Advancing health equity in the aftermath of COVID-19: Confronting intensifying racial disparities.

The COVID-19 pandemic has exposed and exacerbated the persistent racial and ethnic health disparities in the United States. The pandemic has also had profound spillover effects on other aspects of health and wellbeing, such as mental health, chronic diseases, education, and income, for marginalized groups. In this article, we provide a thorough analysis of the pandemic's impact on racial and ethnic health disproportionalities, highlighting the multifaceted and interrelated factors that contribute to these inequities. We also argue for a renewed focus on health equity in healthcare policy and practice, emphasizing the need for systemic changes that address both the immediate and long-term consequences of these imbalances. We propose a framework for achieving health equity that involves creating equitable systems, care, and outcomes for all individuals, regardless of their race or ethnicity.

Rewriting the textbook for pharma: how to adapt and thrive in a digital, personalized and collaborative world.

The pharmaceutical industry is undergoing a sweeping transformation, driven by technological innovations, demographic shifts, regulatory changes and consumer expectations. For adaptive players in pharma to excel in this rapidly changing landscape, which will be markedly different from today by 2030 and beyond, they will require a different set of skills, capabilities and mindsets, as well as a willingness to collaborate and co-create value with multiple stakeholders. The industry needs to rewrite the textbook for pharma by embracing and implementing four key dimensions of change: digitalization, personalization, collaboration and innovation. In this article, we will examine how these dimensions of change are reshaping the industry, and provide practical and strategic guidance based on best practices and examples. Specifically, adaptive pharma companies should embrace the use of advanced digital technologies, such as artificial intelligence and machine learning technologies, to streamline processes and solve challenges rapidly. Personalization, both in medicine and patient engagement, will also be key to success in the 'digital revolution', and a collaborative approach involving partnerships with tech start-ups, health-care providers and regulatory bodies will also be essential to create an integrated and responsive health-care ecosystem. Using these ideas for a rewritten textbook for pharma, adaptive players in pharma will evolve to be personalized and digitized health-focused organizations that provide comprehensive solutions which go beyond drugs and devices.

Patient Perception of Physician Reimbursement by Medicare for Artificial Urinary Sphincter Placement.

INTRODUCTION: Patient perceptions of physician reimbursement commonly differ from actual reimbursement. This study aims to improve health care cost transparency and trust between patients, physicians, and the health care system by evaluating patient perceptions of Medicare reimbursement for artificial urinary sphincter (AUS) placement. METHODS: We identified patients who underwent AUS placement at a single institution from 2014 to 2023. After obtaining informed consent, we administered a telephone survey to ask patients about their perceptions of Medicare reimbursement for AUS surgery and the amount they felt the physician should be compensated. RESULTS: Sixty-four patients were enrolled and completed the survey. On average, patients estimated Medicare physician reimbursement to be $18,920, 25 times the actual average procedure reimbursement. Once informed that the actual amount was $757.52, 97% of respondents felt that the reimbursement was "somewhat lower" (13%) or "much lower" (84%) than what they considered fair. The average amount that patients felt the physician should be paid was $8,844, 12 times the actual average procedure reimbursement. Fifty-four percent of patients estimated their physician's reimbursement to be higher than what they later reported as being "fair," representing a presurvey belief that their physician was overpaid. CONCLUSIONS: Patient perceptions of physician reimbursement for AUS are vastly different than the actual amount paid. The discordance between patient perception and actual reimbursement could impact how patients view health care costs and the relationship with their provider.

Urinary and Oral Microbiota Among Men Undergoing Buccal Urethroplasty.

OBJECTIVE: To assess changes in the urinary microbiota after buccal urethroplasty. METHODS: At the University of California San Francisco, we enrolled 9 adult males with urethral strictures undergoing buccal urethroplasty where we collected urine and oral swabs intraoperatively and 3 months postoperatively. 16S rRNA sequencing was used to profile the microbiota. RESULTS: At baseline, the mouth contains twice the number of unique bacteria (alpha diversity) and the microbial community is significantly distinct compared to the urinary tract. Despite having a buccal mucosa in the urinary tract after urethroplasty, the number of unique bacteria in the urine remained stable. However, the bacterial community composition and structure significantly changed in the urinary tract with the enrichment of Corynebacterium genus at 3 months post-urethroplasty procedure. CONCLUSION: In this pilot study, we showed that the alpha diversity in the urinary microbiota did not significantly change despite having a buccal tissue with the capacity to support high bacterial diversity in the urinary tract. To our surprise, the post-urethroplasty urinary microbiota was not a hybrid of baseline oral and urine microbiotas; the changes detected, such as an enrichment of the Corynebacterium genus, were more nuanced yet could profoundly impact surgical outcomes like graft changes and stricture recurrence. Our study not only established the feasibility but also outlined a blueprint for conducting a large-scale study to assess alterations in the urinary microbiome in relation to surgical outcomes.

Diffusion tensor MRI is sensitive to fibrotic injury in a mouse model of oxalate-induced chronic kidney disease.

Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the standard of care, but these endpoints have limitations in detecting the stage, progression, and spatial distribution of fibrotic pathology in the kidney. MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo both in clinical and preclinical studies. However, these imaging studies have not systematically identified fibrosis particularly deeper in the kidney where biopsy sampling is limited, or completed an extensive analysis of whole organ histology, blood biomarkers, and gene expression to evaluate the relative strengths and weaknesses of MRI for evaluating renal fibrosis. In this study, we performed DTI in the sodium oxalate mouse model of CKD. The DTI parameters fractional anisotropy, apparent diffusion coefficient, and axial diffusivity were compared between the control and oxalate groups with region of interest (ROI) analysis to determine changes in the cortex and medulla. In addition, voxel-based analysis (VBA) was implemented to systematically identify local regions of injury over the whole kidney. DTI parameters were found to be significantly different in the medulla by both ROI analysis and VBA, which also spatially matched with collagen III immunohistochemistry (IHC). The DTI parameters in this medullary region exhibited moderate to strong correlations with histology, blood biomarkers, hydroxyproline, and gene expression. Our results thus highlight the sensitivity of DTI to the heterogeneity of renal fibrosis and importance of whole kidney noninvasive imaging.NEW & NOTEWORTHY Chronic kidney disease (CKD) can be characterized by inflammation and fibrosis of the kidney. Although standard of care methods have been limited in scope, safety, and spatial distribution, MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo. In this study, we performed DTI in an oxalate mouse model of CKD to systematically identify local kidney injury. DTI parameters strongly correlated with histology, blood biomarkers, hydroxyproline, and gene expression.

Healthcare on the brink: navigating the challenges of an aging society in the United States.

The US healthcare system is at a crossroads. With an aging population requiring more care and a strained system facing workforce shortages, capacity issues, and fragmentation, innovative solutions and policy reforms are needed. This paper aims to spark dialogue and collaboration among healthcare stakeholders and inspire action to meet the needs of the aging population. Through a comprehensive analysis of the impact of an aging society, this work highlights the urgency of addressing this issue and the importance of restructuring the healthcare system to be more efficient, equitable, and responsive.

Feed-forward stimulation of CAMK2 by the oncogenic pseudokinase PEAK1 generates a therapeutically 'actionable' signalling axis in triple negative breast cancer.

The PEAK family of pseudokinases, comprising PEAK1-3, are signalling scaffolds that play oncogenic roles in several poor prognosis human cancers, including triple negative breast cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screened for PEAK1 effectors by affinity purification and mass spectrometry, identifying calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promoted CAMK2D/G activation in TNBC cells via a novel feed-forward mechanism involving PEAK1/PLCγ1/Ca 2+ signalling and direct binding via a consensus CAMK2 interaction motif in the PEAK1 N-terminus. In turn, CAMK2 phosphorylated PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurposed RA306, a second generation CAMK2 inhibitor under pre-clinical development for treatment of cardiovascular disease. RA306 demonstrated on-target activity against CAMK2 in TNBC cells and inhibited PEAK1-enhanced migration and invasion in vitro . Moreover, RA306 significantly attenuated TNBC xenograft growth and blocked metastasis in a manner mirrored by CRISPR-mediated PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus, identify a novel mechanism for regulation of Ca 2+ signalling and its integration with tyrosine kinase signals, and identify CAMK2 as a therapeutically 'actionable' target downstream of PEAK1.

Transforming drug development with synthetic biology and AI.

The COVID-19 pandemic has thrust RNA as a platform for drug development into the spotlight. However, identifying promising drug candidates is challenging. With advances in synthetic biology and artificial intelligence (AI) models, we can overcome this hurdle, transforming drug development and ushering in a new era in the pharmaceutical industry.

Exploring the future adult vaccine landscape-crowded schedules and new dynamics.

Amidst the backdrop of the COVID-19 pandemic, vaccine innovation has garnered significant attention, but this field was already on the cusp of a groundbreaking renaissance. Propelling these advancements are scientific and technological breakthroughs, alongside a growing understanding of the societal and economic boons vaccines offer, particularly for non-pediatric populations like adults and the immunocompromised. In a departure from previous decades where vaccine launches could be seamlessly integrated into existing processes, we anticipate potentially than 100 novel, risk-adjusted product launches over the next 10 years in the adult vaccine market, primarily addressing new indications. However, this segment is infamous for its challenges: low uptake, funding shortfalls, and operational hurdles linked to delivery and administration. To unlock the societal benefits of this burgeoning expansion, we need to adopt a fresh perspective to steer through the dynamics sparked by the rapid growth of the global adult vaccine market. This article aims to provide that fresh perspective, offering a detailed analysis of the anticipated number of adult vaccine approvals by category and exploring how our understanding of barriers to adult vaccine uptake might evolve. We incorporated pertinent insights from external stakeholder interviews, spotlighting shifting preferences, perceptions, priorities, and decision-making criteria. Consequently, this article aspires to serve as a pivotal starting point for industry participants, equipping them with the knowledge to skillfully navigate the anticipated surge in both volume and complexity.

Influence of the freezing level on atmospheric rivers in High Mountain Asia: WRF case studies of orographic precipitation extremes.

Atmospheric rivers (ARs) reach High Mountain Asia (HMA) about 10 days per month during the winter and spring, resulting in about 20 mm day-1 of precipitation. However, a few events may exceed 100 mm day-1, providing most of the total winter precipitation and increasing the risk of precipitation-triggered landslides and flooding, particularly when the height of the height of the 0 ∘C isotherm, or freezing level is above-average. This study shows that from 1979 to 2015, integrated water vapor transport (IVT) during ARs that reach Western HMA has increased 16% while the freezing level has increased up to 35 m. HMA ARs that have an above-average freezing level result in 10-40% less frozen precipitation compared to ARs with a below-average freezing level. To evaluate the importance of these trends in the characteristics of ARs, we investigate mesoscale processes leading to orographic precipitation using Advanced Weather Research and Forecasting (ARW-WRF) simulations at 6.7 km spatial resolution. We contrast two above- and below- average freezing level AR events with otherwise broadly similar characteristics and show that with a 50-600 m increase in freezing level, the above-average AR resulted in 10-70% less frozen precipitation than the below-average event. This study contributes to a better understanding of climate change-related impacts within HMA's hydrological cycle and the associated hazards to vulnerable communities living in the region.

Breaking the mold with RNA-a "RNAissance" of life science.

In the past decade, RNA therapeutics have gone from being a promising concept to one of the most exciting frontiers in healthcare and pharmaceuticals. The field is now entering what many call a renaissance or "RNAissance" which is being fueled by advances in genetic engineering and delivery systems to take on more ambitious development efforts. However, this renaissance is occurring at an unprecedented pace, which will require a different way of thinking if the field is to live up to its full potential. Recognizing this need, this article will provide a forward-looking perspective on the field of RNA medical products and the potential long-term innovations and policy shifts enabled by this revolutionary and game-changing technological platform.

Conservative Management of Penile and Urethral Lichen Sclerosus: A Systematic Review.

PURPOSE: We evaluate the efficacy and safety profiles of currently available conservative management options for penile and urethral lichen sclerosus. MATERIALS AND METHODS: A systematic review of existing literature on lichen sclerosus was conducted utilizing the PubMed, Embase, and Web of Science databases. References were assessed for relevance to nonsurgical management of male genital lichen sclerosus by title and abstract by 3 independent reviewers, then reviewed in full and in duplicate by 5 independent reviewers. RESULTS: Seventeen studies describing conservative management of histologically confirmed penile and urethral lichen sclerosus in male patients were included in the final review. We present available evidence supporting the use of 4 major treatment modalities represented in the existing literature: topical corticosteroids, tacrolimus, platelet-rich plasma, and CO2 laser. We also briefly discuss the limited studies on the use of oral acitretin and polydeoxyribonucleotide injections. Outcomes assessed include symptoms, clinical appearance, quality of life, sexual satisfaction, adverse effects, and long-term efficacy of treatment. CONCLUSIONS: Topical corticosteroids remain the mainstay of conservative management of penile and urethral lichen sclerosus, with current literature supporting the use of other therapies such as tacrolimus and platelet-rich plasma as alternatives or adjuvant treatments when escalation of treatment is necessary. Future research should further explore the efficacy and safety of newer therapies through additional controlled clinical trials in the targeted population.

Real-World Complications of the SpaceOAR Hydrogel Spacer: A Review of the Manufacturer and User Facility Device Experience Database.

OBJECTIVE: To characterize adverse events related to use of the perirectal spacing agent SpaceOAR, we examined the Manufacturer and User Facility Device Experience (MAUDE) database. METHODS: The MAUDE database was queried for "SpaceOAR" and "Augmenix" from June 2015 (when SpaceOAR was approved by the Food and Drug Administration) to October 2022. Reports were reviewed for adverse events (AEs), operative procedures performed because of the AE, and changes to the radiation plan. AEs were categorized using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. RESULTS: Six hundred fifty-four reports were reviewed. Eighty-four were excluded and 4 reports reviewed 2 separate cases of SpaceOAR administration. Five hundred seventy-four cases were ultimately included. Three deaths were reported (0.5% of all AEs). One point six percent of cases represented CTCAE grade 4 injuries (life-threatening consequences; urgent intervention indicated), 15.9% grade 3 (severe but not immediately life-threatening; hospitalization), 24.2% grade 2 (moderate; local/noninvasive intervention), and 57% of events were CTCAE grade 1 (mild; asymptomatic or mild symptoms). Bowel diversion occurred in 29 cases (9%). CONCLUSION: Both asymptomatic (n = 311) and debilitating (n = 12) complications of SpaceOAR hydrogel use were identified. Death, gel embolization, anaphylaxis, rectal ulcerations, and infections requiring bowel or urinary diversions were among the complications reviewed. Providers should consider these potential complications before perirectal spacer administration and during patient counseling.

Ergonomics in Urology: Current Landscape and Future Directions.

Optimal ergonomics are essential to improving clinical performance and longevity among urologists, as poor ergonomics can contribute to work-related injury and physician burnout. While a majority of urologists experience muscular injury throughout their career, women and trainees are disproportionately affected. These disparities are exacerbated by the lack of formal ergonomics education within urologic training programs. This review provides an overview of practical approaches to optimize ergonomics across working environments for urologists and trainees. We highlight intraoperative techniques and novel devices which have been shown to reduce work-related injury, and we identify knowledge gaps to guide future areas of ergonomic research.

Risk of Bias in Chest Radiography Deep Learning Foundation Models.

Purpose: To analyze a recently published chest radiography foundation model for the presence of biases that could lead to subgroup performance disparities across biologic sex and race. Materials and Methods: This Health Insurance Portability and Accountability Act-compliant retrospective study used 127 118 chest radiographs from 42 884 patients (mean age, 63 years ± 17 [SD]; 23 623 male, 19 261 female) from the CheXpert dataset that were collected between October 2002 and July 2017. To determine the presence of bias in features generated by a chest radiography foundation model and baseline deep learning model, dimensionality reduction methods together with two-sample Kolmogorov-Smirnov tests were used to detect distribution shifts across sex and race. A comprehensive disease detection performance analysis was then performed to associate any biases in the features to specific disparities in classification performance across patient subgroups. Results: Ten of 12 pairwise comparisons across biologic sex and race showed statistically significant differences in the studied foundation model, compared with four significant tests in the baseline model. Significant differences were found between male and female (P < .001) and Asian and Black (P < .001) patients in the feature projections that primarily capture disease. Compared with average model performance across all subgroups, classification performance on the "no finding" label decreased between 6.8% and 7.8% for female patients, and performance in detecting "pleural effusion" decreased between 10.7% and 11.6% for Black patients. Conclusion: The studied chest radiography foundation model demonstrated racial and sex-related bias, which led to disparate performance across patient subgroups; thus, this model may be unsafe for clinical applications.Keywords: Conventional Radiography, Computer Application-Detection/Diagnosis, Chest Radiography, Bias, Foundation Models Supplemental material is available for this article. Published under a CC BY 4.0 license.See also commentary by Czum and Parr in this issue.

Outlook of pandemic preparedness in a post-COVID-19 world.

The COVID-19 pandemic was met with rapid, unprecedented global collaboration and action. Even still, the public health, societal, and economic impact may be felt for years to come. The risk of another pandemic occurring in the next few decades is ever-present and potentially increasing due to trends such as urbanization and climate change. While it is difficult to predict the next pandemic pathogen threat, making reasonable assumptions today and evaluating prior efforts to plan for and respond to disease outbreaks and pandemics may enable a more proactive, effective response in the future. Lessons from the COVID-19 response and pandemic influenza preparedness underscore the importance of strengthening surveillance systems, investing in early-stage research on pandemic pathogens and development of platform technologies, and diversifying response plans across a range of tactics to enable earlier access to safe and effective interventions in the next pandemic. Further, sustaining the robust vaccine manufacturing capacity built because of COVID-19 will keep it ready for rapid response in the future. These actions will not be successful without improved global coordination and collaboration. Everyone, including the biopharmaceutical industry, has a role to play in pandemic preparedness, and working together will ensure that the most lives are saved in the next pandemic.

Harnessing synthetic biology for advancing RNA therapeutics and vaccine design.

Recent global events have drawn into focus the diversity of options for combatting disease across a spectrum of prophylactic and therapeutic approaches. The recent success of the mRNA-based COVID-19 vaccines has paved the way for RNA-based treatments to revolutionize the pharmaceutical industry. However, historical treatment options are continuously updated and reimagined in the context of novel technical developments, such as those facilitated through the application of synthetic biology. When it comes to the development of genetic forms of therapies and vaccines, synthetic biology offers diverse tools and approaches to influence the content, dosage, and breadth of treatment with the prospect of economic advantage provided in time and cost benefits. This can be achieved by utilizing the broad tools within this discipline to enhance the functionality and efficacy of pharmaceutical agent sequences. This review will describe how synthetic biology principles can augment RNA-based treatments through optimizing not only the vaccine antigen, therapeutic construct, therapeutic activity, and delivery vector. The enhancement of RNA vaccine technology through implementing synthetic biology has the potential to shape the next generation of vaccines and therapeutics.

Urethral Slings for Irradiated Patients With Male Stress Urinary Incontinence: A Meta-analysis.

OBJECTIVE: To systematically compare success, cure and complication rates of urethral sling surgeries in stress urinary incontinence patients with and without a history of pelvic radiotherapy (RT). MATERIALS AND METHODS: We searched PUBMED, EMBASE, and Web of Science to identify relevant articles. The primary outcomes were the success and cure rates. The secondary outcomes included the rates of infection, urethral erosion, total complications, explantation, and satisfaction. Outcomes were analyzed using a random-effects model to calculate the unadjusted odds ratio (OR) in patients with a history of RT compared with those without prior RT. RESULTS: On pooled analysis, we found significantly lower odds of success (OR 0.68; 95% confidence interval [CI] 0.53-0.87, P < .001) and cure (OR 0.67; 95% CI 0.55-0.82, P < .001) in radiated patients than in nonirradiated patients. Subgroup analysis by type of sling showed significantly lower odds of success in Advance subgroup (OR 0.66; 95% CI 0.45-0.95, P < .001) and significantly lower odds of cure in Advance (OR 0.59; 95% CI 0.36-0.95, P < .001) and Atoms subgroups (OR 0.70; 95% CI 0.54-0.93, P < .001). We also found significantly greater odds of sling explantation (OR 2.93; 95% CI 1.62-5.29, P < .001) and infection (OR 3.06, 95% CI 1.03-9.07, P < .001) in radiated patients than in nonradiated patients. CONCLUSION: Patients with a history of pelvic RT have lower odds of success and cure and higher odds of infection and sling explantation than those without a history of pelvic RT.