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.

Estimating intracluster correlation for ordinal data.

In this paper, we consider the estimation of intracluster correlation for ordinal data. We focus on pure-tone audiometry hearing threshold data, where thresholds are measured in 5 decibel increments. We estimate the intracluster correlation for tests from iPhone-based hearing assessment applications as a measure of test/retest reliability. We present a method to estimate the intracluster correlation using mixed effects cumulative logistic and probit models, which assume the outcome data are ordinal. This contrasts with using a mixed effects linear model which assumes that the outcome data are continuous. In simulation studies, we show that using a mixed effects linear model to estimate the intracluster correlation for ordinal data results in a negative finite sample bias, while using mixed effects cumulative logistic or probit models reduces this bias. The estimated intracluster correlation for the iPhone-based hearing assessment application is higher when using the mixed effects cumulative logistic and probit models compared to using a mixed effects linear model. When data are ordinal, using mixed effects cumulative logistic or probit models reduces the bias of intracluster correlation estimates relative to using a mixed effects linear model.

Role of Routine Suppressive Antibiotic Therapy After Debridement, Antibiotics, and Implant Retention for Acute Periprosthetic Joint Infections.

Background: The first-line management strategy for acute periprosthetic joint infections (PJIs) is debridement, antibiotics, and implant retention (DAIR). Suppressive antibiotic therapy (SAT) after DAIR is proposed to improve outcomes, yet its efficacy remains under scrutiny. Methods: We conducted a multicenter retrospective study in patients with acute PJI of the hip or knee who were treated with DAIR in centers from Europe and the United States. We analyzed the effect of SAT using a Cox model landmarked at 12 weeks. The primary covariate of interest was SAT, which was analyzed as a time-varying covariate. Patients who experienced treatment failure or were lost to follow-up within 12 weeks were excluded from the analysis. Results: The study included 510 patients with 66 treatment failures with a median follow-up of 801 days. We did not find a statistically significant association between SAT and treatment failure (hazard ratio, 1.37; 95% CI, .79-2.39; P = .27). Subgroup analyses for joint, country cohort, and type of infection (early or late acute) did not show benefit for SAT. Secondary analysis of country cohorts showed a trend toward benefit for the US cohort (hazard ratio, 0.36; 95% CI, .11-1.15; P = .09), which also had the highest risk of treatment failure. Conclusions: The utility of routine SAT as a strategy for enhancing DAIR's success in acute PJI remains uncertain. Our results suggest that SAT's benefits might be restricted to specific groups of patients, underscoring the need for randomized controlled trials. Identifying patients most likely to benefit from SAT should be a priority in future studies.

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.

Soft classification and regression analysis of audiometric phenotypes of age-related hearing loss.

Age-related hearing loss has a complex etiology. Researchers have made efforts to classify relevant audiometric phenotypes, aiming to enhance medical interventions and improve hearing health. We leveraged existing pattern analyses of age-related hearing loss and implemented the phenotype classification via quadratic discriminant analysis (QDA). We herein propose a method for analyzing the exposure effects on the soft classification probabilities of the phenotypes via estimating equations. Under reasonable assumptions, the estimating equations are unbiased and lead to consistent estimators. The resulting estimator had good finite sample performances in simulation studies. As an illustrative example, we applied our proposed methods to assess the association between a dietary intake pattern, assessed as adherence scores for the dietary approaches to stop hypertension diet calculated using validated food-frequency questionnaires, and audiometric phenotypes (older-normal, metabolic, sensory, and metabolic plus sensory), determined based on data obtained in the Nurses' Health Study II Conservation of Hearing Study, the Audiology Assessment Arm. Our findings suggested that participants with a more healthful dietary pattern were less likely to develop the metabolic plus sensory phenotype of age-related hearing loss.

Comparison between inverse-probability weighting and multiple imputation in Cox model with missing failure subtype.

Identifying and distinguishing risk factors for heterogeneous disease subtypes has been of great interest. However, missingness in disease subtypes is a common problem in those data analyses. Several methods have been proposed to deal with the missing data, including complete-case analysis, inverse-probability weighting, and multiple imputation. Although extant literature has compared these methods in missing problems, none has focused on the competing risk setting. In this paper, we discuss the assumptions required when complete-case analysis, inverse-probability weighting, and multiple imputation are used to deal with the missing failure subtype problem, focusing on how to implement these methods under various realistic scenarios in competing risk settings. Besides, we compare these three methods regarding their biases, efficiency, and robustness to model misspecifications using simulation studies. Our results show that complete-case analysis can be seriously biased when the missing completely at random assumption does not hold. Inverse-probability weighting and multiple imputation estimators are valid when we correctly specify the corresponding models for missingness and for imputation, and multiple imputation typically shows higher efficiency than inverse-probability weighting. However, in real-world studies, building imputation models for the missing subtypes can be more challenging than building missingness models. In that case, inverse-probability weighting could be preferred for its easy usage. We also propose two automated model selection procedures and demonstrate their usage in a study of the association between smoking and colorectal cancer subtypes in the Nurses' Health Study and Health Professional Follow-Up Study.

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.

An overview of propensity score matching methods for clustered data.

Propensity score matching is commonly used in observational studies to control for confounding and estimate the causal effects of a treatment or exposure. Frequently, in observational studies data are clustered, which adds to the complexity of using propensity score techniques. In this article, we give an overview of propensity score matching methods for clustered data, and highlight how propensity score matching can be used to account for not just measured confounders, but also unmeasured cluster level confounders. We also consider using machine learning methods such as generalized boosted models to estimate the propensity score and show that accounting for clustering when using these methods can greatly reduce the performance, particularly when there are a large number of clusters and a small number of subjects per cluster. In order to get around this we highlight scenarios where it may be possible to control for measured covariates using propensity score matching, while using fixed effects regression in the outcome model to control for cluster level covariates. Using simulation studies we compare the performance of different propensity score matching methods for clustered data across a number of different settings. Finally, as an illustrative example we apply propensity score matching methods for clustered data to study the causal effect of aspirin on hearing deterioration using data from the conservation of hearing study.

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.

Marginal structural models for multilevel clustered data.

Marginal structural models (MSMs), which adopt inverse probability treatment weighting in the estimating equations, are powerful tools to estimate the causal effects of time-varying exposures in the presence of time-dependent confounders. Motivated by the Conservation of Hearing Study (CHEARS) Audiology Assessment Arm (AAA) where repeated hearing measurements were clustered by study participants, time, and testing sites, we propose two methods to account for the multilevel correlation structure when fitting the MSMs. The first method directly models the covariance of the repeated outcomes when solving the weighted generalized estimating equations for MSMs, while the second two-stage analysis approach fits cluster-specific MSMs first and then combines the estimated parameters using mixed-effects meta-analysis. Finite sample simulation results suggest that our methods can obtain less biased and more efficient estimates of the parameters by accounting for the multilevel correlation. Moreover, we explore the effects of using fixed- or mixed-effects model to estimate the treatment probability on the parameter estimates of the MSMs in the presence of unmeasured cluster-level confounders. Lastly, we apply our methods to the CHEARS AAA data set, to estimate the causal effects of aspirin use on hearing loss.

Delay in the Effect of Restricting Community Mobility on the Spread of COVID-19 During the First Wave in the United States.

BACKGROUND: It remains unclear how changes in human mobility shaped the transmission dynamic of coronavirus disease 2019 (COVID-19) during its first wave in the United States. METHODS: By coupling a Bayesian hierarchical spatiotemporal model with reported case data and Google mobility data at the county level, we found that changes in movement were associated with notable changes in reported COVID-19 incidence rates about 5 to 7 weeks later. RESULTS: Among all movement types, residential stay was the most influential driver of COVID-19 incidence rate, with a 10% increase 7 weeks ago reducing the disease incidence rate by 13% (95% credible interval, 6%-20%). A 10% increase in movement from home to workplaces, retail and recreation stores, public transit, grocery stores, and pharmacies 7 weeks ago was associated with an increase of 5%-8% in the COVID-10 incidence rate. In contrast, parks-related movement showed minimal impact. CONCLUSIONS: Policy-makers should anticipate such a delay when planning intervention strategies restricting human movement.

Association of PIK3CA mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma.

Immunotherapy targeting the CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint axis has emerged as a promising treatment strategy for various cancers. Experimental evidence suggests that phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) signaling may upregulate CD274 expression. Thus, we hypothesized that PIK3CA mutation, PTEN loss, or their combined status might be associated with CD274 overexpression in colorectal carcinoma. We assessed tumor CD274 and PTEN expression by immunohistochemistry and assessed PIK3CA mutation by pyrosequencing in 753 patients among 4,465 incident rectal and colon cancer cases that had occurred in two U.S.-wide prospective cohort studies. To adjust for potential confounders and selection bias due to tissue availability, inverse probability weighted multivariable ordinal logistic regression analyses used the 4,465 cases and tumoral data including microsatellite instability, CpG island methylator phenotype, KRAS and BRAF mutations. PIK3CA mutation and loss of PTEN expression were detected in 111 of 753 cases (15%) and 342 of 585 cases (58%), respectively. Tumor CD274 expression was negative in 306 (41%), low in 195 (26%), and high in 252 (33%) of 753 cases. PTEN loss was associated with CD274 overexpression [multivariable odds ratio (OR) 1.83; 95% confidence interval (CI), 1.22-2.75; P = .004]. PIK3CA mutation was statistically-insignificantly (P = .036 with the stringent alpha level of 0.005) associated with CD274 overexpression (multivariable OR, 1.54; 95% CI, 1.03-2.31). PIK3CA-mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than PIK3CA-wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) (P = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.

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.

Individual Variation of Human Cortical Structure Is Established in the First Year of Life.

BACKGROUND: Individual differences in cortical gray matter (GM) structure are associated with cognitive function and psychiatric disorders with developmental origins. Identifying when individual differences in cortical structure are established in childhood is critical for understanding the timing of abnormal cortical development associated with neuropsychiatric disorders. METHODS: We studied the development of cortical GM and white matter volume, cortical thickness, and surface area using structural magnetic resonance imaging in two unique cohorts of singleton (121 male and 131 female) and twin (99 male and 83 female) children imaged longitudinally from birth to 6 years. RESULTS: Cortical GM volume increases rapidly in the first year of life, with more gradual growth thereafter. Between ages 1 and 6 years, total surface area expands 29%, while average cortical thickness decreases about 3.5%. In both cohorts, a large portion of individual variation in cortical GM volume (81%-87%) and total surface area (73%-83%) at age 6 years is present by age 1 year. Regional heterogeneity of cortical thickness observed at age 6 is largely in place at age 1. CONCLUSIONS: These findings indicate that individual differences in cortical GM structure are largely established by the end of the first year of life, following a period of rapid postnatal GM growth. This suggests that alterations in GM structure associated with psychiatric disorders with developmental origins may largely arise in the first year of life and that interventions to normalize or mitigate abnormal GM development may need to be targeted to very early childhood.

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.

GDNF-expressing macrophages restore motor functions at a severe late-stage, and produce long-term neuroprotective effects at an early-stage of Parkinson's disease in transgenic Parkin Q311X(A) mice.

There is an unmet medical need in the area of Parkinson's disease (PD) to develop novel therapeutic approaches that can stop and reverse the underlying mechanisms responsible for the neuronal death. We previously demonstrated that systemically administered autologous macrophages transfected ex vivo to produce glial cell line-derived neurotrophic factor (GDNF) readily migrate to the mouse brain with acute toxin-induced neuroinflammation and ameliorate neurodegeneration in PD mouse models. We hypothesized that the high level of cytokines due to inflammatory process attracted GDNF-expressing macrophages and ensured targeted drug delivery to the PD brain. Herein, we validated a therapeutic potential of GDNF-transfected macrophages in a transgenic Parkin Q311X(A) mice with slow progression and mild brain inflammation. Systemic administration of GDNF-macrophages at a severe late stage of the disease leaded to a near complete restoration of motor functions in Parkin Q311X(A) mice and improved brain tissue integrity with healthy neuronal morphology. Furthermore, intravenous injections of GDNF-macrophages at an early stage of disease resulted in potent sustained therapeutic effects in PD mice for more than a year after the treatment. Importantly, multiple lines of evidence for therapeutic efficacy were observed including: diminished neuroinflammation and α-synuclein aggregation, increased survival of dopaminergic neurons, and improved locomotor functions. In summary, GDNF-transfected macrophages represent a promising therapeutic strategy for PD at both late- and early-stages of the disease.