The Effect of Hearing-Protection Devices on Auditory Situational Awareness and Listening Effort.

OBJECTIVES: Hearing-protection devices (HPDs) are made available, and often are required, for industrial use as well as military training exercises and operational duties. However, these devices often are disliked, and consequently not worn, in part because they compromise situational awareness through reduced sound detection and localization performance as well as degraded speech intelligibility. In this study, we carried out a series of tests, involving normal-hearing subjects and multiple background-noise conditions, designed to evaluate the performance of four HPDs in terms of their modifications of auditory-detection thresholds, sound-localization accuracy, and speech intelligibility. In addition, we assessed their impact on listening effort to understand how the additional effort required to perceive and process auditory signals while wearing an HPD reduces available cognitive resources for other tasks. DESIGN: Thirteen normal-hearing subjects participated in a protocol, which included auditory tasks designed to measure detection and localization performance, speech intelligibility, and cognitive load. Each participant repeated the battery of tests with unoccluded ears and four hearing protectors, two active (electronic) and two passive. The tasks were performed both in quiet and in background noise. RESULTS: Our findings indicate that, in variable degrees, all of the tested HPDs induce performance degradation on most of the conducted tasks as compared to the open ear. Of particular note in this study is the finding of increased cognitive load or listening effort, as measured by visual reaction time, for some hearing protectors during a dual-task, which added working-memory demands to the speech-intelligibility task. CONCLUSIONS: These results indicate that situational awareness can vary greatly across the spectrum of HPDs, and that listening effort is another aspect of performance that should be considered in future studies. The increased listening effort induced by hearing protectors may lead to earlier cognitive fatigue in noisy environments. Further study is required to characterize how auditory performance is limited by the combination of hearing impairment and the use of HPDs, and how the effects of such limitations can be linked to safe and effective use of hearing protection to maximize job performance.

Measured body composition and geometrical data of four "virtual family" members for thermoregulatory modeling.

The purpose of this paper is to develop a database of tissue composition, distribution, volume, surface area, and skin thickness from anatomically correct human models, the virtual family. These models were based on high-resolution magnetic resonance imaging (MRI) of human volunteers, including two adults (male and female) and two children (boy and girl). In the segmented image dataset, each voxel is associated with a label which refers to a tissue type that occupies up that specific cubic millimeter of the body. The tissue volume was calculated from the number of the voxels with the same label. Volumes of 24 organs in body and volumes of 7 tissues in 10 specific body regions were calculated. Surface area was calculated from the collection of voxels that are touching the exterior air. Skin thicknesses were estimated from its volume and surface area. The differences between the calculated and original masses were about 3 % or less for tissues or organs that are important to thermoregulatory modeling, e.g., muscle, skin, and fat. This accurate database of body tissue distributions and geometry is essential for the development of human thermoregulatory models. Data derived from medical imaging provide new effective tools to enhance thermal physiology research and gain deeper insight into the mechanisms of how the human body maintains heat balance.

Cost Comparison From a Patient Perspective for Intracranial Stereotactic Radiation Therapy.

PURPOSE: Historically, opaque health care pricing in the US has prevented patients from identifying opportunities to lower costs. Attempting to promote price transparency, the US government recently mandated that hospitals publish prices for all services in a document called a chargemaster. Patients often travel to tertiary centers for intracranial stereotactic radiation therapy (SRT), but cost comparison is complicated by multiple delivery systems and fractionation schemes. We hypothesized that prices published in chargemasters vary widely between SRT techniques and institutions. METHODS AND MATERIALS: We obtained chargemasters published online by National Cancer Institute-designated clinical centers. Technical charges for Gamma Knife single-fraction stereotactic radiosurgery (GK), single-fraction linear-accelerator stereotactic radiation surgery (SRS), and 3-fraction fractionated stereotactic radiation therapy (FSRT) were obtained from chargemasters by billing code and keyword searches. Prices were adjusted by the Medicare geographic cost price index (GPCI). Pairwise comparisons were conducted to compare prices between modalities and geographic regions. Relationships with cost index were examined using Spearman correlations, as was the price interrelationship between modalities across institutions. RESULTS: Of 62 chargemasters obtained, 58 listed SRT prices. Median prices were $49,529 for GK, $31,834 for FSRT, and $22,915 for SRS. Prices varied widely, with large ranges corresponding to 2 to 9 times the magnitude of median prices (GK, $111,298; FSRT, $312,480; and SRS, $104,396). Adjusting for GPCI, GK (P = .0003) and FSRT (P = .001) were more expensive than SRS, and no difference in price was noted between regions. The FSRT price was positively correlated with GPCI (P = .033), but prices for the other techniques were not. Modality prices were all positively correlated (all P < .001), meaning that institutions with prices greater than the median price for SRS were similarly expensive for GK and FSRT. CONCLUSIONS: Published prices for SRT vary by delivery system, fractionation, and institution without a clear explanation. Obtaining personalized price estimates may offer cost savings for patients. Policy changes encouraging reliable access to insurer-negotiated cost estimates for SRT are needed.

List Prices for Proton Radiation Therapy.

PURPOSE: Some patients elect for self-pay proton radiation therapy (PT) in the United States, but price transparency is a significant concern. The U.S. government recently declared that hospitals must provide a comprehensive list of "standard" charges for all services. Yet, the proportion of compliant proton centers is unknown, as is the extent to which prices vary nationally. METHODS AND MATERIALS: We obtained online chargemasters from U.S. proton centers. Technical charges for per fraction delivery of PT of varying complexity were obtained by billing code (77520, 77522, 77523, 77525) and keyword searches. Prices were adjusted for cost-of-living differences using the Medicare geographic cost price index. The relationship between prices for each PT billing code and cost of living was assessed. The interrelationship in cost between codes was examined. The effect of geographic region and other key variables on pricing was explored. RESULTS: Thirty-six proton centers were identified. Twenty-eight (78%) had accessible chargemasters with 20 (56%) listing at least one PT charge. The median prices for billing codes 77520, 77522, 77523, 77525 were $4707, $4712, $5904, and $6690, respectively, with a trend toward greater cost for more complex therapy (77523, 77525; P = .056). Large ranges ($16,863, $16,059, $18,414, $22,143) resulted in ratios of maximum/minimum prices of 5 to 10x. Only prices for code 77522 were associated with cost of living (P = .039). Across institutions, prices for all 4 codes were positively interrelated (all P < .0001). Prices differed between regions (P < .0001) but not by National Cancer Institute designation. CONCLUSIONS: List prices for PT differ dramatically between institutions and regions without obvious explanation, raising the concerning possibility that such variation is largely arbitrary. Policy solutions that promote rationalized pricing would greatly benefit this patient population.

Development of a Financial Toxicity Screening Tool for Radiation Oncology: A Secondary Analysis of a Pilot Prospective Patient-Reported Outcomes Study.

PURPOSE: Financial toxicity is highly prevalent in oncology. Early identification of at-risk patients is essential because financial toxicity is associated with inferior outcomes. Validated general oncology screening tools are cumbersome and not specific to challenges related to radiation therapy, such as daily treatments. In the population of radiation oncology patients, no standardized, validated, rapid screening tool exists. We sought to develop a rapid, no-cost, and reliable financial-toxicity screening tool for clinical radiation oncology. METHODS AND MATERIALS: We retrospectively analyzed data from a prospective survey study conducted at a large referral center with a heterogeneous population. Before treatment, a 25-item modified comprehensive survey for financial toxicity incorporating subjective and objective patient-reported measures was administered to identify factors linked to the risk of developing financial toxicity, which was defined as radiation therapy resulting in any of the following: loss of income, job, or spouse or difficulty paying for meals, housing, or transportation. We applied a logistic regression model with a stepwise, backward model selection procedure. Estimated probabilities of experiencing financial toxicity were computed using the inverse-logit transformation of the sum of patient-specific predictor values multiplied by the coefficients of the selected logistic regression model. The Youden index was used to determine a reasonable risk threshold. RESULTS: A total of 157 patients completed the questionnaire, and 34 (22%) were assessed as experiencing financial toxicity. The model retained 3 factors: age, money owed, and copayment-related worries. It resulted in a concordance statistic of 0.85, developed with a risk threshold of 18% (Youden index, 0.59). This model conferred a sensitivity of 89%, specificity of 70%, positive predictive value of 44%, and negative predictive value of 96%. CONCLUSIONS: Our proposed financial-toxicity screen is rapid, free, sensitive, and specific, and in this study, it identified early-onset, patient-reported financial toxicity after radiation therapy with just 3 simple variables: age, money owed, and copayment-related concerns. Future research steps should include a validation cohort and identification of interventions to mitigate financial toxicity.

Detecting Pathogen Exposure During the Non-symptomatic Incubation Period Using Physiological Data: Proof of Concept in Non-human Primates.

Background and Objectives: Early warning of bacterial and viral infection, prior to the development of overt clinical symptoms, allows not only for improved patient care and outcomes but also enables faster implementation of public health measures (patient isolation and contact tracing). Our primary objectives in this effort are 3-fold. First, we seek to determine the upper limits of early warning detection through physiological measurements. Second, we investigate whether the detected physiological response is specific to the pathogen. Third, we explore the feasibility of extending early warning detection with wearable devices. Research Methods: For the first objective, we developed a supervised random forest algorithm to detect pathogen exposure in the asymptomatic period prior to overt symptoms (fever). We used high-resolution physiological telemetry data (aortic blood pressure, intrathoracic pressure, electrocardiograms, and core temperature) from non-human primate animal models exposed to two viral pathogens: Ebola and Marburg (N = 20). Second, to determine reusability across different pathogens, we evaluated our algorithm against three independent physiological datasets from non-human primate models (N = 13) exposed to three different pathogens: Lassa and Nipah viruses and Y. pestis. For the third objective, we evaluated performance degradation when the algorithm was restricted to features derived from electrocardiogram (ECG) waveforms to emulate data from a non-invasive wearable device. Results: First, our cross-validated random forest classifier provides a mean early warning of 51 ± 12 h, with an area under the receiver-operating characteristic curve (AUC) of 0.93 ± 0.01. Second, our algorithm achieved comparable performance when applied to datasets from different pathogen exposures - a mean early warning of 51 ± 14 h and AUC of 0.95 ± 0.01. Last, with a degraded feature set derived solely from ECG, we observed minimal degradation - a mean early warning of 46 ± 14 h and AUC of 0.91 ± 0.001. Conclusion: Under controlled experimental conditions, physiological measurements can provide over 2 days of early warning with high AUC. Deviations in physiological signals following exposure to a pathogen are due to the underlying host's immunological response and are not specific to the pathogen. Pre-symptomatic detection is strong even when features are limited to ECG-derivatives, suggesting that this approach may translate to non-invasive wearable devices.

MicroRNA-206 Downregulation Improves Therapeutic Gene Expression and Motor Function in mdx Mice.

Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by a mutation in the dystrophin gene. Numerous gene therapies have been developed to replace or repair the defective dystrophin gene; however, these treatments cannot restore the full-length protein or completely resolve dystrophic symptoms. Secondary pathological mechanisms, such as functional ischemia and fibrosis, are thought to exacerbate the primary defect and cause the profound muscle degeneration found in dystrophic muscle. Surrogate therapies utilizing alternative therapeutic genes, or "booster genes," such as VEGFA and utrophin, seek to address these secondary mechanisms and have shown impressive benefit in mdx mice. A skeletal muscle-specific microRNA, miR-206, is particularly overexpressed in dystrophic muscle and inhibits the expression of known booster genes. Thus, we aimed to determine if miR-206 contributes to dystrophic pathology by repressing beneficial gene expression. Here, we show that AAV-mediated expression of a miR-206 decoy target effectively downregulated miR-206 expression and increased endogenous therapeutic gene expression in mature mdx muscle. Furthermore, treatment significantly improved motor function and dystrophic pathology in mdx mice. In summary, we have identified a contributing factor to the dystrophic phenotype and characterized a novel therapeutic avenue for DMD.

Patients Undergoing Radiation Therapy Are at Risk of Financial Toxicity: A Patient-based Prospective Survey Study.

PURPOSE: Little is known about the financial burden experienced by patients receiving radiation therapy. Furthermore, currently, no financial toxicity screening tools have been validated for use in radiation oncology. METHODS AND MATERIALS: Physician surveys were used to gauge provider understanding of treatment costs and their willingness to adopt the use of financial toxicity screening tools. Post-treatment patient surveys were used to investigate the covariates of treatment-induced financial risk. RESULTS: Of the 210 radiation oncologists who completed our survey, 53% reported being "very concerned" with treatment-related costs negatively affecting their patients, and 80% believed that a financial toxicity screening tool would be useful in practice. An analysis of patient surveys using logistic regression found age and cancer site to be the most important variables associated with financial toxicity. Thirty-four patients (22%) experienced financial toxicity related to treatment. The financial toxicities experienced were loss of job (28%), loss of income (24%), difficulty paying their rent or mortgage (20%), difficulty paying for transportation (15%), and difficulty paying for meals (13%). CONCLUSIONS: Financial toxicity is an important measure for patients and providers and is experienced by approximately one quarter of patients. Further studies to improve models to predict financial toxicity and how financial toxicity is related to patient outcomes and quality of life are warranted.

A history of low back pain affects pelvis and trunk coordination during a sustained manual materials handling task.

PURPOSE: The purpose of this study was to compare the coordination between the trunk and the pelvis during a sustained asymmetric repetitive lifting task between a group with a history of low back pain (LBP; HBP) and a group with no history of LBP (NBP). METHODS: Volunteers lifted a 11-kg box from ankle height in front to a shelf 45° off-center at waist height, and lowered it to the start position at 12 cycles/min for 10 min. Lifting side was alternated during the trial. Continuous relative phase was used to calculate coordination between the pelvis and trunk rotation at the beginning (Min 1), middle (Min 5), and end of the bout (Min 9). RESULTS: While there were no main effects for group, a significant interaction between time and group indicated that, in the frontal plane, the NBP group coordination was more anti-phase toward the end of the bout, with no such differences for the HBP group. Analysis of sagittal-axial (bend and twist) coordination revealed the HBP group coordination was more in-phase at the end of the bout over the entire cycle and for the lifting phase alone, with no such differences for the NBP group. CONCLUSION: Differences between groups demonstrate residual consequences of LBP in an occupational scenario, even though the HBP group was pain-free for >6 months prior to data collection. More in-phase coordination in the HBP group may represent a coordination pattern analogous to "guarded gait" which has been observed in other studies, and may lend insight as to why these individuals are at increased risk for re-injury.

Exosomes as drug delivery vehicles for Parkinson's disease therapy.

Exosomes are naturally occurring nanosized vesicles that have attracted considerable attention as drug delivery vehicles in the past few years. Exosomes are comprised of natural lipid bilayers with the abundance of adhesive proteins that readily interact with cellular membranes. We posit that exosomes secreted by monocytes and macrophages can provide an unprecedented opportunity to avoid entrapment in mononuclear phagocytes (as a part of the host immune system), and at the same time enhance delivery of incorporated drugs to target cells ultimately increasing drug therapeutic efficacy. In light of this, we developed a new exosomal-based delivery system for a potent antioxidant, catalase, to treat Parkinson's disease (PD). Catalase was loaded into exosomes ex vivo using different methods: the incubation at room temperature, permeabilization with saponin, freeze-thaw cycles, sonication, or extrusion. The size of the obtained catalase-loaded exosomes (exoCAT) was in the range of 100-200nm. A reformation of exosomes upon sonication and extrusion, or permeabilization with saponin resulted in high loading efficiency, sustained release, and catalase preservation against proteases degradation. Exosomes were readily taken up by neuronal cells in vitro. A considerable amount of exosomes was detected in PD mouse brain following intranasal administration. ExoCAT provided significant neuroprotective effects in in vitro and in vivo models of PD. Overall, exosome-based catalase formulations have a potential to be a versatile strategy to treat inflammatory and neurodegenerative disorders.

Structural and mechanistic insights into the recruitment of talin by RIAM in integrin signaling.

Plasma membrane (PM)-bound GTPase Rap1 recruits the Rap1-interacting-adaptor-molecule (RIAM), which in turn recruits talin to bind and activate integrins. However, it is unclear how RIAM recruits talin and why its close homolog lamellipodin does not. Here, we report that, although RIAM possesses two talin-binding sites (TBS1 and TBS2), only TBS1 is capable of recruiting cytoplasmic talin to the PM, and the R8 domain is the strongest binding site in talin. Crystal structure of an R7R8:TBS1 complex reveals an unexpected kink in the TBS1 helix that is not shared in the homologous region of lamellipodin. This kinked helix conformation is required for the colocalization of RIAM and talin at the PM and proper activation of integrin. Our findings provide the structural and mechanistic insight into talin recruitment by RIAM that underlies integrin activation and explain the differential functions of the otherwise highly homologous RIAM and lamellipodin in integrin signaling.

Comparison of methods for estimating Wet-Bulb Globe Temperature index from standard meteorological measurements.

Environmental heat illness and injuries are a serious concern for the Army and Marines. Currently, the Wet-Bulb Globe Temperature (WBGT) index is used to evaluate heat injury risk. The index is a weighted average of dry-bulb temperature (Tdb), black globe temperature (Tbg), and natural wet-bulb temperature (Tnwb). The WBGT index would be more widely used if it could be determined using standard weather instruments. This study compares models developed by Liljegren at Argonne National Laboratory and by Matthew at the U.S. Army Institute of Environmental Medicine that calculate WBGT using standard meteorological measurements. Both models use air temperature (Ta), relative humidity, wind speed, and global solar radiation (RG) to calculate Tnwb and Tbg. The WBGT and meteorological data used for model validation were collected at Griffin, Georgia and Yuma Proving Ground (YPG), Arizona. Liljegren (YPG: R(2) = 0.709, p < 0.01; Griffin: R(2) = 0.854, p < 0.01) showed closer agreement between calculated and actual WBGT than Matthew (YPG: R(2) = 0.630, p < 0.01; Griffin: R(2) = 0.677, p < 0.01). Compared to actual WBGT heat categorization, the Matthew model tended to underpredict compared to Liljegren's classification. Results indicate Liljegren is an acceptable alternative to direct WBGT measurement, but verification under other environmental conditions is needed.

EEG and MRI data fusion for early diagnosis of Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is rising alarmingly as the average age of our population increases. There is no treatment to halt or slow the pathology responsible for AD, however, new drugs are promising to reduce the rate of progression. On the other hand, the efficacy of these new medications critically depends on our ability to diagnose AD at the earliest stage. Currently AD is diagnosed through longitudinal clinical evaluations, which are available only at specialized dementia clinics, hence beyond financial and geographic reach of most patients. Automated diagnosis tools that can be made available to community hospitals would therefore be very beneficial. To that end, we have previously shown that the event related potentials obtained from different scalp locations can be effectively used for early diagnosis of AD using an ensemble of classifiers based decision fusion approach. In this study, we expand our data fusion approach to include MRI based measures of regional brain atrophy. Our initial results indicate that ERPs and MRI carry complementary information, and the combination of these heterogeneous data sources using a decision fusion approach can significantly improve diagnostic accuracy.