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Abstract Porcine circoviruses are circular single-stranded DNA viruses that infect swine and wild boars. Two species of porcine circoviruses exist. Porcine circovirus type 1 is non pathogenic contrary to porcine circovirus type 2 which is associated with the disease known as Post-weaning Multisystemic Wasting Syndrome. Porcine circovirus DNA has been shown to replicate by a rolling circle mechanism. Other studies have revealed similar mechanisms of rolling-circle replication in plasmids and single-stranded viruses such as Geminivirus. Three elements are important in rolling-circle replication: i) a gene encoding initiator protein, ii) a double strand origin, and iii) a single strand origin. However, differences exist between viruses and plasmids and between viruses. Porcine circovirus replication probably involves a "melting pot" rather than "cruciform" rolling-circle mechanism. This review provides a summary of current knowledge of replication in porcine circoviruses as models of the Circovirus genus. Based on various studies, the factors affecting replication are defined and the mechanisms involved in the different phases of replication are described or proposed.

Barriers to medical care include lack of proper infrastructure and equipment; however, cultural barriers to care and poorly perceived quality of care, especially surgical care, can also negatively impact a patient's utilization of healthcare services. This study used patient-survey data from three unique municipalities in Nicaragua to examine pre-hospital barriers to care, including previous experience with healthcare, and how those experiences impact patient perceptions of surgery and care-seeking behavior. Surveys were administered in Siuna, Rosita, and Bonanza, Nicaragua between July 2019 and September 2020. Survey participants were aged 18-years or older that live in communities served by the Ministry of Health. The surveys were open response and multiple-choice format. Surveys included questions about structural/cultural/financial barriers to care, communication barriers, and knowledge of healthcare services. Data was managed using REDCap tools and analysis was completed using R. Individuals that previously visited a health post were significantly more likely to have a positive perception of surgery compared to those who had not (OR = 1.4) (p = 0.019). This finding remained significant after adjustment for education, age, and municipality. However, previous hospital visits did not have a significant impact on perception of surgery. Individuals with higher transportation costs reported a negative perception of surgery (40.4%), as well as those who used private transportation (29.1%) (p<0.001). Participants that reported travel obstacles were 2.64 times as likely to have a positive perception of surgery (p<0.001), even when adjusted for all demographics except site. These findings suggest that individuals who previously interacted with only lower-level healthcare environments were significantly more likely to have a positive perception of surgery. Counterintuitive findings show that access to public transport, transportation costs >2USD, and cell-phone usage increased negative perception of surgery. This study demonstrates the complexity of variables that impact perceptions of healthcare services while highlighting areas of focus for future targeted investments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dutton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences., Competing Interests: Declaration of interests S.R.V. has consulted for Jnana Therapeutics within the past 3 years and receives research support from Bayer. C.-Z.Z. is a co-founder, consultant, and equity holder of Pillar Biosciences, a for-profit company specialized in assay development for targeted DNA sequencing. C.B. is currently an employee of Inocras Inc., a for-profit company specialized in whole-genome sequencing of cancer and rare diseases. T.K.C. reports institutional and/or personal, paid and/or unpaid support for research, advisory boards, consultancy, and/or honoraria past 5 years, ongoing or not, from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO, and others), and outside the submitted work; has institutional patents filed on molecular alterations and immunotherapy response/toxicity and ctDNA; holds equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, and Primium; and is on the committees of NCCN, GU Steering Committee, ASCO (BOD 6-2024-, ESMO, ACCRU, and KidneyCan (medical writing and editorial assistance support may have been funded by Communications companies in part); and has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. D.J.E. received research funding to institution from Bristol-Myers Squibb, Cardiff Oncology, MiNK Therapeutics, Novartis, Sanofi, and Puma. Discounted research sequencing from Foundation Medicine., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC)., Patients and Methods: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected., Results: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS., Conclusion: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC., Competing Interests: Disclosure Parvaneh Fallah Scientific advisor/consultant: BMS, Seagen, Pfizer, Astrazeneca, EMD Sereno Canada Honoraria: Astrazeneca, EMD Sereno Canada, Gilead, Merck, Janssen Rohit K Jain Receiving honoraria from FLASCO, Curio Science, DAVA Oncology, NCCN/Pfizer, and OncLive/MJH Life Sciences Consulting for AVEO, Bristol Myers Squibb, Sanofi, EMD Serono, Gilead Sciences, IDEOlogy Pfizer, and Seattle Genetics/Astellas In the speakers’ bureau of Gilead Sciences, Seagen, and Seattle Genetics/Astellas Receiving research funding from Bristol Myers Squibb, Gilead Sciences, and NCI. Praful Ravi Research funding to institution: Lilly, Bayer, Telix Speaker's fees: OncLive Charlene Mantia Consulting/advisory role: Aadi Bioscience, Synthekine, Nextech Institutional research funding: Bristol Myers Squibb Bradley Alexander McGregor Received funds for consulting: Arcus, BMS, Eisai, Exelixis, Gliead, Pfizer, SeaGen Funding to institution - BMS, Exelixis, Gilead, Pfizer, SeaGen Roger Li Research support: Predicine; Veracyte; CG Oncology; Valar labs; Merck. Clinical trial protocol committee: CG Oncology; Merck; Janssen. Scientific advisor/consultant: BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, Janssen, Thericon. Honoraria: SAI MedPartners, Solstice Health Communications, Putnam Associates, UroToday. Wassim Kassouf Consultant or advisory roles: Sesen Bio, Ferring, Roche, BMS, Merck, Janssen, Bayer, Astellas, Seagen, Pfizer/EMD Serono, Photocure Clinical trials: BMS, Roche, Janssen, Theralase, Pfizer, CG Oncology Gregory Russell Pond Received honorariums from Astra-Zeneca and Takeda Received consulting fees from Merck and Profound Medical. Close family member who is employed by Roche Canada, and who owns stock in Roche Ltd. Raskesh K. Jain Received consultant fees from Cur, DynamiCure, Elpis, Merck, SPARC, SynDevRx Owns equity in Accurius, Enlight, SynDevRx Served on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund Received grants from Boehringer Ingelheim and Sanofi. Research is supported by NIH R01CA259253, R01CA269672, R01-NS118929, U01CA261842, and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Niles Albright Research Foundation, and Harvard Ludwig Cancer Center. Guru Sonpavde Advisory Board: EMD Serono, BMS, Merck, Seattle Genetics/Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly/Loxo Oncology, Vial, PrecisCa, Atkis, Kura Oncology, Daiichi-Sankyo Consultant/Scientific Advisory Board (SAB): Syapse, Merck, Servier, Syncorp Research Support to institution: EMD Serono, Jazz Therapeutics, BMS Speaker: Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Merck, Pfizer Data safety monitoring committee (honorarium): Mereo Employment: Spouse employed by Myriad Travel: BMS, Astellas, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to characterize the epidemiology of human seasonal coronaviruses (HCoVs) in southern Malawi., Methods: We tested for HCoVs 229E, OC43, NL63, and HKU1 using real-time polymerase chain reaction (PCR) on upper respiratory specimens from asymptomatic controls and individuals of all ages recruited through severe acute respiratory illness (SARI) surveillance at Queen Elizabeth Central Hospital, Blantyre, and a prospective influenza-like illness (ILI) observational study between 2011 and 2017. We modeled the probability of having a positive PCR for each HCoV using negative binomial models, and calculated pathogen-attributable fractions (PAFs)., Results: Overall, 8.8% (539/6107) of specimens were positive for ≥1 HCoV. OC43 was the most frequently detected HCoV (3.1% [191/6107]). NL63 was more frequently detected in ILI patients (adjusted incidence rate ratio [aIRR], 9.60 [95% confidence interval {CI}, 3.25-28.30]), while 229E (aIRR, 8.99 [95% CI, 1.81-44.70]) was more frequent in SARI patients than asymptomatic controls. In adults, 229E and OC43 were associated with SARI (PAF, 86.5% and 89.4%, respectively), while NL63 was associated with ILI (PAF, 85.1%). The prevalence of HCoVs was similar between children with SARI and controls. All HCoVs had bimodal peaks but distinct seasonality., Conclusions: OC43 was the most prevalent HCoV in acute respiratory illness of all ages. Individual HCoVs had distinct seasonality that differed from temperate settings., Competing Interests: Potential conflicts of interest. J. M. R. has received funding from UK Research and Innovation (UKRI) (MR/V038613/1). A. H. was supported by a Wellcome Trust Clinical PhD Fellowship (097464) and receives funding from UKRI, the Medical Research Council, British Society for Antimicrobial Chemotherapy, Wellcome Trust, and the Medical Research Foundation, unrelated to this work. S. A. was supported by a Wellcome Trust Clinical PhD Fellowship (099962). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Study Question: What is the nature of women's care-seeking for difficulties conceiving in sub-Saharan Africa (SSA), including the correlates of seeking biomedical infertility care at a health facility?, Summary Answer: Care-seeking for difficulties getting pregnant was low, much of which involved traditional or religious sources of care, with evidence of sociodemographic disparities in receipt of biomedical care., What Is Known Already: Nearly all research on infertility care-seeking patterns in SSA is limited to clinic-based studies among the minority of people in these settings who obtain facility-based services. In the absence of population-based data on infertility care-seeking, we are unable to determine the demand for services and disparities in the use of more effective biomedical sources of care., Study Design, Size, Duration: We used cross-sectional, population-based data from the Performance Monitoring for Action (PMA) female survey in eight geographies in SSA, including nationally representative data from Burkina Faso, Côte d'Ivoire, Kenya, and Uganda and regionally representative data from two provinces in the Democratic Republic of the Congo (DRC) (Kinshasa and Kongo Central) and two states in Nigeria (Kano and Lagos). We employed a multi-stage cluster random sampling design with probability proportional to size selection of clusters within each geography to produce representative samples of women aged 15-49. Samples ranged from 1144 in Kano, Nigeria, to 9489 in Kenya. PMA collected these data between November 2021 and December 2022., Participants/materials, Setting, Methods: We restricted the sample to women who had ever had sex, with analytic samples ranging from 854 in Kano to 8,059 in Kenya, then conducted descriptive and bivariable analyses to examine characteristics of those who sought care for difficulties getting pregnant. Among those who reported seeking care, we conducted bivariable and multivariable logistic regression analyses to determine factors associated with receipt of biomedical services from a health facility. All analyses were conducted separately by geography., Main Results and the Role of Chance: Our study found low levels of care-seeking for difficulties getting pregnant among sexually active women in eight geographies in SSA, ranging from 3.7% (Kenya) to 15.3% (Côte d'Ivoire). Of this, 51.8% (Burkina Faso) to 86.7% (Kinshasa) involved receipt of biomedical services in health facilities. While many factors were consistently associated with infertility care-seeking from any source across geographies, factors associated with receipt of biomedical care specifically were less pronounced. This may be a result of the highly limited sources of infertility services in SSA; thus, even privileged groups may struggle to obtain effective treatment for difficulties getting pregnant. However, we did observe disparities in biomedical care-seeking in our bivariable results in several geographies, with the wealthiest women, those with more education, and those residing in urban areas generally more likely to have sought biomedical care for difficulties getting pregnant., Limitations, Reasons for Caution: Our data lacked details on the nature of the services received and outcomes, and we do not have information on reasons why women chose the sources they did. Small samples of women who sought care limited our power to detect significant differences in care-seeking by women's characteristics in several geographies., Wider Implications of the Findings: Infertility and access to appropriate treatment are issues of reproductive health and human rights. While our results do not indicate to what extent use of non-biomedical sources of care is driven by preferences, cost, or lack of accessible services, it is clear from our results and existing literature that more needs to be done to ensure access to affordable, quality, cost-effective infertility services in SSA., Study Funding/competing Interest(s): This study was supported by grants from the Bill & Melinda Gates Foundation (INV009639) and the National Institute of Child Health and Human Development (K01HD107172). The funders were not involved in the study design, analyses, manuscript writing, or the decision to publish. The authors have no conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We characterized the global epidemiology and seasonality of human coronaviruses (HCoVs) OC43, NL63, 229E, and HKU1., Methods: In this systematic review, we searched MEDLINE, EMBASE, Web of Science, SCOPUS, CINAHL, and backward citations for studies published until 1 September 2023. We included studies with ≥12 months of consecutive data and tested for ≥1 HCoV species. Case reports, review articles, animal studies, studies focusing on SARS-CoV-1, SARS-CoV-2, and/or Middle East respiratory syndrome, and those including <100 cases were excluded. Study quality and risk of bias were assessed using Joanna Briggs Institute Critical Appraisal Checklist tools. We reported the prevalence of all HCoVs and individual species. Seasonality was reported for studies that included ≥100 HCoVs annually. This study is registered with PROSPERO, CRD42022330902., Results: A total of 201 studies (1 819 320 samples) from 68 countries were included. A high proportion were from China (19.4%; n = 39), whereas the Southern Hemisphere was underrepresented. Most were case series (77.1%, n = 155) with samples from secondary care (74.1%, n = 149). Seventeen (8.5%) studies included asymptomatic controls, whereas 76 (37.8%) reported results for all 4 HCoV species. Overall, OC43 was the most prevalent HCoV. Median test positivity of OC43 and NL63 was higher in children, and 229E and HKU1 in adults. Among 18 studies that described seasonality (17 from the Northern Hemisphere), circulation of all HCoVs mostly peaked during cold months., Conclusions: In our comprehensive review, few studies reported the prevalence of individual HCoVs or seasonality. Further research on the burden and circulation of HCoVs is needed, particularly from Africa, South Asia, and Central/South America., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy., Competing Interests: Declaration of interests S.R.V. reports consulting (current or past 3 years) for Jnana Therapeutics, research support from Bayer, and that their spouse is an employee of and holds equity in Kojin Therapeutics. D.A.B. reports honoraria from LM Education/Exchange Services; advisory board fees from Exelixis and AVEO; consulting fees from Merck, Pfizer, and Elephas; equity in Elephas, Fortress Biotech (subsidiary), and CurIOS Therapeutics; personal fees from Schlesinger Associates, Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Accolade 2nd.MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, and Scholar Rock; and research support from Exelixis and AstraZeneca, outside of the submitted work. S.C.B., T.K.C., and M.L.F. are co-founders and shareholders of Precede Biosciences., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce., Methods: In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT)., Results: Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS., Conclusions: Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS., Competing Interests: Competing interests: AHN receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology. Consulting fees: Guidepoint Global. RRM: Consulting/Advisory Board – Aveo, AstraZeneca, Bayer, Bristol Myers Squibb, Blue Earth Diagnostics, Calithera, Caris, Denderon, Exelixis, Janssen, Merck, Myovant, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Tempus. Institutional Research Funding – AstraZeneca, BMS, Exelixis, Artera, Oncternal, Bayer, Tempus. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR080659, R01 AR077607, P30 AR070253, and P30 AR072577), the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award funded by the Gordon and Llura Gund Foundation. JAS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, and Sobi unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health. AC received grants for consultancies/advisory boards: MSD, OncoC4, IQVIA, AstraZeneca, Access Infinity, Ardelis Health, Alpha Sight. Speaker fees: AstraZeneca, Eisai, Pierre-Fabre, MSD. Writing/Editorial activity: BMS. Travel support: Sanofi and MSD. ARN reports Funding to Institution for Trials he is PI on:Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelixis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals. ARN receives Consultant Editor Compensation: JCO Precision Oncology. Consulting/Advisory Board: Foundation Med. ARN reports Travel Compensation from: SITC/ AACR/ Conquer Cancer Foundation, Jazz Pharmaceuticals, Binay Tara Foundation, Foundation Med., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n = 222 plasma samples) and qualified it achieving an AUC > 0.93 for detecting pathology-confirmed CRPC-NE (n = 136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification., Significance: Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. We describe the development and validation of a plasma cell-free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. This article is featured in Selected Articles from This Issue, p. 384., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Comprehensive profiling of autoantibodies (AAbs) in metastatic urothelial cancer (mUC) has not been performed to date. This may aid in diagnosis of UC, uncover novel therapeutic targets in this disease as well as identify associations between AAbs and response and toxicity to systemic therapies., Methods: We used serum from patients with mUC collected prior to and after systemic therapy (immune checkpoint inhibitor (ICI) or platinum-based chemotherapy (PBC)) at Dana-Farber Cancer Institute. 38 age-matched and sex-matched healthy controls (HCs) from healthy blood donors were also evaluated. The SeroTag immuno-oncology discovery array (Oncimmune) was used, with quantification of the AAb reactivity toward 1132 antigens. Bound AAbs were detected using an anti-immunoglobulin G-specific detection antibody conjugated to the fluorescent reporter dye phycoerythrin. The AAb reactivity was reported as the median fluorescence intensity for each color and sample using a Luminex FlexMAP3D analyzer. Clinical outcomes of interest included radiographic response and development of immune-related adverse events (irAEs). Significance analysis of microarray was used to compare mUC versus HC and radiographic response. Associations with irAE were evaluated using a logistic regression model. P<0.05 was considered statistically significant., Results: 66 patients were included with a median age of 68 years; 54 patients (82%) received ICI and 12 patients (18%) received PBC. Compared with HCs, AAbs against the cancer/testis antigens (CTAG1B, CTAG2, MAGEB18), HSPA1A, TP53, KRAS, and FGFR3 were significantly elevated in patients with mUC. AAbs against BRCA2, TP53, and CTNBB1 were associated with response, and those against BICD2 and UACA were associated with resistance to ICI therapy. AAbs against MITF, CDH3, and KDM4A were associated with development of irAEs in patient who received an ICI. A higher variance in pre-to-post treatment fold change in AAb levels was seen in patients treated with ICI versus PBC and was associated with response to ICI., Conclusions: This is the first report of comprehensive AAb profiling of patients with mUC and identified key AAbs that were elevated in patients with mUC versus HCs as well as AAbs associated with therapeutic response to ICI. These findings are hypothesis generating and further mechanistic studies evaluating humoral immunity in UC are required., Competing Interests: Competing interests: PR: research funding (to institution) from Lilly, Bayer, and Telix and speaker’s fees from OncLive. BAM: consulting fees from BMS, Eisai, Exelixis, Gilead, Pfizer, and Seagen and research funding (to institution) from BMS, Exelixis, Pfizer, and Seagen. JEB: speaker honoraria from Guardant Health; consulting fees from Guardant Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo, and JucaBio; equity in Cityblock Health, Genome Medical, Oncotect, Precede, TracerDx, and Musculo; and filed an institutional patent on methods to detect neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis. GS: in advisory board of BMS, Genentech, EMD Serono, Merck, AstraZeneca, Sanofi, Seattle Genetics/Astellas, AstraZeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, and Primum; in consultant/scientific advisory board of Suba Therapeutics, Syapse, Servier, Merck, and Syncorp; received research support (to institution) from Sanofi, AstraZeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, and Jazz Therapeutics; received speaker's fees from Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, and Aveo; received data safety monitoring committee honorarium from Mereo; received writing/editor fees from UpToDate, Practice Update, and Onviv; and spouse employed in Myriad. PB, BAA, ER, JG, AS-S, ALK, MB, and H-DZ are employees of Oncimmune., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Postoperative care protocols for ankle fracture surgery remain controversial with variability among care providers. This prospective controlled trial compared 12-week postoperative outcomes for immediate unprotected weightbearing (IMWB) vs nonweightbearing (NWB) for 2 weeks in a splint followed by weightbearing as tolerated (WBAT) in a boot after surgical fixation of selected low-energy ankle fractures without superior articular involvement., Methods: Eighty-seven patients undergoing surgical fixation of ankle fractures at a single level 1 trauma center were recruited according to specific criteria and enrolled by presentation date. The first 43 eligible patients were allocated to the control group, with NWB in a splint for 2 weeks followed by WBAT in a walker boot. The next 44 patients recruited were allocated to the IMWB group. The primary outcome was the Olerud-Molander score (OMAS). Secondary outcome measures included the Euroquol-5D (EQ5D) score and Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) scores, ankle range of motion (ROM), wound complications, time to return to work, radiograph measurements, and fracture reduction loss. In this perioperative-focused study, we collected data on patients until 12 weeks postoperation., Results: The IMWB group had 5 superficial wound complications vs 1 in the control group. At 12 weeks, we found no difference in OMAS, EQ5D, WPAI:SHP scores, ROM, time to return to work, or radiographic measurements., Conclusion: In this short-term and relatively small prospective trial, we found more wound complications among patients treated with immediate unprotected weightbearing compared with patients treated with 2 weeks of NWB followed by protected weightbearing. Given the low incidence and small sample size, we do not know if these observed findings are generalizable. However, we also found no difference in functional outcomes at 12 weeks postoperation between these 2 groups. In light of that, we do not recommend IMWB after open reduction internal fixation of low-energy ankle fractures with plate and/or screw fixation., Level of Evidence: Level II, prospective controlled trial., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online.

Campylobacter infections in humans are traced mainly to poultry products. While vaccinating poultry against Campylobacter could reduce the incidence of human infections, no vaccine is yet available on the market. In our previous study using a plasmid DNA prime/recombinant protein boost vaccine regimen, vaccine candidate YP437 induced partial protective immune responses against Campylobacter in broilers. In order to optimise vaccine efficacy, the vaccination protocol was modified using a protein prime/protein boost regimen with a different number of boosters. Broilers were given two or four intramuscular protein vaccinations (with the YP437 vaccine antigen) before an oral challenge by C. jejuni during a 42-day trial. The caecal Campylobacter load, specific systemic and mucosal antibody levels and caecal microbiota in the vaccinated groups were compared with their respective placebo groups and a challenge group ( Campylobacter infection only). Specific humoral immune responses were induced, but no reduction in Campylobacter caecal load was observed in any of the groups ( p > 0.05). Microbiota beta diversity analysis revealed that the bacterial composition of the groups was significantly different ( p ≤ 0.001), but that vaccination did not alter the relative abundance of the main bacterial taxa residing in the caeca. The candidate vaccine was ineffective in inducing a humoral immune response and therefore did not provide protection against Campylobacter spp. infection in broilers. More studies are required to find new candidates.

Background: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors., Methods: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons., Results: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher., Conclusions: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To describe how a sample of people working in community health promotion projects perceive and implement community engagement approaches., Method: Mixed qualitative-quantitative study. Data was collected through: semi-structured interviews with 10 people representing the projects, and workshops in which 53 people participated and responded to a questionnaire prepared ad hoc to identify levels of community engagement. Descriptive statistical analysis of the questionnaires and framework analysis of the interviews, observations and workshops recordings., Results: Although the projects are described as highly participatory, community engagement appeared mainly in the form of attending events, with few examples of consultation or community involvement., Conclusions: This difference may be due to the lack of a culture of participation, both in individuals and institutions, and lack of training in community engagement. It is proposed to change the language from participation-attendance to using expressions such as consulting or involving people., (Copyright © 2023 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.)

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer.

Objectives: The aims of the study were to investigate if feline middle ear anatomy can be visualized using endoscopy via a lateral bulla approach and to determine if scope-assistance increases rates of successful entry into the hypotympanum during feline total ear canal ablation and lateral bulla osteotomy (TECA-LBO)., Methods: A total of 13 feline cadaver heads underwent CT to confirm the absence of pre-existing middle ear disease. For each head, an electronic coin toss was used to determine which ear would undergo endoscope-assisted TECA-LBO; a traditional TECA-LBO without the use of the scope was performed on the contralateral side. In endoscope-assisted procedures, a 1.9 mm scope was intermittently inserted into the tympanic bulla via a lateral bulla approach and used to identify middle ear structures, visualize the bony septum and confirm entry into the hypotympanum. After the bilateral TECA-LBO, the cadaver heads were imaged again and assessed for evidence of entry through the septum., Results: Soft tissue and osseus structures of the middle ear were readily visualized with a 1.9 mm scope. Success rates for entry into the hypotympanum were high between both endoscope-assisted and traditional procedures, with entry confirmed for 12/13 ears in each group., Conclusions and Relevance: Endoscope assistance can facilitate the identification and examination of middle ear structures but does not appear to increase the success rate of entry into the hypotympanum during feline TECA-LBO, as entry through the bony septum was consistently accomplished even without scope-assisted visualization. Alternative benefits to scope assistance may exist, and future studies to elucidate its impact on rates of intraoperative trauma to middle ear structures are indicated., Competing Interests: Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Minimizing hemolysis during phlebotomy ensures accurate chemistry results and reduces test cancellations and specimen recollections. We developed videos demonstrating best practices to reduce hemolysis and tested whether distribution to clinical nurse educators (CNEs) for provision to nursing staff affected the degree of specimen hemolysis in hospital inpatient units and outpatient clinics., Methods: Videos of common blood collections demonstrating best practices to reduce hemolysis were filmed and then distributed via email link to all hospital-based CNEs in Calgary, Alberta, Canada. (https://vimeo.com/user18866730/review/159869683/a0cec9827f). Roche Cobas hemolysis index (H-index) results from specimens collected +/- 12 months from the date of video distribution were extracted from Roche Cobas IT middleware (cITM) and linked to collection location. An interrupted time series (ITS) analysis with collection location as the unit of anlaysis was used to quantify impact of video distribution on the trajectory of weekly mean log-H-index weighted by inverse variance., Results: In +/- 3 months of data flanking video distribution (n = 137 241 collections), where overall impact was strongest, H-index trajectory (change in units per week) decreased immediately following video distribution (-5.7% / week, p < 0.01). This was accompanied by a 22% drop in overall H-index from the week before to the week after video distribution (y-intercept change, or gap). There was also a small but significant overall decrease in the proportion of hemolyzed specimens (-0.3%, p < 0.01). These changes were not observed at all collection locations, and in fact increases occured at some locations., Conclusions: We developed a novel and convenient educational aid that, when distributed, was associated with beneficial changes in specimen hemolysis at hospital inpatient units and outpatient clinics. Including it in ongoing nursing education will fill a knowledge gap that may help to reduce specimen hemolysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Purpose: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer., Methods: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC)., Results: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS., Conclusion: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Background: Measurement of minimal/measurable residual disease (MRD) in B-lymphoblastic leukemia/lymphoma (B-ALL) has become a routine clinical evaluation tool and remains the strongest predictor of treatment outcome. In recent years, new targeted anti-CD19 and anti-CD22 antibody-based and cellular therapies have revolutionized the treatment of the high-risk B-ALL. The new treatments raise challenges for diagnostic flow cytometry, which relies on the presence of specific surface antigens to identify the population of interest. So far, reported flow cytometry-based assays are developed to either achieve a deeper MRD level or to accommodate the loss of surface antigens post-target therapies, but not both., Methods: We developed a single tube flow cytometry assay (14-color-16-parameters). The method was validated using 94 clinical samples as well as spike-in and replicate experiments., Results: The assay was well suited for monitoring response to targeted therapies and reached a sensitivity below 10 -5 with acceptable precision (coefficient of variation < 20%), accuracy, and interobserver variability (κ = 1)., Conclusions: The assay allows for sensitive disease detection of B-ALL MRD independent of CD19 and CD22 expression and allows uniform analysis of samples regardless of anti-CD19 and CD22 therapy., (© 2023 International Clinical Cytometry Society.)

Campylobacter infections, traced to poultry products, are major bacterial foodborne zoonoses, and vaccination is a potential solution to reduce these infections. In a previous experimental trial using a plasmid DNA prime/recombinant protein boost vaccine regimen, two vaccine candidates (YP437 and YP9817) induced a partially protective immune response against Campylobacter in broilers, and an impact of the protein batch on vaccine efficacy was suspected. This new study was designed to evaluate different batches of the previously studied recombinant proteins (called YP437A, YP437P and YP9817P) and to enhance the immune responses and gut microbiota studies after a C. jejuni challenge. Throughout the 42-day trial in broilers, caecal Campylobacter load, specific antibodies in serum and bile, the relative expression of cytokines and β-defensins, and caecal microbiota were assessed. Despite there being no significant reduction in Campylobacter in the caecum of vaccinated groups, specific antibodies were detected in serum and bile, particularly for YP437A and YP9817P, whereas the production of cytokines and β-defensins was not significant. The immune responses differed according to the batch. A slight change in microbiota was demonstrated in response to vaccination against Campylobacter . The vaccine composition and/or regimen must be further optimised.

Background: Lineage infidelity is characteristic of mixed phenotype acute leukemia and is also seen in blast phase of chronic myeloid leukemia (CML), myeloid/lymphoid neoplasia with eosinophilia and gene rearrangements, and subtypes of acute myeloid leukemia. Driver genetic events often occur in multipotent progenitor cells in myeloid neoplasms, suggesting that multilineage output may be more common than appreciated. This phenomenon is not well studied in myelodysplastic syndrome (MDS) and non-CML myeloproliferative neoplasms (MPN)., Methods: We systematically evaluated phenotypic lineage infidelity by reviewing bone marrow pathology and flow cytometry (FC) studies of 1262 consecutive patients with a diagnosis of MDS and/or non-CML MPN. We assessed B- and T-cells in these patients by FC. When abnormal B-lymphoblast (ABLB) populations were detected, we additionally evaluated immature B-cells using a high sensitivity FC assay for B-lymphoblastic leukemia/lymphoma (B-ALL)., Results: We identified 9 patients (7 MDS, 7/713, 1%; 2 non-CML MPN, 2/312, 0.6%; 0 in MDS/MPN) with low-level ABLB populations (0.012%-3.6% of WBCs in marrow) with abnormal immunophenotypes. Genetic studies on flow sorted cell populations confirmed that some ABLB populations were clonally related to myeloid blasts (4/6, 67%). On follow-up, ABLB populations in 8/9 patients remained stable or disappeared. Only 1 case progressed to B-ALL., Conclusions: These findings demonstrate that phenotypically detectable abnormal immature B lineage output occurs in MDS and non-CML MPN, albeit rarely. While presence of ABLB does not necessarily reflect blast crisis, the underlying disease biology of our findings may ultimately be relevant to patient management and warrants further investigation., (© 2021 International Clinical Cytometry Society.)

Geriatric patients with complex health care needs can benefit from interprofessional (IP) care; however, a major gap in health professional education is determining how to prepare future providers for IP collaboration. Effective IP team behavior assessment tools are needed to teach, implement, and evaluate IP practice skills. After review of IP evaluation tools, the Standardized Patient Encounter Evaluation Rubric (SPEER) was created to evaluate team dynamics in IP practice sites.Independent sample t-tests between faculty and learner SPEER scores showed learners scored themselves 15 points higher than their faculty scores ( p < .001). Cronbach's α showed high internal consistency (α = 0.91). Paired t-tests found that learners identified improvements in the team's ability to address the patient's education needs and to allow the patients to voice their expectations. Faculty identified improvements in the teams' ability to make recommendations. Faculty evaluations of learner teams showed improvements in raw ratings on all but two items. Qualitative data analysis for emergent themes showed learners desired team functioning feedback and how teamwork could improve to provide optimal IP care.In conclusion, the SPEER can help faculty and learners identify growth in their teams' ability to perform key IP skills in clinical sites.

Campylobacter infections traced mainly to poultry products are major bacterial foodborne zoonoses. Among the many control strategies evaluated at primary poultry level to reduce these infections, vaccination could be a solution, but no effective vaccines are available to date. A better understanding of the immune mechanisms involved in protection against Campylobacter would be helpful for designing novel vaccine strategies. The present study was designed to analyze in more depth the immune responses developed in broilers in order to potentially identify which immune parameters may be important for establishing protection against Campylobacter by comparing the immune responses obtained here with those obtained in a previous study performed on vaccinated specific-pathogen-free Leghorn chickens that presented a partial reduction of Campylobacter after experimental challenge. The protection against Campylobacter colonization was evaluated at different time points over 40 d of rearing, by measuring specific IgY levels in serum and IgA antibodies in bile reflecting the systemic and mucosal humoral responses respectively and the relative expressions of 9 cecal immune marker genes (cytokines and antimicrobial peptides), which reflect the innate and cellular immune responses. Despite no reduction of Campylobacter in the cecum, a systemic immune response over time characterized by the production of specific anti-flagellin IgY was observed, in addition to upregulation of the antimicrobial peptide avian β-defensin (AvBD) 12 gene expression in the cecum of vaccinated broilers compared with the placebo group. However, the levels of specific anti-flagellin mucosal IgA antibodies in the bile as well as the relative expression of other cecal cytokines studied was underexpressed in the vaccinated group or similar in both groups., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

There are 5.8 million Americans with Alzheimer's disease and this number is rising. Social Work can play a key role. Yet, like other disciplines, the field is ill prepared for the growing number of individuals and family members who are impacted physically, emotionally and financially. Compounding the challenge, the number of social work students identifying interest in the field is low. This mixed methods concurrent study assessed the preliminary efficacy of a day-long education event among social work students from eight social work programs. Pre- post-training survey included: 1) dementia knowledge, assessed with the Dementia Knowledge Assessment Scale, and 2) negative attitudes towards dementia, assessed by asking students to identify three words that reflected their thoughts on dementia, which were later rated as positive, negative or neutral by three external raters. Bivariate analyses showed that dementia knowledge (mean difference= 9.9) and attitudes (10% lower) improved from pre- to post-training (p<0.05). Collaboration between social work programs can increase student access to strength-based dementia education. Such programs hold the potential of improving dementia capability within the field of Social Work., Competing Interests: Disclosure: The authors report no conflicts of interest

Objective. Health professions students must develop collaborative skills to disclose errors effectively and improve patient safety. We proposed that an interprofessional simulation using telehealth technology would provide medical and pharmacy students the opportunity to practice, develop, and grow in their confidence and skills of working collaboratively and disclosing medication errors. Methods. A three-phase interprofessional student simulation was developed. Phase 1 included individual student preparation. An interprofessional telehealth consultation encounter occurred in phase 2 for the error disclosure between the pharmacy and medical students. Phase 3 included faculty-led interprofessional debrief sessions. A pre- and postsimulation survey assessed students' experiences regarding their confidence in error disclosure, use of telehealth technology, and the role of the community pharmacist. Faculty evaluated pharmacy student performance using a 12-point rubric. Results. Presimulation survey responses (n=173) were compared to postsimulation survey responses (n=140). Significant changes were seen for all students' confidence in error disclosure and use of telehealth technology. No significant change was noted in the students' understanding of the community pharmacists' role on the interprofessional team. Pharmacy student performance-based rubric data (n=148) revealed a median score of seven out of 12 for error disclosure and interprofessional communication items. Conclusion. Medical and pharmacy students perceived their confidence improved in interprofessional error disclosure and use of telehealth consultation technology through this interprofessional simulation. Pharmacy students' error disclosure and interprofessional communication skill development were assessed through this simulation., (© 2023 American Association of Colleges of Pharmacy.)

Introduction: Consumption of complementary and alternative medicine (CAM) is widely described in cancer patient. However, their composition is not clearly defined and the proofs of safety or effectiveness are quite low. We reported here the case of a CAM-induced hepatitis., Case Summary: A 33-years-old men with Non-Small Cell Lung Cancer and treated by combination of immunotherapy and chemotherapy developed hepatitis during 5 months. Viral and iatrogenic etiologies were excluded., Management and Outcome: Medication reconciliation found concomitant utilisation of CAM. Some of the plants which composed CAM were found to be possible hepatotoxic. After discontinuation of this CAM, liver fonctions normalized. Close monitoring of liver function showed no other hepatitis., Discussion: CAM induced hepatotoxicity was suspected. Medication reconciliation included CAM is needed in cancer patient to detect drug interactions and CAM side effects to improve cancer patient management.

Background: The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown., Patients and Methods: A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline variants. Descriptive statistics were generated., Results: Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n = 5), MSH2 (n = 5), MLH1 (n = 4), ATM (n = 3), and CHEK2 (n = 2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer., Conclusion: Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy., (Copyright © 2022. Published by Elsevier Inc.)

Background: Anterior cruciate ligament (ACL) reconstructions (ACLRs) with graft diameters <8mm have been shown to have higher revision rates. The 5-strand (5S) hamstring autograft configuration is a proposed option to increase graft diameter., Purpose: To investigate the differences in clinical outcomes between 4-strand (4S) and 5S hamstring autografts for ACLR in patients who underwent ACLR alone or concomitantly with a lateral extra-articular tenodesis (LET) procedure., Study Design: Cohort study; Level of evidence, 2., Methods: Data from the STABILITY study were analyzed to compare a subgroup of patients undergoing ACLR alone or with a concomitant LET procedure (ACLR + LET) with a minimum graft diameter of 8mm that had either a 4S or 5S hamstring autograft configuration. The primary outcome was clinical failure, a composite of rotatory laxity and/or graft failure. The secondary outcome measures consisted of 2 patient-reported outcome scores (PROs)-namely, the ACL Quality of Life Questionnaire (ACL-QoL) and the International Knee Documentation Committee (IKDC) score at 24 months postoperatively., Results: Of the 618 patients randomized in the STABILITY study, 399 (228 male; 57%) fit the inclusion criteria for this study. Of these, 191 and 208 patients underwent 4S and 5S configurations of hamstring ACLR, respectively, with a minimum graft diameter of 8mm. Both groups had similar characteristics other than differences in anthropometric factors-namely, sex, height, and weight, and Beighton scores. The primary outcomes revealed no difference between the 2 groups in rotatory stability (odds ratio [OR], 1.19; 95% CI, 0.77-1.84; P = .42) or graft failure (OR, 1.13; 95% CI, 0.51-2.50; P = .76). There was no significant difference between the groups in Lachman ( P = .46) and pivot-shift ( P = .53) test results at 24 months postoperatively. The secondary outcomes revealed no differences in the ACL-QoL ( P = .67) and IKDC ( P = .83) scores between the 2 subgroups., Conclusion: At the 24-month follow-up, there were no significant differences in clinical failure rates and PROs in an analysis of patients with 4S and 5S hamstring autografts of ≥8mm diameter for ACLR or ACLR + LET. The 5S hamstring graft configuration is a viable option to produce larger-diameter ACL grafts.

Objectives: To identify individual and clinical risk factors of aggressiveness, including exposure to different forms of childhood trauma, in a sample of Lebanese patients with schizophrenia., Methods: A total of 131 patients diagnosed with schizophrenia participated in this cross-sectional study., Results: Higher physical (Beta = 0.24, p < 0.001) and sexual (Beta = 0.29, p = 0.003) abuse, alcohol drinking (Beta = 1.46, p = 0.008), having a history of head trauma (Beta = 1.10, p = 0.041), and male gender (Beta = -1.59, p = 0.009) were significantly associated with higher mean aggression scores., Practical Implications: Our investigation of the factors linked to aggressiveness in patients with schizophrenia complement those of earlier findings, showing that the relationship between interacting individual and environmental risk factors and later aggressiveness is quite complex, and needs further longitudinal and prospective studies., (© 2022 Wiley Periodicals LLC.)

Background: Agitated patients constitute 10% of all emergency psychiatric treatment. Management guidelines, the preferred treatment of clinicians differ in opinion and practice. In Lebanon, the use of the triple therapy haloperidol plus promethazine plus chlorpromazine (HPC) is frequently used but no studies involving this combination exists., Method: A pragmatic randomised open trial (September 2018-July 2019) in the Lebanese Psychiatric Hospital of the Cross in Beirut Lebanon involving 100 people requiring urgent intramuscular sedation due to aggressive behaviour were given intramuscular chlorpromazine 100 mg plus haloperidol 5 mg plus promethazine 25 mg (HPC) or intramuscular haloperidol 5 mg plus promethazine 25 mg., Results: Primary outcome data were available for 94 (94%) people. People allocated to the haloperidol plus promethazine (HP) group showed no clear difference at 20 min compared with patients allocated to the HPC group [relative risk (RR) 0.84, 95% confidence interval (CI) 0.47-1.50]., Conclusions: Neither intervention consistently impacted the outcome of 'calm', or 'asleep' and had no discernible effect on the use of restraints, use of additional drugs or recurrence. If clinicians are faced with uncertainty on which of the two intervention combinations to use, the simpler HP is much more widely tested and the addition of chlorpromazine adds no clear benefit with a risk of additional adverse effects.

Background: Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI., Methods: This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR)., Results: Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034)., Conclusions: RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients., Competing Interests: Disclosures Ziad Bakouny: Research support from Bristol-Myers Squibb and Genentech/imCORE. Honoraria from UpToDate. Toni K: Choueiri reports grants, personal fees, nonfinancial support, and other from BMS, Merck, Roche, Pfizer, EMD, Exelixis, Novartis, and AstraZeneca [advisory board, consultancy, honorarium, payments (personal and for institution)], and a patent for IO biomarkers pending, issued, and licensed to DFCI (related to IO). Rana R: McKay received research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion. Guru Sonpavde: Advisory Board: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics; Research Support to Institution: Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine, BMS; Steering committee of studies: BMS, Bavarian Nordic, Seattle Genetics, QED, G1 Therapeutics (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid).; Data safety monitoring committee: Mereo; Travel costs: BMS (2019), Astrazeneca (2018); Writing/Editor fees: Uptodate, Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; Speaking fees: Physicians Education Resource (PER), Onclive, Research to Practice, Medscape (all educational). Rakesh Jain has received an Honorarium from Amgen; Consultant fees from Elpis, SPARC, SynDevRx; Owns equity in Accurius, Enlight, SynDevRx; Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a Research Grant from Boehringer Ingelheim. The remaining authors have stated that they have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Psychiatric patients could be at risk of worse outcomes from COVID-19 than the general population. The primary objective of the present study was to describe the symptoms and clinical characteristics of COVID-19 patients living in long-term hospital for mental illness in Lebanon. The secondary objective was to evaluate the factors related to COVID-19 disease severity among these patients., Methods: A retrospective observational study was conducted from September 2020 to January 2021 at the Psychiatric Hospital of the Cross. The total number of COVID-19 patients in the infected floors is 410 out of 548. The outcome variable was the severity of COVID-19 illness classified into five categories: asymptomatic, mild, moderate, severe and critically ill., Results: The rate of infection in the affected floors was 74.81%. Almost half of the patients were asymptomatic (49.3%), 43.4% had hyperthermia and only 28.0% had tachycardia and 25.1% developed hypoxia. The multivariate regression analysis showed that higher temperature (ORa = 6.52), lower saturation (ORa = 0.88), higher BMI (ORa = 1.12), higher CRP (ORa = 1.01), being a female (ORa = 4.59), having diabetes (ORa = 8.11) or COPD (ORa = 10.03) were significantly associated with the increase of the COVID-19 severity., Conclusions: The current study showed that a high rate of infection from COVID-19 was detected in a psychiatric hospital with the majority having asymptomatic to mild symptoms. Female psychiatric patients, desaturation, increase inflammation and comorbidities such as diabetes and COPD were associated with the severity of COVID-19 among psychiatric patients. Future studies are needed to better understand the causal relation of the factors with severity and long term effects or sequelae of the disease., (© 2022. The Author(s).)

Background: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported., Objective: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia., Design: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505)., Setting: 46 U.S. and Canadian hospitals., Participants: Patients aged 50 years or older undergoing hip fracture surgery., Intervention: Spinal or general anesthesia., Measurements: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care., Results: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups., Limitation: Missing outcome data and multiple outcomes assessed., Conclusion: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia., Primary Funding Source: Patient-Centered Outcomes Research Institute .

Campylobacteriosis is reported to be the leading zoonosis in Europe, and poultry is the main reservoir of Campylobacter. Despite all the efforts made, there is still no efficient vaccine to fight this bacterium directly in poultry. Recent studies have reported interactions between the chicken immune system and gut microbiota in response to Campylobacter colonisation. The present study was designed to analyse in more depth the immune responses and caecal microbiota following vaccination with a DNA prime/protein boost flagellin-based vaccine that induces some protection in specific-pathogen-free White Leghorn chickens, as shown previously. These data may help to improve future vaccination protocols against Campylobacter in poultry. Here a vaccinated and a placebo group were challenged by C. jejuni at the age of 19 days. A partial reduction in Campylobacter loads was observed in the vaccinated group. This was accompanied by the production of specific systemic and mucosal antibodies. Transient relatively higher levels of Interleukin-10 and antimicrobial peptide avian β-defensin 10 gene expressions were observed in the vaccinated and placebo groups respectively. The analysis of caecal microbiota revealed the vaccination's impact on its structure and composition. Specifically, levels of operational taxonomic units classified as Ruminococcaceae and Bacillaceae increased on day 40.

This analysis of urban Indigenous women's experiences on the Homeland of the Métis and Treaty One (Winnipeg, Manitoba, Canada), Treaty Four (Regina, Saskatchewan, Canada), and Treaty Six (Saskatoon, Saskatchewan, Canada) territories illustrates that Indigenous women have recently experienced coercion when interacting with healthcare and social service providers in various settings. Drawing on analysis of media, study conversations, and policies, this collaborative, action-oriented project with 32 women and Two-Spirit collaborators demonstrated a pattern of healthcare and other service providers subjecting Indigenous women to coercive practices related to tubal ligations, long-term contraceptives, and abortions. We foreground techniques Indigenous women use to assert their rights within contexts of reproductive coercion, including acts of refusal, negotiation, and sharing community knowledge. By recognizing how colonial relations shape Indigenous women's experiences, decision-makers and service providers can take action to transform institutional cultures so Indigenous women can navigate their reproductive decision-making with safety and dignity.

Neonatal bloodstream infections (BSI) can lead to sepsis, with high morbidity and mortality, particularly in low-income settings. The high prevalence of third-generation cephalosporin-resistant organisms (3GC-RO) complicates the management of BSI. Whether BSI is linked to carriage of 3GC-RO, or to acquisition from the hospital environment is important for infection prevention and control, but the relationship remains unclear, especially in low-income settings. At a tertiary hospital in Mwanza, Tanzania, we screened neonatal blood and rectal samples from 200 neonates, and 400 (hospital) environmental samples. We used logistic regression to identify risk factors, and Kolmogorov-Smirnov tests and randomisation analyses to compare distributions of species and resistance patterns to assess potential routes of transmission. We found that BSIs caused by 3GC-RO were frequent (of 59 cases of BSI, 55 were caused by 3GC-RO), as was carriage of 3GC-RO, particularly Escherichia coli, Klebsiella pneumoniae, and Acinetobacter species. In the 28 infants with both a carriage and blood isolate, there were more (4 of 28) isolate pairs of the same species and susceptibility profile than expected by chance (p < 0.05), but most pairs were discordant (24 of 28). Logistic regression models found no association between BSI and carriage with either 3GC-RO or only 3GC-R K. pneumoniae. These analyses suggest that carriage of 3GC-RO is not a major driver of BSI caused by 3GC-RO in this setting. Comparison with environmental isolates showed very similar distributions of species and resistance patterns in the carriage, BSI, and the environment. These similar distributions, a high frequency of Acinetobacter spp. isolations, the lack of strong association between carriage and BSI, together with the high proportion of 3GC-RO in BSI all suggest that these neonates acquire multidrug-resistant carriage and blood isolates directly from the hospital environment., (© 2022. The Author(s).)

Serial evaluation of circulating tumor DNA may allow noninvasive assessment of drivers of resistance to immune checkpoint inhibitors (ICIs) in advanced urothelial cancer (aUC). We used a novel, amplicon-based next-generation sequencing assay to identify genomic alterations (GAs) pre- and post-therapy in 39 patients with aUC receiving ICI and 6 receiving platinum-based chemotherapy (PBC). One or more GA was seen in 95% and 100% of pre- and post-ICI samples, respectively, commonly in TP53 (54% and 54%), TERT (49% and 59%), and BRCA1/BRCA2 (33% and 33%). Clearance of ≥1 GA was seen in 7 of 9 patients responding to ICI, commonly in TP53 (n = 4), PIK3CA (n = 2), and BRCA1/BRCA2 (n = 2). A new GA was seen in 17 of 20 patients progressing on ICI, frequently in BRCA1/BRCA2 (n = 6), PIK3CA (n = 3), and TP53 (n = 3), which seldom emerged in patients receiving PBC. These findings highlight the potential for longitudinal circulating tumor DNA evaluation in tracking response and resistance to therapy., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non-RA-MIBC are unknown., Objective: To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non-RA-MIBC., Design, Setting, and Participants: We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC., Outcome Measurements and Statistical Analysis: We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non-RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival., Results and Limitations: We identified 19 RA-MIBC patients with available tumor tissue (n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non-RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53, KDM6A, and RB1, as well as copy number alterations such as CDKN2A loss was similar in RA-MIBC and non-RA-MIBC., Conclusions: We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC., Patient Summary: Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To report data related to the short- and long-term survival of dogs undergoing adrenalectomy for pheochromocytoma, and to determine the influence of preoperative alpha-blocker therapy., Study Design: Retrospective., Animals: Fifty-three dogs., Methods: Medical records were reviewed for dogs diagnosed with pheochromocytoma and treated with adrenalectomy between 2010 and 2020. Preoperative management, imaging studies, intraoperative cardiovascular instability, complications, and procedural information were recorded. When applicable, duration of survival and cause of death, time to recurrence or metastasis, and postoperative complications were recorded., Results: During anesthesia, a hypertensive episode was documented in 46/53 dogs and arrhythmias were recorded in 16/53 dogs. Of these, 37/46 hypertensive dogs and 11/16 dogs with arrhythmias were treated with an alpha-blocker before surgery. Intraoperative systolic blood pressures reached higher levels by a magnitude of nearly 20% in dogs that were treated preoperatively with an alpha-blocker (P = .01). All dogs survived surgery and 44 survived to discharge. Follow up ranged from 6 to 1653 days (median 450 days). Median survival time for dogs discharged from the hospital was 1169 days (3.2 years). Recurrence and metastasis were suspected in 3 and 8 dogs, respectively., Conclusion: Most dogs survived the immediate postoperative period and achieved long-term survival with a low reported incidence of tumor recurrence or metastasis. Preoperative alpha-blocker therapy was not associated with increased survival., Clinical Significance: The favorable outcomes reported in this study should be taken into consideration when discussing treatment options for dogs with pheochromocytomas. This study provides no evidence to support preoperative alpha-blocker therapy., (© 2022 American College of Veterinary Surgeons.)

Background: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials., Methods: UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy., Results: The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06)., Conclusions: In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities., Lay Summary: Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations., (© 2021 American Cancer Society.)