Quantification of circulating TCR-engineered T cells targeting a human endogenous retrovirus post-adoptive transfer using nanoplate digital PCR.

In vivo expansion of genetically modified T cells in cancer patients following adoptive transfer has been linked to both anti-tumor activity and T cell-mediated toxicities. The development of digital PCR has improved the accuracy in quantifying the in vivo status of adoptively infused T cells compared to qPCR or flow cytometry. Here, we developed and evaluated the feasibility and performance of nanoplate-based digital PCR (ndPCR) to quantify adoptively infused T cells engineered with a T cell receptor (TCR) that recognizes a human endogenous retrovirus type E (HERV-E) antigen. Analysis of blood samples collected from patients with metastatic kidney cancer following the infusion of HERV-E TCR-transduced T cells established the limit of detection of ndPCR to be 0.3 transgene copies/µL of reaction. The lower limit of quantification for ndPCR was one engineered T cell per 10,000 PBMCs, which outperformed both qPCR and flow cytometry by 1 log. High inter-test and test-retest reliability was confirmed by analyzing blood samples collected from multiple patients. In conclusion, we demonstrated the feasibility of ndPCR for detecting and monitoring the fate of TCR-engineered T cells in adoptive cell therapy.

Per- and polyfluoroalkyl substances (PFAS) in drinking water in Southeast Los Angeles: Industrial legacy and environmental justice.

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals of increasing concern to human health. PFAS contamination in water systems has been linked to a variety of sources including hydrocarbon fire suppression activities, industrial and military land uses, agricultural applications of biosolids, and consumer products. To assess PFAS in California tap water, we collected 60 water samples from inside homes in four different geographic regions, both urban and rural. We selected mostly small water systems with known history of industrial chemical or pesticide contamination and that served socioeconomically disadvantaged communities. Thirty percent of the tap water samples (18) had a detection of at least one of the 32 targeted PFAS and most detections (89 %) occurred in heavily industrialized Southeast Los Angeles (SELA). The residents of SELA are predominately Latino and low-income. Concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) ranged from 6.8 to 13.6 ng/L and 9.4-17.8 ng/L, respectively in SELA and were higher than State (PFOA: 0.007 ng/L; PFOS: 1.0 ng/L) and national health-based goals (zero). To look for geographic patterns, we mapped potential sources of PFAS contamination, such as chrome plating facilities, airports, landfills, and refineries, located near the SELA water systems; consistent with the multiple potential sources in the area, no clear spatial associations were observed. The results indicate the importance of systematic testing of PFAS in tap water, continued development of PFAS regulatory standards and advisories for a greater number of compounds, improved drinking-water treatments to mitigate potential health threats to communities, especially in socioeconomically disadvantaged and industrialized areas.

Regression of renal cell carcinoma by T cell receptor-engineered T cells targeting a human endogenous retrovirus.

BACKGROUND: We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells). METHODS: We isolated a CD8+ T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells. RESULTS: The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8+ T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11+ ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC. CONCLUSIONS: This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).

Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy.

Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.

Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes.

Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes.

AVIAN HAEMOSPORIDIANS IN GREATER SCAUP (AYTHYA MARILA) AND LESSER SCAUP (AYTHYA AFFINIS) FROM WISCONSIN.

Avian haemosporidians are a diverse group of protozoan parasites that infect a wide range of host species. Waterfowl are an ecologically and economically important group of hosts that have been underrepresented in studies of haemosporidians. Diving ducks have unique life history traits, and morphological, behavioral, and dietary differences separate them from more common dabbling ducks. Greater scaup (Aythya marila) and lesser scaup (Aythya affinis) are closely related diving ducks with declining population trends in North America. To better understand the diversity of haemosporidians within diving ducks and factors related to host infections in scaup, we surveyed 82 hunter-donated waterfowl from 8 species of divers, sea ducks, and dabblers from Green Bay, Wisconsin from 2019 to 2021. We used molecular detection methods and phylogenetic and statistical analyses to describe the diversity, host associations, and prevalence of haemosporidians. We detected 14 unique genetic lineages of haemosporidians, including 4 novel lineages. We identified at least 1 lineage of haemosporidian in each of the 8 host species of divers, sea ducks, and dabblers examined. Lesser scaup had more diverse haemosporidian communities than did greater scaup, but lineages showed no clustering among these hosts when incorporated in phylogenetic analyses with lineages from other Nearctic waterfowl. Female lesser scaup had the highest infection prevalence, but there was no effect of host age or year of sampling. Our findings underscore the importance of species and sex differences that could lead to a higher risk of infections. Our results also fill an important geographical sampling gap for haemosporidians along a key migratory route. Increased monitoring of haemosporidians in waterfowl could contribute to insights into parasite evolution and ecology and the conservation and management of host populations.

The RAL Small G Proteins Are Clinically Relevant Targets in Triple Negative Breast Cancer.

Breast cancer (BC) is the most frequent cancer and second-leading cause of cancer deaths in women in the United States. While RAS mutations are infrequent in BC, triple-negative (TN) and HER2-positive (HER2+) BC both exhibit increased RAS activity. Here, we tested the RAS effectors RALA and RALB, which are overexpressed in BC, as tractable molecular targets in these subtypes. While analysis of the breast cancer patient sample data suggests that the RALs are associated with poor outcome in both TNBC and HER2+ BC, our in vivo and in vitro experimental findings revealed the RALs to be essential in only the TNBC cell lines. While testing the response of the BC cell lines to the RAL inhibitors RBC8 and BQU57, we observed no correlation between drug efficacy and cell line dependency on RAL expression for survival, suggesting that these compounds kill via off-target effects. Finally, we report the discovery of a new small molecule inhibitor, OSURALi, which exhibits strong RAL binding, effectively inhibits RAL activation, and is significantly more toxic to RAL-dependent TNBC cells than RAL-independent HER2+ and normal cell lines. These results support the RALs as viable molecular targets in TNBC and the further investigation of OSURALi as a therapeutic agent.

Cancer in multi-lineage mosaic RASopathies due to pathogenic variants in HRAS or KRAS: a systematic review and meta-analysis.

PURPOSE: To determine the cancer risk and spectrum in patients with multi-lineage mosaic RASopathies with pathogenic variants (PV) in HRAS or KRAS. METHODS: We conducted a systematic literature review to identify multi-lineage mosaic RASopathy cases with a PV in HRAS or KRAS to create a retrospective cohort. We calculated cumulative incidence, cancer-free survival and hazard rates (HR) for cancer and standardized incidence rates (SIR). RESULTS: This study identified 69 patients. Seventeen percent had cancer, including rhabdomyosarcoma located in the urogenital region (n=7), skin cancer (n=3), Wilms tumor (n=1), and bladder cancer (n=1). Cumulative cancer incidence by age 20 was 20% (95% CI, 4 to 37%). The annual cancer HR peaked at 14% within the first two years of life. The highest SIR was found for rhabdomyosarcoma (SIR = 800, 95% CI, 300 to 1648). CONCLUSIONS: This is the first investigation of cancer risk in KRAS or HRAS PV-positive mosaic RASopathies to date. The high incidence and SIR values found highlight the need for rigorous rhabdomyosarcoma surveillance in young children and skin cancer surveillance in adults with this high-risk condition.

Correlation between renal sonographic measurements and differential renal function obtained from nuclear renography in children with unilateral hydronephrosis.

INTRODUCTION: Children with higher grades of hydronephrosis often undergo mercaptoacetyltriglycine nuclear renography scans (MAG3) to assess differential renal function (DRF) and drainage. Although MAG3 helps identify the potential need for pyeloplasty, its use incurs increased costs, radiation exposure, and stress for children and families. Several studies demonstrate pyramidal thickness (PT) ≤ 3 mm as a reliable predictive risk factor for pyeloplasty in children with a history of prenatal hydronephrosis. Our hypothesis was that renal sonographic measurements including PT and parenchymal thickness (ParT) correlate with DRF in children with high-grade unilateral hydronephrosis and may be used to better select the need and frequency of MAG3 scans in children at increased risk for diminished relative renal function. The objective of this project was to determine the correlation between sonographic renal measurements and DRF in patients with unilateral hydronephrosis, we assessed: 1) the correlation between PT, ParT, and the ratio of PT/ParT in hydronephrotic kidneys to DRF, 2) the correlation between the ratio of hydronephrotic PT/contralateral non-hydronephrotic PT and DRF, 3) the correlation between the ratio of hydronephrotic ParT/contralateral non-hydronephrotic ParT and DRF, and 4) the correlation between the ratio of (hydronephrotic PT/ParT)/(contralateral non-hydronephrotic PT/ParT) and DRF. MATERIALS AND METHODS: We retrospectively reviewed 71 children with grades 3 or 4 unilateral hydronephrosis. Most patients presented with a history of prenatally detected hydronephrosis at median age (IQR) of 112 days (43-274). Measurements of PT and ParT were completed on 98 renal ultrasounds and DRF was collected from corresponding MAG3 scans. Threshold values were identified visually through scatterplots. Spearman's correlation coefficient and Fisher's p-values were calculated. DISCUSSION: Ratios of PT and ParT in hydronephrotic kidneys to contralateral non-hydronephrotic kidneys were positively correlated with DRF. Ratios of hydronephrotic PT/non-hydronephrotic PT > 0.8 and hydronephrotic ParT/non-hydronephrotic ParT >0.7 occurred more frequently in patients with a DRF >40% (p = 0.11 and p = 0.001, respectively). A PT > 3 mm and ParT >5 mm occurred significantly more frequently in patients with a DRF >40% (p = 0.008 and p = 0.006, respectively). CONCLUSIONS: Renal sonographic measurements including threshold values of PT > 3 mm, ParT > 5 mm, ratio of hydronephrotic PT/contralateral non-hydronephrotic PT (>0.8), and ratio of hydronephrotic ParT/contralateral non-hydronephrotic ParT (>0.7) are good predictors of DRF >40% in unilateral high-grade hydronephrosis. These identified threshold values have potential utility in determining the need for nuclear renal scans in children with high-grade hydronephrosis.

Advanced Practice Providers in the Medical Genetics Workforce: A Nationwide Survey.

PURPOSE: This study characterizes the current landscape of genetics advanced practice providers (APPs) in the United States. METHODS: A 35-question survey was emailed to the Genetics APP Listserv in the fall of 2023. Questions represented five domains: demographics, practice, onboarding, compensation, and perceptions. RESULTS: A total of 105 genetics APPs (93%) completed the survey. Genetics APPs evaluate various patient types and populations in multiple settings, working an average of 41.3 hours and seeing 15 patients weekly. Nearly all see new (96%) and follow-up (98%) patients and utilize telemedicine (93%). Half (51%) have only worked in the genetics specialty during their career. Overall, APPs are generally satisfied with their career as a genetics APP (98%) and work-life balance (86%), and most (86%) feel they function at the top of their scope. CONCLUSION: Study findings elucidate the current state of genetics APPs. Results define the characteristics and role of an APP in the genetics specialty and will guide employers and genetics organizations to utilize APPs at the top of their scope and recruit new APPs to this exciting field. A collaborative effort is needed to increase the overall genetics workforce, decrease patient wait times, and increase access to genetics care.

Associations Between Gender Dysphoria, Eating Disorders, and Mental Health Diagnoses Among Adolescents.

PURPOSE: Transgender adolescents and adolescents with eating disorders (EDs) are known to have increased mental health comorbidity; however, little is understood about how gender dysphoria (GD), disordered eating and mental health disorders relate to each other. The purpose of this study was to examine associations between GD, ED, and mental health diagnoses among adolescents. METHODS: Data were extracted from the electronic health records of 57,353 patients aged 9-18 seen at a single pediatric health system between 2009 and 2022. Adjusted logistic regression models tested for associations between GD, ED, and mental health diagnoses. RESULTS: Youth with a GD diagnosis had significantly greater odds of also having an ED diagnosis compared to those without a GD diagnosis (adjusted odds ratio [aOR] = 3.72, 95% confidence interval [CI]: 2.98-4.64). Among those with an ED diagnosis, youth with a GD diagnosis had significantly lower odds of having an anorexia nervosa diagnosis (aOR = 0.34, 95% CI: 0.18-0.61) and significantly greater odds of having an unspecified or other specified ED diagnosis (aOR = 2.48, 95% CI: 1.56-3.93) compared to those without a GD diagnosis. Youth with both GD and ED diagnoses had significantly greater odds of also having a diagnosis of anxiety (aOR = 24.01, 95% CI: 14.85-38.83), depression (aOR = 48.41, 95% CI: 30.38-77.12), suicidality (aOR = 26.15, 95% CI: 16.65-41.05) and self-harm (aOR = 35.79, 95% CI: 22.48-56.98) as compared to those with neither a GD nor an ED diagnosis. DISCUSSION: Adolescents with co-occurring GD and ED diagnoses are at greater risk for anxiety, depression, suicidality, and self-harm as compared to youth with neither diagnosis. Further research is essential to understand the complex interplay of mental health concerns and EDs among gender diverse adolescents and to inform appropriate interventions.

Defining fatigue from the experiences of patients living with chronic fatigue.

Introduction: Fatigue is a multidimensional, highly individualized symptom experience perceived by people, regardless of health status. It is the most common complaint among those seeking primary care, yet, despite being a frequently reported symptom, it remains poorly understood. Methods: This is an exploratory study utilizing a qualitative descriptive approach that aims to explore the description of fatigue from the personal experiences of 16 participants living with chronic fatigue. Themes were generated from transcripts of in-depth interviews that focused on a central question: "how would you describe your fatigue from your own experience?" Results: Analysis of the participants' interview transcripts revealed three themes. The first theme focused on fatigue as a unique personal experience, which included experiential descriptions or measures of fatigue that the participants used to describe their symptoms. The second theme focused on fatigue as an experience beyond self, which highlighted the consequences of fatigue on interpersonal interactions and the performance of social roles, as well as the potential of utilizing social support to cope with the limitations caused by this condition. The last theme was on living with fatigue, which focused on ways participants attempted to discern their condition and manage the consequences of fatigue. Discussion: Experiences of chronic fatigue have patterns and personal meanings that vary between individuals. Caring for persons experiencing chronic fatigue requires acknowledgment of unique personal experiences and coping strategies. Due to the nature of the method, the results of this study are not generalizable and only reflect the experiences of the participants.

Does Reframing Do-Not-Resuscitate to Beneficial Care Only Increase Acceptance of No-CPR Orders?

BACKGROUND: The terminology of a do not resuscitate (DNR) order can be confusing and controversial for patients at the end of life. We examined whether changing the name to beneficial care only (BCO) would increase patient acceptance. RESEARCH QUESTION: Would individuals be more willing to forgo full code (FC) status and accept a no-CPR order if the order title was BCO? STUDY DESIGN AND METHODS: We conducted a cross-sectional survey of 599 adults residing in the United States, presenting participants with a hypothetical scenario of a terminal patient. One-half were given a choice between FC and DNR status, and one-half were given a choice between FC and BCO status. The 20-item survey included multiple-choice responses and 1 free-response question. RESULTS: In our nationally representative survey of US participants who were 50% female and 26% non-White (99% response rate, 599 of 600), there was no difference in participant preference for BCO or DNR overall (P = .7616) and across participant sociodemographic characteristics. Although themes of participant reasons for choosing against CPR were similar for both DNR and BCO preferences, including harms imposed by CPR, lack of quality of life, trust in the medical team, and avoidance of suffering, 2 additional themes appeared only for BCO responses, including CPR would be useless and the patient would continue to receive beneficial care. INTERPRETATION: We found no statistically significant difference in preference between BCO and DNR orders for a terminally ill patient. These findings suggest changing the terminology of DNR to BCO may not lead to changes in decisions to forgo CPR. The additional themes identified with the use of BCO support the concept that BCO terminology conveys to the recipient that all beneficial care will continue to be provided to the patient.

Identification of micro- and nanoplastic particles in postnatal sprague-dawley rat offspring after maternal inhalation exposure throughout gestation.

Micro-nanoplastic particulates (MNPs) have been identified in both indoor and outdoor environments. From these real-world exposures, MNPs have been identified in human fluids and organ tissues, including the placenta and breastmilk. Laboratory studies have identified MNPs are capable of crossing the placental barrier and depositing in fetal tissues; however, it remained unclear if MNPs persist in offspring tissues after birth. Six pregnant Sprague-Dawley rats were divided equally into two groups: control and exposed to polyamide-12 (PA-12) MNP aerosols (11.46 ± 3.78 mg/m3) over an average of 4.35 h ± 0.39 for 10 non-consecutive days between gestational day (GD) 6 - GD 19, in our custom rodent exposure chamber, allowing for whole-body inhalation. Two-weeks after delivery in-house, offspring tissues (i.e. lung, liver, kidney, heart, brain) from 1 male and 1 female pup per litter were fixed in 4 % paraformaldehyde, sectioned, stained with hematoxylin and eosin, and assessed using hyperspectral dark-field microscopy. PA-12 MNPs were identified in all offspring tissues of the exposed dams. No MNPs were visualized in control tissues. These findings have important implications for human MNPs translocation, deposition, maternal/fetal health, and the developmental origins of health and disease. Further research is warranted to quantify MNPs mass deposition, biological accumulation, and systemic toxicity.

Using machine learning to dissect host kinases required for Leishmania internalization and development.

The Leishmania life cycle alternates between promastigotes, found in the sandfly, and amastigotes, found in mammals. When an infected sandfly bites a host, promastigotes are engulfed by phagocytes (i.e., neutrophils, dendritic cells, and macrophages) to establish infection. When these phagocytes die or break down, amastigotes must be re-internalized to survive within the acidic phagolysosome and establish disease. To define host kinase regulators of Leishmania promastigote and amastigote uptake and survival within macrophages, we performed an image-based kinase regression screen using a panel of 38 kinase inhibitors with unique yet overlapping kinase targets. We also targeted inert beads to complement receptor 3 (CR3) or Fcγ receptors (FcR) as controls by coating them with complement/C3bi or IgG respectively. Through this approach, we identified several putative host kinases that regulate receptor-mediated phagocytosis and/or the uptake of L. amazonensis. Findings included kinases previously implicated in Leishmania uptake (such as Src family kinases (SFK), Abl family kinases (ABL1/c-Abl, ABL2/Arg), and spleen tyrosine kinase (SYK)), but we also uncovered many novel kinases. Our methods also predicted host kinases necessary for promastigotes to convert to amastigotes or for amastigotes to survive within macrophages. Overall, our results suggest that the concerted action of multiple interconnected networks of host kinases are needed over the course of Leishmania infection, and that the kinases required for the parasite's life cycle may differ substantially depending on which receptors are bound and the life cycle stage that is internalized. In addition, using our screen, we identified kinases that appear to preferentially regulate the uptake of parasites over beads, indicating that the methods required for Leishmania to be internalized by macrophages may differ from generalized phagocytic mechanisms. Our findings are intended to be used as a hypothesis generation resource for the broader scientific community studying the roles of kinases in host-pathogen interactions.

Convergent evolution of plant prickles by repeated gene co-option over deep time.

An enduring question in evolutionary biology concerns the degree to which episodes of convergent trait evolution depend on the same genetic programs, particularly over long timescales. In this work, we genetically dissected repeated origins and losses of prickles-sharp epidermal projections-that convergently evolved in numerous plant lineages. Mutations in a cytokinin hormone biosynthetic gene caused at least 16 independent losses of prickles in eggplants and wild relatives in the genus Solanum. Homologs underlie prickle formation across angiosperms that collectively diverged more than 150 million years ago, including rice and roses. By developing new Solanum genetic systems, we leveraged this discovery to eliminate prickles in a wild species and an indigenously foraged berry. Our findings implicate a shared hormone activation genetic program underlying evolutionarily widespread and recurrent instances of plant morphological innovation.

PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases.

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, ß/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (ß/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

Plant volatiles: Herbivores shush the chatty tree.

Plant-insect interactions can be complex and elusive. A new study shows that sap-feeding herbivores reduce tree emissions of specific volatile organic compounds that attract natural enemies. Sap-feeding insects thereby provide enemy-free space for chewing herbivores living on the same tree.

Practice Readiness? Trends in Chief Resident Case Logs vs Subsequent Case Log Data in Clinical Practice.

INTRODUCTION: Limited information exists regarding the association between resident surgical case experience and subsequent case mix in practice. We compare the case log distribution residents completed during their chief year to those completed by these graduates in their first 2 years in independent practice. METHODS: Resident chief year case logs from 10 institutions were analyzed across 4 categories of index procedures: (1) general urology, (2) endourology, (3) reconstructive urology, and (4) urologic oncology. Current Procedural Terminology codes for associated index procedures were used to query case log data during their first 2 years in practice collected by the American Board of Urology. Interactions were tested between the trends of chief year case logs relative to trends in practice case logs. RESULTS: Amongst 292 residents, a total of 104,827 cases were logged during chief year and 77,976 cases in the first 2 years as an attending. Most cases completed during chief year were in oncology followed by general urology, endourology, and reconstructive urology. As attendings, most cases completed were in general urology, followed by endourology, reconstructive urology, and oncology. Chief year case logs showed decreasing trends in the median number of case logs in reconstructive urology, endourology, and general urology, while case logs in independent practice noted increasing trends in all index procedure categories over time. CONCLUSIONS: Urology residents perform more cases during their chief year compared to their first 2 years of independent practice. Case types completed as chief residents vs subsequent clinical practice also differ significantly. These observations may have implications for residency training, particularly regarding curriculum design.