Optimizing optimization: A six-year quality improvement project focused on students' APPE preferences.

PROBLEM DESCRIPTION: The advanced pharmacy practice experience (APPE) component of the entry-level doctor of pharmacy degree program is essential in contributing to student pharmacists' education. Establishing an optimization process to assist students in matching to their highest preferred clinical sites is extremely important. QUALITY IMPROVEMENT METHODS: The University of Colorado Skaggs School of Pharmacy & Pharmaceutical Sciences uses a fourth year APPE match process designed to yield the best possible matches for the entire class while being perceived as fair and relatively easy to navigate. This article describes the evolution of this process. RESULTS OF CQI INQUIRY: Across six years of data, satisfaction with the match process has been rated consistently high by students. Fairness with the process is also rated highly. Changes to the process have resulted in students receiving higher ranked preferences in more recent years. This was achieved while still following institution requirements for rural rotations and pre-matching. INTERPRETATION AND DISCUSSION: The APPE year yields a tremendous amount of learning for students as a culminating experience applying skills and knowledge to actual patients. Improving students' ability to customize their own schedule allows them to optimize these learning opportunities. CONCLUSIONS: A robust match process has been established and refined to meet the needs of the student pharmacists as they approach their fourth year of the curriculum. This process has been perceived as fair and relatively easy to navigate. Achievement of higher overall student rankings has been accomplished.

Patterns of indoor radon concentrations, radon-hazard potential, and radon testing on a small geographic scale in Utah.

INTRODUCTION: Currently, there are no publicly-available estimates of indoor radon concentration at scales smaller than the county. Radon-hazard potential soil maps that reflect underlying geologic factors can be created at small geographic scale and linked to residential and census data. We determined the association between residential radon tests and high radon-hazard potential soil at the residential and block group levels using a large Utah-based dataset. We also identified characteristics of block groups with limited tests in the dataset. METHODS: We geocoded a dataset of residential radon tests obtained from 2001 to 2017 by a statewide educational program. We linked each location to maps of radon-hazard potential soil, the Environmental Protection Agency's (EPA) county radon zones. We also calculated the number of tests conducted in each block group and linked block groups to demographic data from the 2020 United States census. Log-linear and logistic models identified the association between residential home test results and 1) radon-hazard potential soil of each residence, 2) percent of residences on high radon-hazard potential soils in block groups, and 3) EPA's radon zones. We compared demographic characteristics among block groups with ≥5 or <5 residential tests in our dataset. RESULTS: Approximately 42% of homes in the dataset tested ≥4 pCi/L. We found significant positive associations for residential radon test results with 1) residential location on high radon-hazard potential soil and 2) block groups with >0% of residences on high radon-hazard potential soil. EPA radon zones were not associated with residential test results. Block groups with <5 tests had higher than the statewide median percentage of Hispanic residents (OR = 2.46, 95% CI = 1.89-3.21) and were located in rural counties. DISCUSSION: Radon-hazard potential soil has a significant association with residential home radon tests. More efforts are needed to improve radon testing in block groups that are rural and have greater percentages of racial minorities.

Radiographic Landmarks for Ideal Port Placement in Wrist Arthroscopy.

Background The placement of wrist arthroscopy portals is traditionally performed using distances from anatomic landmarks. We sought to evaluate the safety of traditional portal placement and determine if radiographic landmarks could provide an additional method of identifying tendon intervals. Methods Six cadaveric specimens were used to evaluate the accuracy of portal placement based on anatomic and radiographic landmarks. Fluoroscopic images were used to document the location of previously described surface landmarks. Soft tissue was dissected away to identify the relationship between the transcutaneously placed portals and the extensor tendons. With soft tissue removed, tendon intervals were identified in relationship to anatomic carpal bone landmarks, and interval distances measured. Portals were then placed under radiographic imaging on the final three specimens and accuracy was examined by the removal of overlying soft tissue to confirm accurate interval placement Results The 3,4 portal was safely placed using only surface anatomic landmarks, however the 4,5 and midcarpal ulnar (MCU) portal sites were not consistently placed in the intended tendon interval, especially in larger wrists. Radiographic interval targets for the 3,4 portal were identified at the ulnar aspect of the scaphoid and the 4,5 portal at the ulnar one-third of the lunate. The radiographic site for the MCR was located at the inferior radial one-third of the capitate and the MCU portal was located at the radial aspect of the hamate. The 6R portal radiographic landmark is at the radial aspect of the triquetrum and 6U at the ulnar aspect of the triquetrum. Conclusion Portal placement in wrist arthroscopy based on anatomic landmarks alone can be unreliable in larger wrists. Radiographic imaging based on carpal bone landmarks provides an additional tool for consistent placement of portals in wrist arthroscopy and may limit unintended injury to extensor tendons. Level of Evidence This is a Level VI study.

A Weighted Head Accelerator Mechanism (WHAM) for visualizing brain rheology using magnetic resonance imaging.

BACKGROUND: A device for moving the head during MR imaging, called a Weighted Head Accelerator Mechanism (WHAM), rotates the head of a supine subject within programmable rotation limits and acceleration profiles. The WHAM can be used with custom MRI sequences to visualize the deformation and recoil of in vivo brain parenchyma with high temporal resolution, allowing element-wise calculation of strain and shear forces in the brain. Unlike previous devices, the WHAM can be configured to provide a wide range of motion and acceleration profiles. NEW METHOD: The WHAM was calibrated using a high-speed camera on a laboratory bench and in 1.5 Tesla and 3.0 Tesla MRI scanners using gel phantoms and human subjects. The MR imaging studies employed a spatial spin-saturation tagging sub-sequence, followed by serial image acquisition. In these studies, 256 images were acquired with a temporal resolution of 2.56 ms. Deformation of the brain was quantified by following the spatial tags in the images. RESULTS: MR imaging showed that the WHAM drove quantifiable brain motions using g forces less than those typically observed in day-to-day activities, with peak accelerations of ∼250 rad/sec2. COMPARISON WITH EXISTING METHODS: The peak pre-contact accelerations and velocities achieved by the WHAM device in this study are both higher than devices used in previous studies, while also allowing for modification of these factors. CONCLUSIONS: MR imaging performed with the WHAM provides a direct method to visualize and quantify "brain slosh" in response to rotational acceleration. Consequently, this approach might find utility in evaluating strategies to protect the brain from mild traumatic brain injury (mTBI).

rECHOmmend: An ECG-Based Machine Learning Approach for Identifying Patients at Increased Risk of Undiagnosed Structural Heart Disease Detectable by Echocardiography.

BACKGROUND: Timely diagnosis of structural heart disease improves patient outcomes, yet many remain underdiagnosed. While population screening with echocardiography is impractical, ECG-based prediction models can help target high-risk patients. We developed a novel ECG-based machine learning approach to predict multiple structural heart conditions, hypothesizing that a composite model would yield higher prevalence and positive predictive values to facilitate meaningful recommendations for echocardiography. METHODS: Using 2 232 130 ECGs linked to electronic health records and echocardiography reports from 484 765 adults between 1984 to 2021, we trained machine learning models to predict the presence or absence of any of 7 echocardiography-confirmed diseases within 1 year. This composite label included the following: moderate or severe valvular disease (aortic/mitral stenosis or regurgitation, tricuspid regurgitation), reduced ejection fraction <50%, or interventricular septal thickness >15 mm. We tested various combinations of input features (demographics, laboratory values, structured ECG data, ECG traces) and evaluated model performance using 5-fold cross-validation, multisite validation trained on 1 site and tested on 10 independent sites, and simulated retrospective deployment trained on pre-2010 data and deployed in 2010. RESULTS: Our composite rECHOmmend model used age, sex, and ECG traces and had a 0.91 area under the receiver operating characteristic curve and a 42% positive predictive value at 90% sensitivity, with a composite label prevalence of 17.9%. Individual disease models had area under the receiver operating characteristic curves from 0.86 to 0.93 and lower positive predictive values from 1% to 31%. Area under the receiver operating characteristic curves for models using different input features ranged from 0.80 to 0.93, increasing with additional features. Multisite validation showed similar results to cross-validation, with an aggregate area under the receiver operating characteristic curve of 0.91 across our independent test set of 10 clinical sites after training on a separate site. Our simulated retrospective deployment showed that for ECGs acquired in patients without preexisting structural heart disease in the year 2010, 11% were classified as high risk and 41% (4.5% of total patients) developed true echocardiography-confirmed disease within 1 year. CONCLUSIONS: An ECG-based machine learning model using a composite end point can identify a high-risk population for having undiagnosed, clinically significant structural heart disease while outperforming single-disease models and improving practical utility with higher positive predictive values. This approach can facilitate targeted screening with echocardiography to improve underdiagnosis of structural heart disease.

Delayed Detection of Predominantly Pericentral Hydroxychloroquine Toxicity in a Dominican Patient.

Purpose: To describe delayed detection of pericentral hydroxychloroquine (HCQ) toxicity. Methods: 67-year-old Dominican woman with rheumatoid arthritis on HCQ presented for examination. Results: Spectral-domain optical coherence tomography (SD-OCT) demonstrated bilateral cystoid macular edema with parafoveal attenuation of the external limiting membrane (ELM) and the ellipsoid zone (EZ). ELM and EZ disruption was present in inferior macula. While subtle superior defects were present on 10-2 visual fields, superior pericentral defects were noted on 24-2 testing. Hyperautofluorescence along inferior arcades corresponded to SD-OCT and visual fields. Examination 2 years prior demonstrated nonspecific points of depression on 10-2 visual fields and normal central SD-OCT findings. EZ and ELM disruption was present in the perifoveal inferior macula. Conclusions: Early pericentral distribution of HCQ toxicity is not limited to Asian patients. Detecting pericentral HCQ toxicity involves reviewing entire macular cube on OCT. When OCT changes are suspected on parafoveal OCT B-scans, visual field testing with 24-2 may be more sensitive than 10-2.

Risk factors for loss to follow-up of persons who inject drugs enrolled at syringe services programs in Kentucky.

BACKGROUND: Syringe services programs (SSP) are an effective strategy to reduce blood-borne infections of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in persons who inject drugs (PWID). The objectives of this study were to determine the frequency and risk factors for loss to follow-up (LTFU) in PWID enrolled at SSPs in Kentucky. METHODS: A retrospective cohort study was conducted which included data of PWID enrolled at 32 SSP. Demographics, use of drugs, HIV testing, HCV testing, and medical services were analyzed. A generalized linear model (GLM), family binomial was used to determine risk factors for LTFU. RESULTS: The analysis included 5742 PWID. LTFU by year of enrollment was 287/770 (37.3%) in 2017, 796/1874 (42.5%) in 2018, and 1479/3,098 (47.7%) in 2019. LTFU was significantly associated with distance to SSP from home of more than five miles (RR 1.25; 95%CI 1.09-1.43; p = 0.002) and SSPs housed in rural counties (RR 1.22; 95%CI 1.06-1.40; p = 0.004), adjusted by age, sex, and race. The use of buprenorphine was associated with less risk of LTFU (RR 0.79, p = 0.034). CONCLUSION: The distance to an SSP from home and SSPs in rural counties were identified as risk factors for LTFU. Initiatives that bring health services closer to PWID homes and offer opioid use disorder treatment may improve repeated participation in SSPs.

Molecular Subtyping of Diffuse Large B-Cell Lymphoma Using a Novel Quantitative RT-PCR Assay.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. Cell-of-origin classification in DLBCL has identified activated B cell (ABC) and germinal center B cell (GCB) as two major subtypes. Patients with the ABC subtype show reduced overall survival with standard therapies. Development of a quantitative RT-PCR-based lymphoma cell-of-origin (LCOO) assay to determine ABC, GCB, and unclassifiable subtypes in formalin-fixed, paraffin-embedded tissue (FFPET) DLBCL samples is reported. The LCOO classifier was trained on two DLBCL cohorts with validation performed by using an analytical grade assay in an independent cohort of 60 FFPET DLBCL samples. In the validation cohort, LCOO classification was 88.1%, 84.7%, and 84.7% concordant with microarray, immunohistochemistry (Hans classification), and Lymphoma Subtyping Test, respectively. Importantly, LCOO and Lymphoma Subtyping Test assays commonly assigned subtypes in 17 (94.4%) of 18 ABC samples and 34 (89.5%) of 38 GCB DLBCL samples from this cohort. Progression-free survival and overall survival of ABC and GCB subtypes, as classified by all platforms, were not significantly different in the validation cohort. LCOO classification using publicly available microarray gene expression from two independent data sets (414 fresh frozen and 474 FFPET DLBCL biopsies) revealed a significantly worse outcome for the ABC subtype compared with that of the GCB subtype. Thus, a sensitive, reproducible, LCOO assay developed on an easy to standardize quantitative RT-PCR platform may be an important clinical tool for DLBCL cell-of-origin classification.

Pain: Pathways and Physiology.

Pain involves a complex interplay between messages sent from the periphery to the central nervous system and vice versa. Specific pathways play a vital role in carrying these messages, and modulating, or exacerbating their downstream effects. This review describes the anatomy and physiology of pain emphasizing targeted treatment pathways of pain.

Access to Syringe Services Programs - Kentucky, North Carolina, and West Virginia, 2013-2017.

The Appalachian region of the United States is experiencing a large increase in hepatitis C virus (HCV) infections related to injection drug use (IDU) (1). Syringe services programs (SSPs) providing sufficient access to safe injection equipment can reduce hepatitis C transmission by 56%; combined SSPs and medication-assisted treatment can reduce transmission by 74% (2). However, access to SSPs has been limited in the United States, especially in rural areas and southern and midwestern states (3). This report describes the expansion of SSPs in Kentucky, North Carolina, and West Virginia during 2013-August 1, 2017. State-level data on the number of SSPs, client visits, and services offered were collected by each state through surveys of SSPs and aggregated in a standard format for this report. In 2013, one SSP operated in a free clinic in West Virginia, and SSPs were illegal in Kentucky and North Carolina; by August 2017, SSPs had been legalized in Kentucky and North Carolina, and 53 SSPs operated in the three states. In many cases, SSPs provide integrated services to address hepatitis and human immunodeficiency virus (HIV) infection, overdose, addiction, unintended pregnancy, neonatal abstinence syndrome, and other complications of IDU. Prioritizing development of SSPs with sufficient capacity, particularly in states with counties vulnerable to epidemics of hepatitis and HIV infection related to IDU, can expand access to care for populations at risk.

IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor α (IL-4Rα) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4Rα was observed on pulmonary CD11b+ myeloid dendritic cells (mDCs) suggesting a role for IL-4Rα on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b+ mDCs expressed higher levels of IL-4Rα than their adult counterparts. Because CD11b+ mDCs mainly present antigens to CD4+ T cells, we hypothesized that increased expression of IL-4Rα on neonatal CD11b+ mDCs was responsible for Th2 - biased RSV immunopathophysiology. Indeed, when IL-4Rα was selectively deleted from CD11b+ mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4Rα on adult CD11b+ DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4Rα levels on CD11c+ cells were inversely correlated with maturation status of CD11b+ mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4Rα expression is critical for the maturity of pulmonary CD11b+ mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.

Regulatory T cells and IL10 suppress pulmonary host defense during early-life exposure to radical containing combustion derived ultrafine particulate matter.

BACKGROUND: Exposure to elevated levels of particulate matter (PM) is associated with increased risk of morbidity and mortality due to respiratory tract viral infections in infants. Recent identification of environmentally persistent free radicals (EPFRs) in the PM from a variety of combustion sources suggests its role in the enhancement of disease severity of lower respiratory tract infections (LRTI). Our previous studies demonstrated that acute exposure to EPFRs induces pulmonary immunosuppression allowing for enhanced influenza disease severity. Here, we determine the mechanism of EPFR-induced immunosuppression and its impact on the immune response towards influenza infection. METHODS: Neonatal mice (3 days old) were acutely exposed to DCB (combustion derived PM with chemisorbed EPFR) for seven consecutive days. Four days post-exposure (dpe), mice were infected with influenza virus. Pulmonary T cell phenotypes including regulatory T cells (Tregs) were analyzed by flow cytometry. The role of IL10 in EPFR-induced exacerbation of influenza disease severity was determined by administering recombinant IL10 (rIL10) to wild type mice or by using IL10 deficient (IL10-/-) neonatal mice. Mice were assessed for morbidity by measuring percent weight change and pulmonary viral load. RESULTS: Neonatal mice exposed to EPFRs had a significant increase in pulmonary Tregs and the immunosuppressive cytokine IL10 following influenza infection, which coincided with decreased protective T cell responses to influenza infection at 6 dpi. Depletion of Tregs in EPFR-exposed neonatal mice resulted in increased protective, adaptive T cell responses, whereas adoptive transfer of Tregs from EPFR-exposed neonates to air-exposed neonatal mice suppressed adaptive T cell responses towards influenza infection. Further, treatment with rIL10 could recapitulate EPFR-induced exacerbation of morbidity and pulmonary viral load compared to air exposed and influenza infected mice, whereas, EPFR-exposed IL10-/- neonates exhibited significant reductions in morbidity, pulmonary viral load and adaptive T cell responses following influenza infection. CONCLUSIONS: Neonatal exposure to EPFRs induced Tregs and IL10 resulting in suppressed adaptive T cell responses and enhanced influenza disease severity in neonatal mice. Depletion of Tregs increased adaptive T cell responses and deficiency of IL10 reduced morbidity and conferred enhanced protection against influenza virus.

Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33.

Respiratory syncytial virus (RSV) is the most common cause of infant hospitalizations and severe RSV infections are a significant risk factor for childhood asthma. The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive. Using an age-appropriate mouse model of RSV, we show that IL-33 plays a critical role in the immunopathogenesis of severe RSV, which is associated with higher group 2 innate lymphoid cells (ILC2s) specifically in neonates. Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice; this was not observed in adult mice. Blocking IL-33 with antibodies or using an IL-33 receptor knockout mouse during infection was sufficient to inhibit RSV immunopathogenesis (i.e., airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction); whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence. In summary, IL-33 is necessary, either directly or indirectly, to induce ILC2s and the Th2 biased immunopathophysiology observed following neonatal RSV infection. This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.

Noah's Ark conservation will not preserve threatened ecological communities under climate change.

BACKGROUND: Effective conservation of threatened ecological communities requires knowledge of where climatically suitable habitat is likely to persist into the future. We use the critically endangered Lowland Grassland community of Tasmania, Australia as a case study to identify options for management in cases where future climatic conditions become unsuitable for the current threatened community. METHODS: We model current and future climatic suitability for the Lowland Themeda and the Lowland Poa Grassland communities, which make up the listed ecological community. We also model climatic suitability for the structurally dominant grass species of these communities, and for closely related grassland and woodland communities. We use a dynamically downscaled regional climate model derived from six CMIP3 global climate models, under the A2 SRES emissions scenario. RESULTS: All model projections showed a large reduction in climatically suitable area by mid-century. Outcomes are slightly better if closely related grassy communities are considered, but the extent of suitable area is still substantially reduced. Only small areas within the current distribution are projected to remain climatically suitable by the end of the century, and very little of that area is currently in good condition. CONCLUSIONS: As the climate becomes less suitable, a gradual change in the species composition, structure and habitat quality of the grassland communities is likely. Conservation management will need to focus on maintaining diversity, structure and function, rather than attempting to preserve current species composition. Options for achieving this include managing related grassland types to maintain grassland species at the landscape-scale, and maximising the resilience of grasslands by reducing further fragmentation, weed invasion and stress from other land uses, while accepting that change is inevitable. Attempting to maintain the status quo by conserving the current structure and composition of Lowland Grassland communities is unlikely to be a viable management option in the long term.

Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection.

BACKGROUND: Exposures to elevated levels of particulate matter (PM) enhance severity of influenza virus infection in infants. The biological mechanism responsible for this phenomenon is unknown. The recent identification of environmentally persistent free radicals (EPFRs) associated with PM from a variety of combustion sources suggests its role in the enhancement of influenza disease severity. METHODS: Neonatal mice (< seven days of age) were exposed to DCB230 (combustion derived PM with a chemisorbed EPFR), DCB50 (non-EPFR PM sample), or air for 30 minutes/day for seven consecutive days. Four days post-exposure, neonates were infected with influenza intranasally at 1.25 TCID50/neonate. Neonates were assessed for morbidity (% weight gain, peak pulmonary viral load, and viral clearance) and percent survival. Lungs were isolated and assessed for oxidative stress (8-isoprostanes and glutathione levels), adaptive immune response to influenza, and regulatory T cells (Tregs). The role of the EPFR was also assessed by use of transgenic mice expressing human superoxide dismutase 2. RESULTS: Neonates exposed to EPFRs had significantly enhanced morbidity and decreased survival following influenza infection. Increased oxidative stress was also observed in EPFR exposed neonates. This correlated with increased pulmonary Tregs and dampened protective T cell responses to influenza infection. Reduction of EPFR-induced oxidative stress attenuated these effects. CONCLUSIONS: Neonatal exposure to EPFR containing PM resulted in pulmonary oxidative stress and enhanced influenza disease severity. EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.

Improving the use of species distribution models in conservation planning and management under climate change.

Choice of variables, climate models and emissions scenarios all influence the results of species distribution models under future climatic conditions. However, an overview of applied studies suggests that the uncertainty associated with these factors is not always appropriately incorporated or even considered. We examine the effects of choice of variables, climate models and emissions scenarios can have on future species distribution models using two endangered species: one a short-lived invertebrate species (Ptunarra Brown Butterfly), and the other a long-lived paleo-endemic tree species (King Billy Pine). We show the range in projected distributions that result from different variable selection, climate models and emissions scenarios. The extent to which results are affected by these choices depends on the characteristics of the species modelled, but they all have the potential to substantially alter conclusions about the impacts of climate change. We discuss implications for conservation planning and management, and provide recommendations to conservation practitioners on variable selection and accommodating uncertainty when using future climate projections in species distribution models.