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There have been few studies on sexuality, relationships, and HIV prevention issues among HIV+ adolescents and fewer still that have dealt with youth living with HIV/AIDS since birth. In the present qualitative study, we conducted individual, semi-structured, taped interviews on these topics with 29 youth perinatally infected with HIV. The 15 girls and 14 boys, 10-18 years of age, have been followed at the Centre Maternel et Infantile sur le SIDA (CMIS), Centre Hospitalier Universitaire Sainte-Justine in Montreal. Content analysis of the interview transcripts revealed two dimensions related to HIV prevention. From a rational perspective, the youth were generally knowledgeable about modes of HIV transmission and modes of prevention, including consistent condom use, From an affective perspective, they were clear about their responsibility to protect their current or future partners but fearful that efforts to do so might disclose their HIV status with subsequent threat of rejection, stigmatization and compromised relationships. The concealment strategies they adopted to address the tensions inherent in this situation are discussed in terms of their own psychosexual development and of interventions by parents, caregivers and professionals to foster healthy and satisfying sexuality for HIV+ youth and their partners. [ABSTRACT FROM AUTHOR]

Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E) and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC) markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu (HER2) protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH). Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC) ≥ 0.9). Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B) subtypes (92%), but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74%) and Luminal A tumors were less likely to have high proliferation (11% vs 77%). Seventy-seven percent (30/39) of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57%) and HER2-E (30%) subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as shown in a multivariate analysis. Conclusions The standard immunohistochemical panel for breast cancer (ER, PR, and HER2) does not adequately identify the PAM50 gene expression subtypes. Although there is high agreement between biomarker scoring by protein immunohistochemistry and gene expression, the gene expression determinations for ESR1 and ERBB2 status was more prognostic.

Abstract Background High throughput signature sequencing holds many promises, one of which is the ready identification of in vivo transcription factor binding sites, histone modifications, changes in chromatin structure and patterns of DNA methylation across entire genomes. In these experiments, chromatin immunoprecipitation is used to enrich for particular DNA sequences of interest and signature sequencing is used to map the regions to the genome (ChIP-Seq). Elucidation of these sites of DNA-protein binding/modification are proving instrumental in reconstructing networks of gene regulation and chromatin remodelling that direct development, response to cellular perturbation, and neoplastic transformation. Results Here we present a package of algorithms and software that makes use of control input data to reduce false positives and estimate confidence in ChIP-Seq peaks. Several different methods were compared using two simulated spike-in datasets. Use of control input data and a normalized difference score were found to more than double the recovery of ChIP-Seq peaks at a 5% false discovery rate (FDR). Moreover, both a binomial p-value/q-value and an empirical FDR were found to predict the true FDR within 2–3 fold and are more reliable estimators of confidence than a global Poisson p-value. These methods were then used to reanalyze Johnson et al.'s neuron-restrictive silencer factor (NRSF) ChIP-Seq data without relying on extensive qPCR validated NRSF sites and the presence of NRSF binding motifs for setting thresholds. Conclusion The methods developed and tested here show considerable promise for reducing false positives and estimating confidence in ChIP-Seq data without any prior knowledge of the chIP target. They are part of a larger open source package freely available from http://useq.sourceforge.net/.

This research measured daily 24-hour PM10 concentrations at various locations in Salt Lake City, Utah, from November 1994 to May 1995. Between four and six indoor locations were sampled at each of three hospitals. Indoor data were compared with outdoor roof data from each respective hospital and with the city's central monitoring location. The study goals were to: (1) evaluate variation of PM10 concentrations at four different outdoor sampling locations across the Salt Lake Valley; (2) determine if a centrally located monitor can predict PM10 concentrations across the valley; (3) compare indoor/outdoor roof concentrations at three hospitals to determine if an outdoor roof sampler can be used to predict indoor concentrations; (4) evaluate variation in PM10 concentrations inside hospitals to see if a single indoor sampler can estimate exposure for an entire hospital; and (5) determine if a centrally located monitor can predict indoor concentrations in the three hospitals. Results from outdoor samplers indicate that variation occurred between thefour sites. When the concentrations measured by the hospital roof samples are regressed against those of the central sampler, the slopes of each hospital were linear but statistically different. Because thethree hospitals had similar y intercepts, at low outdoor PM10 concentrations the central monitor predicted hospital roof concentrations. As outdoor PM10 concentrations increased, the central monitor had higher concentrations and overestimated PM10 relative to the three hospital sites. Results from indoor samplers indicate large variation in PM10 concentrations both within and between hospitals. Data indicate that one indoor location does not adequately represent the variation in indoor PM10 concentrations at other locations in the same hospital, and that hospital roof PM10 concentrations account for a varying percenta [ABSTRACT FROM AUTHOR]

Clinical genetic testing for mutations in CDKN2A (cyclin-dependent kinase inhibitor 2A), a melanoma susceptibility gene, is now available. The International Melanoma Genetics Consortium advocates that genetic testing for CDKN2A should be done only as part of a research protocol. Experience with genetic testing for other cancer-susceptibility genes indicates that CDKN2A testing has enormous potential for the prevention and detection of a deadly disease. However, clinicians need to understand the benefits and shortcomings of clinical CDKN2A testing so that it can be used advantageously. Here, we examine whether CDKN2A meets the recommendations of the American Society of Clinical Oncology (ASCO) for cancer-susceptibility genetic testing. Although genetic testing for hereditary melanoma should, whenever possible, occur within research protocols, it might be successfully done outside of research protocols if attention is paid to selection, education, and counselling needs of patients; valid test interpretation; and the changing of medical management in appropriate individuals. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes is a foodborne intracellular bacterial model pathogen. Protective immunity against Listeria depends on an effective CD8 + T cell response, but very few T cell epitopes are known in mice as a common animal infection model for listeriosis. To identify epitopes, we screened for Listeria immunopeptides presented in the spleen of infected mice by mass spectrometry-based immunopeptidomics. We mapped more than 6000 mouse self-peptides presented on MHC class I molecules, including 12 high confident Listeria peptides from 12 different bacterial proteins. Bacterial immunopeptides with confirmed fragmentation spectra were further tested for their potential to activate CD8 + T cells, revealing VTYNYINI from the putative cell wall surface anchor family protein LMON_0576 as a novel bona fide peptide epitope. The epitope showed high biological potency in a prime boost model and can be used as a research tool to probe CD8 + T cell responses in the mouse models of Listeria infection. Together, our results demonstrate the power of immunopeptidomics for bacterial antigen identification., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although various types of mRNA-based vaccines have been explored, the optimal conditions for induction of both humoral and cellular immunity remain rather unknown. In this study, mRNA vaccines of nucleoside-modified mRNA in lipoplexes (LPXs) or lipid nanoparticles (LNPs) were evaluated after administration in mice through different routes, assessing mRNA delivery, tolerability and immunogenicity. In addition, we investigated whether mRNA vaccines could benefit from the inclusion of the adjuvant alpha-galactosylceramide (αGC), an invariant Natural Killer T (iNKT) cell ligand. Intramuscular (IM) vaccination with ovalbumin (OVA)-encoding mRNA encapsulated in LNPs adjuvanted with αGC showed the highest antibody- and CD8 + T cell responses. Furthermore, we observed that addition of signal peptides and endocytic sorting signals of either LAMP1 or HLA-B7 in the OVA-encoding mRNA sequence further enhanced CD8 + T cell activation although reducing the induction of IgG antibody responses. Moreover, mRNA LNPs with the ionizable lipidoid C12-200 exhibited higher pro-inflammatory- and reactogenic activity compared to mRNA LNPs with SM-102, correlating with increased T cell activation and antitumor potential. We also observed that αGC could further enhance the cellular immunity of clinically relevant mRNA LNP vaccines, thereby promoting therapeutic antitumor potential. Finally, a Listeria monocytogenes mRNA LNP vaccine supplemented with αGC showed synergistic protective effects against listeriosis, highlighting a key advantage of co-activating iNKT cells in antibacterial mRNA vaccines. Taken together, our study offers multiple insights for optimizing the design of mRNA vaccines for disease applications, such as cancer and intracellular bacterial infections., Competing Interests: Declaration of competing interest R.V., I.L. and S.D.S. are contributors to patent applications no. WO2020058239A1; Therapeutic nanoparticles and methods of use thereof. and no. WO2023209103; Prevention and treatment of infections with intracellular bacteria., together with I.A., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

During the COVID-19 pandemic, the education and healthcare sectors were severely affected. There is a need to investigate the ways in which these workers in at-risk sectors can be protected and through what mechanisms. The aims of this research are, therefore, (1) to assess the mediating role of job demands and resources in the relationship between psychosocial safety climate (PSC) and work engagement and emotional exhaustion, and (2) to test for sector-specific differences among education and healthcare professionals during the COVID-19 pandemic. In the study, which employed a longitudinal design including three measurement times, 70 education professionals and 69 healthcare professionals completed a questionnaire measuring PSC, psychological demands, social support, recognition, work engagement, and emotional exhaustion. The results show that PSC was significantly higher among education professionals than among healthcare professionals. When considering both job sectors together, mediation analyses show that social support mediates the PSC-work engagement relationship, while psychological demands mediate the PSC-emotional exhaustion relationship. Moderated mediation analyses show that job sector is a moderator: among education professionals, colleague support and recognition mediate the PSC-work engagement relationship, and psychological demands mediate the PSC-emotional exhaustion relationship. PSC is associated with more balanced job demands and resources, higher work engagement, and lower emotional exhaustion among education and healthcare professionals. The study of these two sectors, which are both vital to society but also more exposed to adverse work conditions, shows the importance that managers and executives must attach to their mental health by improving their respective working conditions.

Background: Both germline and somatic BReast CAncer gene (BRCA) mutations are poor prognostic markers in men with localized or metastatic prostate cancer. For instance, men with these mutations often are diagnosed with prostate cancer earlier and develop metastatic disease earlier compared with those who do not harbor similar mutations. Patients with germline alterations typically have more advanced disease and shorter overall survival (Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882). The risk of disease progression to metastatic disease is significant in patients with this genotype of prostate cancer. The percentage of patients free from metastatic disease was 90%, 72%, and 50%, respectively, compared with 97%, 94%, and 84% at 3, 5, and 10 years for patients with intact DNA repair (P < .001) (Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022). DNA damage repair non-BRCA mutations include alterations in genes such as ATM, CHEK2, PALB2, and RAD51. While less common than BRCA mutations, they have emerged as significant prognostic markers in prostate cancer. These BRCAness mutations are associated with a higher risk of aggressive disease and poorer survival outcomes. Given the debilitating physical and psychological side effects of androgen deprivation therapy (ADT) in relatively younger men with prostate cancer, delaying ADT in these men may be an attractive strategy. Given the proven efficacy of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the castration-resistant prostate cancersetting, PARP inhibitor monotherapy in a nonmetastatic castration-sensitive (nmCSPC) setting has the potential to delay metastasis and delay the onset of ADT related symptoms., Methods: This is a single-arm, single-center, open-label, phase II trial to assess the efficacy of rucaparib in patients with high-risk biochemically recurrent (BCR) nmHSPC, which was defined as PSA doubling time of <9 months, demonstrating a "BRCAness" genotype (BRCA1/2 and other homologous recombination repair mutations). A total of 15 patients were intended to be enrolled, with an expected enrollment duration of 12 months. Patients were given rucaparib 600 mg orally twice daily and were allowed to remain on study treatment until PSA progression defined by Prostate Cancer Working Group 3, with 2 years of follow-up after study treatment. We anticipated a total of 2-3 years until completion of the clinical trial. The primary endpoint was to assess the PSA progression-free survival (PSA-PFS). The secondary endpoints of the study were safety, the proportion of patients with a PSA 50% response (PSA 50), and an undetectable PSA. A 4-week treatment duration comprised one cycle., Results: The study started enrolling in June 2019 and was prematurely terminated in June 2022 after the accrual of 7 patients because of changing standard of care treatments with the introduction of next-generation scans, eg, prostate-specific membrane antigen positron emission tomography (PSMA-PET). Seven patients were enrolled in the study with the following pathogenic alterations: ATM (n = 3), BRCA2 (n = 2), BRCA1 (n = 1), BRIP1 (n = 1), and RAD51 (n = 1). The median duration of follow-up was 18 months. A median of 20 cycles (range 4-42) was completed, median PSA-PFS was 35.37 months (95% CI, 0-85.11 months). In total, 2 patients achieved PSA50; both also achieved nadir PSA as undetectable. Grade ≥ 3 adverse events (AEs) were anemia and rash (in 1 patient each). No dose-limiting toxicities or severe AEs were seen., Conclusion: Rucaparib demonstrated acceptable toxicity and efficacy signal as an ADT-sparing approach in patients with biochemically recurrent nonmetastatic prostate cancer. It is currently challenging to understand the optimal value of systemic therapy in this disease setting due to the rapidly changing standard of care. Additionally, there are relatively few patients with BRCAness who present with nonmetastatic hormone-sensitive prostate cancer (ClinicalTrials.gov Identifier: NCT03533946)., (© The Author(s) 2024. Published by Oxford University Press.)

With current trends in proteomics, especially regarding clinical and low input (to single cell) samples, it is increasingly important to both maximize the throughput of the analysis and maintain as much sensitivity as possible. The new generation of mass spectrometers (MS) are taking a huge leap in sensitivity, allowing analysis of samples with shorter liquid chromatography (LC) methods while digging as deep in the proteome. However, the throughput can be doubled by implementing a dual column nano-LC-MS configuration. For this purpose, we used a dual-column setup with a two-outlet electrospray source and compared it to a classic dual-column setup with a single-outlet source.

Background: Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas., Methods: Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry., Results: The MTD of minocycline was 150 mg twice per day ( N  = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1., Conclusions: Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma., Competing Interests: A.L.C. has institutional research funding from Chimerix, Nuvox, Novartis, Acrotech, and BPGbio. H.C. is an advisor/consultant for Best Doctors/Teladoc, Orbus Therapeutics, Bristol Myers Squibb, Regeneron, Novocure, PPD/Chimerix, AnHeart Therapeutics, and Alpha Biopharma, and has institutional research funding from Orbus, GCAR, Array BioPharma, Nuvation Bio, Bayer, Bristol Myers Squibb, Sumitomo Dainippon Pharma Oncology, Samus Therapeutics, Erasca, and AnHeart Therapeutics., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in FGFR3 . It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia., Methods: We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 μg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007)., Findings: Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity., Interpretation: Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia., Funding: This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical., Competing Interests: AD and NM have served as consultants for BioMarin, but all compensation has been paid to Children's National Hospital and neither author has received any personal compensation from BioMarin. AD received an investigator-initiated grant from BioMarin to fund the current study. RKS has received an investigator-initiated grant from BioMarin to fund a study of vosoritide in girls with Turner syndrome. The remaining authors have nothing to disclose., (© 2024 The Author(s).)

Context: Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention., Objective: To determine whether high dose GH can overcome GH resistance in this specific patient resulting in normal IGF-1 levels and improved growth rates., Design: Single patient trial of ascending doses of GH followed by dose stable phase; total 12 months of treatment., Patient: Patient has a heterozygous variant in GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature., Interventions: Daily subcutaneous GH starting at 50 micrograms/kg/day and escalating to 250 micrograms/kg/day until goal IGF-1 achieved. Subject continued 250 micrograms/kg/day for a total treatment duration of 12 months., Outcome Measures: The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the mid-point of the normal range. Secondary endpoints included height velocity and the change in height SDS during the 1st year of treatment., Results: A dose of GH of 250 micrograms/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height., Conclusions: A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Dominant narratives about late life promote active aging, while anti-aging ones mobilize tropes of decline and irrelevance. In contrast, counter-narratives raise questions that spark new conversations about the promising practices that could foster more age-friendly cities. In this article, we describe our feminist and ethnographic approach to interviews and digital storytelling that aim to amplify the voices of marginalized older adults living with disability, violence, and colonialism, and share findings from this endeavor. We discuss the interviews with, and stories shared, by two disabled older adults - an Indigenous woman and a white paraplegic man - and the aging futures their counter-stories suggest. These stories reveal these participants' ongoing struggles to create meaning in their lives, and how their relationships to the physical, cultural, and social environment of the city, including its supports and services, can both support and hinder this becoming., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sixteen cycles of Brentuximab vedotin (BV) after autologous stem cell transplant (ASCT) in high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated an improved 2-year progression-free survival (PFS) over placebo. However, most patients are unable to complete all 16 cycles at full dose due to toxicity. This retrospective, multicenter study investigated the effect of cumulative maintenance BV dose on 2-year PFS. Data were collected from patients who received at least one cycle of BV maintenance after ASCT with one of the following high-risk features: primary refractory disease (PRD), extra-nodal disease (END), or relapse <12 months (RL<12) from the end of frontline therapy. Cohort 1 had patients with >75% of the planned total cumulative dose, cohort 2 with 51-75% of dose, and cohort 3 with ≤50% of dose. The primary outcome was 2-year PFS. A total of 118 patients were included. Fifty percent had PRD, 29% had RL<12, and 39% had END. Forty-four percent of patients had prior exposure to BV and 65% were in complete remission before ASCT. Only 14% of patients received the full planned BV dose. Sixty-one percent of patients discontinued maintenance early and majority of those (72%) were due to toxicity. The 2-year PFS for the entire population was 80.7%. The 2-year PFS was 89.2% for cohort 1 (n=39), 86.2% for cohort 2 (n=33), and 77.9% for cohort 3 (n=46) (P=0.70). These data are reassuring for patients who require dose reductions or discontinuation to manage toxicity.

Purpose: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial., Methods and Materials: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD2 3 ). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test., Results: The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD2 3 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences., Conclusions: Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD2 3 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Conflicting data exist on the diagnostic sensitivity of core-needle biopsy (CNB) compared to fine-needle aspiration (FNA) in the evaluation of axillary lymph node metastasis from breast cancer. Our purpose was to evaluate the sensitivity of CNB and FNA using subsequent axillary surgery as the gold standard and to compare the patients' subjective pain levels for each biopsy method., Methods: This IRB-approved prospective study enrolled 140 patients from February 2014 to May 2019 with known or suspected breast cancer. Patients underwent both US-guided FNA and 14-gauge CNB of the same node with clip placement and rated their pain level using a verbal numerical rating scale of 0 to 10. The diagnostic sensitivities were determined by pathology of the surgically excised lymph node using the McNemar test of correlated proportions. Changes in pain scores for CNB and FNA were determined using the Wilcoxon rank sum test., Results: A total of 94 patients had confirmatory excision of the biopsied node with nodal metastasis detected in 71.3% (67/94). The sensitivity of CNB for detection of nodal metastasis was 95.5% (64/67), while the sensitivity of FNA was 67.2% (45/67) (P < 0.05). Overall pain score ratings for CNB increased by 0.6 from baseline on an 11-point numerical rating scale, while overall pain score rating for FNA decreased by 0.2 from baseline (P < 0.05)., Conclusion: Our study demonstrates that 14-gauge CNB has superior sensitivity for detection of axillary nodal metastases and mildly increased pain compared with 25-gauge FNA in patients with breast cancer., (© Society of Breast Imaging 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes., Methods: Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into 'highly active' and'not-highly active'(≥ / < 18 MET hrs/wk). BMI (kg/m 2 ) was categorized into 'normal weight', 'overweight', and 'obese'. Patients were further classified into combined physical activity and BMI groups. Cox-proportional hazard models with Firth correction were computed to assess associations [hazard ratio (HR), 95% profile HR likelihood confidence interval (95% CI) between individual and combined physical activity and BMI groups with overall and disease-free survival in colorectal cancer patients., Results: 'Not-highly active' compared to 'highly active' and 'overweight'/ 'obese' compared to 'normal weight' patients had a 40-50% increased risk of death or recurrence (HR: 1.41 (95% CI: 0.99-2.06), p = 0.03; HR: 1.49 (95% CI: 1.02-2.21) and HR: 1.51 (95% CI: 1.02-2.26), p = 0.04, respectively). 'Not-highly active' patients had worse disease-free survival outcomes, regardless of their BMI, compared to 'highly active/normal weight' patients. 'Not-highly active/obese' patients had a 3.66 times increased risk of death or recurrence compared to 'highly active/normal weight' patients (HR: 4.66 (95% CI: 1.75-9.10), p = 0.002). Lower activity thresholds yielded smaller effect sizes., Conclusion: Physical activity and BMI were individually associated with disease-free survival among colorectal cancer patients. Physical activity seems to improve survival outcomes in patients regardless of their BMI., (© 2023. The Author(s).)

Objective: APPEASE is a phase I study to assess the safety, dosing, and efficacy of rivoceranib (a selective, small-molecule inhibitor of VEGFR2) in combination with pembrolizumab. We aimed to treat patients with metastatic malignancies who have progressed through at least first-line therapy, with pembrolizumab 200 mg every 3 weeks, as well as escalating doses of rivoceranib until disease progression or unacceptable toxicity., Results: Five patients were enrolled on the starting dose of rivoceranib 300 mg once daily. There were no dose-limiting toxicities observed in combination with pembrolizumab. The dose of rivoceranib was not escalated due to study closure. We note a treatment related grade 3 adverse event (AE) rate of 40%, predominantly in urothelial cancer patients, with no deaths related to treatment related AEs. The disease control rate was 75% (3 of 4) and the median progression free survival (PFS) was 3.6 months. Tumor shrinkage was noted in patients who were previously progressing on pembrolizumab alone. Apatinib 300 mg is safe and demonstrates anti-tumor activity in advanced solid tumors in combination with pembrolizumab. Further dose escalation and efficacy need to be investigated in larger disease-specific patient populations., Trial Registration Number: Clinical trial registration number: NCT03407976. Date of registration: January 17, 2018., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors., 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. David S. Ziegler is a consultant, or on the advisory board, of Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Amgen, Alexion, and Norgine. Angela J. Waanders is on the advisory board of Alexion and Day One., (Copyright © 2022. Published by Elsevier Inc.)

Associations of energy balance components, including physical activity and obesity, with colorectal cancer risk and mortality are well established. However, the gut microbiome has not been investigated as underlying mechanism. We investigated associations of physical activity, BMI, and combinations of physical activity/BMI with gut microbiome diversity and differential abundances among colorectal cancer patients. N=179 patients with colorectal cancer (stages I-IV) were included in the study. Pre-surgery stool samples were used to perform 16S rRNA gene sequencing (Illumina). Physical activity (MET hrs/wk) during the year before diagnosis was assessed by questionnaire and participants were classified as being active vs. inactive based on guidelines. BMI at baseline was abstracted from medical records. Patients were classified into four combinations of physical activity levels/BMI. Lower gut microbial diversity was observed among 'inactive' vs. 'active' patients (Shannon: P =0.01, Simpson: P =0.03), 'obese' vs. 'normal weight' patients (Shannon, Simpson, and Observed species: P =0.02, respectively), and 'overweight/obese/inactive' vs. 'normal weight/active' patients (Shannon: P =0.02, Observed species: P =0.04). Results differed by sex and tumor site. Two phyla and 12 genera (Actinobacteria and Fusobacteria, Adlercreutzia, Anaerococcus, Clostridium, Eubacterium, Mogibacteriaceae, Olsenella, Peptinophilus, Pyramidobacter, RFN20, Ruminococcus, Succinivibrio, Succiniclasticum ) were differentially abundant across physical activity and BMI groups. This is the first evidence for associations of physical activity with gut microbiome diversity and abundances, directly among colorectal cancer patients. Our results indicate that physical activity may offset gut microbiome dysbiosis due to obesity. Alterations in gut microbiota may contribute mechanistically to the energy balance-colorectal cancer link and impact clinical outcomes., Competing Interests: None., (AJCR Copyright © 2022.)

Listeria monocytogenes is a foodborne intracellular bacterial pathogen leading to human listeriosis. Despite a high mortality rate and increasing antibiotic resistance no clinically approved vaccine against Listeria is available. Attenuated Listeria strains offer protection and are tested as antitumor vaccine vectors, but would benefit from a better knowledge on immunodominant vector antigens. To identify novel antigens, we screen for Listeria peptides presented on the surface of infected human cell lines by mass spectrometry-based immunopeptidomics. In between more than 15,000 human self-peptides, we detect 68 Listeria immunopeptides from 42 different bacterial proteins, including several known antigens. Peptides presented on different cell lines are often derived from the same bacterial surface proteins, classifying these antigens as potential vaccine candidates. Encoding these highly presented antigens in lipid nanoparticle mRNA vaccine formulations results in specific CD8 +  T-cell responses and induces protection in vaccination challenge experiments in mice. Our results can serve as a starting point for the development of a clinical mRNA vaccine against Listeria and aid to improve attenuated Listeria vaccines and vectors, demonstrating the power of immunopeptidomics for next-generation bacterial vaccine development., (© 2022. The Author(s).)

Life expectancy for people living with HIV has increased, but management of HIV is now more complex due to comorbidities. This study aimed to measure the prevalence of comorbidities among women living with HIV in Canada. We conducted a cross-sectional analysis using data from the 18-months survey (2014−2016) of the Canadian HIV Women’s Sexual and Reproductive Health Cohort Study (CHIWOS). Self-report of diagnosed conditions was used to measure lifetime prevalence of chronic physical conditions, current mental health conditions, and disabilities. We examined frequency of overlapping conditions and prevalence stratified by gender identity, ethnicity, and age. Among 1039 participants, 70.1% reported a physical health diagnosis, 57.4% reported a current mental health diagnosis, 19.9% reported a disability, and 47.1% reported both physical and mental health comorbidities. The most prevalent comorbidities were depression (32.3%), anxiety (29.5%), obesity (26.7%, defined as body mass index >30 kg/m2), asthma/chronic obstructive pulmonary disease (23.3%), sleep disorder (22.0%), drug addiction (21.9%), and arthritis/osteoarthritis (20.9%). These results highlight the complexity of HIV care and the important prevalence of comorbidities. Personalized health care that integrates care and prevention of all comorbidities with HIV, with attention to social determinants of health, is necessary to optimize health and well-being of women living with HIV.

Disparities in colorectal cancer (CRC) mortality among White, Black, and American Indian/Alaska Native (AIAN) men are attributable to differences in early detection screening. Determining how masculinity barriers influence CRC screening completion is critical for cancer prevention and control. To determine whether masculinity barriers to medical care are associated with lower rates of ever completing CRC screening, a survey-based study was employed from December 2020-January 2021 among 435 White, Black, and AIAN men (aged 45-75) who resided in the US. Logistic regression models were fit to four Masculinity Barriers to Medical Care subscales predicting ever completing CRC screening. For all men, being strong was associated with 54% decreased odds of CRC screening completion (OR 0.46, 95% CI 0.23 to 0.94); each unit increase in negative attitudes toward medical professionals and exams decreased the odds of ever completing CRC screening by 57% (OR 0.43, 95% CI 0.21 to 0.86). Black men who scored higher on negativity toward medical professionals and exams had decreased odds of ever screening. Consideration of masculinity in future population-based and intervention research is critical for increasing men's participation in CRC screening, with more salience for Black men.

Lessons Learned: Long-term safety of radium-223 with enzalutamide was confirmed in this clinical trial. PSA-PFS2 was prolonged with the combination compared with enzalutamide alone., Background: Previously, we showed the combination of radium-223 and enzalutamide to be safe and associated with improved efficacy based on a concomitant decline in serum bone metabolism markers compared with enzalutamide alone in a phase II trial of men with metastatic castration-resistant prostate cancer (mCRPC) [1]., Methods: Secondary endpoints were not included in our initial report, and we include them herein, after a median follow-up of 22 months. These objectives included long-term safety, prostate-specific antigen (PSA)-progression-free survival (PFS), and radiographic progression-free survival; PSA-PFS2 (time from start of protocol therapy to PSA progression on subsequent therapy); time to next therapy (TTNT); and overall survival (OS). Survival analysis and log-rank tests were performed using the R statistical package v.4.0.2 (https://www.r-project.org). Statistical significance was defined as p < .05., Results: Of 47 patients (median age, 68 years), 35 received the combination and 12 enzalutamide alone. After a median follow-up of 22 months, final safety results did not show any increase in fractures or other adverse events in the combination arm. PSA-PFS2 was significantly improved, and other efficacy parameters were numerically improved in the combination over the enzalutamide arm., Conclusion: The combination of enzalutamide and radium-223 was found to be safe and associated with promising efficacy in men with mCRPC. These hypothesis-generating results portend well for the ongoing phase III PEACE III trial in this setting., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Antiretroviral therapy effectively prevents sexual and vertical transmission of HIV. Yet, some women living with HIV report having unmet needs for reproductive health care. This study measured the prevalence of women discussing reproductive goals with any current healthcare provider and assessed the effect of the current HIV care provider's gender on such discussions and whether comfort was a mediator. We analysed baseline and 18-month survey data from 533 women living with HIV enrolled in the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS) (2013-2017), a community-based participatory study, restricting the analysis to participants aged 16-45 years. We used causal mediation analysis to estimate direct and indirect effects of the gender of one's HIV care provider on reproductive discussions, incorporating mediating and interaction effects of women having any provider with whom they felt comfortable discussing reproductive goals. Between the baseline and 18-month follow-up surveys, 34.3% (183/533) of women discussed their reproductive goals with a healthcare provider. Having a woman HIV care provider was associated with a 1.18 excess relative risk (ERR) of discussion (95%CI: 0.15, 2.20). The mediating effect of comfort was primarily explained by the fact that those participants with women providers felt more comfortable discussing their reproductive goals compared to participants with men providers, accounting for 66% (95%CI: 32%, 99%) of the total effect. Findings support that HIV provider gender affects women's comfort and whether they discuss reproductive goals, which must be acknowledged and addressed in care delivery.

Purpose Our 1-year longitudinal study tracked the development of cognate awareness among second (L2) and third language (L3) learners of French in French immersion in Grades 1 and 2 to explore the impact of orthographic overlap and cognate status (true vs. false) on children's ability to recognize cognate relationships. We also assessed the impact of French L2/L3 status on performance. Method We compared performance on three conditions (true cognates with same and similar spellings, false cognates with same spellings) within and across grades. We used a direct measure of cognate awareness that required children ( n = 81) to distinguish true from false cognates presented orally and in print. Results Overall, Grade 1 children failed to recognize cognate relationships between true cognates with similar spellings, but successfully recognized true cognates with same spellings. Performance on all conditions increased significantly between Grades 1 and 2. The greatest improvement was seen on true cognates with similar spellings. Performance on false cognates was inferior to performance on true cognates with same spellings in Grade 1, and inferior to performance on both same and similar spelled true cognates in Grade 2. No differences were found due to L2/L3 status. Conclusions Among sequential learners of L2/L3 French in the early stages of additional language learning, cognate awareness is impacted by the degree of orthographic overlap, as well as by cognate status. Children's ability to recognize cross-language orthographic and semantic relationships improves substantially across the early elementary grades. Supplemental Material https://doi.org/10.23641/asha.16821106.

RNF213 is a large, poorly characterized interferon-induced protein. Mutations in RNF213 are associated with predisposition for Moyamoya disease (MMD), a rare cerebrovascular disorder. Recently, RNF213 was found to have broad antimicrobial activity in vitro and in vivo , yet the molecular mechanisms behind this function remain unclear. Using mass spectrometry-based proteomics and validation by real-time PCR we report here that knockdown of RNF213 leads to transcriptional upregulation of MVP and downregulation of CYR61, in line with reported pro- and anti-bacterial activities of these proteins. Knockdown of RNF213 also results in downregulation of DDAH1, which we discover to exert antimicrobial activity against Listeria monocytogenes infection. DDAH1 regulates production of nitric oxide (NO), a molecule with both vascular and antimicrobial effects. We show that NO production is reduced in macrophages from RNF213 KO mice, suggesting that RNF213 controls Listeria infection through regulation of DDAH1 transcription and production of NO. Our findings propose a potential mechanism for the antilisterial activity of RNF213 and highlight NO as a potential link between RNF213-mediated immune responses and the development of MMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Martina, Asselman, Thery, Boucher, Delhaye, Maia, Dermaut, Eyckerman and Impens.)

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we use a virus-like particle trapping technology to identify ISG15-binding proteins and discover Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We report that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We show that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1, human respiratory syncytial virus and coxsackievirus B3, and we observe a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector., (© 2021. The Author(s).)