Covalent Fragment Screening and Optimization Identifies the Chloroacetohydrazide Scaffold as Inhibitors for Ubiquitin C-terminal Hydrolase L1.

Dysregulation of the ubiquitin-proteasome systems is a hallmark of various disease states including neurodegenerative diseases and cancer. Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is expressed primarily in the central nervous system under normal physiological conditions, however, is considered an oncogene in various cancers, including melanoma, lung, breast, and lymphoma. Thus, UCHL1 inhibitors could serve as a viable treatment strategy against these aggressive cancers. Herein, we describe a covalent fragment screen that identified the chloroacetohydrazide scaffold as a covalent UCHL1 inhibitor. Subsequent optimization provided an improved fragment with single-digit micromolar potency against UCHL1 and selectivity over the closely related UCHL3. The molecule demonstrated efficacy in cellular assays of metastasis. Additionally, we report a ligand-bound crystal structure of the most potent molecule in complex with UCHL1, providing insight into the binding mode and information for future optimization.

Identification of covalent fragment inhibitors for Plasmodium falciparum UCHL3 with anti-malarial efficacy.

Malaria continues to be a major burden on global health, responsible for 619,000 deaths in 2021. The causative agent of malaria is the eukaryotic parasite Plasmodium. Resistance to artemisinin-based combination therapies (ACTs), the current first-line treatment for malaria, has emerged in Asia, South America, and more recently Africa, where >90% of all malaria-related deaths occur. This has necessitated the identification and investigation of novel parasite proteins and pathways as antimalarial targets, including components of the ubiquitin proteasome system. Here, we investigate Plasmodium falciparum deubiquitinase ubiquitin C-terminal hydrolase L3 (PfUCHL3) as one such target. We carried out a high-throughput screen with covalent fragments and identified seven scaffolds that selectively inhibit the plasmodial UCHL3, but not human UCHL3 or the closely related human UCHL1. After assessing toxicity in human cells, we identified four promising hits and demonstrated their efficacy against asexual P. falciparum blood stages and P. berghei sporozoite stages.

Screening for diminished ovarian reserve in Portugal: a cost-saving answer to shorten the fertility journey.

Aim: Assess the budget impact of nationwide screening for diminished ovarian reserve (OR), via anti-Müllerian hormone (AMH) levels, to the Portugal National Health System (NHS). Patients & methods: The clinical journey was determined using literature and the family planning decision-making process/response using survey results. A panel of four local clinicians validated all assumptions/inputs. Results: Screening for OR led to an expected savings of € 9.4 million for the NHS, driven by a 24% reduction in medically assisted reproduction (MAR) use. When needed, referral for MAR was earlier and more women used first-line versus second-line techniques. The model estimated a 12% decrease in failure. Conclusion: This model shows AMH screening may allow more informed decisions, leading to a shorter fertility journey, more efficient use of treatments, and substantial cost-savings for the NHS.

Economic Evaluation of Catheter Ablation Versus Medical Therapy for the Treatment of Atrial Fibrillation from the Perspective of the UK.

Randomised evidence supports an early rhythm control strategy as treatment for AF, and catheter ablation outperforms medical therapy in terms of effectiveness when studied as first- and second-line treatment. Despite evidence consistently showing that catheter ablation treatment is superior to medical therapy in most AF patients, only a small proportion receive ablation, in some cases after a prolonged trial of ineffective medical therapy. Health economics research in electrophysiology remains limited but is recognised as being important in influencing positive change to ensure early access to ablation services for all eligible patients. Such information has informed the updated recommendations from the recently published National Institute for Health and Care Excellence clinical guideline on the diagnosis and management of AF, but increased awareness is needed to drive real-world adoption and to ensure patients are quickly referred to specialists. In this article, economic evaluations of catheter ablation versus medical therapy are reviewed.

Structure-activity relationship studies for inhibitors for vancomycin-resistant Enterococcus and human carbonic anhydrases.

Vancomycin-resistant enterococci (VRE), consisting of pathogenic Enterococcus faecalis and E. faecium, is a leading cause of hospital-acquired infections (HAIs). We recently repurposed the FDA-approved human carbonic anhydrase (CA) inhibitor acetazolamide (AZM) against VRE agent with the likely mechanism of action for the molecules being inhibition of one, or both, of the bacterial CA isoforms expressed in VRE. To elucidate how inhibitor binding to the enzymes relates to MIC, we further characterised the inhibition constants (Ki) against the E. faecium α-CA (Efα-CA) and γ-CA (Efγ-CA), as well as against human CA I (hCAI) and human CA II (hCAII) to assess selectivity. We have also utilised homology modelling and molecular dynamics (MD) simulations to gain a better understanding of the potential interactions the molecules are making with the targets. In this paper, we elaborate on the SAR for the AZM analogs as it pertains to MIC and Ki for each CA.

SPECT/CT versus planar imaging to determine treatment strategy for non-small-cell lung cancer: a cost-effectiveness analysis.

Aim: SPECT/CT has been found to improve predicted postoperative forced expiratory volume in one second (ppoFEV1) assessments in patients with non-small-cell lung cancer (NSCLC). Methods: An economic simulation was developed comparing the cost-effectiveness of SPECT/CT versus planar scintigraphy for a US payer. Clinical outcomes and cost data were obtained through review of the published literature. Results: SPECT/CT increased the accuracy ppoFEV1 assessment, changing the therapeutic decision for 1.3% of nonsurgical patients to a surgical option, while 3.3% of surgical patients shifted to more aggressive procedures. SPECT/CT led to an expected cost of $4694 per life year gained, well below typical thresholds. Conclusion: SPECT/CT resulted in substantially improved health outcomes and was found to be highly cost-effective.

Cost-effectiveness of catheter ablation versus medical therapy for the treatment of atrial fibrillation in the United Kingdom.

INTRODUCTION: Research evidence has shown that catheter ablation is a safe and superior treatment for atrial fibrillation (AF) compared to medical therapy, but real-world practice has been slow to adopt an early interventional approach. This study aims to determine the cost effectiveness of catheter ablation compared to medical therapy from the perspective of the United Kingdom. METHODS: A patient-level Markov health-state transition model was used to conduct a cost-utility analysis. The population included patients previously treated for AF with medical therapy, including those with heart failure (HF), simulated over a lifetime horizon. Data sources included published literature on utilization and cardiovascular event rates in real world patients, a systematic literature review and meta-analysis of randomized controlled trials for AF recurrence, and publicly available government data/reports on costs. RESULTS: Catheter ablation resulted in a favorable incremental cost-effectiveness ratio (ICER) of £8614 per additional quality adjusted life years (QALY) gained when compared to medical therapy. More patients in the medical therapy group failed rhythm control at any point compared to catheter ablation (72% vs. 24%) and at a faster rate (median time to treatment failure: 3.8 vs. 10 years). Additionally, catheter ablation was estimated to be more cost-effective in patients with AF and HF (ICER = £6438) and remained cost-effective over all tested time horizons (10, 15, and 20 years), with the ICER ranging from £9047-£15 737 per QALY gained. CONCLUSION: Catheter ablation is a cost-effective treatment for atrial fibrillation, compared to medical therapy, from the perspective of the UK National Health Service.

Economic Evaluation of Contact Force Catheter Ablation for Persistent Atrial Fibrillation in the United States.

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, and it increases the risk of stroke, heart failure, and other cardiac complications. Catheter ablation is well-established as a treatment for paroxysmal AF, and the recent PRECEPT (Prospective Review of the Safety and Effectiveness of the THERMOCOOL SMARTTOUCH SF Catheter Evaluated for Treating Symptomatic Persistent AF) clinical trial resulted in the catheter gaining approval for the treatment of persistent AF in the United States. Objectives: To construct an economic simulation model, based on the results of the PRECEPT trial, to monetize the impact of radiofrequency catheter ablation (RFCA) compared with medical therapy (MT). Methods: Cost-offset and break-even analyses were performed to assess the economic impact of RFCA vs MT for adult persistent AF patients. Three perspectives were considered: commercial payers, Medicare, and self-insured employers. A cohort-level decision tree model was developed and validated in TreeAge Pro 2019. Sensitivity analyses were performed to determine the robustness of findings. Results: For all 3 types of payer, RFCA had a higher initial cost compared with MT. However, reductions in health care utilization after ablation, driven by decreased cardiovascular hospitalizations, led to an annual cost offset of between $5037 and $8402 after the first year. Projecting this forward resulted in an estimated cost break-even after 5.9, 4.2, and 5.1 years for commercial payers, Medicare, and self-insured employers, respectively. Conclusion: In addition to providing clinical benefits, RFCA may be a valuable economic investment for U.S. payers, substantially reducing utilization after the first year.

Optimization and Anti-Cancer Properties of Fluoromethylketones as Covalent Inhibitors for Ubiquitin C-Terminal Hydrolase L1.

The deubiquitinating enzyme (DUB) UCHL1 is implicated in various disease states including neurodegenerative disease and cancer. However, there is a lack of quality probe molecules to gain a better understanding on UCHL1 biology. To this end a study was carried out to fully characterize and optimize the irreversible covalent UCHL1 inhibitor VAEFMK. Structure-activity relationship studies identified modifications to improve activity versus the target and a full cellular characterization was carried out for the first time with this scaffold. The studies produced a new inhibitor, 34, with an IC50 value of 7.7 µM against UCHL1 and no observable activity versus the closest related DUB UCHL3. The molecule was also capable of selectively inhibiting UCHL1 in cells and did not demonstrate any discernible off-target toxicity. Finally, the molecule was used for initial probe studies to assess the role of UCHL1 role in proliferation of myeloma cells and migration behavior in small cell lung cancer cells making 34 a new tool to be used in the biological evaluation of UCHL1.

Budget Impact of a Steroid-Eluting Sinus Implant Versus Sinus Surgery for Adult Chronic Sinusitis Patients with Nasal Polyps.

BACKGROUND: A corticosteroid-eluting sinus implant was recently approved by the FDA as a drug to treat adult patients with nasal polyps who have undergone previous endoscopic sinus surgery (ESS) of the ethmoid sinuses. ESS is performed in an operating room under general anesthesia, whereby diseased tissue and bone are removed to provide improved drainage. ESS typically involves dissection of 1 or more of the 4 paired sinus cavities (maxillary, ethmoid, sphenoid, or frontal). The implant, containing 1,350 mcg of mometasone furoate, is inserted by a physician in an office setting and offers controlled localized release of corticosteroid to the polypoid sinus tissue. The implant has demonstrated significant improvements in clinical testing; however, little research has been conducted on its economic impact. OBJECTIVE: To evaluate and quantify the budget impact to a commercial payer of using this implant instead of ESS in patients with nasal polyps after a previous ESS. Since essentially all patients with recurrent nasal polyps after ESS are patients with chronic sinusitis (CS) diagnosis, this study also identified patients with CS with nasal polyposis (CSwNP) for consistency with the patient population studied in clinical trials evaluating the implant. METHODS: A budget impact analysis was conducted from a U.S. commercial payer perspective over a 1-year time horizon with patients who received the implant or revision ESS. Primary outcomes of interest were annual total and per-member per-month (PMPM) direct health care costs. Costs were estimated using a decision analysis model, assuming 50% implant utilization as an alternative to revision ESS in eligible patients, with other levels (25%, 75%) also considered. The model utilized the results of a recently published analysis of 86,052 patients in the Blue Health Intelligence database, results from published clinical trials evaluating the implant, a literature review, and published Medicare national payment amounts. RESULTS: A commercial health plan with 1 million members could anticipate 1,000 CSwNP patients as candidates for receiving the implant or revision ESS. Estimated direct treatment costs for refractory CSwNP using only revision ESS are $11.03 million ($0.92 PMPM). If the implant replaced surgery in 50% of cases and if 63% those patients received a second treatment with the implant during the year, the estimated total cost savings would be $2.56 million ($0.21 PMPM). Cost savings associated with using the implant changed to $0.11 PMPM and $0.32 PMPM with implant adoption of 25% and 75%, respectively. CONCLUSIONS: In a large commercially insured U.S. population, annual revision ESS costs are substantial. Using the implant instead of revision ESS could result in considerable cost savings for payers at various levels of adoption. DISCLOSURES: This study was sponsored by Intersect ENT, which was involved in study design and manuscript review. Ernst and Imhoff are employed by CTI Clinical Trial and Consulting Services, which contracted with Intersect ENT to conduct this study. Ernst and Imhoff also report other financial support from Intersect ENT during the conduct of the study. DeConde reports personal fees from Intersect ENT during the conduct of the study, as well as personal fees from Optinose, Stryker Endoscopy, and Olympus, outside the submitted work. Manes reports grants from Intersect ENT during the conduct of the study, as well as grants from Optinose and Sanofi outside the submitted work.

Cost minimization analysis of catheter ablation for paroxysmal atrial fibrillation by catheter technology.

AIM: Compare the 1-year costs of three catheter ablation technologies for the treatment of paroxysmal atrial fibrillation (PAF). MATERIALS & METHODS: A decision tree model was developed to estimate 1-year hospital costs associated with an index and potential repeat PAF ablation procedure using the Thermocool® Smarttouch® Catheter (ST), Thermocool SF Catheter (SF) or Arctic Front Advance Cryoballoon (CB). Model parameters were estimated using the results of two recently published studies. RESULTS: The ST resulted in average per-patient savings for combined inpatient and outpatient populations of US$1488 and US$4494 compared with SF and  CB, respectively. These cost savings were greater in the inpatient setting. CONCLUSION: The 1-year expected hospital visit costs for PAF ablation were lower with ST than with SF or CB.

Cost-Effectiveness of Bone SPECT/CT in Painful Total Knee Arthroplasty.

The purpose of this study was to quantify the economic value of bone SPECT/CT versus CT or metal artifact reduction sequence (MARS)-MRI for the diagnostic assessment of recurrent moderate-to-severe pain after total knee arthroplasty (TKA). Methods: An Excel-based simulation model was developed to compare bone SPECT/CT versus CT or MARS-MRI from a payer perspective. Clinical endpoints (diagnosis-delayed or otherwise, and the subsequent treatment and complications) and their corresponding cost data (2017 U.S. dollars) were obtained by performing a best evidence review of the published literature. Studies were pooled and parameters weighted by sample size. A cost-utility analysis was performed estimating the incremental cost per quality-adjusted life years gained between bone SPECT/CT and the comparative scans. One-way (±25%) sensitivity analysis was performed to gauge the model robustness. Results: For every 1,000 TKA patients, diagnostic bone SPECT/CT was expected to lead to 3-y cost savings up to $1,867,695 versus CT (or $622.6 per patient per year) and $1,723,435 versus MARS-MRI (or $574.5 per patient per year) for a payer. With corresponding incremental quality-adjusted life years gains of 39.7 and 41.0 against CT and MARS-MRI, SPECT/CT can be considered as a cost-saving and dominant strategy in the workup of persistent/recurrent pain in TKA patients. The model was limited by the still sparse literature data, was most sensitive to imaging-related sensitivity/specificity, but proved robust for varying prevalence of surgical/nonsurgical causes of pain. Conclusion: Bone SPECT/CT is a potentially highly cost-saving and dominant imaging intervention versus CT or MARS-MR scanning in patients with recurrent and persistent knee pain after TKA.

Congruence of Patient Self-Rating of Health with Family Physician Ratings.

BACKGROUND: A single self-rated health (SRH) question is associated with health outcomes, but agreement between SRH and physician-rated patient health (PRPH) has been poorly studied. We studied patient and physician reasoning for health ratings and the role played by patient lifestyle and objective health measures in the congruence between SRH and PRPH. METHODS: Surveys of established family medicine patients and their physicians, and medical record review at 4 offices. Patients and physicians rated patient health on a 5-point scale and gave reasons for the rating and suggestions for improving health. Patients' and physicians' reasons for ratings and improvement suggestions were coded into taxonomies developed from the data. Bivariate relationships between the variables and the difference between SRH and PRPH were examined and all single predictors of the difference were entered into a multivariable regression model. RESULTS: Surveys were completed by 506 patients and 33 physicians. SRH and PRPH ratings matched exactly for 38% of the patient-physician dyads. Variables associated with SRH being lower than PRPH were higher patient body mass index (P = .01), seeing the physician previously (P = .04), older age, (P < .001), and a higher comorbidity score (P = .001). Only 25.7% of the dyad reasons for health status rating and 24.1% of needed improvements matched, and these matches were unrelated to SRH/PRPH agreement. Physicians focused on disease in their reasoning for most patients, whereas patients with excellent or very good SRH focused on feeling well. CONCLUSIONS: Patients' and physicians' beliefs about patient health frequently lack agreement, confirming the need for shared decision making with patients.

Provision of Recommended Chronic Pain Assessment and Management in Primary Care: Does Patient-Centered Medical Home (PCMH) Recognition Make a Difference?

BACKGROUND: Chronic pain (CP) care in the patient-centered medical home (PCMH) model has not been well studied. We assessed whether PCMH recognition is associated with increased provision of key practice recommendations for CP assessment and management. METHODS: Chart reviews were completed for 12 primary care practices affiliated with one health system in the Cincinnati Area Research and Improvement Group (CARInG). Recommendations were abstracted and compared based on PCMH status: 3 practices had received prior PCMH level 3 recognition, 5 were in an ongoing process of applying, and 4 had no recognition and were not applying. RESULTS: A total of 485 charts were reviewed from 65 PCPs. Eight of 10 key recommendations were documented more often in the prior and ongoing PCMH cohorts, including assessing pain severity, function, psychosocial distress, and substance abuse, and using structured instruments for these assessments. There were fewer differences between the cohorts in the management of chronic opioids, with only the ongoing PCMH cohort having higher documentation for 5 of the 7 recommendations, including performing urine drug screens and using a structured instrument to assess for misuse. CONCLUSIONS: These findings support the usefulness of the PCMH model in managing patients with CP, but patient outcomes need to be addressed in future studies.