Treating amyotrophic lateral sclerosis with allogeneic Schwann cell-derived exosomal vesicles: a case report.

Schwann cells are essential for the maintenance and function of motor neurons, axonal networks, and the neuromuscular junction. In amyotrophic lateral sclerosis, where motor neuron function is progressively lost, Schwann cell function may also be impaired. Recently, important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported. This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles, marking, to our knowledge, the first instance of such treatment. An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis. After initial diagnosis, the patient underwent a combination of generic riluzole, sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis, and taurursodiol. The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function. We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired (senescent) and that exposure of the patient's Schwann cells to allogeneic Schwann cell-derived exosomal vesicles, cultured expanded from a cadaver donor improved their growth capacity in vitro. After a period of observation lasting 10 weeks, during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored, the patient received weekly consecutive infusions of 1.54 × 10 12 (×2), and then consecutive infusions of 7.5 × 10 12 (×6) allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco's phosphate-buffered saline. None of the infusions were associated with adverse events such as infusion reactions (allergic or otherwise) or changes in vital signs. Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend. A more sensitive in-house assay suggested possible inflammasome activation during the disease course. A trend for clinical stabilization was observed during the infusion period. Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles. Initial findings suggest that this approach is safe.

The effect of posture on the age dependence of neurovascular coupling.

Previous studies report contradicting age-related neurovascular coupling (NVC). Few studies assess postural effects, but less investigate relationships between age and NVC within different postures. Therefore, this study investigated the effect of age on NVC in different postures with varying cognitive stimuli. Beat-to-beat blood pressure, heart rate and end-tidal carbon dioxide were assessed alongside middle and posterior cerebral artery velocities (MCAv and PCAv, respectively) using transcranial Doppler ultrasonography in 78 participants (31 young-, 23 middle- and 24 older-aged) with visuospatial (VST) and attention tasks (AT) in various postures at two timepoints (T2 and T3). Between-group significance testing utilized one-way analysis-of-variance (ANOVA) (Tukey post-hoc). Mixed three-way/one-way ANOVAs explored task, posture, and age interactions. Significant effects of posture on NVC were driven by a 3.8% increase from seated to supine. For AT, mean supine %MCAv increase was greatest in younger (5.44%) versus middle (0.12%) and older-age (0.09%) at T3 (p = 0.005). For VST, mean supine %PCAv increase was greatest at T2 and T3 in middle (10.99%/10.12%) and older-age (17.36%/17.26%) versus younger (9.44%/8.89%) (p = 0.004/p = 0.002). We identified significant age-related NVC effects with VST-induced hyperactivation. This may reflect age-related compensatory processes in supine. Further work is required, using complex stimuli while standing/walking, examining NVC, aging and falls.

Establishing and characterizing the molecular profiles, cellular features, and clinical utility of a patient-derived xenograft model using benign prostatic tissues.

Benign Prostatic Hyperplasia (BPH) is a common condition marked by the enlargement of the prostate gland, which often leads to significant urinary symptoms and a decreased quality of life. The development of clinically relevant animal models is crucial for understanding the pathophysiology of BPH and improving treatment options. This study aims to establish a patient-derived xenograft (PDX) model using benign prostatic tissues to explore the molecular and cellular mechanisms of BPH. PDXs were generated by implanting fresh BPH (transition zone) and paired normal (peripheral zone) prostate tissue from eight patients under the renal capsule of immunodeficient male mice. Tissue weight, architecture, cellular proliferation, apoptosis, prostate-specific marker expression, and molecular profiles of PDXs were assessed after 1 week, 1 month, 2 months, or 3 months of implantation by immunohistochemistry, ELISA, transcriptomics, and proteomics. Responses to finasteride, a standard-of-care therapy, were evaluated. PDXs maintained the histological and molecular characteristics of the parental human tissues. BPH, but not normal PDXs, demonstrated significant increases in weight and cellular proliferation, particularly at 1 month. Molecular profiling revealed specific gene and protein expression patterns correlating with BPH pathophysiology. Specifically, an increased immune and stress response was observed at 1 week, followed by increased expression of proliferation markers and BPH-specific stromal signaling molecules, such as BMP5 and CXCL13, at 1 month. Graft stabilization to pre-implant characteristics was apparent between 2 and 3 months. Treatment with finasteride reduced proliferation, increased apoptosis, and induced morphological changes consistent with therapeutic responses observed in human BPH. Our PDX model recapitulates the morphological, histological, and molecular features of human BPH, offering a significant advancement in modeling the complex interactions of cell types in BPH microenvironments. These PDXs respond to therapeutic intervention as expected, providing a valuable tool for preclinical testing of new therapeutics which will improve the well-being for BPH patients.

British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for genetic testing in epithelial ovarian cancer in the United Kingdom.

Standard of care genetic testing has undergone significant changes in recent years. The British Gynecological Cancer Society and the British Association of Gynecological Pathologists (BGCS/BAGP) has re-assembled a multidisciplinary expert consensus group to update the previous guidance with the latest standard of care for germline and tumor testing in patients with ovarian cancer. For the first time, the BGCS/BAGP guideline group has incorporated a patient advisor at the initial consensus group meeting. We have used patient focused groups to inform discussions related to reflex tumor testing - a key change in this updated guidance. This report summarizes recommendations from our consensus group deliberations and audit standards to support continual quality improvement in routine clinical settings.

UniChromCD for Demultiplexing Time-Resolved Charge Detection-Mass Spectrometry Data.

Charge detection mass spectrometry (CD-MS) enables characterization of large, heterogeneous analytes through the analysis of individual ion signals. Because hundreds to thousands of scans must be acquired to produce adequate ion statistics, CD-MS generally requires long analysis times. The slow acquisition speed of CD-MS complicates efforts to couple it with time-dispersive techniques, such as chromatography and ion mobility, because it is not always possible to acquire enough scans from a single sample injection to generate sufficient ion statistics. Multiplexing methods based on Hadamard and Fourier transforms offer an attractive solution to this problem by improving the duty cycle of the separation while preserving retention/drift time information. However, integrating multiplexing with CD-MS data processing is complex. Here, we present UniChromCD, a new module in the open-source UniDec package that incorporates CD-MS time-domain data processing with demultiplexing tools. Following a detailed description of the algorithm, we demonstrate its capabilities using two multiplexed CD-MS workflows: Hadamard-transform size-exclusion chromatography and Fourier-transform ion mobility. Overall, UniChromCD provides a user-friendly interface for analysis and visualization of time-resolved CD-MS data.

Are Drug Novelty Characteristics Associated With Greater Health Benefits?

OBJECTIVE: The aim of this study was to examine the association between characteristics of novel drugs and incremental health gains relative to standard of care, in terms of quality-adjusted life-years (QALYs). METHODS: This study's unit of analysis is the drug-indication pair. For pairs approved by the US FDA from 1999 to 2018, we quantified incremental health gains using QALYs from the published literature and characterized each pair's novelty in terms of a series of six binary (yes/no) characteristics of novel drugs given special consideration by Health Technology Assessment agencies: Novel mechanism of action, Indicated for a rare disease, Indicated for a pediatric population, Treats a serious condition, Offers meaningful improvement over available therapies, and Potential to address unmet clinical needs. We analyzed measures of bivariate association (Mann-Whitney U and Kolmogorov-Smirnov tests) and multivariable regression, accounting for the influence of multiple novelty characteristics simultaneously. RESULTS: Our sample of 146 drugs represents 21% of drugs approved the FDA in the time period (1999-2018). Median and mean QALY gains for 'novel' drug-indication pairs exceeded corresponding QALY gains for non-novel drug-indication pairs. For most comparisons, the bivariate relationships between QALY gains and novelty characteristics were significant at p < 0.05 except for novel mechanism of action (Kolmogorov-Smirnov test) and pediatric indication (both bivariate tests). Multivariable models revealed an independent association between novelty characteristics and QALY gain except for unmet clinical need and indicated for a rare disease. CONCLUSIONS: Drugs with novelty characteristics conferred larger health gains than drugs without these characteristics in bivariate analysis, multivariable models, or both. Future research should examine other aspects of drug novelty, such as patient and health system costs and equitable access.

Disease severity and activity in bronchiectasis: A paradigm shift in bronchiectasis management.

Bronchiectasis has an increasing prevalence and substantial clinical and economic burden. Therefore, physicians should identify patients with bronchiectasis at high risk of disease progression to ensure optimal management in advance. The heterogeneity of bronchiectasis means it is unlikely that any single parameter could identify high-risk patients, therefore disease severity is usually assessed using validated composite tools, such as the Bronchiectasis Severity Index, FACED, and Bronchiectasis Aetiology Comorbidity Index, to predict long-term outcomes in bronchiectasis. Disease severity, however, implies an advanced process with lung destruction. Earlier intervention may prevent disease progression and improve outcomes. To identify patients at risk, rather than patients with established advanced disease, we need to shift our focus from disease severity to disease activity. Disease activity denotes the activation level of underlying pathophysiological processes and can be measured using clinical presentations and biomarkers. This review discusses a paradigm shift in bronchiectasis management, focusing on disease activity rather than severity, to prevent disease progression.

Dietary patterns during pregnancy and maternal and birth outcomes in women with type 1 diabetes: the Environmental Determinants of Islet Autoimmunity (ENDIA) study.

AIMS/HYPOTHESIS: Dietary patterns characterised by high intakes of vegetables may lower the risk of pre-eclampsia and premature birth in the general population. The effect of dietary patterns in women with type 1 diabetes, who have an increased risk of complications in pregnancy, is not known. The aim of this study was to investigate the relationship between dietary patterns and physical activity during pregnancy and maternal complications and birth outcomes in women with type 1 diabetes. We also compared dietary patterns in women with and without type 1 diabetes. METHODS: Diet was assessed in the third trimester using a validated food frequency questionnaire in participants followed prospectively in the multi-centre Environmental Determinants of Islet Autoimmunity (ENDIA) study. Dietary patterns were characterised by principal component analysis. The Pregnancy Physical Activity Questionnaire was completed in each trimester. Data for maternal and birth outcomes were collected prospectively. RESULTS: Questionnaires were completed by 973 participants during 1124 pregnancies. Women with type 1 diabetes (n=615 pregnancies with dietary data) were more likely to have a 'fresh food' dietary pattern than women without type 1 diabetes (OR 1.19, 95% CI 1.07, 1.31; p=0.001). In women with type 1 diabetes, an increase equivalent to a change from quartile 1 to 3 in 'fresh food' dietary pattern score was associated with a lower risk of pre-eclampsia (OR 0.37, 95% CI 0.17, 0.78; p=0.01) and premature birth (OR 0.35, 95% CI 0.20, 0.62, p<0.001). These associations were mediated in part by BMI and HbA1c. The 'processed food' dietary pattern was associated with an increased birthweight (ß coefficient 56.8 g, 95% CI 2.8, 110.8; p=0.04). Physical activity did not relate to outcomes. CONCLUSIONS/INTERPRETATION: A dietary pattern higher in fresh foods during pregnancy was associated with sizeable reductions in risk of pre-eclampsia and premature birth in women with type 1 diabetes.

Disease resistance gene count increases with rainfall in Silphium integrifolium.

Intracellular plant defense against pathogens is mediated by a class of disease resistance genes known as NB-LRRs or NLRs (R genes). Many of the diseases these genes protect against are more prevalent in regions of higher rainfall, which provide better growth conditions for the pathogens. As such, we expect a higher selective pressure for the maintenance and proliferation of R genes in plants adapted to wetter conditions. In this study, we enriched libraries for R genes using RenSeq from baits primarily developed from the common sunflower (Helianthus annuus) reference genome. We sequenced the R gene libraries of Silphium integrifolium Michx, a perennial relative of sunflower, from 12 prairie remnants across a rainfall gradient in the Central Plains of the United States, with both Illumina short-read (n = 99) and PacBio long-read (n = 10) approaches. We found a positive relationship between the mean effective annual precipitation of a plant's source prairie remnant and the number of R genes in its genome, consistent with intensity of plant pathogen coevolution increasing with precipitation. We show that RenSeq can be applied to the study of ecological hypotheses in non-model relatives of model organisms.

A systematic literature review of the clinical and socioeconomic burden of bronchiectasis.

BACKGROUND: The overall burden of bronchiectasis on patients and healthcare systems has not been comprehensively described. Here, we present the findings of a systematic literature review that assessed the clinical and socioeconomic burden of bronchiectasis with subanalyses by aetiology (PROSPERO registration: CRD42023404162). METHODS: Embase, MEDLINE and the Cochrane Library were searched for publications relating to bronchiectasis disease burden (December 2017-December 2022). Journal articles and congress abstracts reporting on observational studies, randomised controlled trials and registry studies were included. Editorials, narrative reviews and systematic literature reviews were included to identify primary studies. PRISMA guidelines were followed. RESULTS: 1585 unique publications were identified, of which 587 full texts were screened and 149 were included. A further 189 citations were included from reference lists of editorials and reviews, resulting in 338 total publications. Commonly reported symptoms and complications included dyspnoea, cough, wheezing, sputum production, haemoptysis and exacerbations. Disease severity across several indices and increased mortality compared with the general population was reported. Bronchiectasis impacted quality of life across several patient-reported outcomes, with patients experiencing fatigue, anxiety and depression. Healthcare resource utilisation was considerable and substantial medical costs related to hospitalisations, treatments and emergency department and outpatient visits were accrued. Indirect costs included sick pay and lost income. CONCLUSIONS: Bronchiectasis causes significant clinical and socioeconomic burden. Disease-modifying therapies that reduce symptoms, improve quality of life and reduce both healthcare resource utilisation and overall costs are needed. Further systematic analyses of specific aetiologies and paediatric disease may provide more insight into unmet therapeutic needs.

A modern approach to multiple pulmonary resections in children with recurrent metastatic pulmonary disease.

Implications of repeated resections of pulmonary metastasis (PM) are not well documented in the modern era. Fifteen children underwent two (n = 8), three (n = 3), or four or more (n = 3) resections (total = 38 procedures), most commonly for osteosarcoma (71%). Operative approach included muscle-sparing thoracotomy (71%), non-muscle-sparing thoracotomy (18%), and video-assisted thoracoscopy (11%). Median resected nodules per procedure was four (range = 1-95). Prolonged air leaks were the most common postoperative complication (29%). Median hospital stay was 4 days, and no children were discharged with or have required oxygen. Event-free survival is 67% at median follow-up time of 54 months, with an overall survival rate of 64%. Repeat resection of PM appears to be well tolerated, without prolonged hospital stays or compromised pulmonary function.

US Commercial Plans Increase Choice Of Biosimilar And Originator Products; Market Net Prices Decrease.

Biosimilars drugs are almost identical copies of original biologic products. Early biosimilars had slower adoption and savings than expected; however, biosimilars launched in recent years have had more success. With several biosimilar launches planned in the next few years, it is important to understand how the state of the market might foretell significant market savings in the future. To do so, we explored how the introduction of biosimilars affected originator-biosimilar markets during the period 2017-22. We found that after biosimilar availability, payers increasingly allowed choice of preferred products. By 2022, 76 percent of commercial payers' coverage policies listed two or more products (originator or biosimilar) as first-line options. Biosimilar market shares exceeded those of originators a mean of three years after first biosimilar launch, and originator-biosimilar market average sales price declined substantially. Taken together, these findings provide evidence of a functioning competitive market.

Biotic and abiotic factors affecting Atlantic ghost crab (Ocypode quadrata) spatiotemporal activity at an important shorebird nesting site in Virginia.

Atlantic ghost crabs (Ocypode quadrata) are predators of beach-nesting shorebird nests and chicks on the United States' Atlantic and Gulf coasts. Ghost crabs may also disturb birds, altering foraging, habitat use, or nest and brood attendance patterns. Shorebird conservation strategies often involve predator and disturbance management to improve reproductive success, but efforts rarely target ghost crabs. Despite the threat to shorebird reproductive success, ghost crabs are a poorly understood part of the beach ecosystem and additional knowledge about ghost crab habitat selection is needed to inform shorebird conservation. We monitored ghost crab activity, defined as burrow abundance, throughout the shorebird breeding season on Metompkin Island, Virginia, an important breeding site for piping plovers (Charadrius melodus) and American oystercatchers (Haematopus palliatus). We counted burrows at shorebird nests and random locations throughout the breeding season and investigated whether ghost crab activity was greater at nest sites relative to random locations without shorebird nests. While we observed burrows at all nest sites (n = 63 nests), we found that burrow counts were lower at piping plover nests with shell cover, relative to random locations with no shell cover. Ghost crabs may avoid piping plover nest sites due to anti-predator behaviors from incubating adults or differences in microhabitat characteristics selected by piping plovers. We also investigated the effects of habitat type, date, and air temperature on the abundance of ghost crab burrows. We found that while crab burrows were present across the barrier island landscape, there were more burrows in sandy, undisturbed habitats behind the dunes, relative to wave-disturbed beach. Additionally, ghost crab activity increased later in the shorebird breeding season. Understanding when and where ghost crabs are most likely to be active in the landscape can aid decision-making to benefit imperiled shorebird populations.

Data Safety Monitoring Boards: Overview of Structure and Role in Spinal Cord Injury Studies.

This paper provides an overview of the history, composition, organization, responsibilities, and regulatory requirements of Data Safety Monitoring Boards (DSMB), with particular reference to the context of clinical trials in spinal cord injury. It is intended to help potential members of such boards and those undertaking the design of new clinical trials to understand the important role of the DSMB in safeguarding the integrity of complex trials, promoting safety, and countering potential bias. An independent DSMB helps to protect research subjects by providing study oversight and serves as an additional step to assure that clinical trials are performed to existing and appropriate standards. The DSMB must meet on a regular schedule, diligently evaluate all the information it receives, and report in a timely and decisive manner. Members must be free of significant conflicts of interest throughout the study and be adequately trained and experienced to serve their roles within the group. DSMB service can be a valuable learning experience and a gratifying opportunity to participate in advancing medicine and helping to maintain and improve the standards of research.

Disparities in Surgical Intervention and Health-Related Quality of Life Among Racial/Ethnic Groups With Degenerative Lumbar Spondylolisthesis.

BACKGROUND AND OBJECTIVES: Racial and socioeconomic disparities in spine surgery for degenerative lumbar spondylolisthesis persist in the United States, potentially contributing to unequal health-related quality of life (HRQoL) outcomes. This is important as lumbar spondylolisthesis is one of the most common causes of surgical low back pain, and low back pain is the largest disabler of individuals worldwide. Our objective was to assess the relationship between race, socioeconomic factors, treatment utilization, and outcomes in patients with lumbar spondylolisthesis. METHODS: This cohort study analyzed prospectively collected data from 9941 patients diagnosed with lumbar spondylolisthesis between 2015 and 2020 at 5 academic hospitals. Exposures were race, socioeconomic status, health coverage, and HRQoL measures. Main outcomes and measures included treatment utilization rates between racial groups and the association between race and treatment outcomes using logistic regression, adjusting for patient characteristics, socioeconomic status, health coverage, and HRQoL measures. RESULTS: Of the 9941 patients included (mean [SD] age, 67.37 [12.40] years; 63% female; 1101 [11.1%] Black, Indigenous, and People of Color [BIPOC]), BIPOC patients were significantly less likely to use surgery than White patients (odds ratio [OR] = 0.68; 95% CI, 0.62-0.75). Furthermore, BIPOC race was associated with significantly lower odds of reaching the minimum clinically important difference for physical function (OR = 0.74; 95% CI, 0.60; 0.91) and pain interference (OR = 0.77; 95% CI, 0.62-0.97). Medicaid beneficiaries were significantly less likely (OR = 0.65; 95% CI, 0.46-0.92) to reach a clinically important improvement in HRQoL when accounting for race. CONCLUSION: This study found that BIPOC patients were less likely to use spine surgery for degenerative lumbar spondylolisthesis despite reporting higher pain interference, suggesting an association between race and surgical utilization. These disparities may contribute to unequal HRQoL outcomes for patients with lumbar spondylolisthesis and warrant further investigation to address and reduce treatment disparities.

Psychological Factors Protecting Against Suicidality in Older Adults: A Systematic Review.

OBJECTIVE: Suicide rates in older adults are often the highest of any age group, particularly among high income countries. However, there is a limited understanding of the factors that could protect against suicidality in older age. This systematic review aimed to identify and evaluate the psychological factors that protect against suicidality in older age. METHOD: An a priori protocol was established and registered on PROSPERO (CRD42022343694). EMBASE, MEDLINE, PsycINFO, Web of Science and Scopus were searched. Papers were quality assessed using the Quality Assessment with Diverse Studies (QuADSs) tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Seventeen papers were included and narratively synthesised. RESULTS: The initial searches identified 10,673 records, resulting in the screening of 5441 records after the removal of duplicates. The protective factors identified were (1) meaning/purpose in life, (2) reasons for living, (3) coping styles, (4) psychological wellbeing, (5) life satisfaction, (6) personality factors, (7) cognitive functioning, and (8) sense of belonging. The factors with the most empirical support were meaning in life, followed by psychological wellbeing and coping responses, such as primary control strategies, and personality traits, such as positive affect and agency. There was also evidence to suggest that the influence of some protective factors, for example meaning in life, may depend upon stage in older life and gender. CONCLUSION: This review identified several psychological factors that have been found to protect against suicidal ideation in older adults, representing potential treatment targets for reducing suicide in older adults. Recommendations for future research includes greater use of longitudinal and case-control designs, measuring outcomes across the continuum of suicidality and using samples that allow comparison between younger and older adults and within the spectrum of old age.

Recall of Flavor at First E-cigarette Use and its Association with E-cigarette Progression: The Mediating Effects of First Sensory Experience.

OBJECTIVE: To test whether the association between flavor at first vape and continued use is mediated through subjective experience at first vape. STUDY DESIGN: In a 2020 cross-sectional survey, 955 young adult ever-vapers recalled their first flavor vaped, subjective experiences at first use, current vaping behavior, nicotine dependence, and quit attempts. A latent class model grouped first-use subjective experiences into classes. Two-part negative binomial hurdle models for each vaping behavior evaluated whether the association of first flavor used with vaping outcomes was mediated by positive experience. RESULTS: Four latent classes (positive, positive and negative, negative, and minimal experience) were further reduced to "any positive experience" (only positive, positive and negative) vs "no positive experience" (negative or minimal). Class membership mediated the association of first flavor used (mint/menthol/ice [ie, "cooling"] or sweet vs other) with each vaping outcome. For example, cooling flavor (vs. other) was associated with positive class membership (OR=3.5; 95%CI:1.5,8.1), which was then associated with any past 30-day vaping (OR=3.9; 95%CI:2.7,5.8) and greater number of vaping days among current vapers (RR=1.9; 95%CI:1.3,2.7) in the two-part hurdle model. Similar results were observed for nicotine dependence and quit attempts, and for sweet (vs. other) flavor for any dependence or quit attempts, but not number of dependence symptoms or quit attempts. CONCLUSIONS: Use of a cooling or sweet flavor at first use was associated with having a positive first vaping sensory experience, and then greater likelihood as a young adult of reporting past 30-day vaping, more vaping days, and greater risk for nicotine dependence, suggesting a key mediating role of first use experience.

Upgrading of Grade Group 1 Prostate Cancer at Prostatectomy: Germline Risk Factors in a Prospective Cohort.

BACKGROUND: Localized prostate tumors show significant spatial heterogeneity, with regions of high-grade disease adjacent to lower-grade disease. Consequently, prostate cancer biopsies are prone to sampling bias, potentially leading to underestimation of tumor grade. To study the clinical, epidemiologic and molecular hallmarks of this phenomenon, we conducted a prospective study of grade upgrading: differences in detected prostate cancer grade between biopsy and surgery. METHODS: We established a prospective, multi-institutional cohort of men with Grade Group 1 (GG1) prostate cancer on biopsy who underwent radical prostatectomy. Upgrading was defined as detection of GG2+ in the resected tumor. Germline DNA from 192 subjects was subjected to whole-genome sequencing to quantify ancestry, pathogenic variants in DNA damage response genes and polygenic risk. RESULTS: Of 285 men, 67% upgraded at surgery. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. No assessed genetic risk factor was predictive of upgrading, including polygenic risk scores for prostate cancer diagnosis. CONCLUSIONS: In a cohort of low-grade prostate cancer patients, a majority upgraded at radical prostatectomy. PSA density and percent of cancer in pre-prostatectomy positive biopsy cores portended the presence of higher-grade disease, while germline genetics was not informative in this setting. Patients with low-risk prostate cancer, but elevated PSA density or percent cancer in positive biopsy cores, may benefit from repeat biopsy, additional imaging or other approaches to complement active surveillance. IMPACT: Further risk stratification of patients with low-risk prostate cancer may provide useful context for active surveillance decision-making.