Publications by authors named "Brian White"

152 Publications

Mutant U2AF1-induced alternative splicing of H2afy (macroH2A1) regulates B-lymphopoiesis in mice.

Cell Rep 2021 Aug;36(9):109626

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address:

Somatic mutations in spliceosome genes are found in ∼50% of patients with myelodysplastic syndromes (MDS), a myeloid malignancy associated with low blood counts. Expression of the mutant splicing factor U2AF1(S34F) alters hematopoiesis and mRNA splicing in mice. Our understanding of the functionally relevant alternatively spliced target genes that cause hematopoietic phenotypes in vivo remains incomplete. Here, we demonstrate that reduced expression of H2afy1.1, an alternatively spliced isoform of the histone H2A variant gene H2afy, is responsible for reduced B cells in U2AF1(S34F) mice. Deletion of H2afy or expression of U2AF1(S34F) reduces expression of Ebf1 (early B cell factor 1), a key transcription factor for B cell development, and mechanistically, H2AFY is enriched at the EBF1 promoter. Induced expression of H2AFY1.1 in U2AF1(S34F) cells rescues reduced EBF1 expression and B cells numbers in vivo. Collectively, our data implicate alternative splicing of H2AFY as a contributor to lymphopenia induced by U2AF1(S34F) in mice and MDS.
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http://dx.doi.org/10.1016/j.celrep.2021.109626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454217PMC
August 2021

Pan-drug resistant contributing to a fatal case of COVID-19.

J Med Microbiol 2021 Aug;70(8)

Infectious Disease Service, Brooke Army Medical Center, San Antonio, Texas, USA.

Following prolonged hospitalization that included broad-spectrum antibiotic exposure, a strain of was cultured from the blood of a patient undergoing extracorporeal membrane oxygenation treatment for hypoxic respiratory failure due to COVID-19. The strain was resistant to all antimicrobials tested including the novel siderophore cephalosporin, cefiderocol. Whole genome sequencing detected ten antimicrobial resistance genes, including the metallo-β-lactamase , the extended-spectrum β-lactamase , and the rare 16S methyltransferase .
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http://dx.doi.org/10.1099/jmm.0.001406DOI Listing
August 2021

Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia.

NPJ Precis Oncol 2021 Jul 23;5(1):71. Epub 2021 Jul 23.

Computational Oncology, Sage Bionetworks, Seattle, WA, USA.

The FDA recently approved eight targeted therapies for acute myeloid leukemia (AML), including the BCL-2 inhibitor venetoclax. Maximizing efficacy of these treatments requires refining patient selection. To this end, we analyzed two recent AML studies profiling the gene expression and ex vivo drug response of primary patient samples. We find that ex vivo samples often exhibit a general sensitivity to (any) drug exposure, independent of drug target. We observe that this "general response across drugs" (GRD) is associated with FLT3-ITD mutations, clinical response to standard induction chemotherapy, and overall survival. Further, incorporating GRD into expression-based regression models trained on one of the studies improved their performance in predicting ex vivo response in the second study, thus signifying its relevance to precision oncology efforts. We find that venetoclax response is independent of GRD but instead show that it is linked to expression of monocyte-associated genes by developing and applying a multi-source Bayesian regression approach. The method shares information across studies to robustly identify biomarkers of drug response and is broadly applicable in integrative analyses.
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http://dx.doi.org/10.1038/s41698-021-00209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302655PMC
July 2021

Optical Detection of Intracranial Pressure and Perfusion Changes in Neonates With Hydrocephalus.

J Pediatr 2021 Sep 15;236:54-61.e1. Epub 2021 May 15.

Division of Neurology, Department of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania. Electronic address:

Objective: To demonstrate that a novel noninvasive index of intracranial pressure (ICP) derived from diffuse optics-based techniques is associated with intracranial hypertension.

Study Design: We compared noninvasive and invasive ICP measurements in infants with hydrocephalus. Infants born term and preterm were eligible for inclusion if clinically determined to require cerebrospinal fluid (CSF) diversion. Ventricular size was assessed preoperatively via ultrasound measurement of the fronto-occipital (FOR) and frontotemporal (FTHR) horn ratios. Invasive ICP was obtained at the time of surgical intervention with a manometer. Intracranial hypertension was defined as invasive ICP ≥15 mmHg. Diffuse optical measurements of cerebral perfusion, oxygen extraction, and noninvasive ICP were performed preoperatively, intraoperatively, and postoperatively. Optical and ultrasound measures were compared with invasive ICP measurements, and their change in values after CSF diversion were obtained.

Results: We included 39 infants, 23 with intracranial hypertension. No group difference in ventricular size was found by FOR (P = .93) or FTHR (P = .76). Infants with intracranial hypertension had significantly higher noninvasive ICP (P = .02) and oxygen extraction fraction (OEF) (P = .01) compared with infants without intracranial hypertension. Increased cerebral blood flow (P = .005) and improved OEF (P < .001) after CSF diversion were observed only in infants with intracranial hypertension.

Conclusions: Noninvasive diffuse optical measures (including a noninvasive ICP index) were associated with intracranial hypertension. The findings suggest that impaired perfusion from intracranial hypertension was independent of ventricular size. Hemodynamic evidence of the benefits of CSF diversion was seen in infants with intracranial hypertension. Noninvasive optical techniques hold promise for aiding the assessment of CSF diversion timing.
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http://dx.doi.org/10.1016/j.jpeds.2021.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403158PMC
September 2021

Surgical Treatment of Upper Extremity Segmental Myoclonus in an Adolescent with Chiari Malformation and Cervicothoracic Syrinx.

Pediatr Neurosurg 2021 11;56(4):373-378. Epub 2021 May 11.

Division of Neurosurgery, Department of Neurosurgery, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Background: Myoclonus is an involuntary movement disorder characterized by semirhythmic jerking movements of muscle groups but is rarely seen in association with Chiari malformation type I (CM-1). CM-1 is a frequently encountered clinical entity in pediatric neurosurgery characterized by caudal displacement of the cerebellar tonsils with or without syringomyelia. We report a pediatric patient who presented with upper extremity myoclonus and was found to have CM-1 and a complex septated cervicothoracic syrinx eccentric to the left.

Case Presentation: A 12-year-old female presented with 6 months of headaches and upper extremity paresthesias who subsequently developed a left upper extremity segmental myoclonus after a fall. MRI demonstrated a CM-1 and a large complex cervicothoracic syrinx with a midline and left paracentral cavities. Her myoclonus was nonepileptic and refractory to clonazepam, cyclobenzaprine, and gabapentin. She underwent an intradural Chiari decompression and duraplasty. Postoperatively, she had complete resolution of her segmental myoclonus.

Discussion: This case demonstrates a durable resolution of posttraumatic upper extremity segmental myoclonus after surgical decompression of a CM-1 with syringomyelia. Thus, Chiari decompression should be considered in cases of myoclonus with CM-1 and syringomyelia.
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http://dx.doi.org/10.1159/000515519DOI Listing
May 2021

Effects of circulatory arrest and cardiopulmonary bypass on cerebral autoregulation in neonatal swine.

Pediatr Res 2021 May 4. Epub 2021 May 4.

Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Background: Cerebral autoregulation mechanisms help maintain adequate cerebral blood flow (CBF) despite changes in cerebral perfusion pressure. Impairment of cerebral autoregulation, during and after cardiopulmonary bypass (CPB), may increase risk of neurologic injury in neonates undergoing surgery. In this study, alterations of cerebral autoregulation were assessed in a neonatal swine model probing four perfusion strategies.

Methods: Neonatal swine (n = 25) were randomized to continuous deep hypothermic cardiopulmonary bypass (DH-CPB, n = 7), deep hypothermic circulatory arrest (DHCA, n = 7), selective cerebral perfusion (SCP, n = 7) at deep hypothermia, or normothermic cardiopulmonary bypass (control, n = 4). The correlation coefficient (LDx) between laser Doppler measurements of CBF and mean arterial blood pressure was computed at initiation and conclusion of CPB. Alterations in cerebral autoregulation were assessed by the change between initial and final LDx measurements.

Results: Cerebral autoregulation became more impaired (LDx increased) in piglets that underwent DH-CPB (initial LDx: median 0.15, IQR [0.03, 0.26]; final: 0.45, [0.27, 0.74]; p = 0.02). LDx was not altered in those undergoing DHCA (p > 0.99) or SCP (p = 0.13). These differences were not explained by other risk factors.

Conclusions: In a validated swine model of cardiac surgery, DH-CPB had a significant effect on cerebral autoregulation, whereas DHCA and SCP did not.

Impact: Approximately half of the patients who survive neonatal heart surgery with cardiopulmonary bypass (CPB) experience neurodevelopmental delays. This preclinical investigation takes steps to elucidate and isolate potential perioperative risk factors of neurologic injury, such as impairment of cerebral autoregulation, associated with cardiac surgical procedures involving CPB. We demonstrate a method to characterize cerebral autoregulation during CPB pump flow changes in a neonatal swine model of cardiac surgery. Cerebral autoregulation was not altered in piglets that underwent deep hypothermic circulatory arrest (DHCA) or selective cerebral perfusion (SCP), but it was altered in piglets that underwent deep hypothermic CBP.
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http://dx.doi.org/10.1038/s41390-021-01525-3DOI Listing
May 2021

Variability in atlas registration of optical intrinsic signal imaging and its effect on functional connectivity analysis.

J Opt Soc Am A Opt Image Sci Vis 2021 Feb;38(2):245-252

To compare neuroimaging data between subjects, images from individual sessions need to be aligned to a common reference or "atlas." Atlas registration of optical intrinsic signal imaging of mice, for example, is commonly performed using affine transforms with parameters determined by manual selection of canonical skull landmarks. Errors introduced by such procedures have not previously been investigated. We quantify the variability that arises from this process and consequent errors from misalignment that affect interpretation of functional neuroimaging data. We propose an improved method, using separately acquired high-resolution images and demonstrate improvements in variability and alignment using this method.
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http://dx.doi.org/10.1364/JOSAA.410447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993363PMC
February 2021

Venous Flow Variation Predicts Preoperative Pulmonary Venous Obstruction in Children with Total Anomalous Pulmonary Venous Connection.

J Am Soc Echocardiogr 2021 Jul 16;34(7):775-785. Epub 2021 Feb 16.

Division of Pediatric Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Identifying preoperative pulmonary venous obstruction in total anomalous pulmonary venous connection is important to guide treatment planning and risk prognostication. No standardized echocardiographic definition of obstruction exists in the literature. Definitions based on absolute velocities are affected by technical limitations and variations in pulmonary venous return. The authors developed a metric to quantify pulmonary venous blood flow variation: pulmonary venous variability index (PVVI). The aim of this study was to demonstrate its accuracy in defining obstruction.

Methods: All patients with total anomalous pulmonary venous connection at a single institution were identified. Echocardiograms were reviewed, and maximum (V), mean (V), and minimum (V) velocities along the pulmonary venous pathway were measured. PVVI was defined as (V - V)/V. These metrics were compared with pressures measured on cardiac catheterization. Echocardiographic measures were then compared between patients with and without clinical preoperative obstruction (defined as a need for preoperative intubation, catheter-based intervention, or surgery within 1 day of diagnosis), as well as pulmonary edema by chest radiography and markers of lactic acidosis. One hundred thirty-seven patients were included, with 22 having catheterization pressure recordings.

Results: V and V were not different between patients with catheter gradients ≥ 4 and < 4 mm Hg, while PVVI was significantly lower and V higher in those with gradients ≥ 4 mm Hg. The composite outcome of preoperative obstruction occurred in 51 patients (37%). Absolute velocities were not different between patients with and without clinical obstruction, while PVVI was significantly lower in patients with obstruction. All metrics except V were associated with pulmonary edema; none were associated with blood gas metrics.

Conclusions: The authors developed a novel quantitative metric of pulmonary venous flow, which was superior to traditional echocardiographic metrics. Decreased PVVI was highly associated with elevated gradients measured by catheterization and clinical preoperative obstruction. These results should aid risk assessment and diagnosis preoperatively in patients with total anomalous pulmonary venous connection.
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http://dx.doi.org/10.1016/j.echo.2021.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263465PMC
July 2021

Wavelength censoring for spectroscopy in optical functional neuroimaging.

Phys Med Biol 2021 03 12;66(6):065026. Epub 2021 Mar 12.

Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104, United States of America.

Optical neuromonitoring provides insight into neurovascular physiology and brain structure and function. These methods rely on spectroscopy to relate light absorption changes to variation of concentrations of physiologic chromophores such as oxy- and deoxyhemoglobin. In clinical or preclinical practice, data quality can vary significantly across wavelengths. In such situations, standard spectroscopic methods may perform poorly, resulting in data loss and limiting field-of-view. To address this issue, and thereby improve the robustness of optical neuromonitoring, we develop, in this manuscript, novel methods to perform spectroscopy even when data quality exhibits wavelength-dependent spatial variation. We sought to understand the impact of spatial, wavelength-based censoring on the physiologic accuracy and utility of hemoglobin spectroscopy. The principles of our analysis are quite general, but to make the methodology tangible we focused on optical intrinsic signal imaging of resting-state functional connectivity in mice. Starting with spectroscopy using four sources, all possible subset spectroscopy matrices were assessed theoretically, using simulated data, and using experimental data. These results were compared against the use of the full spectroscopy matrix to determine which subsets yielded robust results. Our results demonstrated that accurate calculation of changes in hemoglobin concentrations and the resulting functional connectivity network maps was possible even with censoring of some wavelengths. Additionally, we found that the use of changes in total hemoglobin (rather than oxy- or deoxyhemoglobin) yielded results more robust to experimental noise and allowed for the preservation of more data. This new and rigorous image processing method should improve the fidelity of clinical and preclinical functional neuroimaging studies.
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http://dx.doi.org/10.1088/1361-6560/abd418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059274PMC
March 2021

Patient Awareness of Reported Adverse Effects Associated with Proton Pump Inhibitors in a Medically Underserved Community.

Healthcare (Basel) 2020 Nov 19;8(4). Epub 2020 Nov 19.

Department of Biomedical Sciences, Cooper Medical School of Rowan University, 401 S Broadway, Camden, NJ 08103, USA.

Reports of adverse effects associated with proton pump inhibitors (PPIs) are concerning because of high usage and over-the-counter availability. We sought to determine the awareness of PPI adverse effects among our patient population, which is medically underserved, low-income, and racially diverse. A 21-item survey was administered to gastroenterology-clinic outpatients. It collected information about age, gender, education, race, specialty of the prescriber, specific PPI, indication, knowledge of dose, adherence, duration of use and awareness of any risks. Medical records were reviewed to verify survey responses pertaining to indication, dosing, and adherence. A vast majority (96%) of 101 participants were not aware of PPI adverse effects. In total, 63% of the patients completed a high school education or less, which was associated with a higher risk of long-term PPI use than completion of at least an undergraduate degree ( = 0.05). In contrast to other studies, the shockingly low patient awareness about PPI adverse effects in our patient population is particularly concerning, especially as it is tied to their demographic attributes. This may lead to long-term and high-dose PPI use. Our study highlights the need for effective provider-driven education regarding medication risks, especially in the communities with significant health disparities.
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http://dx.doi.org/10.3390/healthcare8040499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712036PMC
November 2020

Fatal Isoniazid Hepatotoxicity in the Deployed Environment.

Mil Med 2021 05;186(5-6):619-622

Craig Joint Theater Hospital, 455th Expeditionary Medical Group, Bagram, AE 09354, Afghanistan.

Deployed clinicians have limited resources at their disposal to augment medical decision-making and management. All deploying personnel undergo predeployment medical assessment to evaluate their fitness for deployment. The purpose of predeployment screening is to allow for anticipation of medical needs that may arise which could challenge the available medical resources in an expeditionary environment. Medical standards for deployment are published, identifying disqualifying conditions and medications. A history of latent tuberculosis infection is not disqualifying for deployment. Isoniazid is not specifically mentioned as a disqualifying medication, though it is well known to have the potential of causing drug-induced liver injury. Here, a case of fatal isoniazid-induced drug-induced liver injury in a deployed setting is presented with a review of current latent tuberculosis infection literature. Our goal is for the reader to form their own opinion whether or not isoniazid should be used in the forward environment.
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http://dx.doi.org/10.1093/milmed/usaa414DOI Listing
May 2021

Editorial Commentary: No Longer a Salvage Procedure: Allograft Labral Reconstruction of the Hip Rivals the Results of Labral Repair.

Authors:
Brian J White

Arthroscopy 2020 10;36(10):2611-2613

Denver, Colorado.

In the past 5 years, arthroscopic labral reconstruction of the hip has rapidly evolved from a salvage procedure used primarily in the setting of multiple failed prior hip surgical procedures to an alternative, and even preferable, primary treatment option for labral pathology and femoroacetabular impingement. As opposed to labral repair, labral reconstruction allows for complete removal of all damaged, pain-generating tissue; optimal correction of underlying bony impingement; and consistent creation of a graft that appropriately restores the fluid hip seal, improves pressurization and stabilization, and decreases contact pressure. Allograft tissue, in particular, allows for accurate and reliable graft length creation and does not rely on native tissue quality. Hips that undergo labral reconstruction have been shown to have positive outcomes at minimum 2-year follow-up, despite the fact that in many cases, these hips have more damage and a poorer preoperative prognosis. Patients report decreased pain, increased function, and greater quality of life after labral reconstruction, and this new evidence suggests that they can resume high-level physical activity as well. Circumferential labral reconstruction is no longer a salvage procedure and is an important tool for the hip arthroscopist; however, it requires high proficiency in hip arthroscopy to perform.
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http://dx.doi.org/10.1016/j.arthro.2020.06.027DOI Listing
October 2020

The clonal evolution of metastatic colorectal cancer.

Sci Adv 2020 Jun 10;6(24):eaay9691. Epub 2020 Jun 10.

The Alvin J. Siteman Comprehensive Cancer Center, Washington University in St. Louis, St. Louis, MO, USA.

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.
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http://dx.doi.org/10.1126/sciadv.aay9691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286679PMC
June 2020

Novel Miniaturized Drug Conjugate Leverages HSP90-driven Tumor Accumulation to Overcome PI3K Inhibitor Delivery Challenges to Solid Tumors.

Mol Cancer Ther 2020 08 4;19(8):1613-1622. Epub 2020 Jun 4.

Tarveda Therapeutics Inc, Watertown, Massachusetts.

The PI3K pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target for pharmacologic intervention. While substantial efforts have been made to develop drugs targeting PI3K signaling, few drugs have been able to achieve the inhibition necessary for effective tumor control at tolerated doses. HSP90 is a chaperone protein that is overexpressed and activated in many tumors and as a consequence, small-molecule ligands of HSP90 are preferentially retained in tumors up to 20 times longer than in normal tissue. We hypothesize that the generation of conjugates that use a HSP90-targeting ligand and a payload such as copanlisib, may open the narrow therapeutic window of this and other PI3K inhibitors. In support of this hypothesis, we have generated a HSP90-PI3K drug conjugate, T-2143 and utilizing xenograft models, demonstrate rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy than the PI3K inhibitor on its own. Selective delivery of T-2143 and the masking of the inhibitor active site was also able to mitigate a potentially dose-limiting side effect of copanlisib, hyperglycemia. These data demonstrate that by leveraging the preferential accumulation of HSP90-targeting ligands in tumors, we can selectively deliver a PI3K inhibitor leading to efficacy in multiple tumor models without hyperglycemia in mice. These data highlight a novel drug delivery strategy that allows for the potential opening of a narrow therapeutic window through specific tumor delivery of anticancer payloads and reduction of toxicity.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0964DOI Listing
August 2020

Hip Arthroscopy in Patients Aged 40 Years and Older: Greater Success With Labral Reconstruction Compared With Labral Repair.

Arthroscopy 2020 08 28;36(8):2137-2144. Epub 2020 Apr 28.

Professional Research Institute for Sports Medicine, Chapel Hill, North Carolina, U.S.A.

Purpose: To assess the outcomes of complete, primary, arthroscopic hip labral reconstruction among patients aged 40 years and older compared with those who underwent primary labral repair and compared with patients aged 30 to 39 years who underwent complete, primary labral reconstruction.

Methods: We recruited all patients who underwent arthroscopic labral reconstruction between March 2010 and June 2015 and were aged 30 to 65 years or who underwent arthroscopic labral repair between June 2009 and June 2015 and were aged 40 to 65 years. The modified Harris Hip Score (mHHS), Lower Extremity Function Score, and visual analog scale score for average pain were collected preoperatively and at minimum 2-year follow-up. Failure was defined as the need for revision ipsilateral hip surgery. The rate of conversion to total hip arthroplasty (a subset of failure) was assessed separately.

Results: A total of 363 hips in 343 patients met the inclusion criteria. Follow-up was available for 312 hips (86.0%), and the average time to follow-up was 4.2 years (range, 2.0-8.5 years). After adjustment for differences in follow-up time between groups, failure was 3.29 times more likely for hips in the repair group aged 40 years and older than for hips in the reconstruction group aged 40 years and older (relative rate, 3.29; 95% confidence interval, 1.25-8.69; P = .02), and there was no difference in the failure rate for hips in the reconstruction group aged 40 years and older compared with hips in the reconstruction group aged 30 to 39 years (relative rate, 0.58; 95% confidence interval, 0.18-1.89; P = .37). The rate of conversion to total hip arthroplasty was not meaningfully different between the 3 groups. Among hips for which treatment did not fail, average improvement in the mHHS measured 35 points and both labral reconstruction groups saw a greater mHHS improvement than the labral repair group of patients aged 40 years and older (P = .01 and P < .01).

Conclusions: Labral reconstruction led to a lower failure rate, greater average improvement in the mHHS, and equivalent postoperative patient-reported outcome scores compared with labral repair among patients aged 40 years and older in this study population, and the outcomes of labral reconstruction were similar between patients aged 40 years and older and those aged 30 to 39 years. Complete labral reconstruction may be particularly advantageous in patients aged 40 years and older.

Level Of Evidence: Level III, retrospective comparative study.
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http://dx.doi.org/10.1016/j.arthro.2020.04.031DOI Listing
August 2020

Multiple Myeloma DREAM Challenge reveals epigenetic regulator PHF19 as marker of aggressive disease.

Leukemia 2020 07 14;34(7):1866-1874. Epub 2020 Feb 14.

GNS Healthcare, Cambridge, MA, USA.

While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients does not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involves assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post-challenge analysis identified a novel expression-based risk marker, PHF19, which has recently been found to have an important biological role in multiple myeloma. Lastly, we show that a simple four feature predictor composed of age, ISS, and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included.
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http://dx.doi.org/10.1038/s41375-020-0742-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326699PMC
July 2020

Training and Certifying Users of the National Institutes of Health Stroke Scale.

Stroke 2020 03 28;51(3):990-993. Epub 2020 Jan 28.

Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.).

Background and Purpose- The National Institutes of Health Stroke Scale, designed and validated for use in clinical stroke trials, is now required for all patients with stroke at hospital admission. Recertification is required annually but no data support this frequency; the effect of mandatory training before recertification is unknown. Methods- To clarify optimal recertification frequency and training effect, we assessed users' mastery of the National Institutes of Health Stroke Scale over several years using correct scores (accuracy) on each scale item of the 15-point scale. We also constructed 9 technical errors that could result from misunderstanding the scoring rules. We measured accuracy and the frequency of these technical errors over time. Using multivariable regression, we assessed the effect of time, repeat testing, and profession on user mastery. Results- The final dataset included 1.3×10 examinations. Data were consistent among all 3 online vendors that provide training and certification. Test accuracy showed no significant changes over time. Technical error rates were remarkably low, ranging from 0.48 to 1.36 per 90 test items. Within 2 vendors (that do not require training), the technical error rates increased negligibly over time (<0.05). In data from a third vendor, mandatory training before recertification improved (reduced) technical errors but not accuracy. Conclusions- The data suggest that mastery of National Institutes of Health Stroke Scale scoring rules is stable over time, and the recertification interval should be lengthened. Mandatory retraining may be needed after unsuccessful recertifications, but not routinely otherwise.
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http://dx.doi.org/10.1161/STROKEAHA.119.027234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402267PMC
March 2020

Brain segmentation, spatial censoring, and averaging techniques for optical functional connectivity imaging in mice.

Biomed Opt Express 2019 Nov 29;10(11):5952-5973. Epub 2019 Oct 29.

Department of Physics and Astronomy, University of Pennsylvania. 3231 Walnut St., Philadelphia, PA 19104, USA.

Resting-state functional connectivity analysis using optical neuroimaging holds the potential to be a powerful bridge between mouse models of disease and clinical neurologic monitoring. However, analysis techniques specific to optical methods are rudimentary, and algorithms from magnetic resonance imaging are not always applicable to optics. We have developed visual processing tools to increase data quality, improve brain segmentation, and average across sessions with better field-of-view. We demonstrate improved performance using resting-state optical intrinsic signal from normal mice. The proposed methods increase the amount of usable data from neuroimaging studies, improve image fidelity, and should be translatable to human optical neuroimaging systems.
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http://dx.doi.org/10.1364/BOE.10.005952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865125PMC
November 2019

Recent advances in our understanding of neurodevelopmental outcomes in congenital heart disease.

Curr Opin Pediatr 2019 12;31(6):783-788

Department of Anesthesiology and Critical Care Medicine.

Purpose Of Review: Patients with congenital heart disease (CHD) suffer from a pattern of neurodevelopmental abnormalities including deficits in language and executive function. In this review, we summarize recent studies that examine these outcomes, their risk factors, possible biomarkers, and attempts to develop therapeutic interventions.

Recent Findings: The latest literature has highlighted the role of genetics in determining neurologic prognosis, as we have increased our understanding of potentially modifiable perioperative risk factors. The role of potentially neurotoxic medical therapies has become more salient. One recent focus has been how neurodevelopment affects quality of life and leads to a high prevalence of mental illness. Neuroimaging advances have provided new insights into the pathogenesis of deficits.

Summary: Although many risk factors in CHD are not modifiable, there is promise for interventions to improve neurodevelopmental outcomes in patients with CHD. Biomarkers are needed to better understand the timing and prognosis of injury and to direct therapy. Research into psychosocial interventions is urgently needed to benefit the many survivors with CHD.
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http://dx.doi.org/10.1097/MOP.0000000000000829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852883PMC
December 2019

Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer.

Mol Cancer Ther 2019 11;18(11):1926-1936

Tarveda Therapeutics Inc., Watertown, Massachusetts.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate with no improvement to treatment in decades, and new therapies are desperately needed. PEN-221 is a miniaturized peptide-drug conjugate (∼2 kDa) designed to target SCLC via a Somatostatin Receptor 2 (SSTR2)-targeting ligand and to overcome the high proliferation rate characteristic of this disease by using the potent cytotoxic payload, DM1. SSTR2 is an ideal target for a drug conjugate, as it is overexpressed in SCLC with limited normal tissue expression. , PEN-221 treatment of SSTR2-positive cells resulted in PEN-221 internalization and receptor-dependent inhibition of cellular proliferation. , PEN-221 exhibited rapid accumulation in SSTR2-positive SCLC xenograft tumors with quick clearance from plasma. Tumor accumulation was sustained, resulting in durable pharmacodynamic changes throughout the tumor, as evidenced by increases in the mitotic marker of G-M arrest, phosphohistone H3, and increases in the apoptotic marker, cleaved caspase-3. PEN-221 treatment resulted in significant antitumor activity, including complete regressions in SSTR2-positive SCLC xenograft mouse models. Treatment was effective using a variety of dosing schedules and at doses below the MTD, suggesting flexibility of dosing schedule and potential for a large therapeutic window in the clinic. The unique attributes of the miniaturized drug conjugate allowed for deep tumor penetration and limited plasma exposure that may enable long-term dosing, resulting in durable tumor control. Collectively, these data suggest potential for antitumor activity of PEN-221 in patients with SSTR2-positive SCLC.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0022DOI Listing
November 2019

A standardized imaging protocol improves quality and reduces practice variability in echocardiographic assessment of ventricular function by first-year pediatric cardiology fellows.

Echocardiography 2019 08 5;36(8):1515-1523. Epub 2019 Aug 5.

Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Background: Echocardiography education for pediatric cardiology fellows has been a recent focus leading to the implementation of "boot camps." Less is described about continuing education through fellowship and improving image quality. We noticed practice variation in echocardiograms assessing ventricular function performed on nights and weekends. Thus, we implemented a standardized protocol and assessed its impact on imaging and reporting completeness.

Methods: We created an imaging protocol for the assessment of ventricular function in the acute setting. The protocol included demographic information, a list of images to be obtained, and the methods to quantify ventricular function. The protocol was explained to first-year fellows and distributed on an electronic quick reference card. Echocardiograms independently performed by first-year fellows during their first 4 months of on-call time were assessed pre- and postintervention using a standard rubric.

Results: Compliance with demographic reporting was high pre- and postintervention, but significantly improved after the standardized protocol (P < 0.001). Use of the protocol increased the median number of unique images obtained per echocardiogram from 13 to 17 (out of 23 required views, P < 0.001). Particularly improved was the performance of quantitative evaluations of function, including Simpson's method for left ventricular ejection fraction (four chamber: 40% vs 67%, P < 0.001; two chamber: 33% vs 67%, P < 0.001) and tricuspid annular plane systolic excursion (45% vs 80%, P < 0.001).

Conclusions: The introduction of a standardized imaging protocol and its distribution to first-year fellows resulted in improvements in echocardiographic reporting completeness and increased the quality of information obtained by providing more quantitative assessments of ventricular function.
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http://dx.doi.org/10.1111/echo.14441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717032PMC
August 2019

Outbreak of cyclosporiasis in a U.S. Air Force training population, Joint Base San Antonio-Lackland, TX, 2018.

MSMR 2019 Jun;26(6):14-17

Diarrheal illnesses have an enormous impact on military operations in the deployed and training environments. While bacteria and viruses are the usual causes of gastrointestinal disease outbreaks, 2 Joint Base San Antonio-Lackland, TX, training populations experienced an outbreak of diarrheal illness caused by the parasite Cyclospora cayetanensis in June and July 2018. Cases were identified from outpatient medical records and responses to patient questionnaires. A confirmed case was defined by diarrhea and laboratory confirmation, and patients without a positive lab were classified as suspected cases. In cluster 1, 46 suspected and 7 confirmed cases occurred among technical training students who reported symptom onset from 12 June to 21 June. In cluster 2, 18 suspected and 14 confirmed cases in basic military training trainees reported symptom onset from 29 June to 8 July. Numerous lessons from cluster 1 were applied to cluster 2. Crucial lessons learned during this cyclosporiasis outbreak included the importance of maintaining clinical suspicion for cyclosporiasis in persistent gastrointestinal illness and obtaining confirmatory laboratory testing for expedited diagnosis and treatment.
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June 2019

Superior colliculus encodes visual saliency during smooth pursuit eye movements.

Eur J Neurosci 2019 May 11. Epub 2019 May 11.

Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.

The saliency map has played a long-standing role in models and theories of visual attention, and it is now supported by neurobiological evidence from several cortical and subcortical brain areas. While visual saliency is computed during moments of active fixation, it is not known whether the same is true while engaged in smooth pursuit of a moving stimulus, which is very common in real-world vision. Here, we examined extrafoveal saliency coding in the superior colliculus, a midbrain area associated with attention and gaze, during smooth pursuit eye movements. We found that SC neurons from the superficial visual layers showed a robust representation of peripheral saliency evoked by a conspicuous stimulus embedded in a wide-field array of goal-irrelevant stimuli. In contrast, visuomotor neurons from the intermediate saccade-related layers showed a poor saliency representation, even though most of these neurons were visually responsive during smooth pursuit. These results confirm and extend previous findings that place the SCs in a unique role as a saliency map that monitors peripheral vision during foveation of stationary and now moving objects.
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http://dx.doi.org/10.1111/ejn.14432DOI Listing
May 2019

Echocardiographic Assessment of Diastolic Function in Children with Incident Systemic Lupus Erythematosus.

Pediatr Cardiol 2019 Jun 30;40(5):1017-1025. Epub 2019 Apr 30.

Division of Cardiology, Children's Hospital of Philadelphia, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.

The timing and etiology of diastolic impairment in pediatric-onset systemic lupus erythematosus (SLE) are poorly understood. We compared echocardiographic metrics of left ventricular diastolic function in children at SLE diagnosis to controls and identified factors associated with diastolic indices. Echocardiograms of children aged 5-18 years within 1 year of SLE diagnosis and age-/sex-matched controls were retrospectively read by blinded cardiologists. Clinical characteristics were abstracted separately. Z-scores for diastolic indices (E/A, e', E/e', and isovolumetric relaxation time (IVRT)) were calculated using published normative data and study controls, and compared using linear mixed-effects models adjusted for blood pressure. Pericardial effusions and valvular disease were also evaluated. Linear regression was used to identify factors associated with diastolic measures. 85 children with incident SLE had echocardiograms performed a median of 6 days after diagnosis (interquartile range (IQR) 1-70). Prior cumulative prednisone exposure was minimal (median 60 mg, IQR 0-1652). SLE cases had lower E/A, lower e', higher E/e', and longer IVRT compared to controls. Though none met criteria for Grade I diastolic dysfunction, Z-scores for e', E/e', and IVRT were abnormal in 30%, 25%, and 6% of SLE cases, respectively. Greater disease activity was associated with lower septal e' (p < 0.01), higher E/e' (p = 0.02), and longer IVRT (p < 0.01). Children with incident SLE have worse diastolic indices at diagnosis compared to peers without SLE, independent of blood pressure and prior to significant prednisone exposure. Longitudinal studies will determine whether diastolic dysfunction develops in this population over time.
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http://dx.doi.org/10.1007/s00246-019-02107-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093038PMC
June 2019

Echocardiographic Assessment of Right Ventricular Function in Clinically Well Pediatric Heart Transplantation Patients and Comparison With Normal Control Subjects.

J Am Soc Echocardiogr 2019 04;32(4):537-544.e3

Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Echocardiographic follow-up after pediatric heart transplantation is important because of the lifelong risk for rejection and resultant ventricular dysfunction. Although adult studies have shown that echocardiographic measures of right ventricular function are changed after transplantation, similar results have not been reported in the pediatric population.

Methods: A single-center retrospective study of echocardiograms obtained among pediatric heart transplant recipients was conducted. All echocardiograms were selected remote from transplantation, rejection, or graft vasculopathy. These criteria identified 127 patients. Right ventricular systolic function was measured using tricuspid annular plane systolic excursion, fractional area change (FAC), and peak systolic tricuspid annular tissue velocity (S'). Results were compared with those in 380 healthy age-matched echocardiographic control subjects.

Results: Tricuspid annular plane systolic excursion values in pediatric heart transplant recipients were significantly lower than in control subjects at all ages (P < .0001), with a mean Z score of -3.38. FAC and S' did not vary by age in control patients >6 months of age. FAC values in transplantation patients were significantly decreased compared with those in control subjects (P < .0001), but 83% of transplantation patients had FAC values within the control-derived normal range. S' values were also significantly lower in transplantation patients than control subjects (P < .0001).

Conclusions: Heart transplantation patients have significantly decreased quantitative metrics of right ventricular function relative to healthy control subjects; longitudinal shortening (tricuspid annular plane systolic excursion and S') is particularly affected. FAC is relatively preserved and may be a better metric in this population. These results establish nomograms of RV function in pediatric heart transplantation patients and in normal pediatric control subjects, which may allow quantification of changes in this vulnerable population.
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http://dx.doi.org/10.1016/j.echo.2019.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452881PMC
April 2019

Repair of Total Anomalous Pulmonary Venous Connection: Risk Factors for Postoperative Obstruction.

Ann Thorac Surg 2019 07 16;108(1):122-129. Epub 2019 Mar 16.

Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Pulmonary venous obstruction after repair of total anomalous pulmonary venous connection (TAPVC) results in substantial morbidity and mortality. Risk factors for postoperative obstruction remain ambiguous. In addition, the existing literature has no standard definition for preoperative obstruction, making patient counseling difficult.

Methods: All patients undergoing repair of TAPVC at our institution from January 1, 2006, to October 23, 2017, were identified. The primary outcome was the development of postoperative obstruction, analyzed as a time-to-event outcome. Clinical information was extracted to assess risk factors. Degrees of preoperative obstruction were defined based on echocardiographic, catheterization, and clinical findings. Univariable and multivariable Cox proportional hazard regression methods were used to identify factors associated with the primary outcome.

Results: During the study interval, 119 patients underwent repair of TAPVC (40% single ventricle), and postoperative obstruction developed in 25 patients (21%). Risk factors associated with obstruction were heterotaxy syndrome, single-ventricle heart disease, additional procedures at the time of vein repair, mixed-type TAPVC, and preoperative obstruction. Having even mild preoperative obstruction (≥1.2 m/s by Doppler echocardiography) was predictive of postoperative obstruction. A multivariable model showed mixed-type TAPVC and the presence of preoperative obstruction were associated with a more than twofold greater hazard of obstruction.

Conclusions: TAPVC in the setting of heterotaxy and a single ventricle remains challenging, with high rates of postoperative obstruction. Mixed-type TAPVC is an independent risk factor for postoperative obstruction, particularly in patients with isolated TAPVC. Even mild preoperative obstruction is a risk factor for postoperative obstruction. These results may help risk-stratify TAPVC patients.
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http://dx.doi.org/10.1016/j.athoracsur.2019.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591098PMC
July 2019

Teaching Antimicrobial Stewardship to Infectious Disease Fellows Through Simulated Interdisciplinary Scenarios.

MedEdPORTAL 2018 03 16;14:10693. Epub 2018 Mar 16.

Infectious Disease Specialist, Brooke Army Medical Center.

Introduction: While several approaches have been described to teach antimicrobial stewardship (AS) practices, fewer have been aimed at infectious disease physicians. We developed a series of simulated AS meetings to train infectious disease fellows in the synthesis of AS interventions.

Methods: Three simulated AS committee scenarios were developed. Background lectures were given 1 week prior to the simulation during which multidisciplinary roles were assigned. Precourse work included review of primary literature pertinent to the scenario. Simulations were conducted over 1.5 hours. Individual and team performances were evaluated. Pre- and postsurveys were collected from fellows and faculty members to assess the format.

Results: Six infectious disease fellows participated in the series. Fellows demonstrated information synthesis and improvements in individual and team performance. Eighty-three percent of fellows before the simulation series and 100% postseries reported educating others on AS principles in the previous month. Fellows were satisfied with the series and requested more scenarios. Eight faculty members completed surveys. Thirty-eight percent of faculty before the series and 63% after completion reported that fellows viewed antimicrobial preauthorization as useful or necessary. Faculty supported the format, found it useful in evaluation of learners, and perceived that fellows benefited from the approach.

Discussion: Simulation is an effective and enjoyable way to train infectious disease fellows in AS and team utilization. Fellows demonstrated improvement in AS knowledge, skills, and attitudes and developed evidence-based interdisciplinary plans to solve AS challenges. Faculty also viewed this strategy as effective and sustainable.
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http://dx.doi.org/10.15766/mep_2374-8265.10693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342414PMC
March 2018

Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo.

J Med Chem 2019 03 28;62(5):2708-2719. Epub 2019 Feb 28.

Tarveda Therapeutics , 134 Coolidge Avenue , Watertown , Massachusetts 02472 , United States.

Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein, we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2-targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr-octreotate. PEN-221 demonstrates in vitro activity which is both potent (IC = 10 nM) and receptor-dependent (IC shifts 90-fold upon receptor blockade). PEN-221 targets high levels of DM1 to SSTR2-expressing xenograft tumors, which has led to tumor regressions in several SSTR2-expressing xenograft mouse models. The safety and efficacy of PEN-221 is currently under evaluation in human clinical trials.
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http://dx.doi.org/10.1021/acs.jmedchem.8b02036DOI Listing
March 2019

Physical and Mental Health of US Air Force Military Training Instructors.

Mil Med 2019 05;184(5-6):e248-e254

Military Training Consult Service, 737th Training Group, 1618 Truemper Street, JBSA-Lackland, TX.

Introduction: Many epidemiologic studies have been performed in military recruit populations, but little is known about the health of those who conduct the training. This study aims to characterize the physical and mental health of a military trainer cohort.

Materials And Methods: All US Air Force military training instructors (MTIs) who served between 1 October 2011 and 30 September 2016 were included in this retrospective descriptive study. All International Classification of Diseases, Ninth or Tenth Revision codes received by MTIs as inpatients or outpatients in the TRICARE system were obtained and mapped to Clinical Classifications Software levels. After excluding routine and administrative codes, the relative burden of disease by diagnostic category and subcategory was calculated, with further classification of musculoskeletal conditions by anatomic site. For all conditions accounting for at least 1.0% of the burden of care, incidence density rates and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated to compare males and females.

Results: A total of 1,269 MTIs received 32,601 non-administrative, non-routine diagnoses while accumulating 50,376 person-months of exposure during the surveillance period. Musculoskeletal conditions were the greatest contributor to overall disease burden, accounting for 39.1% of all diagnoses, followed by mental health (10.4%), respiratory (10.1%), and neurologic and sensory (9.8%). The burden attributed to mental health conditions decreased by 54% over the 5-year period. Twenty-three conditions accounted for at least 1.0% of the healthcare burden. The highest incidence conditions were connective tissue disease (27.18 per 1,000 person-months), non-traumatic joint disorders (25.74), upper respiratory infections (25.14), and back pain (23.70). As compared to males, females had a higher incidence of several conditions, including adjustment disorders (IRR: 2.57; 95% CI: 1.61, 4.11) and anxiety disorders (IRR: 2.24; 95% CI: 1.33, 3.77).

Conclusions: Musculoskeletal conditions are the leading contributor to burden of care among US Air Force MTIs, followed by mental health, respiratory, and neurologic and sensory conditions. The burden of healthcare among US Air Force MTIs more closely resembles active component service members than recruit trainees.
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http://dx.doi.org/10.1093/milmed/usy418DOI Listing
May 2019
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