Faculty Bibliography

BACKGROUND:Overprescribing of antibiotics for acute respiratory infections (ARIs) remains a major issue in outpatient settings. Use of clinical prediction rules (CPRs) can reduce inappropriate antibiotic prescribing but they remain underutilized by physicians and advanced practice providers. A registered nurse (RN)-led model of an electronic health record-integrated CPR (iCPR) for low-acuity ARIs may be an effective alternative to address the barriers to a physician-driven model. METHODS:Following qualitative usability testing, we will conduct a stepped-wedge practice-level cluster randomized controlled trial (RCT) examining the effect of iCPR-guided RN care for low acuity patients with ARI. The primary hypothesis to be tested is: Implementation of RN-led iCPR tools will reduce antibiotic prescribing across diverse primary care settings. Specifically, this study aims to: (1) determine the impact of iCPRs on rapid strep test and chest x-ray ordering and antibiotic prescribing rates when used by RNs; (2) examine resource use patterns and cost-effectiveness of RN visits across diverse clinical settings; (3) determine the impact of iCPR-guided care on patient satisfaction; and (4) ascertain the effect of the intervention on RN and physician burnout. DISCUSSION:This study represents an innovative approach to using an iCPR model led by RNs and specifically designed to address inappropriate antibiotic prescribing. This study has the potential to provide guidance on the effectiveness of delegating care of low-acuity patients with ARIs to RNs to increase use of iCPRs and reduce antibiotic overprescribing for ARIs in outpatient settings. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04255303, Registered February 5 2020, https://clinicaltrials.gov/ct2/show/NCT04255303 .

BACKGROUND:Mobile technology can support HIV care, but studies in youth are limited. In 2014, youth receiving HIV care at several health care facilities in Nairobi, Kenya spontaneously formed peer support groups using the social media platform WhatsApp. OBJECTIVE:Inspired by youth-initiated groups, we aimed to evaluate the use of WhatsApp to deliver a social support intervention to improve HIV treatment and psychosocial outcomes in youth. We developed a facilitated WhatsApp group intervention (named Vijana-SMART), which was grounded in social support theory and guided by the design recommendations of youth living with HIV. This paper evaluates the intervention's acceptability and pre-post changes in health outcomes. METHODS:The intervention involved interactive WhatsApp groups facilitated by study staff for 6 months, with each group having approximately 25 members. Study staff sent weekly structured messages, and the message content was based on social support theory and encouraged unstructured peer-to-peer messaging and support. We conducted a single-arm pilot among 55 youth living with HIV aged 14-24 years recruited from a government health care facility serving a mixed-income area of Nairobi. At enrollment and follow-up, self-report questionnaires assessed acceptability; antiretroviral therapy (ART) information, motivation, and behavioral skills (IMB); depression; social support; stigma; resilience; and ART adherence. All participants received the intervention. We used generalized estimating equations (GEEs) clustered by participant to evaluate changes in scores from baseline to follow-up, and correlates of participant WhatsApp messaging. RESULTS:The median participant age was 18 years, and 67% (37/55) were female. Intervention acceptability was high. All participants reported that it was helpful, and 73% (38/52) sent ≥1 WhatsApp message. Messaging levels varied considerably between participants and were higher during school holidays, earlier in the intervention period, and among youth aged ≥18 years. IMB scores increased from enrollment to follow-up (66.9% to 71.3%; P<.001). Stigma scores also increased (8.3% to 16.7%; P=.001), and resilience scores decreased (75.0% to 70.0%; P<.001). We found no significant change in ART adherence, social support, or depression. We detected a positive association between the level of messaging during the study and the resilience score, but no significant association between messaging and other outcomes. Once enrolled, it was common for participants to change their phone numbers or leave the groups and request to be added back, which may present implementation challenges at a larger scale. CONCLUSIONS:Increased IMB scores following WhatsApp group participation may improve HIV outcomes. Increased stigma and decreased resilience were unintended consequences and may reflect transient effects of group sharing of challenging experiences, which should be addressed in larger randomized evaluations. WhatsApp groups present a promising and acceptable modality to deliver supportive interventions to youth living with HIV beyond the clinic, and further evaluation is warranted. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov (NCT05634265); https://clinicaltrials.gov/study/NCT05634265.

AIMS:Interleukin-6 (IL-6) and interleukin-18 (IL-18), important cytokines implicated in atherosclerosis and inflammaging, were assessed for associations with global cardiovascular disease (CVD), atrial fibrillation (AF), and death in older adults. METHODS AND RESULTS:Participants from Atherosclerosis Risk in Communities study Visit 5 (mean age 75.4 ± 5.1 years) with IL-6 and IL-18 measurements were included (n = 5672). Cox regression models were used to assess associations of IL-6 and IL-18 with coronary heart disease (CHD), ischaemic stroke, heart failure (HF) hospitalization, global CVD (composite of CHD, stroke, and HF), AF, and all-cause death. Over a median follow-up of 7.2 years, there were 1235 global CVD events, 530 AF events, and 1173 deaths. Higher IL-6 [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.44-1.72 per log unit increase] and IL-18 (HR 1.13, 95% CI 1.01-1.26) were significantly associated with global CVD after adjustment for cardiovascular risk factors. Association between IL-6 and global CVD remained significant after further adjustment for high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT) but was no longer significant for IL-18 after further adjustments. Interleukin-6 was also associated with increased risk for CHD, HF, and AF after adjustment for covariates. Both IL-6 and IL-18 were associated with increased risk for all-cause death independent of cardiovascular risk factors and other biomarkers. CONCLUSION:Among older adults, both IL-6 and IL-18 were associated with global CVD and death. The association between IL-6 with CVD appears to be more robust and was independent of hs-CRP, NT-proBNP, and hs-TnT.

BACKGROUND:Few studies have examined the effectiveness of telephone smoking cessation interventions by severity of behavioral health symptoms. Using data from a telephone counseling study, we examined whether abstinence rates varied by level of behavioral health symptoms. METHODS:The parent study recruited adults who smoke cigarettes (N = 577) referred by mental health providers at six Veterans Health Administration facilities. Participants were randomized to specialized telephone counseling (intervention) or state Quitline referral (control). Participants completed assessments at baseline and 6 months, including the BASIS-24, a self-report measure of behavioral health symptoms and functioning. We used the BASIS-24 median to dichotomize participants as having high or low scores. The primary outcome was 30-day self-reported abstinence at 6 months. We compared groups on outcomes by logistic regression and performed an interaction effect analysis between treatment assignment and groups. RESULTS:At baseline, those with high behavioral health symptoms scores reported heavier nicotine dependence and more sedative and/or antidepressant use, compared to participants with low behavioral health symptoms. At 6 months, participants with low behavioral health symptoms scores in the intervention reported higher rates of 30-day abstinence compared to those in the control arm (26% vs 13%, OR = 2.3, 95% CI = 1.8, 2.9). People with high behavioral health symptoms scores reported no difference in 30-day abstinence between the treatment assignments at 6 months (12% vs. 13%, OR = 1.1, 95% CI = 0.6, 2.0). CONCLUSIONS:Only participants with low behavioral health symptoms scores reported higher abstinence rates in the intervention compared to the state Quitline. Future research can examine alternative approaches for people with worse mental well-being and functioning. TRIAL REGISTRATION:The parent study is registered at www. CLINICALTRIALS:gov NCT00724308.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

BACKGROUND:Acute-care interventions that identify patients with substance use disorders (SUDs), initiate treatment, and link patients to community-based services, have proliferated in recent years. Yet, much is unknown about the specific strategies being used to support continuity of care from emergency department (ED) or inpatient hospital settings to community-based SUD treatment. In this scoping review, we synthesize the existing literature on patient transition interventions, and form an initial typology of reported strategies. METHODS:We searched Pubmed, Embase, CINAHL and PsychINFO for peer-reviewed articles published between 2000 and 2021 that studied interventions linking patients with SUD from ED or inpatient hospital settings to community-based SUD services. Eligible articles measured at least one post-discharge treatment outcome and included a description of the strategy used to promote linkage to community care. Detailed information was extracted on the components of the transition strategies and a thematic coding process was used to categorize strategies into a typology based on shared characteristics. Facilitators and barriers to transitions of care were synthesized using the Consolidated Framework for Implementation Research. RESULTS:Forty-five articles met inclusion criteria. 62% included ED interventions and 44% inpatient interventions. The majority focused on patients with opioid (71%) or alcohol (31%) use disorder. The transition strategies reported across studies were heterogeneous and often not well described. An initial typology of ten transition strategies, including five pre- and five post-discharge transition strategies is proposed. The most common strategy was scheduling an appointment with a community-based treatment provider prior to discharge. A range of facilitators and barriers were described, which can inform efforts to improve hospital-to-community transitions of care. CONCLUSIONS:Strategies to support transitions from acute-care to community-based SUD services, although critical for ensuring continuity of care, vary greatly across interventions and are inconsistently measured and described. More research is needed to classify SUD care transition strategies, understand their components, and explore which lead to the best patient outcomes.

CONTEXT/BACKGROUND:Children with medical complexity (CMC) are at risk for adverse outcomes after discharge. Difficulties with comprehension of and adherence to discharge instructions contribute to these errors. Comprehensive reviews of patient-, caregiver-, provider-, and system-level characteristics and interventions associated with discharge instruction comprehension and adherence for CMC are lacking. OBJECTIVE:To systematically review the literature related to factors associated with comprehension of and adherence to discharge instructions for CMC. DATA SOURCES/METHODS:PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, PsycInfo, Cumulative Index to Nursing and Allied Health Literature, Web of Science (database initiation until March 2023), and OAIster (gray literature) were searched. STUDY SELECTION/METHODS:Original studies examining caregiver comprehension of and adherence to discharge instructions for CMC (Patient Medical Complexity Algorithm) were evaluated. DATA EXTRACTION/METHODS:Two authors independently screened titles/abstracts and reviewed full-text articles. Two authors extracted data related to study characteristics, methodology, subjects, and results. RESULTS:Fifty-one studies were included. More than half were qualitative or mixed methods studies. Few interventional studies examined objective outcomes. More than half of studies examined instructions for equipment (eg, tracheostomies). Common issues related to access, care coordination, and stress/anxiety. Facilitators included accounting for family context and using health literacy-informed strategies. LIMITATIONS/CONCLUSIONS:No randomized trials met inclusion criteria. Several groups (eg, oncologic diagnoses, NICU patients) were not examined in this review. CONCLUSIONS:Multiple factors affect comprehension of and adherence to discharge instructions for CMC. Several areas (eg, appointments, feeding tubes) were understudied. Future work should focus on design of interventions to optimize transitions.

BACKGROUND:Sickle cell trait affects approximately 8% of Black individuals in the United States, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests that sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including kidney failure. The mechanisms underlying these associations remain poorly understood. We used proteomic profiling to gain insight into the pathobiology of sickle cell trait. METHODS:We measured proteomics ( N =1285 proteins assayed by Olink Explore) using baseline plasma samples from 592 Black participants with sickle cell trait and 1:1 age-matched Black participants without sickle cell trait from the prospective Women's Health Initiative cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait. RESULTS:In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in Black participants from two independent cohorts (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are known biomarkers of kidney function or injury ( e.g. , hepatitis A virus cellular receptor 1 [HAVCR1]/kidney injury molecule-1 [KIM-1], uromodulin [UMOD], ephrins), related to red cell physiology or hemolysis (erythropoietin [EPO], heme oxygenase 1 [HMOX1], and α -hemoglobin stabilizing protein) and/or inflammation (fractalkine, C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 [MCP-1], and urokinase plasminogen activator surface receptor [PLAUR]). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during Women's Health Initiative follow-up (odds ratio, 1.32; 95% confidence interval, 1.10 to 1.58). CONCLUSIONS:We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.

The discrete-time Wright-Fisher (DTWF) model and its diffusion limit are central to population genetics. These models can describe the forward-in-time evolution of allele frequencies in a population resulting from genetic drift, mutation, and selection. Computing likelihoods under the diffusion process is feasible, but the diffusion approximation breaks down for large samples or in the presence of strong selection. Existing methods for computing likelihoods under the DTWF model do not scale to current exome sequencing sample sizes in the hundreds of thousands. Here, we present a scalable algorithm that approximates the DTWF model with provably bounded error. Our approach relies on two key observations about the DTWF model. The first is that transition probabilities under the model are approximately sparse. The second is that transition distributions for similar starting allele frequencies are extremely close as distributions. Together, these observations enable approximate matrix-vector multiplication in linear (as opposed to the usual quadratic) time. We prove similar properties for Hypergeometric distributions, enabling fast computation of likelihoods for subsamples of the population. We show theoretically and in practice that this approximation is highly accurate and can scale to population sizes in the tens of millions, paving the way for rigorous biobank-scale inference. Finally, we use our results to estimate the impact of larger samples on estimating selection coefficients for loss-of-function variants. We find that increasing sample sizes beyond existing large exome sequencing cohorts will provide essentially no additional information except for genes with the most extreme fitness effects.