Occupational therapy practice for post-acute COVID-19 inpatients requiring rehabilitation.

INTRODUCTION: COVID-19 caused significant occupational disruption to people's life roles, with some people requiring an inpatient rehabilitation admission. Occupational therapists assessed and treated these patients using previous knowledge of similar conditions due to limited specificity in available guidelines to inform practice. The aim of this study was to investigate current practice with post-acute COVID-19 (PAC) patients within an inpatient rehabilitation setting in Australia, to better understand the role and impact of occupational therapy. METHODS: A mixed-method study was conducted, including electronic medical record audits (October 2021 October 2022) and descriptive patient interviews at a large metropolitan subacute service. Descriptive statistics and qualitative analysis were used to summarise and interpret data. CONSUMER AND COMMUNITY INVOLVEMENT: No involvement. RESULTS: A total of 24 patient electronic medical records were audited, and 10 patient interviews were completed. Three overarching categories were identified within the 685 occasions of occupational therapy service audited-occupational engagement, education provision and discharge planning. Patients identified the value of occupational therapy by reflecting on their lived experiences of engaging with occupational therapists and associated changes in occupational performance between COVID-19 diagnoses and discharge home. CONCLUSION: Occupational therapists possess a unique skill set that directly addresses the occupational needs and priorities of PAC patients. This study adds to the growing body of evidence supporting the contribution of occupational therapy to the management of COVID-19; however, further research is needed to develop evidence-based practice resources and advocate for system changes that improve quality of life for COVID-19 patients. PLAIN LANGUAGE SUMMARY: During the COVID-19 pandemic, a lot of people got very sick. Some of these people needed more time and support to get better. Occupational therapists were important during this time because they helped these people to do their daily activities again. Because there were not many resources on how to do this, we looked into what occupational therapists were doing to help these people. We looked at patient hospital files and also talked to them to understand this better. We found that occupational therapists focused on three main areas: helping patients do activities that were important to them, teaching them about COVID-19 and helping them plan to leave the hospital. This study shows that occupational therapists are skilled at helping people with COVID-19. But more research is needed to make resources and also help with changing the healthcare system to further help people get better from COVID-19.

Enhancing HIV pre-exposure prophylaxis outcomes among Kenyan adolescent girls and young women with a novel pharmacy-based PrEP delivery platform: protocol for a cluster-randomized controlled trial.

BACKGROUND: In Kenya, 65% of sexually active unmarried women use modern contraceptives, a population at increased risk of HIV acquisition compared to other populations. Anchoring HIV prevention services, including pre-exposure prophylaxis (PrEP), to trusted contraceptive delivery settings offers opportunities to efficiently reach this important population. In Kenya, almost half (40%) of women accessing contraception services do so outside traditional healthcare facilities, such as retail pharmacies. Thus, integrating PrEP services into retail pharmacies may increase options for reaching adolescent girls and young women (AGYW) who could benefit from PrEP. Efforts are underway to define care pathways for pharmacy-delivered PrEP services in Kenya, including unsupported and supported models with nurse navigators. METHODS: The AGYW Pharmacy PrEP study is an unblinded 2-arm cluster-randomized controlled trial in Kisumu, Kenya. The objective is to determine the effect that unsupported versus supported pharmacy-delivered PrEP services has on PrEP initiation, persistence, and adherence among AGYW seeking contraception. Twenty retail pharmacies offering pharmacy provider-led PrEP delivery will be randomized 1:1 to either receive or not receive a nurse navigator to support PrEP delivery. Eligible AGYW (n = 1900 total, n = 950/arm) will be ≥ 15 years old, purchasing a method of contraception at the pharmacy. Trained pharmacy provider will offer eligible AGYW either daily oral PrEP or the monthly DPV vaginal ring. The primary trial outcomes are PrEP initiation (use of PrEP at 1 month), persistence (use of PrEP at 10 months), and adherence (quantified by levels of TFV or DPV in hair samples). Additionally, several secondary (STI incidence, PrEP method selection, predictors of PrEP adherence) and exploratory outcomes (HIV incidence, quality of care, contraceptive method mix) will be explored. DISCUSSION: We hypothesize pharmacy-delivered PrEP services supported with nurse navigator, versus delivered by pharmacy providers alone, will improve PrEP outcomes among AGYW seeking contraception. Our results will help policy makers better understand how to potentially implement this novel differentiated service model for PrEP and prime pharmacies for the delivery of new PrEP agents in the pipeline (e.g., long-acting injectables and multi-purpose technologies). The study was initiated on May 13, 2023, and is expected to be completed by February 2025. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05467306), with registration on July 20, 2022.

Priorities for contraceptive method and service delivery attributes among adolescent girls and young women in Kenya: a qualitative study.

Introduction: Despite increasing global commitment to meeting the family planning needs of adolescent girls and young women (AGYW), there is limited research on how they prioritize contraceptive method and service delivery characteristics. In this qualitative study, we examine the specific elements that drive the contraceptive choices of Kenyan AGYW, and apply our findings to the development of attributes and levels for a discrete choice experiment (DCE). Methods: Our four-stage approach included data collection, data reduction, removing inappropriate attributes, and optimizing wording. Between June-October 2021, we conducted in-depth interviews with 30 sexually-active 15-24 year-old AGYW in Kisumu county, Kenya who were non-pregnant and desired to delay pregnancy. Interviews focused on priorities for contraceptive attributes, how AGYW make trade-offs between among these attributes, and the influences of preferences on contraceptive choice. Translated transcripts were qualitatively coded and analyzed with a constant comparative approach to identify key concepts. We developed and iteratively revised a list of attributes and levels, and pre-tested draft DCE choice tasks using cognitive interviews with an additional 15 AGYW to optimize comprehension and relevance. Results: In-depth interview participants' median age was 18, 70% were current students, and 93% had a primary sexual partner. AGYW named a variety of priorities and preferences related to choosing and accessing contraceptive methods, which we distilled into six key themes: side effects; effectiveness; user control; privacy; source of services; and cost. Bleeding pattern was top of mind for participants; amenorrhea was generally considered an intolerable side effect. Many participants felt more strongly about privacy than effectiveness, though some prioritized duration of use and minimizing chance of pregnancy above other contraceptive characteristics. Most AGYW preferred a clinic setting for access, as they desired contraceptive counseling from a provider, but pharmacies were considered preferable for reasons of privacy. We selected, refined, and pre-tested 7 DCE attributes, each with 2-4 levels. Conclusions: Identifying AGYW preferences for contraceptive method and service delivery characteristics is essential to developing innovative strategies to meet their unique SRH needs. DCE methods may provide valuable quantitative perspectives to guide and tailor contraceptive counseling and service delivery interventions for AGYW who want to use contraception.

Confirmatory Factor Analysis and Validation of the Sexual and Reproductive Empowerment Scale for Adolescents and Young Adults in Kenya.

Understanding the levels of power that adolescent girls and young women exercise in their sexual and reproductive lives is imperative to inform interventions to help them meet their goals. We implemented an adapted version of the Sexual and Reproductive Health Empowerment (SRE) Scale for Adolescents and Young Adults among 500 adolescent girls and young women aged 15-20 in Kisumu, Kenya. We used confirmatory factor analysis (CFA) to assess factor structure, and logistic regression to examine construct validity through the relationship between empowerment scores and ability to mitigate risk of undesired pregnancy through consistent contraceptive use. Participants had a mean age of 17.5, and most were students (61 percent), were currently partnered (94 percent), and reported having sex in the past 3 months (70 percent). The final, 26-item CFA model had acceptable fit. All subscales had Cronbach's alpha scores >0.7, and all items had rotated factor loadings >0.5, indicating good internal consistency and robust factor-variable associations. The total SRE-Kenya (SRE-K) score was associated with increased odds of the consistent method used in the past three months (adjusted odds ratio: 1.98, 95 percent CI: 1.29-3.10). The SRE-K scale is a newly adapted and valid measure of sexual and reproductive empowerment specific to adolescent girls and young women in an East African setting.

Mobile solutions to Empower reproductive life planning for women living with HIV in Kenya (MWACh EMPOWER): Protocol for a cluster randomized controlled trial.

BACKGROUND: Women living with HIV (WLWH) face unique reproductive health (RH) barriers which increase their risks of unmet need for contraception, contraceptive failure, unintended pregnancy, and pregnancy-related morbidity and mortality and may prevent them from achieving their reproductive goals. Patient-centered counseling interventions that support health care workers (HCWs) in providing high-quality RH counseling, tailored to the needs of WLWH, may improve reproductive health outcomes. METHODS AND DESIGN: We are conducting a non-blinded cluster randomized controlled trial (cRCT) of a digital health intervention for WLWH (clinicaltrials.gov #NCT05285670). We will enroll 3,300 WLWH seeking care in 10 HIV care and treatment centers in Nairobi and Western Kenya. WLWH at intervention sites receive the Mobile WACh Empower intervention, a tablet-based RH decision-support counseling tool administered at baseline and SMS support during two years of follow-up. WLWH at control sites receive the standard of care FP counseling. The decision-support tool is a logic-based tool for family planning (FP) counseling that uses branching logic to guide RH questions based on participants' reproductive life plans, tailoring counseling based on the responses. Follow-up SMSs are based in the Information-Motivation-Behavioral (IMB) Skills model of behavioral change and are tailored to participant characteristics and reproductive needs through separate SMS "tracks". Follow-up visits are scheduled quarterly for 2 years to assess plans for pregnancy, pregnancy prevention, and contraceptive use. The primary outcome, FP discontinuation, will be compared using an intent-to-treat analysis. We will also assess the unmet need for FP, dual method use, viral load suppression at conception and unintended pregnancy. DISCUSSION: The Mobile WACh Empower intervention is innovative as it combines a patient-centered counseling tool to support initial reproductive life decisions with longitudinal SMS for continued RH support and may help provide RH care within the context of provision of HIV care.

Individuals' experiences in genetic counseling and predictive testing for familial amyotrophic lateral sclerosis.

As clinical genetic testing in the amyotrophic lateral sclerosis (ALS) diagnostic setting increases, the identification of at-risk family members has also expanded. No practice guidelines specifically for predictive genetic testing exist, and few studies about the psychological impacts of testing in this subgroup have occurred, limiting the ability to tailor recommendations and counseling in this community. We surveyed asymptomatic individuals at risk for inheriting an ALS-associated gene mutation. The 80-question survey was designed using a combination of validated measures (General Anxiety Disorder; FACToR; Decision Regret Scale) and original items. Ninety participants completed the survey, including those who completed predictive genetic testing (N = 42) and those who did not (N = 48). Gene positive individuals experienced greater negativity, uncertainty, and overall psychological impairment (p = 0.002; p < 0.001; p = 0.001). Individuals who had not undergone testing reported thinking about their risk multiple times per day and experiencing more decisional regret than those who tested (p = 0.006). In terms of decision-making, being prepared for potential clinical drug trials was a more important potential benefit among those who underwent testing (p = 0.026). Participants valuing preparedness for clinical drug trials supports the concept that genetic testing for ALS will increase as research in gene-targeted therapeutics progresses. This study describes factors relevant to the genetic testing decision-making process and adaptation to results from the perspective of at-risk individuals, which can ultimately guide genetic counseling practice in this population.

Transcriptional profiles of pulmonary artery endothelial cells in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This "cell biopsy" method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.

Adaptation of the sexual and reproductive empowerment scale for adolescents and young adults in Kenya.

Measuring empowerment is critical to understanding the level of control adolescents and young adults (AYA) have over their sexual and reproductive health (SRH) behaviors, and could provide a key window into addressing their unique SRH needs. We adapted the Sexual and Reproductive Empowerment (SRE) scale for AYA for use in an East African context. This multi-method qualitative study sampled 15-23 year-old female adolescents and young adults in Kisumu, Kenya. We conducted in-depth interviews (n = 30) and analyzed transcripts with an inductive, constant comparison approach. Empowerment domains were integrated with Kabeer's (1999) framework in a conceptual model, which we referenced to revise the original and develop new scale items. Items underwent expert review, and were condensed and translated through team-based consensus-building. We evaluated content validity in cognitive interviews (n = 25), during which item phrasing and word choice were revised to generate an adapted SRE scale. Participants (n = 55) had a median age of 18 (range 16-23), and 75% were under 19 years. We categorize three types of adaptations to the SRE scale: new item generation, item revision, and translation/linguistic considerations. We developed nine new items reflecting AYA's experiences and new domains of empowerment that emerged from the data; new domains relate to self-efficacy in accessing sexual and reproductive health care, and how material needs are met. All items were revised and translated to echo concepts and language relevant to participants, navigating the multilingualism common in many African countries. Centering the voices of female Kenyan AYA, this study provides insight into measuring the latent construct of adolescent sexual and reproductive empowerment in an East African setting, and supports the adapted SRE scale's content validity for Kenya. We detail our multi-method, theory-driven approach, contributing to limited methods guidance for measure adaptation across contexts and among diverse adolescent populations.

Acute protein kinase C beta inhibition preserves coronary endothelial function after cardioplegic hypoxia/reoxygenation.

Objective: Protein kinase C (PKC) influences myocardial contractility and susceptibility to long-term cardiac dysfunction after ischemia-reperfusion injury. In diabetes, PKC inhibition has a protective effect in terms of microvascular dysfunction. SK-channel dysfunction also influences endothelial dysfunction in cardioplegic hypoxia-reoxygenation (CP-H/R). Here, we examine whether acute inhibition of PKC beta protects against CP-H/R-induced coronary endothelial and SK channel dysfunction. Methods: Isolated mouse coronary arterioles, half pretreated with selective PKC inhibitor ruboxistaurin (RBX), were subjected to hyperkalemic, cardioplegic hypoxia (1 hour), and reoxygenation (1 hour) with Krebs buffer. Sham control vessels were continuously perfused with oxygenated Krebs buffer without CP-H/R. After 1 hour of reoxygenation, responses to the endothelium-dependent vasodilator adenosine-diphosphate (ADP) and the SK-channel activator NS309 were examined. Endothelial SK-specific potassium currents from mouse heart endothelial cells were examined using whole-cell path clamp configurations in response to NS309 and SK channel blockers apamin and TRAM34. Results: CP-H/R significantly decreased coronary relaxation responses to ADP (P = .006) and NS309 (P = .0001) compared with the sham control group. Treatment with selective PKC beta inhibitor RBX significantly increased recovery of coronary relaxation responses to ADP (P = .031) and NS309 (P = .004) after CP-H/R. Treatment with RBX significantly increased NS309-mediated potassium currents following CP-H/R (P = .0415). Apamin and TRAM34 sensitive currents were significantly greater in CP-H/R + RBX versus CP-H/R mouse heart endothelial cells (P = .0027). Conclusions: Acute inhibition of PKC beta significantly protected mouse coronary endothelial function after CP-H/R injury. This suggests that acute PKC beta inhibition may be a novel approach for preventing microvascular dysfunction during CP-H/R.

Prevalence and correlates of condom use at last sexual intercourse pre- and post-COVID-19 lockdown among adolescent girls and young women in central and western Kenya.

We investigated condom use at last sexual intercourse among adolescent girls and young women (AGYW) to determine the prevalence and correlates of condom use pre- and post-COVID-19 lockdown. Condom use was compared pre- and post-COVID-19 lockdown using a single group interrupted time series analysis. Multivariable Poisson regression was used to determine the correlates of condom use at last sexual intercourse. We found a statistically significant decrease in prevalence of condom use at last sexual intercourse post-COVID-19 lockdown. Condom use at last sexual intercourse was associated with younger age, current contraceptive use, and higher education. AGYW in concurrent relationships were less likely to use condoms, as were owners of mobile phones. These findings suggest a disconnect between youth knowledge of HIV prevention and their actual condom use, particularly in concurrent sexual partnerships. Future research should explore how dynamic fertility intentions, mobile phone access, concurrent sexual partnerships and empowerment influence condom use among sub-Saharan AGYW.

Deletion of the Npr3 gene increases severity of acute lung injury in obese mice.

Previous studies have shown that atrial natriuretic peptide (ANP) attenuates agonist-induced pulmonary edema and that this effect may be mediated in part by the ANP clearance receptor, natriuretic peptide receptor-C (NPR-C). Obesity has been associated with lower plasma ANP levels due to increased expression of NPR-C, and with decreased severity of acute lung injury (ALI). Therefore, we hypothesized that increased expression of NPR-C may attenuate ALI severity in obese populations. To test this, we examined ALI in Npr3 wild-type (WT) and knockout (KO) mice fed normal chow (NC) or high-fat diets (HFD). After 12 weeks, ALI was induced with intra-tracheal administration of Pseudomonas aeruginosa strain 103 (PA103) or saline. ALI severity was determined by lung wet-to-dry ratio (W/D) along with measurement of cell count, protein levels from bronchoalveolar lavage fluid (BALF), and quantitative polymerase chain reaction was performed on whole lung to measure cytokine/chemokine and Npr3 mRNA expression. ANP levels were measured from plasma. PA103 caused ALI as determined by significant increases in W/D, BALF protein concentration, and whole lung cytokine/chemokine expression. PA103 increased Npr3 expression in the lungs of wild-type (WT) mice regardless of diet. There was a nonsignificant trend toward increased Npr3 expression in the lungs of WT mice fed HFD versus NC. No differences in ALI were seen between Npr3 knockout (KO) mice and WT-fed NC, but Npr3 KO mice fed HFD had a significantly greater W/D and BALF protein concentration than WT mice fed HFD. These findings support the hypothesis that Npr3 may help protect against ALI in obesity.

Impact of DNA damage repair alterations on prostate cancer progression and metastasis.

Prostate cancer is among the most common diseases worldwide. Despite recent progress with treatments, patients with advanced prostate cancer have poor outcomes and there is a high unmet need in this population. Understanding molecular determinants underlying prostate cancer and the aggressive phenotype of disease can help with design of better clinical trials and improve treatments for these patients. One of the pathways often altered in advanced prostate cancer is DNA damage response (DDR), including alterations in BRCA1/2 and other homologous recombination repair (HRR) genes. Alterations in the DDR pathway are particularly prevalent in metastatic prostate cancer. In this review, we summarise the prevalence of DDR alterations in primary and advanced prostate cancer and discuss the impact of alterations in the DDR pathway on aggressive disease phenotype, prognosis and the association of germline pathogenic alterations in DDR genes with risk of developing prostate cancer.

The landscape of BRCA1 and BRCA2 large rearrangements in an international cohort of over 20 000 ovarian tumors identified using next-generation sequencing.

BACKGROUND: Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to poly-ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy. METHODS: Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions. RESULTS: Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene. CONCLUSIONS: Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.

Clinical testing panels for ALS: global distribution, consistency, and challenges.

Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.

Impact of blood factors on endothelial cell metabolism and function in two diverse heart failure models.

Role of blood-based factors in development and progression of heart failure (HF) is poorly characterized. Blood contains factors released during pathophysiological states that may impact cellular function and provide mechanistic insights to HF management. We tested effects of blood from two distinct HF models on cardiac metabolism and identified possible cellular targets of the effects. Blood plasma was obtained from daunorubicin- and myocardial infarction-induced HF rabbits (Dauno-HF and MI-HF) and their controls (Dauno-Control and MI-Control). Effects of plasma on bioenergetics of myocardial tissue from healthy mice and cellular cardiac components were assessed using high-resolution respirometry and Seahorse flux analyzer. Since endothelial cell respiration was profoundly affected by HF plasma, effects of plasma on endothelial cell barrier function and death were further evaluated. Western-blotting and electron microscopy were performed to evaluate mitochondrial proteins and morphology. Brief exposure to HF plasma decreased cardiac tissue respiration. Endothelial cell respiration was most impacted by exposure to HF plasma. Endothelial cell monolayer integrity was decreased by incubation with Dauno-HF plasma. Apoptosis and necrosis were increased in cells incubated with Dauno-HF plasma for 24 h. Down-regulation of voltage-dependent anion-selective channel (VDAC)-1, translocase of outer membrane 20 (Tom20), and mitochondrial fission factor (MFF) in cells exposed to Dauno-HF plasma and mitochondrial signal transducer and activator of transcription 3 (Stat3) and MFF in cells exposed to MI-HF plasma were observed. Mitochondrial structure was disrupted in cells exposed to HF plasma. These findings indicate that endothelial cells and mitochondrial structure and function may be primary target where HF pathology manifests and accelerates. High-throughput blood-based screening of HF may provide innovative ways to advance disease diagnosis and management.

Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound.

PURPOSE: Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study. PATIENTS AND METHODS: Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx. RESULTS: 81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor. CONCLUSIONS: We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.

Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA.

PURPOSE: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment. PATIENTS AND METHODS: Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A. RESULTS: Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients' baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21-0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25-0.47). CONCLUSIONS: When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.

Commercial human pulmonary artery endothelial cells have in-vitro behavior that varies by sex.

It is unknown whether biological sex influences phenotypes of commercially available human pulmonary artery endothelial cells (HPAECs). Ten lots of commercial HPAECs were used (Lonza Biologics; PromoCell). Five (50%) were confirmed to be genotypically male (SRY+) and five (50%) were confirmed to be female (SRY-). Experiments were conducted between passages five and eight. HPAEC phenotype was confirmed with a panel of cell expression markers. Standard assays for proliferation, migration and tube formation were performed in triplicate with technical replicates, under three treatment conditions (EndoGRO; Sigma-Aldrich). Apoptosis was assessed by exposing cells treated with complete media or low serum media to hypoxic (1% oxygen) or normoxic (20% oxygen) conditions. Laboratory staff was blinded. The median (range) age of male and female donors from whom the HPAECs were derived was 58 (48-60) and 56 (33-67), respectively. Our results suggest decreased proliferation in genotypically female cells compared with male cells (p = 0.09). With increasing donor age, female cells were less proliferative and male cells were more proliferative (p = 0.001). Female cells were significantly more apoptotic than male cells by condition (p = 0.001). Female cells were significantly more migratory than male cells in complete media but less migratory than male cells under vascular endothelial growth factor enriched conditions (p = 0.001). There are subtle sex-based differences in the behavior of HPAECs that depend on donor sex and, less so, age. These differences may undermine rigor and reproducibility. Future studies should define whether biological sex is an important regulator of HPAEC function in health and disease.

Patient, Caregiver, and Oncologist Experiences With and Perceptions of Racial Bias and Discrimination in Cancer Care Delivery.

BACKGROUND: Cancer prevention and treatment systems are significantly impacted by interpersonal, organizational, and structural and systemic racism. A wide body of research has found that racial disparities in access to guideline-adherent cancer care are pervasive throughout the United States and contributing factors include social determinants of health, insurance status, and bias and discrimination in care delivery. Although the existence of racial disparities in cancer care and outcomes is well established, there has been limited research exploring the patient and caregiver experience with bias and discrimination in cancer care. METHODS: Two national surveys were conducted, one of patients and caregivers and one of oncologists. The surveys examined patient and caregiver experiences with and oncologist perceptions of racial disparities in cancer care. RESULTS: The surveys found that when patients and caregivers were asked about negative care experiences, differences across race were observed. Patients and caregivers identifying as African American/Black (AA/B) or Hispanic/Latino (H/L) were more likely to report at least one negative care experience than patients and caregivers identifying as White (W). Patients who were AA/B or H/L were also more likely than W patients to report that the healthcare system treats people unfairly based on their racial or ethnic background and that racial bias occurs often or very often when a patient and doctor are of different racial/ethnic background. A slight majority of oncologists reported that the healthcare system treats people unfairly based on their racial or ethnic background. CONCLUSIONS: The survey results highlight a need for improved racial representation in the oncology professional workforce, improved implicit bias training, and improved clinical trial recruitment efforts.