Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library.

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.

Library Synthesis: Building Block Selection, Handling, and Tracking.

Careful selection and manipulation of small molecule building blocks is crucial to the success of a DNA-encoded library. Building block selection impacts the quality of the hits arising out of a selection assay, while proper sample handling and tracking ensure follow-up synthetic work is done with the appropriate synthetic map in mind. In this chapter, possible strategies for building block selection are outlined, as well as best practices for handling and tracking samples to be used for validation and library synthesis.

Library Synthesis: Building Block Validation.

Completing a validation process to assess the reactivity of potential building blocks that can be included in a DNA-encoded library is important for ensuring the quality of a library. Here we describe the validation method used to assess the reactivity of potential building blocks to be included in a DNA-encoded library, with HATU acylation of carboxylic acid building blocks with an on-DNA amine substrate as an example.

Engaging the Medicinal Chemists of Tomorrow.

The Young Medicinal Chemists Committee (YMCC) is a part of the larger ACS Division of Medicinal Chemistry (MEDI) and was formed to ensure that MEDI meets the needs of all medicinal chemists, including students and early career scientists. There is a clear need to offer additional, specific opportunities to this group of medicinal chemists within the MEDI division. Primary functions of YMCC include facilitating networking and mentorship opportunities, collaborating with international medicinal chemistry societies, and offering social programming for all MEDI members at ACS National Meetings. We are excited to continue to engage students and early career chemists through new initiatives and programming in the future. In this Editorial we highlight current initiatives relevant to early career medicinal chemists and solicit input from the larger medicinal chemistry community.

Clinical and Patient-reported Outcome Measures in Men Referred for Consideration of Surgery to Treat Lower Urinary Tract Symptoms: Baseline Results and Diagnostic Findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM).

BACKGROUND: Clinical evaluation of male lower urinary tract symptoms (MLUTS) in secondary care uses a range of assessments. It is unknown how MLUTS evaluation influences outcome of therapy recommendations and choice, notably urodynamics (UDS; filling cystometry and pressure flow studies). OBJECTIVE: To report participants' sociodemographic and clinical characteristics, and initial diagnostic findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM). UPSTREAM is a randomised controlled trial evaluating whether symptoms are noninferior and surgery rates are lower if UDS is included. DESIGN, SETTING, AND PARTICIPANTS: A total of 820 men (≥18 yr of age) seeking treatment for bothersome LUTS were recruited from 26 National Health Service hospital urology departments. INTERVENTION: Care pathway based on routine, noninvasive tests (control) or routine care plus UDS (intervention arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome is International Prostate Symptom Score (IPSS) and the key secondary outcome is surgery rates 18 mo after randomisation. International Consultation on Incontinence Questionnaires were captured for MLUTS, sexual function, and UDS satisfaction. Baseline clinical and patient-reported outcome measures (PROMs), and UDS findings were informally compared between arms. Trends across age groups for urinary and sexual PROMs were evaluated with a Cuzick's test, and questionnaire items were compared using Pearson's correlation coefficient. RESULTS AND LIMITATIONS: Storage LUTS, notably nocturia, and impaired sexual function are prominent in men being assessed for surgery. Sociodemographic and clinical evaluations were similar between arms. Overall mean IPSS and quality of life scores were 18.94 and 4.13, respectively. Trends were found across age groups, with older men suffering from higher rates of incontinence, nocturia, and erectile dysfunction, and younger men suffering from increased daytime frequency and voiding symptoms. Men undergoing UDS testing expressed high satisfaction with the procedure. CONCLUSIONS: Men being considered for surgery have additional clinical features that may affect treatment decision making and outcomes, notably storage LUTS and impaired sexual function. PATIENT SUMMARY: We describe initial assessment findings from a large clinical study of the treatment pathway for men suffering with bothersome urinary symptoms who were referred to hospital for further treatment, potentially including surgery. We report the patient characteristics and diagnostic test results, including symptom questionnaires, bladder diaries, flow rate tests, and urodynamics.

Macroplastique and Botox are superior to Macroplastique alone in the management of neurogenic vesicoureteric reflux in spinal cord injury population with presumed healthy bladders.

CONTEXT/OBJECTIVE: Vesico-ureteric reflux(VUR) is a known complication of neuropathic bladder in spinal cord injury(SCI) population. Bulking agents such as Macroplastique are new minimally-invasive treatment option for VUR with good results. The aim of this study is to assess the efficacy of Macroplastique alone or in combination with Botox(BTX-A), in managing VUR in SCI population with presumed healthy bladders and correlate the pre-and post-injection urodynamic findings with the outcome. DESIGN: Retrospective comparative study. PARTICIPANTS: SCI patients with VUR and presumed health bladders (normo-compliant, low filling pressures), treated with macroplastique alone or in combination with BTX-A, who had pre and post-intervention Video-urodynamics (VUDS) and followed up for at least 12 months. INTERVENTIONS: Macroplastique and BTX-A injections, VUDS. OUTCOME MEASURES: The primary end point was the overall treatment rate of VUR at 3 months and the secondary outcomes were the success rate (treated + improved) and the comparison of urodynamic parameters (pre-and post-injection). RESULTS: We studied 34 intervention-naïve SCI patients. 19 had only Macroplastique (Group 1) and 15 had Macroplastique and BTX-A (Group 2). The overall treatment rate was 65.4% for group 1 and 88.9% for group 2 (P = 0.029). The overall success rate (treated + improved) was 80.8% and 94.4% respectively (P = 0.123). The comparison of follow up VUDS parameters showed a statistically significant rise in the detrusor pressure of group 1 (34.04cmH2O vs.19.2cmH2O, P = 0.008) and a drop in compliance (19.8mls/cmH2O vs.26.3mls/cmH2O, P = 0.018) as compared to baseline. CONCLUSION: The combination of BTX-A and Macroplastique is more effective that Macroplastique alone in the management of secondary VUR in SCI patients with presumed healthy bladders.

A successful microsurgical approach to treating penile amputation following genital self mutilation.

We present the case of a 33-year-old male who presented to the Emergency Department having amputated his penis as a result of auditory hallucinations triggered by cannabis use. A successful microsurgical technique involving anastomosing the individual structures of the penile shaft enabled a successful cosmetic and functional outcome including restoration of erectile function.

Management of stress urinary incontinence in spinal cord injured female patients with a mid-urethral tape - a single center experience.

Context/Objective Stress urinary incontinence (SUI) affects the quality of life of females with spinal cord injury (SCI), has a negative impact on functional independence and disturbs their psychosocial interaction. Our aim was to assess the efficacy of mid-urethral tapes (MUT) in managing stress urinary incontinence in this population. Design Retrospective cohort study. Participants SCI females with upper motor neuron lesion and urodynamically proven stress or mixed urinary incontinence that was treated with a mid-urethral tape and followed up for at least 12 months. Interventions Mid-urethral tapes such TVT, TOT and mini-Arc. Patient reported outcomes based on the daily use of pads and ICIQ modular questionnaire scores. Outcome measures The primary endpoint was defined as the success rate of MUT surgery in managing stress incontinence at 12. The secondary endpoints included the improvement rate at 12 months, the complication rates and the need for additional treatments. Results 38 females were studied. At 12 months the overall patient reported success rate was 52.6%. 16% reported significant improvement. 68.4% felt the quality of life to improve. Nine patients develop tape related complications (five de novo urgency, one vaginal extrusion, one frequent dysreflexia and one worsening of incontinence). Conclusion Mid-urethral tapes are effective in the management of stress urinary incontinence in female patients with spinal cord injury. There are demonstrable improvements in both continence and quality of life.

Anorectal malformations: what happens in adulthood?

OBJECTIVE: To comprehensively evaluate the outcomes in adults who were born with anorectal malformations (ARMs), to assess the relationships between the major types of ARM and outcomes, and to examine the relationships between bowel and urinary function and sexual well-being, as advances in surgical treatment for ARMs have led to more patients surviving into adult life, and adult data on urinary and bowel function are scant, with even less known about the effect of diagnosis and treatment on sexual and reproductive function. PATIENTS AND METHODS: In all, 74 adult patients with a diagnosis of ARM confirmed by review of paediatric medical records completed a series of validated questionnaires on urinary and bowel function, body esteem, sexual well being, fertility and overall quality of life. RESULTS: There were high levels of urinary and bowel incontinence for both men and women. A high ARM was associated with a greater degree of incontinence. Both men and women scored more poorly than controls on the body esteem, sexual well-being and quality-of-life assessments. Urinary and bowel incontinence was associated with poorer sexual well-being. CONCLUSIONS: Bowel and urinary outcomes in adults appear to be worse than suggested in paediatric reports, with high levels of both urinary and fecal incontinence. Poorer outcomes appeared to affect sexual well-being adversely. To date, attention to issues during transition from childhood to adulthood, particularly concerns about sexual function and well-being, has been conspicuous by its absence. Patient-focused multidisciplinary care during this transition must address these issues, which are central to an acceptable quality of life.

Vaginoplasty.

PURPOSE OF REVIEW: This review summarizes the most recent advances in the field of vaginoplasty. New surgical techniques and recent modifications to existing techniques are included as well as up-to-date outcome data when available. RECENT FINDINGS: It is increasingly clear that vaginal dilation treatment is a successful method of vaginal creation and avoids the risks of surgery. When vaginal dilation is unsuitable or unsuccessful, however, vaginal reconstruction surgery is needed. Most of the novel advances in vaginal reconstruction have been related to the advances made in laparoscopic techniques. It is anticipated that as surgeons become more adept at such procedures, maximally invasive procedures such as intestinal neovagina may be necessary only in a small minority of patients. Autologous vaginal tissue transplantation may also transform this field. Long-term sexual function outcome data are essential for full evaluation and comparison of surgical techniques and the recent literature has begun to include this information. SUMMARY: Vaginal dilation treatment should be the first choice of treatment. If unsuccessful, laparoscopic techniques offer good outcomes and quick recovery. Additional research into the long-term outcomes of sexual satisfaction, orgasm and patient body image is essential, however, to allow a comparison of newer and traditional procedures.