Beyond Unplanned ICU Transfers: Linking a Revised Definition of Deterioration to Patient Outcomes.

OBJECTIVES: To develop an electronic descriptor of clinical deterioration for hospitalized patients that predicts short-term mortality and identifies patient deterioration earlier than current standard definitions. DESIGN: A retrospective study using exploratory record review, quantitative analysis, and regression analyses. SETTING: Twelve-hospital community-academic health system. PATIENTS: All adult patients with an acute hospital encounter between January 1, 2018, and December 31, 2022. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Clinical trigger events were selected and used to create a revised electronic definition of deterioration, encompassing signals of respiratory failure, bleeding, and hypotension occurring in proximity to ICU transfer. Patients meeting the revised definition were 12.5 times more likely to die within 7 days (adjusted odds ratio 12.5; 95% CI, 8.9-17.4) and had a 95.3% longer length of stay (95% CI, 88.6-102.3%) compared with those who were transferred to the ICU or died regardless of meeting the revised definition. Among the 1812 patients who met the revised definition of deterioration before ICU transfer (52.4%), the median detection time was 157.0 min earlier (interquartile range 64.0-363.5 min). CONCLUSIONS: The revised definition of deterioration establishes an electronic descriptor of clinical deterioration that is strongly associated with short-term mortality and length of stay and identifies deterioration over 2.5 hours earlier than ICU transfer. Incorporating the revised definition of deterioration into the training and validation of early warning system algorithms may enhance their timeliness and clinical accuracy.

Reported Unmet Hearing Aid Need in Older People With Dementia: The US National Core Indicators Survey.

OBJECTIVES: Hearing aids have important health benefits for older adults with Alzheimer disease and related dementias (ADRD); however, hearing aid adoption in this group is low. This study aimed to determine where to target hearing aid interventions for American long-term care recipients with ADRD by examining the association of ADRD and residence type with respondent-reported unmet hearing aid need. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the United States National Core Indicators-Aging and Disabilities survey (2015-2019) for long-term care recipients aged ≥65 years. METHODS: We used multivariable logistic regression to model the likelihood of reporting unmet hearing aid need conditional on ADRD status and residence type (own/family house or apartment, residential care, or nursing facility/home), adjusting for sociodemographic factors and response type (self vs proxy). RESULTS: Of the 25,492 respondents [median (IQR) age, 77 (71, 84) years; 7074 (27.8%) male], 5442 (21.4%) had ADRD and 3659 (14.4%) owned hearing aids. Residence types were 17,004 (66.8%) own/family house or apartment, 4966 (19.5%) residential care, and 3522 (13.8%) nursing home. Among non-hearing aid owners, ADRD [adjusted odds ratio (AOR) 0.90, 95% CI 0.80-1.0] and residence type were associated with respondent-reported unmet hearing aid need. Compared to the nursing home reference group, respondents in their own/family home (AOR 1.85, 95% CI 1.61-2.13) and residential care (AOR 1.30, 95% CI 1.10-1.53) were more likely to report unmet hearing aid need. This pattern was significantly more pronounced in people with ADRD than in those without, stemming from an interaction between ADRD and residence type. CONCLUSIONS AND IMPLICATIONS: American long-term care recipients with ADRD living in their own/family home are more likely to report unmet hearing aid need than those with ADRD in institutional and congregate settings. This information can inform the design and delivery of hearing interventions for older adults with ADRD.

HLA-DRB1*15 and Eosinophilia Are Common Among Patients With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Concern exists that medications used to treat patients with systemic juvenile idiopathic arthritis (JIA), particularly interleukin (IL)-1 and IL-6 blocking agents, might be causing adverse drug reactions and lung disease (systemic JIA-LD). Carriage of HLA-DRB1*15 has been reported as a risk factor for adverse drug reactions among patients with systemic JIA. We performed a retrospective chart review to evaluate these factors at our center. METHODS: We reviewed the records of 86 subjects with systemic JIA followed for at least 6 months between 1996 and 2022. HLA typing was performed in 23 of the subjects. We compared characteristics of patients with or without eosinophilia. Among patients with HLA typing, we compared clinical characteristics of subjects with or without DRB1*15 and with or without systemic JIA-LD. RESULTS: Among the 23 patients with HLA typing, 74% carried DRB1*15, and 63% of patients without systemic JIA-LD carried DRB1*15. Seven subjects had systemic JIA-LD, all of whom carried DRB1*15. Patients with systemic JIA-LD were younger at the time of diagnosis and more likely to have had macrophage activation syndrome. Exposure to IL-1 and IL-6 blockers was common, occurring in 95% of patients. Eosinophilia occurred in 39% of patients with systemic JIA, often before IL-1 or IL-6 blockade. Eosinophilia was associated with adverse drug reactions and macrophage activation syndrome. There was 1 death, unrelated to active systemic JIA disease. CONCLUSION: Carriage of DRB1*15 was more common in this cohort of patients with systemic JIA than in the general population. Eosinophilia and systemic JIA-LD were more common among patients with severe systemic JIA complicated by macrophage activation syndrome.

Prognostic role of inflammatory diets in colorectal cancer overall and in strata of tumor-infiltrating lymphocyte levels.

BACKGROUND: Certain dietary patterns can elicit systemic and intestinal inflammatory responses, which may influence adaptive anti-tumor immune responses and tumor behavior. We hypothesized that pro-inflammatory diets might be associated with higher colorectal cancer mortality and that the association might be stronger for tumors with lower immune responses. METHODS: We calculated an empirical dietary inflammatory pattern (EDIP) score in 2829 patients among 3988 incident rectal and colon carcinoma cases in the Nurses' Health Study and Health Professionals Follow-up Study. Using Cox proportional hazards regression analyses, we examined the prognostic association of EDIP scores and whether it might be modified by histopathologic immune reaction (in 1192 patients with available data). RESULTS: Higher EDIP scores after colorectal cancer diagnosis were associated with worse survival, with multivariable-adjusted hazard ratios (HRs) for the highest versus lowest tertile of 1.41 (95% confidence interval [CI]: 1.13-1.77; Ptrend = 0.003) for 5-year colorectal cancer-specific mortality and 1.44 (95% CI, 1.19-1.74; Ptrend = 0.0004) for 5-year all-cause mortality. The association of post-diagnosis EDIP scores with 5-year colorectal cancer-specific mortality differed by degrees of tumor-infiltrating lymphocytes (TIL; Pinteraction = .002) but not by three other lymphocytic reaction patterns. The multivariable-adjusted, 5-year colorectal cancer-specific mortality HRs for the highest versus lowest EDIP tertile were 1.59 (95% CI: 1.01-2.53) in TIL-absent/low cases and 0.48 (95% CI: 0.16-1.48) in TIL-intermediate/high cases. CONCLUSIONS: Pro-inflammatory diets after colorectal cancer diagnosis were associated with increased mortality, particularly in patients with absent or low TIL.

Canonical correlation analysis for elliptical copulas.

Canonical correlation analysis (CCA) is a common method used to estimate the associations between two different sets of variables by maximizing the Pearson correlation between linear combinations of the two sets of variables. We propose a version of CCA for transelliptical distributions with an elliptical copula using pairwise Kendall's tau to estimate a latent scatter matrix. Because Kendall's tau relies only on the ranks of the data this method does not make any assumptions about the marginal distributions of the variables, and is valid when moments do not exist. We establish consistency and asymptotic normality for canonical directions and correlations estimated using Kendall's tau. Simulations indicate that this estimator outperforms standard CCA for data generated from heavy tailed elliptical distributions. Our method also identifies more meaningful relationships when the marginal distributions are skewed. We also propose a method for testing for non-zero canonical correlations using bootstrap methods. This testing procedure does not require any assumptions on the joint distribution of the variables and works for all elliptical copulas. This is in contrast to permutation tests which are only valid when data are generated from a distribution with a Gaussian copula. This method's practical utility is shown in an analysis of the association between radial diffusivity in white matter tracts and cognitive tests scores for six-year-old children from the Early Brain Development Study at UNC-Chapel Hill. An R package implementing this method is available at github.com/blangworthy/transCCA.

Placental genomic risk scores and early neurodevelopmental outcomes.

Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.

Numerical evaluation of spray position for improved nasal drug delivery.

Topical intra-nasal sprays are amongst the most commonly prescribed therapeutic options for sinonasal diseases in humans. However, inconsistency and ambiguity in instructions show a lack of definitive knowledge on best spray use techniques. In this study, we have identified a new usage strategy for nasal sprays available over-the-counter, that registers an average 8-fold improvement in topical delivery of drugs at diseased sites, when compared to prevalent spray techniques. The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Simulated dose in representative models is validated through in vitro spray measurements in 3D-printed anatomic replicas using the gamma scintigraphy technique. This work breaks new ground in proposing an alternative user-friendly strategy that can significantly enhance topical delivery inside human nose. While these findings can eventually translate into personalized spray usage instructions and hence merit a change in nasal standard-of-care, this study also demonstrates how relatively simple engineering analysis tools can revolutionize everyday healthcare. Finally, with respiratory mucosa as the initial coronavirus infection site, our findings are relevant to intra-nasal vaccines that are in-development, to mitigate the COVID-19 pandemic.

White Matter Development from Birth to 6 Years of Age: A Longitudinal Study.

Human white matter development in the first years of life is rapid, setting the foundation for later development. Microstructural properties of white matter are linked to many behavioral and psychiatric outcomes; however, little is known about when in development individual differences in white matter microstructure are established. The aim of the current study is to characterize longitudinal development of white matter microstructure from birth through 6 years to determine when in development individual differences are established. Two hundred and twenty-four children underwent diffusion-weighted imaging after birth and at 1, 2, 4, and 6 years. Diffusion tensor imaging data were computed for 20 white matter tracts (9 left-right corresponding tracts and 2 commissural tracts), with tract-based measures of fractional anisotropy and axial and radial diffusivity. Microstructural maturation between birth and 1 year are much greater than subsequent changes. Further, by 1 year, individual differences in tract average values are consistently predictive of the respective 6-year values, explaining, on average, 40% of the variance in 6-year microstructure. Results provide further evidence of the importance of the first year of life with regard to white matter development, with potential implications for informing early intervention efforts that target specific sensitive periods.

Antibacterial Use Is Associated with an Increased Risk of Hematologic and Gastrointestinal Adverse Events in Patients Treated with Gemcitabine for Stage IV Pancreatic Cancer.

BACKGROUND: Preclinical evidence has demonstrated that common intratumor bacteria metabolize the chemotherapeutic drug gemcitabine. The significance of this bacterial metabolism pathway, relative to the known metabolic pathways by host enzymes, is not known. We hypothesized that bacterial metabolism is clinically significant and that "knockdown" by antibacterial therapy has the unintended effect of increasing the effective dose of gemcitabine, thereby increasing the risk for gemcitabine-associated toxicities. MATERIALS AND METHODS: We reanalyzed the comparator arm of the MPACT trial (NCT01442974), made available through Project Data Sphere, LLC (CEO Roundtable on Cancer's Life Sciences Consortium, Cary, NC; www.projectdatasphere.org). In this arm, 430 patients with metastatic pancreatic adenocarcinoma were treated with gemcitabine. We used the Anderson-Gill survival model to compare the risk of developing an adverse event after antibacterial prescription with time unexposed to antibacterials. Adverse events of grade 3 and greater were considered at three levels of granularity: all aggregated into one endpoint, aggregated by class, and taken individually. Antibiotic exposures were analyzed in aggregate as well as by class. RESULTS: Antibacterial exposure was associated with an increased risk of adverse events (hazard ratio [HR]: 1.77; confidence interval [CI]: 1.46-2.14), any hematologic adverse event (HR: 1.64; CI: 1.26-2.13), and any gastrointestinal adverse event (HR: 2.14; CI: 1.12-4.10) but not a constitutional (HR: 1.33; CI: 0.611-2.90) or hepatologic adverse event (HR: 0.99; CI: 0.363-2.71). Among specific adverse events, antibacterial exposure was associated with an increased risk of anemia (HR: 3.16; CI: 1.59-6.27), thrombocytopenia (HR: 2.52; CI: 1.31-4.85), leukopenia (HR: 3.91; CI: 1.46-10.5), and neutropenia (HR: 1.53; CI: 1.07-2.17) but not any other specific adverse events. CONCLUSION: Antibacterial exposure was associated with an increased risk of gemcitabine-associated, dose-limiting adverse events, including aggregate hematologic and gastrointestinal events, as well as four specific hematologic adverse events, suggesting that intratumor bacteria may be responsible for a clinically significant portion of gemcitabine metabolism. Alternative avenues of evidence will be necessary to confirm this preliminary finding and assess its generalizability. There is plentiful opportunity for similar analyses on other clinical trial data sets, where gemcitabine or other biomimetic small molecules were used. IMPLICATIONS FOR PRACTICE: Patients treated with gemcitabine for metastatic pancreatic ductal adenocarcinoma have an increased rate of gemcitabine-associated toxicity during and after antibiotic therapy. This observation is consistent with preclinical evidence that intratumor bacteria metabolize gemcitabine to an inactive form. Further research is needed to determine whether this observation merits any changes in clinical practice.

The Predictive Value of Developmental Assessments at 1 and 2 for Intelligence Quotients at 6.

Intelligence is an important individual difference factor related to mental health, academic achievement, and life success, yet there is a lack of research into its early cognitive predictors. This study investigated the predictive value of infant developmental assessment scores for school-age intelligence in a large, heterogeneous sample of single- and twin-born subjects (N = 521). We found that Early Learning Composite (ELC) scores from the Mullen Scales of Early Learning have similar predictive power to that of other infant tests. ELC scores at age 2 were predictive of Stanford-Binet abbreviated intelligence (ABIQ) scores at age 6 (r = 0.46) even after controlling for sex, gestation number, and parental education. ELC scores at age 1 were less predictive of 6-year ABIQ scores (r = 0.17). When the sample was split to test robustness of findings, we found that results from the full sample replicated in a subset of children born at ≥32 weeks gestation without birth complications (n = 405), though infant cognitive scores did not predict IQ in a subset born very prematurely or with birth complications (n = 116). Scores at age 2 in twins and singletons showed similar predictive ability for scores at age 6, though twins had particularly high correlations between ELC at age 1 and ABIQ at age 6.