Distortion product otoacoustic mapping measured pre- and post-loud sound exposures.

OBJECTIVE: Sampling distortion product otoacoustic emissions (DPOAEs) at multiple f2/f1 ratios and f2 frequency values produces a DPOAE "map." This study examined the efficacy of DPOAE mapping compared with pure tone audiometry and standard DPOAEs for detecting noise effects in subjects exposed to loud sound. DESIGN: A map significance score was developed as a single measure of map change. Significance scores were evaluated before and after exposure to: loud music (LM), controlled noise (CN), and firing range noise (FR) in three separate sets of subjects. Scores were compared to audiometry and standard DPOAE results in the LM study. STUDY SAMPLE: The LM and CN exposure studies involved 22, and 20 healthy young subjects respectively with normal hearing. Eight Marines were studied before and after FR exposure. RESULTS: After LM exposure, audiometry showed significant changes at 1, 2, 4, and 6 kHz. Standard DPOAE measures were also significantly different at several frequencies. Map significance scores detected changes more effectively and showed the distribution of DPOAE alterations. CONCLUSIONS: Map significance scores detected changes after noise exposure more reliably than audiometry and standard DPOAEs. Additionally, maps showed a diffuse response to sound exposure perhaps explaining why individual DP-grams appear less sensitive.

Fixed-Level Frequency Threshold Testing for Ototoxicity Monitoring.

OBJECTIVES: Hearing loss from ototoxicity is often most pronounced at high frequencies. To improve patient monitoring and compliance, high-frequency testing methods should be short and easy to administer. We evaluated the repeatability and accuracy of a Békésy-like, fixed-level frequency threshold (FLFT) technique. This test takes less than a minute and could provide a rapid and effective way to determine the highest audible frequency. We hypothesized the FLFT test would be repeatable in normal-hearing subjects, and accurate when compared with Békésy fixed-frequency audiometry in the sensitive region for ototoxicity (SRO). DESIGN: Twenty-nine normal-hearing subjects (20 females, 9 males) performed 2 different automated audiometry tests at least 4 times over a period of no less than 3 weeks. Ages ranged from 23 to 35 years (average = 28 years). Subjects completed testing under Sennheiser HDA-200 headsets. Initial fixed-frequency audiometry thresholds were obtained at frequencies ranging from 0.5 to 20 kHz to identify each subject's highest audible frequency, which was used to determine the SRO. The SRO was defined as the seven frequencies at and below the highest audible frequency in 1/6-octave steps. These frequencies were monitored with fixed-frequency audiometry. At each session, the FLFT test was administered at 80 dB SPL. Subjects used a Békésy-style tracking method to determine the frequency threshold. All testing was completed in a sound booth (single wall, Industrial Acoustics Company) using a computerized, laptop-based, system. FLFT repeatability was calculated as the root mean square difference from the first test session. FLFT accuracy was calculated as the difference from the highest audible frequency determined from fixed-frequency audiometry interpolated to 80 dB SPL level. RESULTS: The FLFT average RMSD for intersession variability was 0.05 ± 0.05 octaves. The test showed no learning effect [F(3,78) = 0.7; p = 0.6]. The overall intersession variability for SRO fixed-frequency audiometry thresholds at all frequencies was within clinically acceptable test-retest variability (10 dB) at 5.8 dB (range 2.7 to 9.9 dB). The SRO fixed-frequency audiometry therefore served as a repeatable basis of comparison for accuracy of the FLFT test. The mean absolute difference between the fixed-frequency audiometry and FLFT-determined highest audible frequency was 0.03 octaves. The FLFT and the highest audible frequency via fixed-frequency audiometry at 80 dB SPL were not different statistically (p = 0.12). The FLFT took approximately 30 seconds to complete, compared with approximately 4.5 min for fixed-frequency audiometry SRO and 20 to 25 min for a traditional ototoxic audiometric assessment. CONCLUSIONS: The Békésy-style FLFT was repeatable within 1/12 octave (1 step size in the testing procedure). The FLFT agreed well with the highest audible frequency determined via fixed-frequency audiometry at 80 dB SPL. The FLFT test is amenable to automatic and self-administration and may enable quick, accurate, noise-tolerant ototoxicity, and high-frequency hearing monitoring.

DPOAE level mapping for detecting noise-induced cochlear damage from short-duration music exposures.

Distortion product otoacoustic emission (DPOAE) level mapping provides a comprehensive picture of cochlear responses over a range of DP frequencies and f2/f1ratios. We hypothesized that individuals exposed to high-level sound would show changes detectable by DPOAE mapping, but not apparent on a standard DP-gram. Thirteen normal hearing subjects were studied before and after attending music concerts. Pure-tone audiometry (500-8,000 Hz), DP-grams (0.3-10 kHz) at 1.22 ratio, and DPOAE level maps were collected prior to, as soon as possible after, and the day after the concerts. All maps covered the range of 2,000-6,000 Hz in DP frequency and from 1.3 to -1.3 in ratio using equi-level primary tone stimuli. Changes in the pure-tone audiogram were significant (P ≤ 0.01) immediately after the concert at 1,000 Hz, 4,000 Hz, and 6,000 Hz. The DP-gram showed significant differences only at f2= 4,066 (P = 0.01) and f2= 4,348 (P = 0.04). The postconcert changes were readily apparent both visually and statistically (P ≤ 0.01) on the mean DP level maps, and remained statistically significantly different from baseline the day after noise exposure although no significant changes from baseline were seen on the DP-gram or audiogram the day after exposure. Although both the DP-gram and audiogram showed recovery by the next day, the average DPOAE level maps remained significantly different from baseline. The mapping data showed changes in the cochlea that were not detected from the DP-gram obtained at a single ratio. DPOAE level mapping provides comprehensive information on subtle cochlear responses, which may offer advantages for studying and tracking noise-induced hearing loss (NIHL).

SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia.

While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34(+) /CD38(-) BCR-ABL1(+) CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388 -IL3) and SL-501 (DT388 -IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34(+) /CD38(-) /CD123(+) CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

Improving Surveillance of Human Tick-Borne Disease Risks: Spatial Analysis Using Multimodal Databases.

BACKGROUND: The extent of tick-borne disease (TBD) risk in the United States is generally unknown. Active surveillance using entomological measures, such as presence and density of infected nymphal Ixodes scapularis ticks, have served as indicators for assessing human risk, but results have been inconsistent and passive surveillance via public health systems suggests TBDs are underreported. OBJECTIVE: Research using various data sources and collection methods (eg, Google Trends, apps, and tick bite encounters [TBEs] reports) has shown promise for assessing human TBD risk. In that vein, and engaging a One Health perspective, this study used multimodal databases, geographically overlaying patient survey data on TBEs and concomitant reports of TBDs with data drawn from other sources, such as canine serological reports, to glean insights and to determine and assess the use of various indicators as proxies for human TBD risk. METHODS: This study used a mixed methods research strategy, relying on triangulation techniques and drawing on multiple data sources to provide insights into various aspects of human disease risk from TBEs and TBDs in the United States. A web-based survey was conducted over a 15-month period beginning in December 2020 to collect data on TBEs. To maximize the value of the covariate data, related analyses included TBE reports that occurred in the United States between January 1, 2000, and March 31, 2021. TBEs among patients diagnosed with Lyme disease were analyzed at the county level and compared to I scapularis and I pacificus tick presence, human cases identified by the Centers for Disease Control and Prevention (CDC), and canine serological data. Spatial analyses employed multilayer thematic mapping and other techniques. RESULTS: After cleaning, survey results showed a total of 249 (75.7%) TBEs spread across 148 respondents (61.9% of all respondents, 81.7% of TBE-positive respondents); 144 (4.7%) counties in 30 states (60%) remained eligible for analysis, with an average of 1.68 (SD 1.00) and median of 1 (IQR 1) TBEs per respondent. Analysis revealed significant spatial matching at the county level among patient survey reports of TBEs and disease risk indicators from the CDC and other official sources. Thematic mapping results included one-for-one county-level matching of reported TBEs with at least 1 designated source of human disease risk (ie, positive canine serological tests, CDC-reported Lyme disease, or known tick presence). CONCLUSIONS: Use of triangulation methods to integrate patient data on TBE recall with established canine serological reports, tick presence, and official human TBD information offers more granular, county-level information regarding TBD risk to inform clinicians and public health officials. Such data may supplement public health sources to offer improved surveillance and provide bases for developing robust proxies for TBD risk among humans.

Understanding Habitats and Environmental Conditions of White-Tailed Deer Population Density and Public Health Data to Aid in Assessing Human Tick-Borne Disease Risk.

The extent of tick-borne diseases (TBDs) in the United States is largely unknown and underreported. Equitable diagnostic and treatment options may vary by geographic location. Triangulating multi-modal data sources informed by a One Health approach provides robust proxies for human TBD risk. Using data from the Indiana Department of Natural Resources collected from hunters during the white-tailed deer (Odocoileus virginianus) hunting season and other sources, we employ a mixed-methods approach based on thematic mapping and mixed effects modelling to determine if deer population density aligns with official disease data at the county level from (1) positive canine serological reports for, anaplasmosis, and Lyme Disease (LD); (2) positive human cases of ehrlichiosis, anaplasmosis, LD, and Spotted Fever rickettsioses; and (3) tick infectivity. We propose the need for multimodal data analysis using a variety of potential proxies to better estimate disease risk and inform public health policy and practice. We find similar spatial distributions between deer population density and human and canine TBDs in northeastern and southern Indiana, which are rural and mixed geographic areas. Overall, LD is more prevalent in the northwest, central-western, and southeastern counties, while ehrlichiosis is more common in the southern counties. These findings hold true across humans, canines, and deer.

Assessing Tick-Borne Disease Risk and Surveillance: Toward a Multi-Modal Approach to Diagnostic Positioning and Prediction.

The true extent of tick-borne disease (TBD) incidence and risk among humans is largely unknown, posing significant public health challenges. This study offers an exploratory analysis of a multimodal dataset and is part of a larger ongoing project to determine if entomological data, canine serological reports, self-reported human tick bite encounters (TBEs), and/or associated TBD diagnoses can serve as proxies for human disease risk. Focusing on the United States (U.S.), it characterizes self-reported TBD diagnoses (specifically, anaplasmosis, ehrlichiosis, and Lyme disease), co-infections, and their frequency and distribution across U.S. counties in relation to the presence of other factors related to TBD risk. Survey data was used to construct a list of TBEs localizable to individual U.S. counties. National data regarding these counties­namely the presence of official Lyme Disease (LD) case reports from the Centers for Disease Control and Prevention, as well as the tick vectors I. scapularis and I. pacificus within a given county­were then linked with survey-reported TBEs, tabulated by diagnosis (including co-infections), to determine the distribution of county-level endpoints across diagnostic categories. In addition, data on the presence of positive serological diagnostic tests conducted in canines were considered due to their potential utility as a proxy for TBD and TBE risk. The final dataset contained 249 TBEs localized to a total of 144 counties across 30 states. Diagnostic categories included respondents with LD (n = 70) and those with anaplasmosis and ehrlichiosis diagnoses and co-infections (n < 20 per diagnostic category). TBEs also were indicated by respondents who did not report TBD diagnoses, with some indicating uncertainty. The distribution of respondent-reported TBEs varied between canine TBDs, with LD-positive respondents reporting noticeably larger proportions of TBEs in counties with canine LD and smaller proportions in counties with canine anaplasmosis, compared to respondents without an LD diagnosis; a notional logistic regression suggests these differences may be significant (canine LD: Odds Ratio [OR] = 6.04, p = 0.026) (canine anaplasmosis: OR = 0.50, p = 0.095). These results suggest that certain widely available diagnostic TBD data in animals (in this case, domesticated dogs) may be sensitive to differences in human TBD risk factors and thus may have utility as proxies in future research. In the absence of an available standardized, unified, and national TBD database, such proxies, along with relevant surveys and reports, may provide a much-needed working solution for scientists and clinicians studying TBDs.

Neurological Pain, Psychological Symptoms, and Diagnostic Struggles among Patients with Tick-Borne Diseases.

Public health reports contain limited information regarding the psychological and neurological symptoms of tick-borne diseases (TBDs). Employing a mixed-method approach, this analysis triangulates three sources of symptomology and provides a comparison of official public health information, case reports, medical literature, and the self-reported symptoms of patients with Lyme disease and other TBDs. Out of the fifteen neuropsychiatric symptoms reported in the medical literature for common TBDs, headaches and fatigue and/or malaise are the only two symptoms fully recognized by public health officials. Of TBDs, Lyme disease is the least recognized by public health officials for presenting with neuropsychiatric symptoms; only headaches and fatigue are recognized as overlapping symptoms of Lyme disease. Comparisons from a patient symptoms survey indicate that self-reports of TBDs and the associated symptoms align with medical and case reports. Anxiety, depression, panic attacks, hallucinations, delusions, and pain-ranging from headaches to neck stiffness and arthritis-are common among patients who report a TBD diagnosis. Given the multitude of non-specific patient symptoms, and the number and range of neuropsychiatric presentations that do not align with public health guidance, this study indicates the need for a revised approach to TBD diagnosis and for improved communication from official public health sources regarding the wide range of associated symptoms.

Triangulating the New Frontier of Health Geo-Data: Assessing Tick-Borne Disease Risk as an Occupational Hazard among Vulnerable Populations.

Determining interventions to combat disease often requires complex analyses of spatial-temporal data to improve health outcomes. For some vulnerable populations, obtaining sufficient data for related analyses is especially difficult, thus exacerbating related healthcare, research, and public health efforts. In the United States (U.S.), migrant and seasonal workers are especially affected in this regard, with data on health interventions and outcomes largely absent from official sources. In response, this study offers a multi-modal approach that involves triangulating geographically specified health data that incorporate reports on canine tick species, Lyme disease (LD) incidence, and patient symptom severity indicating potential subsequent disease burden. Spatial alignment of data at the U.S. county level was used to reveal and better understand tick-borne disease (TBD) incidence and risk among the identified populations. Survey data from migrant and seasonal workers in Texas were employed to determine TBD risk based on symptoms, occupations, and locations. Respondents who were found to have a higher likelihood of a TBD were also considerably more likely to report the most common symptoms of LD and other TBDs on the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire. Those in the highly likely scoring group also reported more poor health and mental health days. Overall, a notable number of respondents (22%) were likely or highly likely to have a TBD, with particular relevance attributed to county of residence and living conditions. Also of note, almost a third of those reporting severe symptoms had received a previous Lyme disease diagnosis. These findings underscore the need for further surveillance among vulnerable populations at risk for TBDs.

Vertically-integrated multimode interferometer coupler for 3D photonic circuits in SOI.

Vertical optical coupling is demonstrated in a multimode interferometer structure fabricated using silicon-on-insulator (SOI) material. These CMOS-compatible couplers are suitable to be used to transfer optical power between stacked waveguide layers of a three-dimensional photonic circuit. Coupling between these layers can be restricted to certain regions by selectively fabricating a silicon channel between them, resulting in an isolated multimode waveguide section. Standard photolithography and etching techniques were used to fabricate proof-of-concept devices consisting of a channel waveguide coupling into a silicon waveguide that is vertically multimode. An optical coupling ratio of 93±4% between the upper and lower waveguide regions of the device was achieved with a coupler length of 241 µm.

Tick-Borne Surveillance Patterns in Perceived Non-Endemic Geographic Areas: Human Tick Encounters and Disease Outcomes.

Recent scholarship supports the use of tick bite encounters as a proxy for human disease risk. Extending entomological monitoring, this study was designed to provide geographically salient information on self-reported tick bite encounters by survey respondents who concomitantly reported a Lyme disease (LD) diagnosis in a state perceived as non-endemic to tick-borne illness. Focusing on Texas, a mixed-methods approach was used to compare data on tick bite encounters from self-reported LD patients with county-level confirmed cases of LD from the U.S. Centers for Disease Control and Prevention (CDC), as well as serological canine reports. A greater proportion of respondents reported not recalling a tick bite in the study population, but a binomial test indicated that this difference was not statistically significant. A secondary analysis compared neighboring county-level data and ecological regions. Using multi-layer thematic mapping, our findings indicated that tick bite reports accurately overlapped with the geographic patterns of those patients previously known to be CDC-positive for serological LD and with canine-positive tests for Borrelia burgdorferi, anaplasmosis, and ehrlichiosis, as well as within neighboring counties and ecological regions. LD patient-reported tick bite encounters, corrected for population density, also accurately aligned with official CDC county hot-spots. Given the large number of counties in Texas, these findings are notable. Overall, the study demonstrates that direct, clinically diagnosed patient reports with county-level tick bite encounter data offer important public health surveillance measures, particularly as it pertains to difficult-to-diagnose diseases where testing protocols may not be well established. Further integration of geo-ecological and socio-demographic factors with existing national epidemiological data, as well as increasingly accessible self-report methods such as online surveys, will contribute to the contextual information needed to organize and implement a coordinated public health response to LD.

Intermediate to long term results of stemless metaphyseal reverse shoulder arthroplasty: A five to nine year follow-up.

BACKGROUND: Shoulder arthroplasty incidence is increasing as is the volume of revision surgeries. Revision surgery is easier if humeral bone stock is preserved with minimal bone defects and osteolysis. This has led to an increased focus on the development of various short stemmed and stemless implants which provides stable fixation whilst preserving humeral bone stock. PURPOSE: To review the medium to long term clinical and radiological outcomes, complications and survival rates of a stemless reverse shoulder prosthesis. PATIENTS AND METHOD: Patients with a minimum follow-up of 60 months following a reverse stemless shoulder arthroplasty were deemed eligible. Clinical and radiological data on twenty-one patients operated between 2009 and 2014 were recorded prospectively. Survivorship and patient recorded symptoms with the end point of revision surgery were recorded. RESULTS: Mean follow-up of 78 months (60-114 months). Mean range of active elevation was 136° (80-170°). Mean range of active abduction and active external rotation was 122° (70-170°) and 47° (10-75°) respectively. Mean Oxford score improved from 12 pre-operatively to 44 at final follow up (p < 0.0001). Mean Constant Murley Score improved from 18 to 72 (p < 0.0001). Mean ADLEIR score of 13 pre-operatively increased to 32 post-operatively (p < 0.0001). Notching was seen in 23.5% of cases and no radiolucent areas were observed around the glenoid component. There were two cases of post traumatic peri-prosthetic fractures that were managed conservatively and one case of deep-seated infection that required a washout. The survivorship at the most recent follow-up was 100%. CONCLUSION: The advantages of bone preservation with the stemless metaphyseal prosthesis combined with encouraging medium to long term clinical and radiological results are very promising, particularly with the improved post-operative patient satisfaction scores. This is the first study that reports the results with a minimum of 5 year follow-up and has the longest mean follow-up period. CLINICAL RELEVANCE: The reverse stemless shoulder prosthesis is an effective and reliable option for elective shoulder arthroplasty.

The impact of chronotype on circadian rest-activity rhythm and sleep characteristics across the week.

Circadian rhythms are maintained by a complex "system of systems" that continuously coordinates biological processes with each other and the environment. Although humans predominantly entrain to solar time, individual persons vary in their precise behavioral timing due to endogenous and exogenous factors. Endogenous differences in the timing of individual circadian rhythms relative to a common environmental cue are known as chronotypes, ranging from earlier than average (Morningness) to later than average (Eveningness). Furthermore, individual behavior is often constrained by social constructs such as the 7-day week, and the "sociogenic" impact our social calendar has on our behavioral rhythms is likely modified by chronotype. Our aim in this study was to identify and characterize differences in sleep and rest-activity rhythms (RAR) between weekends and weekdays and between-chronotypes. Male volunteers (n = 24, mean age = 23.46 y) were actigraphically monitored for 4 weeks to derive objective behavioral measures of sleep and RARs. Chronotype was assessed through self-report on the Morningness-Eveningness Questionnaire. Sleep characteristics were derived using Actiware; daily rest-activity rhythms were modeled using a basic 3-parameter cosinor function. We observed that both Eveningness and Morningness Chronotypes were more active and slept later on the weekends than on weekdays. Significant between-chronotype differences in sleep timing and duration were observed within individual days of the week, especially during transitions between weekends and the workweek. Moreover, chronotypes significantly varied in their weekly rhythms: e.g. Morningness Chronotypes generally shifted their sleep duration, timing and quality across work/rest transitions quicker than Eveningness Chronotypes. Although our results should be interpreted with caution due to the limitations of our cosinor model and a homogenous cohort, they reinforce a growing body of evidence that day of the week, chronotype and their interactions must be accounted for in observational studies of human behavior, especially when circadian rhythms are of interest.

Development of digital measures for nighttime scratch and sleep using wrist-worn wearable devices.

Patients with atopic dermatitis experience increased nocturnal pruritus which leads to scratching and sleep disturbances that significantly contribute to poor quality of life. Objective measurements of nighttime scratching and sleep quantity can help assess the efficacy of an intervention. Wearable sensors can provide novel, objective measures of nighttime scratching and sleep; however, many current approaches were not designed for passive, unsupervised monitoring during daily life. In this work, we present the development and analytical validation of a method that sequentially processes epochs of sample-level accelerometer data from a wrist-worn device to provide continuous digital measures of nighttime scratching and sleep quantity. This approach uses heuristic and machine learning algorithms in a hierarchical paradigm by first determining when the patient intends to sleep, then detecting sleep-wake states along with scratching episodes, and lastly deriving objective measures of both sleep and scratch. Leveraging reference data collected in a sleep laboratory (NCT ID: NCT03490877), results show that sensor-derived measures of total sleep opportunity (TSO; time when patient intends to sleep) and total sleep time (TST) correlate well with reference polysomnography data (TSO: r = 0.72, p < 0.001; TST: r = 0.76, p < 0.001; N = 32). Log transformed sensor derived measures of total scratching duration achieve strong agreement with reference annotated video recordings (r = 0.82, p < 0.001; N = 25). These results support the use of wearable sensors for objective, continuous measurement of nighttime scratching and sleep during daily life.

Introduction of a compressed air breathing apparatus for the offshore oil and gas industry.

INTRODUCTION: When a helicopter ditches the majority of crew and passengers have to make an underwater escape. Some may not be able to hold their breath and will drown. For at least 15 yr, military aircrew have been trained to use a scuba system. In the offshore oil and gas industry, there has been more caution about introducing a compressed air system and a rebreather system has been introduced as an alternative. Recently, Canadian industry and authorities approved the introduction of Helicopter Underwater Emergency Breathing Apparatus (HUEBA) training using compressed air. This communication reports the training of the first 1000 personnel. METHODS: Training was introduced in both Nova Scotia and Newfoundland concurrently by the same group of instructors. Trainees filled out a questionnaire concerning their perceived ratings of the ease or difficulty of classroom training and the practical use of the HUEBA. RESULTS: Ninety-eight percent of trainees found the classroom and in-water training to be "good/very good". Trainees found it to be "easy/very easy" to clear the HUEBA and breathe underwater in 84% and 64% of cases, respectively. Divers reported a greater ease in learning all the practical uses of the HUEBA except application of the nose clip. DISCUSSION: There were problems with the nose clip fitting incorrectly, and interference of the survival suit hood with the regulator, which subsequently have been resolved. When carefully applied, the introduction of the HUEBA into training for offshore oil and gas industry helicopter crew and passengers can be safely conducted.

ECG during helicopter underwater escape training.

INTRODUCTION: Coincidental stimulation of the sympathetic and parasympathetic nervous system can cause "autonomic conflict" and consequent cardiac arrhythmias. The present study tested the hypotheses that: 1) cardiac arrhythmias would be seen in those undertaking helicopter underwater escape training (HUET); 2) the occurrence of arrhythmias in individuals could be predicted; and 3) the heart rate response to HUET would habituate with repeated runs. METHODS: There were 26 male volunteers who each undertook 5 HUET submersions into water at 29.5 degrees C, with each run separated by 10 min. Each submersion included a 3-min, 40-s pre-submersion period, a 10-s submersion, and 40-s post-submersion period. Participants wore a three-lead telemetric ECG system beneath an immersion suit and underclothing. Skin temperature was measured in one participant. Each participant undertook tests to establish their autonomic function, including heart rate variability, face immersion, cold pressor test, and aerobic capacity assessment. RESULTS: The heart rate response to HUET was reduced by the fourth run when compared to the first run. Across all runs, 32 cardiac arrhythmias were identified (25%) in 22 different participants; all but 6 of the arrhythmias occurred just after submersion. Only aerobic fitness appeared inversely associated with the occurrence of arrhythmias. CONCLUSIONS: The heart rate response to HUET habituates. HUET produces cardiac arrhythmias; these are asymptomatic and probably of little clinical significance in young, fit individuals. It remains to be seen if this is the case with either an older, less fit cohort of people or in those undertaking longer breath holds in colder water.

The Hawthorne Effect in Eye-blinking: Awareness that One's Blinks are Being Counted Alters Blink Behavior.

Purpose: Spontaneous eye-blink rate is the number of involuntary blinks performed during a certain period of time. Assessing blink rate in humans provides valuable physiological and behavioral data for studying neuropathology and emotional states. Cognitive states, including awareness on the part of the subject that his or her blinks are being counted, may influence blink activity and confound blink rate measurements. The goal of this study was to provide direct experimental evaluation of the hypothesis that subject awareness affects tasked-based blink activity. Materials and methods: 30 young healthy adult males with normal vision underwent a series of tasks - viewing images, talking, sitting quietly, and cross fixation - while being video recorded. Each subject completed the tasks naively, then repeated them after being explicitly told their blink rate was being measured. Blink rate was measured through minute-by-minute blink counts by human raters. Results: We found a transitory impact on blink count during the first and third minute of a passive image-viewing task that occurred immediately after subjects were informed of their eye blinks being counted. However, the overall blink rate across the 7-min passive image-viewing task was not influenced. In three other tasks - fixation, silence, and conversation - we observed no statistically significant difference in minute-by-minute blink count or overall blink rate. Conclusions: We conclude that informing a subject that his eye blinks are being counted exerts a modest but significant acute influence on blinking activity, but critically does not appear to confound blink rate over prolonged tasks.

Variations in rest-activity rhythm are associated with clinically measured disease severity in Parkinson's disease.

The continuous, longitudinal nature of accelerometry monitoring is well-suited to capturing the regular 24-hour oscillations in human activity across the day, the cumulative effect of our circadian rhythm and behavior. Disruption of the circadian rhythm in turn disrupts rest-activity rhythms. Although circadian disruption is a major feature of Parkinson's disease (PD), rest-activity rhythms and their relationship with disease severity have not been well characterized in PD. 13 PD participants (Hoehn & Yahr Stage [H&Y] 1-3) wore a Philips Actiwatch Spectrum PRO continuously for two separate weeks. Rest-activity rhythms were quantified by fitting an oscillating 24-hour cosinor model to each participant-day of activity data. One-way ANOVAs adjusted for demographics revealed significant variation in the amount (MESOR, F = 12.76, p < .01), range (Amplitude, F = 9.62, p < .01), and timing (Acrophase, F = 2.7, p = .05) of activity across H&Y Stages. Those with higher H&Y Stages were significantly more likely to be active later in the day, where-as those who shifted between H&Y Stages during the study were significantly more active than those who did not change H&Y Stage. Being active later in the day was also significantly associated with higher scores on the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Section III (motor symptom severity, p = .02), Section II (self-reported impact of motor symptoms on daily living, p = .01), and Total Score (p = .01) in an adjusted linear regression model; significant associations between MDS-UPDRS scores and activity levels were observed only in the unadjusted model. These findings demonstrate that continuous actigraphy is capable of detecting rest-activity disruption in PD, and provides preliminary evidence that rest-activity rhythms are associated with motor symptom severity and H&Y Stage.

mHealth and wearable technology should replace motor diaries to track motor fluctuations in Parkinson's disease.

Accurately monitoring motor and non-motor symptoms as well as complications in people with Parkinson's disease (PD) is a major challenge, both during clinical management and when conducting clinical trials investigating new treatments. A variety of strategies have been relied upon including questionnaires, motor diaries, and the serial administration of structured clinical exams like part III of the MDS-UPDRS. To evaluate the potential use of mobile and wearable technologies in clinical trials of new pharmacotherapies targeting PD symptoms, we carried out a project (project BlueSky) encompassing four clinical studies, in which 60 healthy volunteers (aged 23-69; 33 females) and 95 people with PD (aged 42-80; 37 females; years since diagnosis 1-24 years; Hoehn and Yahr 1-3) participated and were monitored in either a laboratory environment, a simulated apartment, or at home and in the community. In this paper, we investigated (i) the utility and reliability of self-reports for describing motor fluctuations; (ii) the agreement between participants and clinical raters on the presence of motor complications; (iii) the ability of video raters to accurately assess motor symptoms, and (iv) the dynamics of tremor, dyskinesia, and bradykinesia as they evolve over the medication cycle. Future papers will explore methods for estimating symptom severity based on sensor data. We found that 38% of participants who were asked to complete an electronic motor diary at home missed ~25% of total possible entries and otherwise made entries with an average delay of >4 h. During clinical evaluations by PD specialists, self-reports of dyskinesia were marked by ~35% false negatives and 15% false positives. Compared with live evaluation, the video evaluation of part III of the MDS-UPDRS significantly underestimated the subtle features of tremor and extremity bradykinesia, suggesting that these aspects of the disease may be underappreciated during remote assessments. On the other hand, live and video raters agreed on aspects of postural instability and gait. Our results highlight the significant opportunity for objective, high-resolution, continuous monitoring afforded by wearable technology to improve upon the monitoring of PD symptoms.

Prostaglandin E(2) induces breast cancer related aromatase promoters via activation of p38 and c-Jun NH(2)-terminal kinase in adipose fibroblasts.

Aromatase is the key enzyme for estrogen biosynthesis. A distal promoter, PI.4, maintains baseline levels of aromatase in normal breast adipose tissue. In contrast, malignant breast epithelial cells secrete prostaglandin E(2) (PGE(2)), which stimulates aromatase expression via proximal promoters PI.3/PII in a cyclic AMP (cAMP)- and protein kinase C (PKC)-dependent manner in adjacent breast adipose fibroblasts (BAF), leading to increased local concentrations of estrogen. Although an effective treatment for breast cancer, aromatase inhibitors indiscriminately abolish estrogen synthesis in all tissues, causing major side effects. To identify drug targets to selectively block aromatase and estrogen production in breast cancer, we investigated PGE(2)-stimulated signaling pathways essential for aromatase induction downstream of cAMP and PKC in human BAFs. Here, we show that PGE(2) or its surrogate hormonal mixture dibutyryl cAMP (Bt(2)cAMP) + phorbol diacetate (PDA) stimulated the p38, c-jun NH(2)-terminal kinase (JNK)-1, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathways. Inhibition or small interfering RNA-mediated knockdown of p38 or JNK1, but not ERK, inhibited PGE(2)- or Bt(2)cAMP + PDA-induced aromatase activity and expression via PI.3/PII. Conversely, overexpression of wild-type p38alpha or JNK1 enhanced PGE(2)-stimulated aromatase expression via PII. PGE(2) or Bt(2)cAMP + PDA stimulated c-Jun and activating transcription factor-2 (ATF2) phosphorylation and binding to the PI.3/PII region. Specific activation of protein kinase A (PKA) or EPAC with cAMP analogues stimulated p38 and JNK1; however, only PKA-activating cAMP analogues induced aromatase expression. The PKC activator PDA effectively stimulated p38 and JNK1 phosphorylation but not aromatase expression. Taken together, PGE(2) activation of p38 and JNK1 via PKA and PKC is necessary for aromatase induction in BAFs, and p38 and JNK1 are potential new drug targets for tissue-specific ablation of aromatase expression in breast cancer.