Faculty Bibliography

Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal (GE) cancers are the leading causes of GI cancer- related mortality (5-yr survival rate, 14%, 3% and 5-6%, respectively). T-cell immunotherapy targeting GI-associated tumor antigens has been attempted, but efficacy has been constrained by on-target off-tumor toxicity, limiting the therapeutic window. The Tmod (TM) platform is an AND-NOT logic-gated CAR T modular system, versions of which have a CEA-or MSLN-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor to protect normal cells. Tmod CAR T exploits HLA LOH, common in GI malignancies (10-33% in primary solid tumors [TCGA]) and can kill tumor cells without harming healthy cells in vitro and in vivo. However, the prevalence of HLA LOH across GI tumors is unknown in the real-world setting. We utilized the Tempus xT oncology NGS database of patients with multiple GI tumors. From a standard-of-care NGS assay, GI cancer patients can be readily identified for HLA LOH and future treatment with Tmod CAR T therapy.
Method(s): The occurrence of HLA LOH in GI tumors of 1439 patients was assessed using paired germline and somatic DNA sequencing using a research assay [6]. CRC, PANC and GE patients with >= stage 3 were then extracted, and rates of HLA LOH were identified (ie, whether loss occurred across high-frequency HLA-A alleles). In addition, mutations in KRAS and BRAF, as well as MSI status were stratified to determine any association with HLA-A LOH.
Result(s): HLA-A LOH was detected in 830 (17.3%) of all solid tumor records, and a similar proportion when all GI cancer records were analyzed (17.0%). For GI subtypes, these values ranged from 13.5% to 23.1% (Table). No high-frequency HLA-A allele (A*01, A*02, A*03, A*11) was more likely to be lost. Clinical biomarkers (KRAS, BRAF and MSI status) were not associated with HLA-LOH.
Conclusion(s): The frequency of HLA LOH among advanced solid tumor cancers in this dataset is 17.3%, with a range of 13.5-23% between CRC, PANC and GE. The HLA LOH frequency observed in these GI tumors is consistent with that in primary tumors from TCGA, which also used germline-matched and tumor samples. Clinical biomarkers were not associated with HLA LOH. Tempus NGS was able to identify HLA LOH, which can be used for Tmod CAR T therapy to an enhanced therapeutic window. Identification of these patients in BASECAMP-1 (NCT04981119) will enable novel Tmod CAR T therapy. (Table Presented)

BACKGROUND:Extended-release buprenorphine (XRB) offers a novel approach to sustained monthly treatment for people who use opioids in criminal justice settings (CJS). This study explores the experiences of adults receiving XRB as a jail-to-community treatment. METHODS AND FINDINGS:In-depth qualitative interviews were conducted among adult participants with opioid use disorder (OUD; n  = 16) who were recently released from NYC jails and maintained on XRB after switching from daily sublingual buprenorphine (SLB). Interviews elaborated on the acceptability and barriers and facilitators of XRB treatment pre- and post-release. Interviews were audio recorded, transcribed, and analyzed for content related to factors influencing XRB treatment uptake and community reentry. Important themes were grouped into systems, medication, and patient-level factors. Key systems-level factors influencing initiation of XRB in jail included an alternative to perceived stigmatization and privacy concerns associated with daily in-jail SLB administration and less concerns with buprenorphine diversion. In-jail peer networks positively influenced participant adoption of XRB. XRB satisfaction was attributed to reduced in-jail clinic and medication administration visits, perceived efficacy and blockade effects upon the use of heroin/fentanyl following release, and averting the risk of criminal activities to fund opioid use. Barriers to retention included post-injection withdrawal symptoms and cravings attributed to perceived suboptimal medication dosing, injection site pain, and lack of in-jail provider information about the medication. CONCLUSION:Participants were generally favorable to XRB initiation in jail and retention post-release. Further studies are needed to address factors influencing access to XRB in criminal justice settings, including stigma, ensuring patient privacy following initiation on XRB, and patient-, provider-, and correctional staff education pertaining to XRB. Trial Registration ClinicalTrials.gov Identified: NCT03604159.

OBJECTIVE:To further the precision medicine goal of tailoring medical treatment to individual patient characteristics by providing a method of analysis of the effect of test treatment, T, compared to a reference treatment, R, in participants in a RCT who are likely responders to T. METHODS:Likely responders to T are individuals whose expected response at baseline exceeds a prespecified minimum. A prognostic score, the expected response predicted as a function of baseline covariates, is obtained at trial completion. It is a balancing score that can be used to match likely responders randomized to T with those randomized to R; the result is comparable treatment groups that have a common covariance distribution. Treatments are compared based on observed outcomes in this enriched sample. The approach is illustrated in a RCT comparing two treatments for opioid use disorder. RESULTS:A standard statistical analysis of the opioid use disorder RCT found no treatment difference in the total sample. However, a subset of likely responders to T were identified and in this group, T was statistically superior to R. CONCLUSION/CONCLUSIONS:The causal treatment effect of T relative to R among likely responders may be more important than the effect in the whole target population. The prognostic score function provides quantitative information to support patient specific treatment decisions regarding T furthering the goal of precision medicine.

The impact of COVID-19-related stress on perinatal women is of heightened public health concern given the established intergenerational impact of maternal stress-exposure on infants and fetuses. There is urgent need to characterize the coping styles associated with adverse psychosocial outcomes in perinatal women during the COVID-19 pandemic to help mitigate the potential for lasting sequelae on both mothers and infants. This study uses a data-driven approach to identify the patterns of behavioral coping strategies that associate with maternal psychosocial distress during the COVID-19 pandemic in a large multicenter sample of pregnant women (N = 2876) and postpartum women (N = 1536). Data was collected from 9 states across the United States from March to October 2020. Women reported behaviors they were engaging in to manage pandemic-related stress, symptoms of depression, anxiety and global psychological distress, as well as changes in energy levels, sleep quality and stress levels. Using latent profile analysis, we identified four behavioral phenotypes of coping strategies. Critically, phenotypes with high levels of passive coping strategies (increased screen time, social media, and intake of comfort foods) were associated with elevated symptoms of depression, anxiety, and global psychological distress, as well as worsening stress and energy levels, relative to other coping phenotypes. In contrast, phenotypes with high levels of active coping strategies (social support, and self-care) were associated with greater resiliency relative to other phenotypes. The identification of these widespread coping phenotypes reveals novel behavioral patterns associated with risk and resiliency to pandemic-related stress in perinatal women. These findings may contribute to early identification of women at risk for poor long-term outcomes and indicate malleable targets for interventions aimed at mitigating lasting sequelae on women and children during the COVID-19 pandemic.

AIMS/OBJECTIVE:Heart failure increases the risk of kidney disease progression. However, whether cardiac function and structure are associated with the risk of incident chronic kidney disease (CKD) is not well characterized in a community setting. METHODS AND RESULTS/RESULTS:Among 4188 participants (mean age 75 years and 22% blacks) of the Atherosclerosis Risk in Communities Study without prevalent CKD in 2011-13, we examined the association of echocardiographic measures of left ventricular (LV) mass index, ejection fraction, left atrial volume index (LAVi), right ventricular (RV) fractional area change, and peak RV-right atrium (RA) gradient, with the subsequent risk of incident CKD, as defined by >25% decline to estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, hospitalization with CKD diagnosis, or incident end-stage kidney disease. Multivariable Cox regression models were used to estimate hazard ratios (HRs). The risk of incident CKD was monotonically increased with each of higher LV mass index [adjusted HR 2.61 (1.92-3.55) for highest quartile (Q4) vs. lowest (Q1)], lower ejection fraction [1.54 (1.17-2.04) for Q1 vs. Q4], higher LAVi [2.12 (1.56-2.89) for Q4 vs. Q1], and higher peak RV-RA gradient [2.17 (1.45-3.25) for Q4 vs. Q1] but not with RV function. The associations were consistent between subgroups by sex and race. CONCLUSION/CONCLUSIONS:Among community-dwelling older individuals, LV mass index, ejection fraction, LAVi, and peak RV-RA gradient were independently associated with the risk of incident CKD. Our results further support that heart disease is associated with the risk of kidney disease progression and suggest the value of echocardiography for assessing cardiac and kidney health in older populations.

Prenatal nutrition may significantly impact brain aging. Results from the Dutch Famine Birth Cohort indicated that prenatal undernutrition is negatively associated with cognition, brain volumes, perfusion and structural brain aging in late life, predominantly in men. This study investigates the association between prenatal undernutrition and late-life functional brain network connectivity. In an exploratory resting-state functional magnetic resonance imaging study of 112 participants from the Dutch Famine Birth Cohort, we investigated whether the within- and between-network functional connectivity of the default mode network, salience network and central executive network differ at age 68 in men (N = 49) and women (N = 63) either exposed or unexposed to undernutrition in early gestation. Additionally, we explored sex-specific effects. Compared to unexposed participants, exposed participants revealed multiple clusters of different functional connectivity within and between the three networks studied. Sex-specific analyses suggested a pattern of network desegregation fitting with brain aging in men and a more diffuse pattern of group differences in women. This study demonstrates that associations between prenatal undernutrition and brain network functional connectivity extend late into life.

INTRODUCTION/BACKGROUND:Little is known about how early (eg, commencing antenatally or in the first 12 months after birth) obesity prevention interventions seek to change behaviour and which components are or are not effective. This study aims to (1) characterise early obesity prevention interventions in terms of target behaviours, delivery features and behaviour change techniques (BCTs), (2) explore similarities and differences in BCTs used to target behaviours and (3) explore effectiveness of intervention components in preventing childhood obesity. METHODS AND ANALYSIS/UNASSIGNED:Annual comprehensive systematic searches will be performed in Epub Ahead of Print/MEDLINE, Embase, Cochrane (CENTRAL), CINAHL, PsycINFO, as well as clinical trial registries. Eligible randomised controlled trials of behavioural interventions to prevent childhood obesity commencing antenatally or in the first year after birth will be invited to join the Transforming Obesity in CHILDren Collaboration. Standard ontologies will be used to code target behaviours, delivery features and BCTs in both published and unpublished intervention materials provided by trialists. Narrative syntheses will be performed to summarise intervention components and compare applied BCTs by types of target behaviours. Exploratory analyses will be undertaken to assess effectiveness of intervention components. ETHICS AND DISSEMINATION/UNASSIGNED:The study has been approved by The University of Sydney Human Research Ethics Committee (project no. 2020/273) and Flinders University Social and Behavioural Research Ethics Committee (project no. HREC CIA2133-1). The study's findings will be disseminated through peer-reviewed publications, conference presentations and targeted communication with key stakeholders. PROSPERO REGISTRATION NUMBER/UNASSIGNED:CRD42020177408.

INTRODUCTION/BACKGROUND:Behavioural interventions in early life appear to show some effect in reducing childhood overweight and obesity. However, uncertainty remains regarding their overall effectiveness, and whether effectiveness differs among key subgroups. These evidence gaps have prompted an increase in very early childhood obesity prevention trials worldwide. Combining the individual participant data (IPD) from these trials will enhance statistical power to determine overall effectiveness and enable examination of individual and trial-level subgroups. We present a protocol for a systematic review with IPD meta-analysis to evaluate the effectiveness of obesity prevention interventions commencing antenatally or in the first year after birth, and to explore whether there are differential effects among key subgroups. METHODS AND ANALYSIS/UNASSIGNED:Systematic searches of Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo and trial registries for all ongoing and completed randomised controlled trials evaluating behavioural interventions for the prevention of early childhood obesity have been completed up to March 2021 and will be updated annually to include additional trials. Eligible trialists will be asked to share their IPD; if unavailable, aggregate data will be used where possible. An IPD meta-analysis and a nested prospective meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome will be body mass index z-score at age 24±6 months using WHO Growth Standards, and effect differences will be explored among prespecified individual and trial-level subgroups. Secondary outcomes include other child weight-related measures, infant feeding, dietary intake, physical activity, sedentary behaviours, sleep, parenting measures and adverse events. ETHICS AND DISSEMINATION/UNASSIGNED:Approved by The University of Sydney Human Research Ethics Committee (2020/273) and Flinders University Social and Behavioural Research Ethics Committee (HREC CIA2133-1). Results will be relevant to clinicians, child health services, researchers, policy-makers and families, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION NUMBER/UNASSIGNED:CRD42020177408.

Substance use is increasing throughout Africa, with the prevalence of alcohol, tobacco, cannabis, and other substance use varying regionally. Concurrently, sub-Saharan Africa bears the world's largest HIV burden, with 71% of people living with HIV (PWH) living in Africa. Problematic alcohol, tobacco, and other substance use among PWH is associated with multiple vulnerabilities comprising complex behavioral, physiological, and psychological pathways that include high-risk behaviors (e.g., sexual risk-taking), HIV disease progression, and mental health problems, all of which contribute to nonadherence to antiretroviral therapy. Physiologically, severe substance use disorders are associated with increased levels of biological markers of inflammation; these, in turn, are linked to increased mortality among PWH. The biological mechanisms that underlie the increased risk of substance use among PWH remain unclear. Moreover, the biobehavioral mechanisms by which substance use contributes to adverse health outcomes are understudied in low- and middle-income countries (LMIC). Syndemic approaches to understanding the co-occurrence of substance use and HIV have largely been limited to high-income countries. We propose a syndemic coupling conceptual model to disentangle substance use from vulnerabilities to elucidate underlying disease risk for PWH. This interventionist perspective enables assessment of biobehavioral mechanisms and identifies malleable targets of intervention.

Cancer health disparities remain a significant problem in the USA, compounded by lack of access to care, language barriers and systemic biases in health care. These disparities are particularly evident in areas such as genetics/genomics. For example, Latinas at high risk for hereditary breast and ovarian cancer (HBOC) have extremely low rates of genetic counseling/testing. Long-standing barriers and inequities in access to services such as genetic counseling and testing require innovative solutions. One solution can involve training community outreach and education professionals (CORE-Ps) to bridge the gap between underserved communities and genetic specialists. We sought to develop and pilot test a training program for English-Spanish bilingual CORE-Ps to reduce disparities in access to and uptake of genetic services among Latino populations. Guided by Adult Learning Theory and with input from multiple stakeholders, we developed ÁRBOLES Familiares (Family Trees), an in-person and online training program for bilingual CORE-Ps to facilitate identification, referral, and navigation of Latinas to genetic counseling/testing. We conducted a pilot test of 24 CORE-Ps recruited from across the United States and assessed knowledge, genetic literacy, and self-efficacy at baseline and follow-up. At follow-up, participants in the pilot with complete baseline and follow-up data (N = 15) demonstrated significant improvements in HBOC knowledge, genetic literacy, self-efficacy and reports of fewer barriers to identify/navigate Latinas (ps < .05). Qualitative assessment identified ways to improve the training curriculum. Pilot results suggest ÁRBOLES is a promising approach for training CORE-Ps to identify and refer high-risk Latinas to genetic services. Next steps involve further refinement of ÁRBOLES, development of an online toolkit, and adaptation for virtual delivery.