Faculty Bibliography

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m² increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.

BACKGROUND:Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. METHODS:This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3-5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. DISCUSSION/CONCLUSIONS:In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT04397718. Registered on May 21, 2020.

One pathway by which environments of socioeconomic risk are thought to affect cognitive development is through stress physiology. The biological systems underpinning stress and attention undergo a sensitive period of development during infancy. Psychobiological theory emphasizes a dynamic pattern of context-dependent development, however, research has yet to examine how basal cortisol and attention dynamically covary across infancy in ecologically valid contexts. Thus, to address these gaps, we leveraged longitudinal, multilevel analytic methods to disentangle between- from within-person associations of hypothalamic-pituitary-adrenal (HPA) axis activity and executive attention behaviors across infancy. We use data from a large longitudinal sample (N = 1,292) of infants in predominantly low-income, nonurban communities at 7-, 15-, and 24-months of age. Using multilevel models, we investigated longitudinal associations of infant attention and basal cortisol levels and examined caregiving behaviors as moderators of this relationship. Results indicated a negative between- and within-person association between attention and cortisol across infancy and a within-person moderation by caregiver responsiveness. In other words, on the within-person level, higher levels of cortisol were concomitantly associated with lower infant attention across the first 2 years of life. However, variation in the caregiver's level of responsiveness either buffered or sensitized the executive attention system to the negative effects of physiological stress.

BACKGROUND:Despite the widespread institution of modern massive transfusion protocols with balanced blood product ratios, survival for patients with traumatic hemorrhage receiving ultramassive transfusion (UMT) (defined as ≥20 U of packed red blood cells [RBCs]) in 24 hours) remains low and resource consumption remains high. Therefore, we aimed to identify factors associated with mortality in trauma patients receiving UMT in the modern resuscitation era. METHODS:An Eastern Association for the Surgery of Trauma multicenter retrospective study of 461 trauma patients from 17 trauma centers who received ≥20 U of RBCs in 24 hours was performed (2014-2019). Multivariable logistic regression and Classification and Regression Tree analysis were used to identify clinical characteristics associated with mortality. RESULTS:The 461 patients were young (median age, 35 years), male (82%), severely injured (median Injury Severity Score, 33), in shock (median shock index, 1.2; base excess, -9), and transfused a median of 29 U of RBCs, 22 U of fresh frozen plasma (FFP), and 24 U of platelets (PLT). Mortality was 46% at 24 hours and 65% at discharge. Transfusion of RBC/FFP ≥1.5:1 or RBC/PLT ≥1.5:1 was significantly associated with mortality, most pronounced for the 18% of patients who received both RBC/PLT and RBC/FFP ≥1.5:1 (odds ratios, 3.11 and 2.81 for mortality at 24 hours and discharge; both p < 0.01). Classification and Regression Tree identified that age older than 50 years, low initial Glasgow Coma Scale, thrombocytopenia, and resuscitative thoracotomy were associated with low likelihood of survival (14-26%), while absence of these factors was associated with the highest survival (71%). CONCLUSION:Despite modern massive transfusion protocols, one half of trauma patients receiving UMT are transfused with either RBC/FFP or RBC/PLT in unbalanced ratios ≥1.5:1, with increased associated mortality. Maintaining focus on balanced ratios during UMT is critical, and consideration of advanced age, poor initial mental status, thrombocytopenia, and resuscitative thoracotomy can aid in prognostication. LEVEL OF EVIDENCE:Prognostic, level III.

CONTEXT/BACKGROUND:Health systems have aspired to integrate palliative care (PC) into the emergency department (ED) to improve care quality for over a decade, yet there are very few examples of implemented models in the literature. The coronavirus disease 2019 (COVID-19) pandemic led to an increase in the volume of seriously ill patients in EDs and a consequent rapid increase in PC integration in many EDs. OBJECTIVES/OBJECTIVE:To describe the new PC-ED delivery innovations that emerged during the COVID-19 pandemic. METHODS:For this qualitative study of PC programs in EDs, semistructured interviews were conducted with ED and PC clinicians between June 30, 2020 and August 18, 2020. Participants were asked about PC-ED integration before, during, and after COVID. We conducted a two-phased rapid analysis using a rapid analysis template and consolidated matrix to identify innovations. RESULTS:Using purposive and snowball sampling, we interviewed 31 participants, representing 52 hospitals. Several new innovations in care delivery were identified. These included elements of fully embedded PC, the use of PC extenders, technology both within the electronic medical record and outside it, and innovations in training emergency clinicians in primary PC skills to support care delivery. Most PC efforts focused on increasing goals-of-care conversations. Institutions that implemented these programs reported that they increased PC utilization in the ED, were well received by clinicians, and changed patient's care trajectories. CONCLUSION/CONCLUSIONS:Several new innovations in PC-ED care delivery emerged during COVID. Many innovations leveraged different types of clinicians to deliver care, an increased physical presence of PC in the ED, and used technology to enhance care delivery. These innovations may serve as a framework for institutions as they plan for evolving needs in the ED during and after COVID. Additional research is needed to evaluate the impact of these programs and understand their applicability beyond the pandemic.

INTRODUCTION/BACKGROUND:STRIVE was a 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative (JCV-negative) relapsing-remitting multiple sclerosis (RRMS) patients with disease duration ≤ 3 years. The objective of STRIVE was to examine no evidence of disease activity (NEDA) status and predictors of NEDA in natalizumab-treated patients with early RRMS. METHODS:Proportions of patients with NEDA were evaluated along with baseline predictors of NEDA, annualized relapse rate, 24-week confirmed disability worsening (CDW), magnetic resonance imaging assessments (T2 and gadolinium-enhancing lesions), and serious adverse events. RESULTS:In years 1 and 2, 56.1% (95% confidence interval [CI] 48.7-63.4%) and 73.6% (95% CI 66.2-80.2%) of patients (intent-to-treat population [N = 222]), respectively, achieved NEDA. In years 3 and 4, 84.6% (95% CI 78.0-89.9%) and 91.9% (95% CI 86.4-95.8%) of patients, respectively, achieved Clinical NEDA (no relapses or 24-week CDW). Baseline predictors of NEDA in year 4 were Expanded Disability Status Scale score ≤ 2.0 (odds ratio [OR] = 3.85 [95% CI 1.54-9.63]; p = 0.004) and T2 lesion volume > 4 cc (OR = 0.39 [95% CI 0.15-0.98]; p = 0.046), with the latter also predicting Clinical NEDA in year 4 (OR = 0.21 [95% CI 0.05-0.92]; p = 0.038). The cumulative probability of CDW at year 4 was 19.3%. Serious adverse events were reported in 11.3% of patients. CONCLUSION/CONCLUSIONS:These results support the long-term safety and effectiveness of natalizumab. Baseline predictors of NEDA help to inform benefit-risk assessments of natalizumab treatment in JCV-negative patients with early RRMS. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier NCT01485003.

INTRODUCTION/BACKGROUND:Healthcare systems are increasingly interested in identifying patients' housing-related risks, but minimal information exists to inform screening question selection. The primary study aim is to evaluate discordance among 5 housing-related screening questions used in health care. METHODS:This was a cross-sectional multisite survey of social risks used in a convenience sample of adults seeking care for themselves or their child at 7 primary care clinics and 4 emergency departments across 9 states (2018-2019). Housing-related risks were measured using 2 questions from the Accountable Health Communities screening tool (current/anticipated housing instability, current housing quality problems) and 3 from the Children's HealthWatch recommended housing instability screening measures (prior 12-month: rent/mortgage strain, number of moves, current/recent homelessness). The 2-sided Fisher's exact tests analyzed housing-related risks and participant characteristics; logistic regression explored associations with reported health (2019-2020). RESULTS:Of 835 participants, 52% screened positive for ≥1 housing-related risk (n=430). Comparing the tools, 32.8% (n=274) screened discordant: 11.9% (n=99) screened positive by Children's HealthWatch questions but negative by Accountable Health Communities, and 21.0% (n=175) screened positive by the Accountable Health Communities tool but negative by Children's HealthWatch (p<0.001). Worse health was associated with screening positive for current/anticipated housing instability (AOR=0.56, 95% CI=0.32, 0.96) or current/recent homelessness (AOR=0.57, 95% CI=0.34, 0.96). CONCLUSIONS:The 5 housing questions captured different housing-related risks, contributed to different health consequences, and were relevant to different subpopulations. Before implementing housing-related screening initiatives, health systems should understand how specific measures surface distinct housing-related barriers. Measure selection should depend on program goals and intervention resources.

PURPOSE/OBJECTIVE:Studies have examined trends in cannabis vaping, but research is needed to examine trends in more frequent use as this may increase risk for adverse health outcomes. METHODS:Data were from 12,561 high school seniors participating in the Monitoring the Future national study. Prevalence of self-reported frequent vaping of cannabis (defined as using ≥10 times in the past month) was compared between 2018 and 2019 cohorts. RESULTS:Frequent vaping of cannabis significantly increased from 2.1% to 4.9%, a 131.4% increase. This increase was larger than the increase for any vaping of cannabis (which increased 85.9%). Notable significant increases occurred among students aged ≥18 years (a 154.9% increase), female students (a 183.5% increase), those who go out 4-7 evenings per week (a 163.0% increase), and those reporting past-year nonmedical prescription opioid use (a 184.7% increase). CONCLUSIONS:Frequent vaping of cannabis is increasing among adolescents in the United States, particularly among selected subgroups.