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.

Adjuvant Intravesical Chemohyperthermia Versus Passive Chemotherapy in Patients with Intermediate-risk Non-muscle-invasive Bladder Cancer (HIVEC-II): A Phase 2, Open-label, Randomised Controlled Trial.

BACKGROUND: Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital. INTERVENTIONS: Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat. RESULTS: A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51-69%) in the CHT arm and 60% (95% CI 50-68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control). CONCLUSIONS: CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment. PATIENT SUMMARY: The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non-muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment.

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.

Ureteroscopy in patients with spinal cord injury: outcomes from a spinal injury unit and a review of literature.

BACKGROUND: Spinal cord injury (SCI) patients are at increased risk of developing urolithiasis. Ureteroscopic management for stone disease in SCI patients is underreported. Endourologists face many challenges in the management of stone disease in SCI patients including decreased stone free rates (SFR), increased infection risk, increased complication rate, anatomical variation, increased comorbidity level and challenges to nursing care. We present our experience at a regional SCI centre. METHODS: Retrospective data was collected from 2005-2017 from a single SCI unit for patients who underwent ureteroscopy for stone disease. RESULTS: A total of 21 patients underwent 41 procedures, 7 cases being a planned multi-stage approach. Bladder management included sheath catheter, urethral catheter, suprapubic catheter, intermittent self-catheterisation, mitrofanoff, and ileal conduit. Spinal cord level was cervical (71%) or thoracic (29%), with American Spinal Injury Association (ASIA) grade classification A (86%), C (9%) and D (5%). Median follow-up time for patients was 46 months. Average stone size was 27 mm (range, 5-59 mm) access was achieved 98% of patients, with an access sheath used in 63%. The SFR was 47% with a recurrence rate (RR) of 42%. The complication rate was 24% all being Clavien Dindo grade 2. CONCLUSIONS: Ureteroscopy in SCI can be challenging and careful multidisciplinary team planning for intervention is needed. Ureteroscopy offers a useful treatment option for SCI, however, is associated with a lower SFR and greater complication rate compared to that of the general population.

Malignancies of suprapubic catheter (SPC) tracts in spinal cord injury patients: a case series and review of literature.

Introduction: Spinal cord injury (SCI) patients are at increased risk of bladder cancer. A rare variation of this is a malignancy arising or including the suprapubic catheter (SPC) tract. Case series: We present the first case series of malignancy of the SPC tract in SCI patients, including a case of mucinous adenocarcinoma, squamous cell carcinoma and sarcoma. Presentation of patients ranged from bleeding at the site of the SPC to a rapidly growing mass. All three patients were thoroughly investigated, and management was bespoke to the extent of disease and their physiological state at the time of diagnosis. This ranged from extensive surgical intervention including cystectomy, partial sigmoidectomy, excision of the abdominal wall with reconstruction and ileal conduit formation to palliation. Discussion: SCI patients represent 50% of all known published cases of malignancy of the SPC tract. Presentation and diagnosis can be challenging; however, prompt investigation and intervention are essential given the high degree of morbidity and mortality. Routine check of the SPC site may be indicated in those patients in whom the SPC has been present for more than 5 years.

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.

Alpha-blockers for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review and meta-analysis. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS).

AIM: We aimed to systematically assess the evidence on the efficacy and safety of alpha-blockers in patients with multiple sclerosis (MS) suffering from neurogenic lower urinary tract dysfunction (NLUTD). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to perform this systematic review. An electronic search of Cochrane register, Embase, Medline, Scopus (last search 3 March 2018) and screening of reference lists as well as reviews were used to identify the studies. Articles were included if they reported on efficacy/safety of alpha-blockers for the treatment of NLUTD in patients with MS. RESULTS: After screening of 7'015 abstracts, three studies enrolling a total of 50 patients were included: one randomized, placebo-controlled, single-blind trial and two prospective cohort studies. Alpha-blocker treatment was successful in 50% to 96% of the patients. Pooling data from the three included studies, the relative risk for successful alpha-blocker treatment was 3.89 (95% confidence interval 2.7-7.0). The general safety profile of alpha-blockers was favorable with 8% of the patients reporting adverse events. CONCLUSIONS: Alpha-blockers may be effective and safe for treating NLUTD in female and male patients with MS but the studies were small and the overall quality of evidence was low. To make definitive conclusions, well designed randomized controlled trials are highly warranted.

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.

Does urinary cytology have a role in haematuria investigations?

OBJECTIVES: To determine the diagnostic accuracy of urinary cytology to diagnose bladder cancer and upper tract urothelial cancer (UTUC) as well as the outcome of patients with a positive urine cytology and normal haematuria investigations in patients in a multicentre prospective observational study of patients investigated for haematuria. PATIENT AND METHODS: The DETECT I study (clinicaltrials.gov NCT02676180) recruited patients presenting with haematuria following referral to secondary case at 40 hospitals. All patients had a cystoscopy and upper tract imaging (renal bladder ultrasound [RBUS] and/ or CT urogram [CTU]). Patients, where urine cytology were performed, were sub-analysed. The reference standard for the diagnosis of bladder cancer and UTUC was histological confirmation of cancer. A positive urine cytology was defined as a urine cytology suspicious for neoplastic cells or atypical cells. RESULTS: Of the 3 556 patients recruited, urine cytology was performed in 567 (15.9%) patients from nine hospitals. Median time between positive urine cytology and endoscopic tumour resection was 27 (IQR: 21.3-33.8) days. Bladder cancer was diagnosed in 39 (6.9%) patients and UTUC in 8 (1.4%) patients. The accuracy of urinary cytology for the diagnosis of bladder cancer and UTUC was: sensitivity 43.5%, specificity 95.7%, positive predictive value (PPV) 47.6% and negative predictive value (NPV) 94.9%. A total of 21 bladder cancers and 5 UTUC were missed. Bladder cancers missed according to grade and stage were as follows: 4 (19%) were ≥ pT2, 2 (9.5%) were G3 pT1, 10 (47.6%) were G3/2 pTa and 5 (23.8%) were G1 pTa. High-risk cancer was confirmed in 8 (38%) patients. There was a marginal improvement in sensitivity (57.7%) for high-risk cancers. When urine cytology was combined with imaging, the diagnostic performance improved with CTU (sensitivity 90.2%, specificity 94.9%) superior to RBUS (sensitivity 66.7%, specificity 96.7%). False positive cytology results were confirmed in 22 patients, of which 12 (54.5%) had further invasive tests and 5 (22.7%) had a repeat cytology. No cancer was identified in these patients during follow-up. CONCLUSIONS: Urine cytology will miss a significant number of muscle-invasive bladder cancer and high-risk disease. Our results suggest that urine cytology should not be routinely performed as part of haematuria investigations. The role of urine cytology in select cases should be considered in the context of the impact of a false positive result leading to further potentially invasive tests conducted under general anaesthesia.

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.