Author Correction: FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes.

Mutations in the transcription factor FOXA1 define a unique subset of prostate cancers but the functional consequences of these mutations and whether they confer gain or loss of function is unknown1-9. Here, by annotating the landscape of FOXA1 mutations from 3,086 human prostate cancers, we define two hotspots in the forkhead domain: Wing2 (around 50% of all mutations) and the highly conserved DNA-contact residue R219 (around 5% of all mutations). Wing2 mutations are detected in adenocarcinomas at all stages, whereas R219 mutations are enriched in metastatic tumours with neuroendocrine histology. Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants reveals gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) of wild-type FOXA1 and representative Wing2 and R219 mutants revealed marked, mutant-specific changes in open chromatin at thousands of genomic loci and exposed sites of FOXA1 binding and associated increases in gene expression. Of note, ATAC-seq peaks in cells expressing R219 mutants lacked the canonical core FOXA1-binding motifs (GTAAAC/T) but were enriched for a related, non-canonical motif (GTAAAG/A), which was preferentially activated by R219-mutant FOXA1 in reporter assays. Thus, FOXA1 mutations alter its pioneering function and perturb normal luminal epithelial differentiation programs, providing further support for the role of lineage plasticity in cancer progression.

Statewide Examination of Access to Cancer Surgery During the COVID-19 Pandemic.

INTRODUCTION: The COVID-19 pandemic caused interruptions in the delivery of medical care across a wide range of conditions including cancer. Trends in surgical treatment for cancer during the pandemic have not been well described. We sought to characterize associations between the pandemic and access to surgical treatment for breast, colorectal, and lung cancer in Illinois. METHODS: We performed a retrospective cohort study evaluating inpatient admissions at Illinois hospitals providing surgical care for lung cancer (n = 1913 cases, n = 64 hospitals), breast cancer (n = 910 cases, n = 108 hospitals), and colorectal cancer (n = 5339 cases, n = 144 hospitals). Using discharge data from the Illinois Health and Hospital Association's Comparative Health Care and Hospital Data Reporting Services database, average monthly surgical case volumes were compared from 2019 to 2020. We also compared rates of cancer surgery for each cancer type, by patient characteristics, and hospital type across the three time periods using Pearson chi-squared and ANOVA testing as appropriate. Three discrete time periods were considered: prepandemic (7-12/2019), primary pandemic (4-6/2020), and pandemic recovery (7-12/2020). Hospital characteristics evaluated included hospital type (academic, community, safety net), COVID-19 burden, and baseline cancer surgery volume. RESULTS: There were 2096 fewer operations performed for breast, colorectal, and lung cancer in 2020 than 2019 in Illinois, with the greatest reductions in cancer surgery volume occurring at the onset of the pandemic in April (colorectal, -48.3%; lung, -13.1%) and May (breast, -45.2%) of 2020. During the pandemic, breast (-14.6%) and colorectal (-13.8%) cancer surgery experienced reductions in volume whereas lung cancer operations were more common (+26.4%) compared to 2019. There were no significant differences noted in gender, race, ethnicity, or insurance status among patients receiving oncologic surgery during the primary pandemic or pandemic recovery periods. Academic hospitals, hospitals with larger numbers of COVID-19 admissions, and those with greater baseline cancer surgery volumes were associated with the greatest reduction in cancer surgery during the primary pandemic period (all cancer types, P < 0.01). During the recovery period, hospitals with greater baseline breast and lung cancer surgery volumes remained at reduced surgery volumes compared to their counterparts (P < 0.01). CONCLUSIONS: The COVID-19 pandemic was associated with significant reductions in breast and colorectal cancer operations in Illinois, while lung cancer operations remained relatively consistent. Overall, there was a net reduction in cancer surgery that was not made up during the recovery period. Academic hospitals, those caring for more COVID-19 patients, and those with greater baseline surgery volumes were most vulnerable to reduced surgery rates during peaks of the pandemic and to delays in addressing the backlog of cases.

Nutritional needs, resources, and barriers among unhoused adults cared for by a street medicine organization in Chicago, Illinois: a cross-sectional study.

BACKGROUND: Those experiencing houselessness rely on obtaining food from community organizers and donations. Simultaneously, the houseless face disproportionally high rates of medical conditions that may be affected by diet including diabetes, hypertension, and hyperlipidemia. There is limited literature on the resources and barriers of the houseless community regarding optimal nutrition from an actionable perspective. Further, less data is available on how street medicine organizations may best impact the nutrition of the unhoused they serve. Elucidating this information will inform how organizational efforts may best support the nutrition of the houseless community. METHODS: In partnership with the medical student-run organization, Chicago Street Medicine, at Northwestern University Feinberg School of Medicine, twenty adults experiencing houselessness in Chicago, Illinois participated in the cross-sectional study. A 10-item survey was verbally administered to characterize the participants' daily food intake, food sources, barriers, resources, and nutritional preferences and needs. All data was directly transcribed into REDCap. Descriptive statistics were generated. RESULTS: Individuals consumed a median of 2 snacks and meals per day (IQR: 1-3). No participant consumed adequate servings of every food group, with only one participant meeting the dietary intake requirements for one food group. Participants most often received their food from donations (n = 15), purchasing themselves (n = 11), food pantries (n = 4), and shelters (n = 3). Eleven of nineteen participants endorsed dental concerns as a major barrier to consuming certain foods. Twelve participants had access to a can opener and twelve could heat their meals on a stove or microwave. Seven had access to kitchen facilities where they may prepare a meal. Approximately half of participants had been counseled by a physician to maintain a particular diet, with most related to reducing sugar intake. CONCLUSION: Most houseless participants were unable to acquire a balanced diet and often relied on organizational efforts to eat. Organizations should consider the chronic health conditions, dentition needs, and physical resources and barriers to optimal nutrition when obtaining food to distribute to the unhoused.

Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses' health study.

BACKGROUND: Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses' Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. METHODS: This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures' association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression. RESULTS: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ (ß = 0.16; p = 0.009), and CD163 novel immune scores (ß = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. CONCLUSIONS: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.

Psychosocial Needs of Gynecological Cancer Survivors: Mixed Methods Study.

BACKGROUND: Internet and social media platforms offer insights into the lived experiences of survivors of cancer and their caregivers; however, the volume of narrative data available is often cumbersome for thorough analysis. Survivors of gynecological cancer have unique needs, such as those related to a genetic predisposition to future cancers, impact of cancer on sexual health, the advanced stage at which many are diagnosed, and the influx of new therapeutic approaches. OBJECTIVE: This study aimed to present a unique methodology to leverage large amounts of data from internet-based platforms for mixed methods analysis. We analyzed discussion board posts made by survivors of gynecological cancer on the American Cancer Society website with a particular interest in evaluating the psychosocial aspects of survivorship. METHODS: All posts from the ovarian, uterine, and gynecological cancers (other than ovarian and uterine) discussion boards on the American Cancer Society Cancer Survivors Network were included. Posts were web scraped using Python and organized by psychosocial themes described in the Quality of Cancer Survivorship Care Framework. Keywords related to each theme were generated and verified. Keywords identified posts related to the predetermined psychosocial themes. Quantitative analysis was completed using Python and R Foundation for Statistical Computing packages. Qualitative analysis was completed on a subset of posts as a proof of concept. Themes discovered through latent Dirichlet allocation (LDA), an unsupervised topic modeling technique, were assessed and compared with the predetermined themes of interest. RESULTS: A total of 125,498 posts made by 6436 survivors of gynecological cancer and caregivers between July 2000 and February 2020 were evaluated. Of the 125,489 posts, 23,458 (18.69%) were related to the psychosocial experience of cancer and were included in the mixed methods psychosocial analysis. Quantitative analysis (23,458 posts) revealed that survivors across all gynecological cancer discussion boards most frequently discussed the role of friends and family in care, as well as fatigue, the effect of cancer on interpersonal relationships, and health insurance status. Words related to psychosocial aspects of survivorship most often used in posts included "family," "hope," and "help." Qualitative analysis (20 of the 23,458 posts) similarly demonstrated that survivors frequently discussed coping strategies, distress and worry, the role of family and caregivers in their cancer care, and the toll of managing financial and insurance concerns. Using LDA, we discovered 8 themes, none of which were directly related to psychosocial aspects of survivorship. Of the 56 keywords identified by LDA, 2 (4%), "sleep" and "work," were included in the keyword list that we independently devised. CONCLUSIONS: Web-based discussion platforms offer a great opportunity to learn about patient experiences of survivorship. Our novel methodology expedites the quantitative and qualitative analyses of such robust data, which may be used for additional patient populations.

Experiences and Situations of Shame among Food-insecure Adolescents in South Carolina and Oregon.

Shame experienced with food insecurity and participating in food assistance may affect adolescents. We investigated adolescents' experiences of shame related to food insecurity and situations for these experiences in an ethnically diverse sample of 40 adolescents aged 9-15 years from South Carolina and Oregon. In-depth interviews were recorded, transcribed, coded, and analyzed. Participants described feelings of sadness, anger, and internalized shame with food insecurity. Salient situations were participating in food assistance, seeking food assistance from others or community services, and social encounters at school among peers. Adolescents felt shame knowing that peers were aware of their food insecurity and about them participating in food assistance through school.

Genomic features of rapid versus late relapse in triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. METHODS: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as 'rapid relapse' (rrTNBC; distant relapse or death ≤2 years of diagnosis), 'late relapse' (lrTNBC; > 2 years) or 'no relapse' (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. RESULTS: Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. CONCLUSIONS: We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo.

Approximately one-third of the mammalian proteome is transported from the endoplasmic reticulum-to-Golgi via COPII-coated vesicles. SEC23, a core component of coat protein-complex II (COPII), is encoded by two paralogous genes in vertebrates (Sec23a and Sec23b). In humans, SEC23B deficiency results in congenital dyserythropoietic anemia type-II (CDAII), while SEC23A deficiency results in a skeletal phenotype (with normal red blood cells). These distinct clinical disorders, together with previous biochemical studies, suggest unique functions for SEC23A and SEC23B. Here we show indistinguishable intracellular protein interactomes for human SEC23A and SEC23B, complementation of yeast Sec23 by both human and murine SEC23A/B, and rescue of the lethality of sec23b deficiency in zebrafish by a sec23a-expressing transgene. We next demonstrate that a Sec23a coding sequence inserted into the murine Sec23b locus completely rescues the lethal SEC23B-deficient pancreatic phenotype. We show that SEC23B is the predominantly expressed paralog in human bone marrow, but not in the mouse, with the reciprocal pattern observed in the pancreas. Taken together, these data demonstrate an equivalent function for SEC23A/B, with evolutionary shifts in the transcription program likely accounting for the distinct phenotypes of SEC23A/B deficiency within and across species, a paradigm potentially applicable to other sets of paralogous genes. These findings also suggest that enhanced erythroid expression of the normal SEC23A gene could offer an effective therapeutic approach for CDAII patients.

Metastatic breast cancer patient perceptions of somatic tumor genomic testing.

BACKGROUND: To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. METHODS: In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar's test of agreement. RESULTS: There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04). CONCLUSIONS: This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention. CLINICAL TRIAL INFORMATION: NCT01987726, registered November 13, 2013.

Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.

Mammalian COPII coat component SEC24C is required for embryonic development in mice.

COPII-coated vesicles mediate the transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi. SEC24 is the COPII component primarily responsible for recruitment of protein cargoes into nascent vesicles. There are four Sec24 paralogs in mammals, with mice deficient in SEC24A, -B, and -D exhibiting a wide range of phenotypes. We now report the characterization of mice with deficiency in the fourth Sec24 paralog, SEC24C. Although mice haploinsufficient for Sec24c exhibit no apparent abnormalities, homozygous deficiency results in embryonic lethality at approximately embryonic day 7. Tissue-specific deletion of Sec24c in hepatocytes, pancreatic cells, smooth muscle cells, and intestinal epithelial cells results in phenotypically normal mice. Thus, SEC24C is required in early mammalian development but is dispensable in a number of tissues, likely as a result of compensation by other Sec24 paralogs. The embryonic lethality resulting from loss of SEC24C occurs considerably later than the lethality previously observed in SEC24D deficiency; it is clearly distinct from the restricted neural tube phenotype of Sec24b null embryos and the mild hypocholesterolemic phenotype of adult Sec24a null mice. Taken together, these results demonstrate that the four Sec24 paralogs have developed unique functions over the course of vertebrate evolution.

Increased Food Insecurity Among Mothers of 2 Year Olds with Special Health Care Needs.

The objective of this study is to explore the association between having a child with special health care needs (CSHCN) and food insecurity when the child is 2 years old. We studied women who had a live birth in 2004-2005 and responded to Oregon's Pregnancy Risk Assessment Monitoring System (PRAMS) survey 3 months postpartum (Time 1) and the follow-up survey (PRAMS-2), when the child was 2 years old (Time 2). Women answering affirmatively to the PRAMS-2 question, "In the last 12 months, did you ever eat less than you felt you should because there was not enough money for food?" were considered food insecure. CSHCN status was identified by affirmative responses to questions about needs for ongoing services (Time 2). PRAMS and PRAMS-2 responses were weighted for study design and non-response. Results report weighted analyses, unless noted. Among 1812 mothers completing PRAMS-2, 13.6 % (unweighted) had a 2-year-old CSHCN and 11.9 % (unweighted) were food insecure at Time 2. The estimated prevalence of food insecurity at 2-year follow-up was 20.7 % among families of CSHCN and 9.7 % for others. After adjustment for Time 2 marital status, education, lifetime U.S. residence, income and health conditions, multivariable logistic regression revealed that odds of food insecurity were more than two times as great for CSHCN mothers 2 years post-partum compared to non-CSHCN mothers (adjusted odds ratio 2.6, 95 % confidence interval 1.3, 4.6). Families of CSHCN face increased risk for food insecurity. Improved understanding of causal determinants of food insecurity among households of CSHCN is needed.

Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.

Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations. In this study, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor, and it elucidates the aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression, in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 patients with cancer correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, these data suggest that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents, and may be beneficial in various indications with recurrent ARID1A mutations. Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and cancer patients that can be assessed with a pharmacodynamic gene signature in peripheral blood.

A critical evaluation of the PTW 2D-ARRAY seven29 and OCTAVIUS II phantom for IMRT and VMAT verification.

Quality assurance (QA) for intensity- and volumetric-modulated radiotherapy (IMRT and VMAT) has evolved substantially. In recent years, various commercial 2D and 3D ionization chamber or diode detector arrays have become available, allowing for absolute verification with near real time results, allowing for streamlined QA. However, detector arrays are limited by their resolution, giving rise to concerns about their sensitivity to errors. Understanding the limitations of these devices is therefore critical. In this study, the sensitivity and resolution of the PTW 2D-ARRAY seven29 and OCTAVIUS II phantom combination was comprehensively characterized for use in dynamic sliding window IMRT and RapidArc verification. Measurement comparisons were made between single acquisition and a multiple merged acquisition techniques to improve the effective resolution of the 2D-ARRAY, as well as comparisons against GAFCHROMIC EBT2 film and electronic portal imaging dosimetry (EPID). The sensitivity and resolution of the 2D-ARRAY was tested using two gantry angle 0° modulated test fields. Deliberate multileaf collimator (MLC) errors of 1, 2, and 5 mm and collimator rotation errors were inserted into IMRT and RapidArc plans for pelvis and head & neck sites, to test sensitivity to errors. The radiobiological impact of these errors was assessed to determine the gamma index passing criteria to be used with the 2D-ARRAY to detect clinically relevant errors. For gamma index distributions, it was found that the 2D-ARRAY in single acquisition mode was comparable to multiple acquisition modes, as well as film and EPID. It was found that the commonly used gamma index criteria of 3% dose difference or 3 mm distance to agreement may potentially mask clinically relevant errors. Gamma index criteria of 3%/2 mm with a passing threshold of 98%, or 2%/2 mm with a passing threshold of 95%, were found to be more sensitive. We suggest that the gamma index passing thresholds may be used for guidance, but also should be combined with a visual inspection of the gamma index distribution and calculation of the dose difference to assess whether there may be a clinical impact in failed regions.

Student-driven disability advocacy and education within the health professions: pilot survey results from a single-day virtual conference.

BACKGROUND: Health professional programs can promote equitable healthcare delivery but few programs include disability in these efforts. Limited opportunities exist for health professional students to engage with disability education within the classroom or beyond. The Disability Advocacy Coalition in Medicine (DAC Med) is a national interprofessional student-led organization which hosted a virtual conference for health professional students in October 2021. We describe the impact of this single-day virtual conference on learning and the current state of disability education across health professional programs. METHODS: This cross-sectional study utilized a 17-item post-conference survey. A 5-point Likert scale-based survey was distributed to conference registrants. Survey parameters included background in disability advocacy, curricular exposure to disability, and impact of the conference. RESULTS: Twenty-four conference attendees completed the survey. Participants were enrolled in audiology, genetic counseling, medical, medical scientist, nursing, prosthetics and orthotics, public health, and 'other' health programs. Most participants (58.3%) reported not having a strong background in disability advocacy before the conference, with 26.1% indicating they learned about ableism in their program's curriculum. Almost all students (91.6%) attended the conference to learn how to be a better advocate for patients and peers with disabilities, and 95.8% reported that the conference provided this knowledge. Eighty-eight percent of participants agreed that they acquired additional resources to better care for patients with disabilities. CONCLUSIONS: Few health professional students learn about disability in their curriculum. Single-day virtual, interactive conferences are effective in providing advocacy resources and empowering students to employ them.

Gender Disparities and Differences Among Urologists Included in Top Doctor Lists.

OBJECTIVE: To understand gender trends among urologists included in "Top Doctor" lists as more women practice urology, we (1) Evaluated whether Top Doctor lists reflect a contemporary distribution of urologists by gender; (2) Describe regional differences in gender composition of lists; (3) Report similarities and differences among men and women Top Doctors. METHODS: All urologists in regional Top Doctor Castle Connolly lists published in magazines between January 1, 2020 and June 22, 2021 were included. Physician attributes were abstracted. American Urological Association (AUA) census data was used to compare the number of men and women Top Doctor urologists to the number of practicing men and women urologists within each list's zip codes. Log odds ratios (OR) and (95% confidence intervals) were used to compare likelihood of list inclusion by gender overall and by region. RESULTS: Four hundred and ninety-four Top Doctor urologists from 25 lists were analyzed, of which 42 (8.50%) were women. Women urologists comprised 0%-27.8% of each list, with 7 lists (28.0%) including zero women urologists. Using AUA census data, OR for list inclusion of men urologists compared to women was 1.31 (1.01, 1.70) overall, with OR = 0.78 (0.36, 1.72) in the West, OR = 1.39 (1.03, 1.89) South, OR = 1.46 (0.8, 2.67) Northeast, OR = 1.90 (0.50, 7.18) Midwest. Women top urologists completed fellowship more often than men (66.7%, 55.1%) and were significantly more likely to complete female pelvic medicine and reconstructive surgery (FPMRS) fellowship (P <.001). CONCLUSION: Men urologists were significantly more likely to be included in Top Doctor lists than women urologists. Top women urologists were significantly more likely to complete FPMRS fellowship.

Implementing cone-beam computed tomography-guided online adaptive radiotherapy in cervical cancer.

Background and purpose: Adaptive radiotherapy (ART) in locally advanced cervical cancer (LACC) has shown promising outcomes. This study investigated the feasibility of cone-beam computed tomography (CBCT)-guided online ART (oART) for the treatment of LACC. Material and methods: The quality of the automated radiotherapy treatment plans and artificial intelligence (AI)-driven contour delineation for LACC on a novel CBCT-guided oART system were assessed. Dosimetric analysis of 200 simulated oART sessions were compared with standard treatment. Feasibility of oART was assessed from the delivery of 132 oART fractions for the first five clinical LACC patients. The simulated and live oART sessions compared a fixed planning target volume (PTV) margin of 1.5 cm around the uterus-cervix clinical target volume (CTV) with an internal target volume-based approach. Workflow timing measurements were recorded. Results: The automatically-generated 12-field intensity-modulated radiotherapy plans were comparable to manually generated plans. The AI-driven organ-at-risk (OAR) contouring was acceptable requiring, on average, 12.3 min to edit, with the bowel performing least well and rated as unacceptable in 16 % of cases. The treated patients demonstrated a mean PTV D98% (+/-SD) of 96.7 (+/- 0.2)% for the adapted plans and 94.9 (+/- 3.7)% for the non-adapted scheduled plans (p<10-5). The D2cc (+/-SD) for the bowel, bladder and rectum were reduced by 0.07 (+/- 0.03)Gy, 0.04 (+/-0.05)Gy and 0.04 (+/-0.03)Gy per fraction respectively with the adapted plan (p <10-5). In the live.setting, the mean oART session (+/-SD) from CBCT acquisition to beam-on was 29 +/- 5 (range 21-44) minutes. Conclusion: CBCT-guided oART was shown to be feasible with dosimetric benefits for patients with LACC. Further work to analyse potential reductions in PTV margins is ongoing.

Patient Understanding of Tumor Genomic Testing: A Quality Improvement Effort.

PURPOSE: Tumor genomic testing (TGT) has become increasingly adopted as part of standard cancer care for many cancers. Despite national guidelines around patient education before TGT, available evidence suggests that most patients' understanding of genomics remains limited, particularly lower-income and minority patients, and most patients are not informed regarding potential incidental germline findings. METHODS: To investigate and address limitations in patient understanding of TGT results, a Plan-Do-Study-Act (PDSA) approach is being used to assess needs, identify opportunities for improvement, and implement approaches to optimize patient education. We reviewed published guidelines related to pre-TGT provider-patient education and to identify key points (Plan). A provider quality improvement survey was completed (Do), which highlighted inconsistency in pre-TGT discussion practice across providers and minimal discussion with patients regarding the possibility of incidental germline findings. RESULTS: Patient focus groups and interviews (N = 12 patients) were completed with coding of each transcript (Study), which revealed themes including trouble differentiating TGT from other forms of testing, yet understanding that results could tailor therapy. The integration of data across this initial PDSA cycle identified consistent themes and opportunities, which were incorporated into a patient-directed, concise animated video for pre-TGT education (Act), which will form the foundation of a subsequent PDSA cycle. The video addresses how TGT may/may not inform treatment, the process for TGT using existing tissue or liquid biopsy, insurance coverage, and the potential need for germline genetics follow-up because of incidental findings. CONCLUSION: This PDSA cycle reveals key gaps and opportunities for improvement in patient education before TGT.

Functional divergence of dafachronic acid pathways in the control of C. elegans development and lifespan.

Steroid hormone and insulin/insulin-like growth factor signaling (IIS) pathways control development and lifespan in the nematode Caenorhabditis elegans by regulating the activity of the nuclear receptor DAF-12 and the FoxO transcription factor DAF-16, respectively. The DAF-12 ligands Delta(4)- and Delta(7)-dafachronic acid (DA) promote bypass of the dauer diapause and proper gonadal migration during larval development; in adults, DAs influence lifespan. Whether Delta(4)- and Delta(7)-DA have unique biological functions is not known. We identified the 3-beta-hydroxysteroid dehydrogenase (3betaHSD) family member HSD-1, which participates in Delta(4)-DA biosynthesis, as an inhibitor of DAF-16/FoxO activity. Whereas IIS promotes the cytoplasmic sequestration of DAF-16/FoxO, HSD-1 inhibits nuclear DAF-16/FoxO activity without affecting DAF-16/FoxO subcellular localization. Thus, HSD-1 and IIS inhibit DAF-16/FoxO activity via distinct and complementary mechanisms. In adults, HSD-1 was required for full lifespan extension in IIS mutants, indicating that HSD-1 interactions with IIS are context-dependent. In contrast to the Delta(7)-DA biosynthetic enzyme DAF-36, HSD-1 is dispensable for proper gonadal migration and lifespan extension induced by germline ablation. These findings provide insights into the molecular interface between DA and IIS pathways and suggest that Delta(4)- and Delta(7)-DA pathways have unique as well as overlapping biological functions in the control of development and lifespan.