinary setting. A multi-disciplinary team may consist of a medical provider, pelvic floor physical therapist, and sex therapist. AIM: The aim was to explore the patient perceptions of benefit from management of their sexual dysfunction by a biopsychosocial multi-disciplinary team. METHODS: A survey was e-mailed to women patients seen by multi-disciplinary teams at 2 different settings: San Diego Sexual Medicine or Mayo Clinic Women's Health Clinic during a 27-month period. Data are reported using summary statistics for age and count for remaining survey responses. Cochran-Armitage tests for trend were used to compare pre- and post-comfort levels. OUTCOMES: Main outcome measures included perceived benefit of being managed in a team-based model of care, level of benefit and satisfaction from each provider, and difference from pre-conceived level of comfort to actual comfort after each provider visit. RESULTS: 89 of 270 e-mailed surveys were analyzed. Patient populations (mean age 47.6, range 23-77 years) were similar between sites. Overall, 82% of respondents reported moderate/great benefit from the team-based model; 72.1% reported management by all 3 providers valuable/extremely valuable; and 84.3% were somewhat/very satisfied with the model. Women endorsed specific ways in which they benefitted from the team-based model including: improved sexual function (58.1%), feeling validated (72.1%) and listened to (62.8%), that they better understood their health concerns (65.1%), that their partner better understood their health concerns (46.5%), and feeling normal (46.5%). There were no significant differences between the 2 clinics in terms of patient-perceived benefit, value, or satisfaction. CONCLUSIONS: The team-based model of care for management of sexual dysfunction in women including a medical provider, physical therapist, and sex therapist is associated with patient-perceived benefit, satisfaction, and value. Rullo J, Faubion S, Hartzell R, et al. Biopsychosocial Management of Female Sexual Dysfunction: A Pilot Study of Patient Perceptions From 2 Multi-Disciplinary Clinics. Sex Med 2018;6:217-223.

Improvements to the Vulva, Vestibule, Urethral Meatus, and Vagina in Women Treated With Ospemifene for Moderate to Severe Dyspareunia: A Prospective Vulvoscopic Pilot Study.

INTRODUCTION: Ospemifene, an oral selective estrogen receptor modulator approved for the treatment of mild to moderate dyspareunia from menopause, has been shown to moderate sexual pain and vaginal epithelial cell characteristics. However, no prospective vulvoscopic studies have been performed. AIM: To examine, in menopausal women taking ospemifene 60 mg daily, changes to the vulva, vestibule, urethral meatus, and vaginal region over 20 weeks using vulvoscopy in a prospective open-label pilot study. METHODS: Vulvoscopic photographs taken at screening and the end of therapy assessed for changes in the appearance of the vulva, vestibule, urethral meatus, and vagina rated by a single reviewer using a 10-parameter Likert rating scale, the Vulvoscopic Genital Tissue Appearance Scale (VGTA). In addition, the cotton-tipped swab test and subject diary scores were assessed over the 20-week treatment period and compared before and after the intervention using Wilcoxon signed-rank test. MAIN OUTCOME MEASURE: Changes in VGTA score from baseline to end of study. RESULTS: 8 subjects (age = 59 ± 4.7 years) completed all visits and were included in the analysis of vulvoscopic photographs (n = 258). There were significant changes during the study period for urethral meatal prominence, introital stenosis, vestibular pallor, vestibular erythema, mucosal moisture, vaginal rugation, and anterior wall prominence (P < .05). Total pain score during cotton-tipped swab testing decreased from 11 (interquartile range = 10-16) before the intervention to 1 (interquartile range = 0-3) at the end of the study. Quantitative diary analysis indicated an increase in the number of sexual events, decrease in rates of pain during foreplay and intercourse, and decrease in use of lubricant at study completion (P < .05). CONCLUSIONS: Ospemifene 60 mg daily for 20 weeks showed improvement in physical examination findings in this prospective study of menopausal women with dyspareunia, as documented on vulvoscopic photography. These changes were consistent with improvements in subject-reported pain and sexual function. Goldstein SW, Winter AG, Goldstein I. Improvements to the Vulva, Vestibule, Urethral Meatus, and Vagina in Women Treated With Ospemifene for Moderate to Severe Dyspareunia: A Prospective Vulvoscopic Pilot Study. Sex Med 2018;6:154-161.

Treatment Effects of WST11 Vascular Targeted Photodynamic Therapy for Urothelial Cell Carcinoma in Swine.

PURPOSE: Surgical management of upper tract urothelial carcinoma requires kidney and ureter removal, compromising renal function. Nonsurgical alternatives have potentially prohibitive safety concerns. We examined the feasibility and safety of ablation of the ureter and renal pelvis using endoluminal vascular targeted photodynamic therapy in a porcine model. We also report the efficacy of WST11 vascular targeted photodynamic therapy in a murine model. MATERIALS AND METHODS: After receiving approval we performed a total of 28 endoluminal ablations in the ureters and renal pelvis of 18 swine. Intravenous infusion of WST11 (4 mg/kg) followed by 10-minute laser illumination was done via percutaneous access or a retrograde ureteroscopic approach. Animals were followed clinically with laboratory testing, imaging and histology, which were evaluated at several postablation time points. A murine xenograft was created with the 5637 human urothelial cell carcinoma line to determine sensitivity to this therapy. RESULTS: At 24 hours 50 mW/cm laser fluence produced superficial necrosis of the ureter. Deeper necrosis penetrating the muscularis propria or adventitia was produced by treatment with 200 mW/cm in the ureter and the renal pelvis. At 4 weeks superficial urothelium had regenerated over the treatment site. No symptomatic obstruction, clinically relevant hydronephrosis or abnormality of laboratory testing was noted up to 4 weeks. Of the mice 80% had no evidence of tumor 19 days after WST11 vascular targeted photodynamic therapy. CONCLUSIONS: Urothelial cell carcinoma appears to be sensitive to WST11 vascular targeted photodynamic therapy. The depth of WST11 vascular targeted photodynamic therapy treatment effects can be modulated in a dose dependent manner by titrating light intensity. Moreover, when applied to the porcine upper urinary tract, this treatment modality is feasible via antegrade and retrograde access.

Bilateral adrenal hemorrhage due to heparin-induced thrombocytopenia following partial nephrectomy - a case report.

Heparin-induced thrombocytopenia (HIT) can cause severe life-threatening events such as bilateral adrenal hemorrhage (BAH). A 48-year-old female developed a pulmonary embolus (PE) following partial nephrectomy. The anticoagulation treatment for her PE was complicated by HIT and subsequent BAH. To the author's knowledge, this is the first reported case of HIT-associated BAH following renal surgery.