Mast cell-derived IL-10 protects intestinal barrier integrity during malaria in mice and regulates parasite transmission to Anopheles stephensi with a female-biased immune response.

Malaria is strongly predisposed to bacteremia, which is associated with increased gastrointestinal permeability and a poor clinical prognosis. We previously identified mast cells (MCs) as mediators of intestinal permeability in malaria and described multiple cytokines that rise with parasitemia, including interleukin (IL)-10, which could protect the host from an inflammatory response and alter parasite transmission to Anopheles mosquitoes. Here, we used the Cre-loxP system and non-lethal Plasmodium yoelii yoelii 17XNL to study the roles of MC-derived IL-10 in malaria immunity and transmission. Our data suggest a sex-biased and local inflammatory response mediated by MC-derived IL-10, supported by early increased number and activation of MCs in females relative to males. Increased parasitemia in female MC IL-10 (-) mice was associated with increased ileal levels of chemokines and plasma myeloperoxidase (MPO). We also observed increased intestinal permeability in female and male MC IL-10 (-) mice relative to MC IL-10 (+) mice but no differences in blood bacterial 16S DNA levels. Transmission success of P. yoelii to A. stephensi was higher in female relative to male mice and from female and male MC IL-10 (-) mice relative to MC IL-10 (+) mice. These patterns were associated with increased plasma levels of pro-inflammatory cytokines in female MC IL-10 (-) mice and increased plasma levels of chemokines and markers of neutrophil activation in male MC IL-10 (-) mice. Overall, these data suggest that MC-derived IL-10 protects intestinal barrier integrity, regulates parasite transmission, and controls local and systemic host immune responses during malaria, with a female bias.

A Central Auditory Test reveals differences between drug treatment regimens in adults living with HIV.

OBJECTIVE: This exploratory study examined whether central auditory tests show differences between people living with HIV (PLWH) treated with two predominant antiretroviral drug therapy (ART) regimens. DESIGN: Cross-sectional. STUDY SAMPLE: 253 PLWH (mean age 39.8 years) from the Shanghai Public Health Clinical Centre, China. METHODS: The Hearing in Noise Test speech reception threshold (SRT) assessed central auditory function and the Montreal Cognitive Assessment (MoCA) assessed cognition. The relationship between ART regimen and SRT was evaluated with multivariable linear regression incorporating age, HIV duration, and peripheral hearing ability. Multivariable logistic regression was used to ascertain if SRT and ART regimen predicted MoCA impairment. RESULTS: The two predominant ART regimens differed by one drug (zidovudine or tenofovir). Participants taking the zidovudine-containing regimen had poorer SRT performance (p=.012) independent of age and hearing thresholds. MoCA scores did not differ between drug regimens, but a negative relationship was found between SRT and MoCA impairment (p=.048). CONCLUSIONS: ART regimens differed in their association with central auditory test performance likely reflecting neurocognitive changes in PLWH taking the zidovudine-containing regimen. Central auditory test performance also marginally predicted cognitive impairment, supporting further assessment of central auditory tests to detect neurocognitive deficits in PLWH.

Gap detection responses modelled using the Hill equation in adults with well-controlled HIV.

OBJECTIVE: This study's objective was determining whether gap detection deficits are present in a longstanding cohort of people living with HIV (PLWH) compared to those living without HIV (PLWOH) using a new gap detection modelling technique (i.e. fitting gap responses using the Hill equation and analysing the individual gap detection resulting curves with non-linear statistics). This approach provides a measure of both gap threshold and the steepness of the gap length/correct detection relationship. DESIGN: The relationship between the correct identification rate at each gap length was modelled using the Hill equation. Results were analysed using a nonlinear mixed-effect regression model. STUDY SAMPLE: 45 PLWH (age range 41-78) and 39 PLWOH (age range 38-79) were enrolled and completed gap detection testing. RESULTS: The likelihood ratio statistic comparing the full regression model with the HIV effects to the null model, assuming one population curve for both groups, was highly significant (p < 0.001), suggesting a less precise relationship between gap length and correct detection in PLWH. CONCLUSIONS: PLWH showed degraded gap detection ability compared to PLWOH, likely due to central nervous system effects of HIV infection or treatment. The Hill equation provided a new approach for modelling gap detection ability.

The Resting State Central Auditory Network: a Potential Marker of HIV-Related Central Nervous System Alterations.

OBJECTIVE: HIV positive (HIV+) individuals with otherwise normal hearing ability show central auditory processing deficits as evidenced by worse performance in speech-in-noise perception compared with HIV negative (HIV-) controls. HIV infection and treatment are also associated with lower neurocognitive screening test scores, suggesting underlying central nervous system damage. To determine how central auditory processing deficits in HIV+ individuals relate to brain alterations in the cortex involved with auditory processing, we compared auditory network (AN) functional connectivity between HIV+ adults with or without speech-in-noise perception difficulties and age-matched HIV- controls using resting-state fMRI. DESIGN: Based on the speech recognition threshold of the hearing-in-noise test, twenty-seven HIV+ individuals were divided into a group with speech-in-noise perception abnormalities (HIV+SPabnl, 38.2 ± 6.8 years; 11 males and 2 females) and one without (HIV+SPnl 34.4 ± 8.8 years; 14 males). An HIV- group with normal speech-in-noise perception (HIV-, 31.3 ± 5.2 years; 9 males and 3 females) was also enrolled. All of these younger and middle-aged adults had normal peripheral hearing determined by audiometry. Participants were studied using resting-state fMRI. Independent component analysis was applied to identify the AN. Group differences in the AN were identified using statistical parametric mapping. RESULTS: Both HIV+ groups had increased functional connectivity (FC) in parts of the AN including the superior temporal gyrus, middle temporal gyrus, supramarginal gyrus, and Rolandic operculum compared to the HIV- group. Compared with the HIV+SPnl group, the HIV+SPabnl group showed greater FC in parts of the AN including the middle frontal and inferior frontal gyri. CONCLUSIONS: The classical auditory areas in the temporal lobe are affected by HIV regardless of speech perception ability. Increased temporal FC in HIV+ individuals might reflect functional compensation to achieve normal primary auditory perception. Furthermore, increased frontal FC in the HIV+SPabnl group compared with the HIV+SPnl group suggest that speech-in-noise perception difficulties in HIV-infected adults also affect areas involved in higher-level cognition, providing imaging evidence consistent with the hypothesis that HIV-related neurocognitive deficits can include central auditory processing deficits.

Prospective measurements of hearing threshold during military rifle training with in-ear, protected, noise exposure monitoring.

Although a causal relationship exists between military occupational noise exposure and hearing loss, researchers have struggled to identify and/or characterize specific operational noise exposures that produce measurable changes in hearing function shortly following an exposure. Growing evidence suggests that current standards for noise-exposure limits are not good predictors of true hearing damage. In this study, the aim was to capture the dose-response relationship during military rifle training exercises for noise exposure and hearing threshold. To capture exposure, a wearable system capable of measuring impulse noise simultaneously on-body and in-ear, behind hearing protection was used. To characterize hearing threshold changes, portable audiometry was employed within 2 h before and after exposure. The median 8-h time-weighted, protected, free-field equivalent in-ear exposure was 87.5 dBA at one site and 80.7 dBA at a second site. A significant dose-response correlation between in-ear noise exposure and postexposure hearing threshold changes across our population ( R = 0.40 , p = 0.0281) was observed. The results demonstrate an approach for establishing damage risk criteria (DRC) for in-ear, protected measurements based on hearing threshold changes. While an in-ear DRC does not currently exist, it may be critical for predicting the risk of injury for noise environments where protection is mandatory and fit status can vary.

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.

International Multicenter Registry for Hyperbaric Oxygen Therapy: Results through June 2021.

Introduction: The International Multicenter Registry for Hyperbaric Oxygen Therapy (International Report Registered Identifier DERR1-10.2196/18857) was established in 2011 to capture outcomes and complications data for both Undersea and Hyperbaric Medical Society (UHMS) approved and selected unapproved hyperbaric oxygen (HBO2) therapy indications. Methods: A Research Electronic Data Capture (REDCap) template was designed and distributed to all participating centers for prospective data collection. Centers contributed de-identified demographic, treatment, complications, and outcome data. This report provides summary data on sites and enrollment, as well as pre- and post-treatment data on quality of life (EQ-5D-5L questionnaire), head and neck radiationoutcomes, non-healing wounds (Strauss score), and idiopathic sudden sensorineural hearing loss. Data were analyzed mainly using the Wilcoxon signed-rank test. Results: Twenty-two centers contributed data for 2,880 patients. The most common UHMS-approved indication was delayed radiation injury, followed by enhancement of wound healing, and carbon monoxide poisoning. One hundred and twenty-five patients were treated for non-UHMS approved indications. Quality of life, head and neck radiation symptoms, Strauss wound scores, and hearing were significantly improved after HBO2. Complication rates were low and comparable to previous reports. The registry also offered the ability to analyze factors that affect outcomes, such as smoking and severity of hearing loss. Discussion: The registry accrues prospective data on defined outcomes from multiple centers and allows for analysis of factors affecting outcomes. This registry does not have a control group, which is a limitation. Nevertheless, the registry provides a unique, comprehensive dataset on HBO2 outcomes from multiple centers internationally.

Optic Nerve Length before and after Spaceflight.

PURPOSE: The spaceflight-associated neuro-ocular syndrome (SANS) affects astronauts on missions to the International Space Station (ISS). The SANS has blurred vision and ocular changes as typical features. The objective of this study was to investigate if microgravity can create deformations or movements of the eye or optic nerve, and if such changes could be linked to SANS. DESIGN: Cohort study. PARTICIPANTS: Twenty-two astronauts (age 48 ± 4 years). METHODS: The intervention consisted of time in microgravity at the ISS. We co-registered pre- and postspaceflight magnetic resonance imaging (MRI) scans and generated centerline representations of the optic nerve. The coordinates for the optic nerve head (ONH) and optic chiasm (OC) ends of the optic nerve were recorded along with the entire centerline path. MAIN OUTCOME MEASURES: Optic nerve length, ONH movement, and OC movement after time in microgravity. RESULTS: Optic nerve length increased (0.80 ± 0.74 mm, P < 0.001), primarily reflecting forward ONH displacement (0.63 ± 0.53 mm, P < 0.001). The forward displacement was positively related to mission duration, preflight body weight, and clinical manifestations of SANS. We also detected upward displacement of the OC (0.39 ± 0.50 mm, P = 0.002), indicative of brain movement, but this observation could not be linked to SANS. CONCLUSIONS: The spaceflight-induced optic nerve lengthening and anterior movement of the ONH support that SANS is caused by an altered pressure difference between the brain and the eye, leading to a forward push on the posterior of the eye. Body weight is a potential contributing risk factor. Direct assessment of intracranial pressure in space is required to verify the implicated mechanism behind the ocular findings in SANS.

Use of custom-moulded earmoulds to improve repeatability of DPOAE map measurements.

OBJECTIVE: Distortion product otoacoustic emission (DPOAE) mapping characterises cochlear function, can include both the 2f1-2f2 and 2f2-2f1 DPOAEs, and shows promise for tracking cochlear changes. DPOAE amplitude measurements are not as repeatable longitudinally as pure-tone audiometry, likely due in part to probe placement sensitivity. We hypothesised that DPOAE level map variation over multiple testing sessions could be minimised by replacing traditional rubber tips with custom-moulded probe tips. DESIGN: Traditional rubber tips (TRT) and custom-moulded probes tips (CMPT) were used to measure DPOAE level maps repeatedly over five sessions. Probe placement was assessed using a frequency sweep in the ear canal. Repeatability of the DPOAE level maps was assessed using a Bland-Altman analysis. Overall map repeatability was assessed by measuring differences in distortion product amplitude over sessions. STUDY SAMPLE: Crossover study with a convenience sample size of six adults. RESULTS: The CMPT frequency sweeps showed reduced variability in probe placement. The repeatability coefficient for individual DPOAEs measurements improved from 6.9 dB SPL with the TRT to 5.1 dB SPL with the CMPT. Map repeatability improved for most subjects with the CMPT.

Microgravity-induced ocular changes are related to body weight.

On Earth, tissue weight generates compressive forces that press on body structures and act on the walls of vessels throughout the body. In microgravity, tissues no longer have weight, and tissue compressive forces are lost, suggesting that individuals who weigh more may show greater effects from microgravity exposure. One unique effect of long-duration microgravity exposure is spaceflight-associated neuroocular syndrome (SANS), which can present with globe flattening, choroidal folds, optic disk edema, and a hyperopic visual shift. To determine whether weight or other anthropometric measures are related to ocular changes in space, we analyzed data from 45 individual long-duration astronauts (mean age 47, 36 male, 9 female, mean mission duration 165 days) who had pre- and postflight measures of disk edema, choroidal folds, and manifest ocular refraction. The mean preflight weights of astronauts who developed new choroidal folds [78.6 kg with no new folds vs. 88.6 kg with new folds ( F = 6.2, P = 0.02)] and disk edema [79.1 kg with no edema vs. 95 kg with edema ( F = 9.6, P = 0.003)] were significantly greater than those who did not. Chest and waist circumferences were also significantly greater in those who developed folds or edema. The odds of developing disk edema or new choroidal folds were 55% in the highest- and 9% in the lowest-weight quartile. In this cohort, no women developed disk edema or choroidal folds, although women also weighed significantly less than men [62.9 vs. 85.2 kg ( F = 53.2, P < 0.0001)]. Preflight body weight and anthropometric factors may predict microgravity-induced ocular changes.

Speech in Noise Perception as a Marker of Cognitive Impairment in HIV Infection.

OBJECTIVES: Human immunodeficiency virus positive (HIV+) individuals report hearing difficulties, but standard audiological tests show no, or small, changes in peripheral hearing ability. The hearing complaints may reflect central nervous system (CNS) auditory processing deficits, rather than middle or inner ear problems, and may result from CNS damage due to HIV infection or treatment. If central auditory task performance and cognitive deficits in HIV+ individuals are shown to be related, then central auditory tests might serve as a "window" into CNS function in these patients. DESIGN: We measured cognitive performance (Mandarin Montreal Cognitive Assessment [MoCA]) and speech in noise perception (Mandarin hearing-in-noise test [HINT]) in 166 normal-hearing HIV+ individuals (158 men, 8 women, average age 36 years) at the Shanghai Public Health Clinical Center in Shanghai, China. Data collection included audiometry, tympanometry, and the Amsterdam Inventory of Auditory Handicap (AIAH), which assesses the subjective ability to understand speech and localize sound. RESULTS: Subjects had no middle ear disease and met criteria for normal-hearing sensitivity (all thresholds 20 dB HL or less). A significant negative relationship between speech reception thresholds (SRT) and MoCA scores (r = 0.15, F = 28.2, p < 0.001) existed. Stepwise linear regression showed that when the factors of age, MoCA scores, hearing thresholds, and education level were considered, only age and MoCA scores contributed independently to the SRT results (overall model r = 0.30, F = 38.8, p < 0.001). Subjective hearing complaints from the AIAH supported the HINT results. AIAH and MoCA scores were also related (r = 0.05, F = 8.5, p = 0.004), with those with worse MoCA scores having more problems on the AIAH. When the cohort was divided into those with normal and abnormal performance on the MoCA, those with abnormal performance on the MoCA had significantly higher average SRTs (p < 0.001). CONCLUSIONS: Understanding speech in noise measured both objectively with the HINT and subjectively with the AIAH was inversely related to cognitive abilities despite a normal ability to hear soft sounds determined by audiometry. Although age was also an important independent factor affecting speech perception, the age relationship within the speech findings in this study may represent more than just age-related declines in speech in noise understanding. Although reliable data on disease duration are not available, the older members of this cohort likely had HIV longer and probably had more severe symptoms at presentation than the younger members because early detection and treatment of HIV in Shanghai has improved over time. Therefore, the age relationship may also include elements of disease duration and severity. Speech perception, especially in challenging listening conditions, involves cortical and subcortical centers and is a demanding neurological task. The problems interpreting speech in noise HIV+ individuals have may reflect HIV-related or HIV treatment-related, central nervous damage, suggesting that CNS complications in HIV+ individuals could potentially be diagnosed and monitored using central auditory tests.

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.

Auditory Impairments in HIV-Infected Children.

OBJECTIVES: In a cross-sectional study of human immunodeficiency virus (HIV)-infected adults, the authors showed lower distortion product otoacoustic emissions (DPOAEs) in HIV+ individuals compared with controls as well as findings consistent with a central auditory processing deficit in HIV+ adults on antiretroviral therapy. The authors hypothesized that HIV+ children would also have a higher prevalence of abnormal central and peripheral hearing test results compared with HIV- controls. DESIGN: Pure-tone thresholds, DPOAEs, and tympanometry were performed on 244 subjects (131 HIV+ and 113 HIV- subjects). Thirty-five of the HIV+, and 3 of the HIV- subjects had a history of tuberculosis treatment. Gap detection results were available for 18 HIV- and 44 HIV+ children. Auditory brainstem response results were available for 72 HIV- and 72 HIV+ children. Data from ears with abnormal tympanograms were excluded. RESULTS: HIV+ subjects were significantly more likely to have abnormal tympanograms, histories of ear drainage, tuberculosis, or dizziness. All audiometric results were compared between groups using a two-way ANOVA with HIV status and ear drainage history as grouping variables. Mean audiometric thresholds, gap detection thresholds, and auditory brainstem response latencies did not differ between groups, although the HIV+ group had a higher proportion of individuals with a hearing loss >25 dB HL in the better ear. The HIV+ group had reduced DPOAE levels (p < 0.05) at multiple frequencies compared with HIV- subjects. No relationships were found between treatment regimens or delay in starting treatment and audiological parameters. CONCLUSIONS: As expected, children with HIV+ were more likely to have a history of ear drainage, and to have abnormal tympanograms. Similar to the adult findings, the HIV+ group did not show significantly reduced audiometric thresholds, but did have significantly lower DPOAE magnitudes. These data suggest that (1) HIV+ children often have middle ear damage which complicates understanding the direct effects of HIV on the hearing system, and (2) even when corrected for confounders DPOAEs were lower in the HIV+ group. Previous studies suggest ototoxicity from antiretroviral drugs is an unlikely cause of the reduced DPOAE magnitudes. Other possibilities include effects on efferent pathways connecting to outer hair cells or a direct effect of HIV on the cochlea.

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).

Auditory impairments in HIV-infected individuals in Tanzania.

OBJECTIVES: Abnormal hearing tests have been noted in human immunodeficiency virus (HIV)-infected patients in several studies, but the nature of the hearing deficit has not been clearly defined. The authors performed a cross-sectional study of both HIV+ and HIV- individuals in Tanzania by using an audiological test battery. The authors hypothesized that HIV+ adults would have a higher prevalence of abnormal central and peripheral hearing test results compared with HIV- controls. In addition, they anticipated that the prevalence of abnormal hearing assessments would increase with antiretroviral therapy (ART) use and treatment for tuberculosis (TB). DESIGN: Pure-tone thresholds, distortion product otoacoustic emissions (DPOAEs), tympanometry, and a gap-detection test were performed using a laptop-based hearing testing system on 751 subjects (100 HIV- in the United States, plus 651 in Dar es Salaam, Tanzania, including 449 HIV+ [130 ART- and 319 ART+], and 202 HIV-, subjects. No U.S. subjects had a history of TB treatment. In Tanzania, 204 of the HIV+ and 23 of the HIV- subjects had a history of TB treatment. Subjects completed a video and audio questionnaire about their hearing, as well as a health history questionnaire. RESULTS: HIV+ subjects had reduced DPOAE levels compared with HIV- subjects, but their hearing thresholds, tympanometry results, and gap-detection thresholds were similar. Within the HIV+ group, those on ART reported significantly greater difficulties understanding speech in noise, and were significantly more likely to report that they had difficulty understanding speech than the ART- group. The ART+ group had a significantly higher mean gap-detection threshold compared with the ART- group. No effects of TB treatment were seen. CONCLUSIONS: The fact that the ART+/ART- groups did not differ in measures of peripheral hearing ability (DPOAEs, thresholds), or middle ear measures (tympanometry), but that the ART+ group had significantly more trouble understanding speech and had higher gap-detection thresholds indicates a central processing deficit. These data suggest that: (1) hearing deficits in HIV+ individuals could be a CNS side effect of HIV infection, (2) certain ART regimens might produce CNS side effects that manifest themselves as hearing difficulties, and/or (3) some ART regimens may treat CNS HIV inadequately, perhaps due to insufficient CNS drug levels, which is reflected as a central hearing deficit. Monitoring of central hearing parameters could be used to track central effects of either HIV or ART.

Machine learning for predicting cognitive deficits using auditory and demographic factors.

IMPORTANCE: Predicting neurocognitive deficits using complex auditory assessments could change how cognitive dysfunction is identified, and monitored over time. Detecting cognitive impairment in people living with HIV (PLWH) is important for early intervention, especially in low- to middle-income countries where most cases exist. Auditory tests relate to neurocognitive test results, but the incremental predictive capability beyond demographic factors is unknown. OBJECTIVE: Use machine learning to predict neurocognitive deficits, using auditory tests and demographic factors. SETTING: The Infectious Disease Center in Dar es Salaam, Tanzania. PARTICIPANTS: Participants were 939 Tanzanian individuals from Dar es Salaam living with and without HIV who were part of a longitudinal study. Patients who had only one visit, a positive history of ear drainage, concussion, significant noise or chemical exposure, neurological disease, mental illness, or exposure to ototoxic antibiotics (e.g., gentamycin), or chemotherapy were excluded. This provided 478 participants (349 PLWH, 129 HIV-negative). Participant data were randomized to training and test sets for machine learning. MAIN OUTCOME(S) AND MEASURE(S): The main outcome was whether auditory variables combined with relevant demographic variables could predict neurocognitive dysfunction (defined as a score of <26 on the Kiswahili Montreal Cognitive Assessment) better than demographic factors alone. The performance of predictive machine learning algorithms was primarily evaluated using the area under the receiver operational characteristic curve. Secondary metrics for evaluation included F1 scores, accuracies, and the Youden's indices for the algorithms. RESULTS: The percentage of individuals with cognitive deficits was 36.2% (139 PLWH and 34 HIV-negative). The Gaussian and kernel naïve Bayes classifiers were the most predictive algorithms for neurocognitive impairment. Algorithms trained with auditory variables had average area under the curve values of 0.91 and 0.87, F1 scores (metric for precision and recall) of 0.81 and 0.76, and average accuracies of 86.3% and 81.9% respectively. Algorithms trained without auditory variables as features were statistically worse (p < .001) in both the primary measure of area under the curve (0.82/0.78) and the secondary measure of accuracy (72.3%/74.5%) for the Gaussian and kernel algorithms respectively. CONCLUSIONS AND RELEVANCE: Auditory variables improved the prediction of cognitive function. Since auditory tests are easy-to-administer and often naturalistic tasks, they may offer objective measures or predictors of neurocognitive performance suitable for many global settings. Further research and development into using machine learning algorithms for predicting cognitive outcomes should be pursued.

Basophil-Derived IL-4 and IL-13 Protect Intestinal Barrier Integrity and Control Bacterial Translocation during Malaria.

Our previous work demonstrated that basophils regulate a suite of malaria phenotypes, including intestinal mastocytosis and permeability, the immune response to infection, gametocytemia, and parasite transmission to the malaria mosquito Anopheles stephensi. Given that activated basophils are primary sources of the regulatory cytokines IL-4 and IL-13, we sought to examine the contributions of these mediators to basophil-dependent phenotypes in malaria. We generated mice with basophils depleted for IL-4 and IL-13 (baso IL-4/IL-13 (-)) and genotype controls (baso IL-4/IL-13 (+)) by crossing mcpt8-Cre and Il4/Il13fl/fl mice and infected them with Plasmodium yoelii yoelii 17XNL. Conditional deletion was associated with ileal mastocytosis and mast cell (MC) activation, increased intestinal permeability, and increased bacterial 16S levels in blood, but it had no effect on neutrophil activation, parasitemia, or transmission to A. stephensi. Increased intestinal permeability in baso IL-4/IL-13 (-) mice was correlated with elevated plasma eotaxin (CCL11), a potent eosinophil chemoattractant, and increased ileal MCs, proinflammatory IL-17A, and the chemokines MIP-1α (CCL3) and MIP-1ß (CCL4). Blood bacterial 16S copies were positively but weakly correlated with plasma proinflammatory cytokines IFN-γ and IL-12p40, suggesting that baso IL-4/IL-13 (-) mice failed to control bacterial translocation into the blood during malaria infection. These observations suggest that basophil-derived IL-4 and IL-13 do not contribute to basophil-dependent regulation of parasite transmission, but these cytokines do orchestrate protection of intestinal barrier integrity after P. yoelii infection. Specifically, basophil-dependent IL-4/IL-13 control MC activation and prevent infection-induced intestinal barrier damage and bacteremia, perhaps via regulation of eosinophils, macrophages, and Th17-mediated inflammation.

Pure-tone audiometric threshold assessment with in-ear monitoring of noise levels.

OBJECTIVE: Our objective was to obtain reliable threshold measurements without a sound booth by using a passive noise-attenuating hearing protector combined with in-ear 1/3-octave band noise measurements to verify the ear canal was suitably quiet. DESIGN: We deployed laptop-based hearing testing systems to Tanzania as part of a study of HIV infection and hearing. An in-ear probe containing a microphone was used under the hearing protector for both the in-ear noise measurements and threshold audiometry. The 1/3-octave band noise spectrum from the microphone was displayed on the operator's screen with acceptable levels in grey and unacceptable levels in red. Operators attempted to make all bars grey, but focused on achieving grey bars at 2000 Hz and above. STUDY SAMPLE: 624 adults and 197 children provided 3381 in-ear octave band measurements. Repeated measurements from 144 individuals who returned for testing on three separate occasions were also analysed. RESULTS: In-ear noise levels exceeded the maximum permissible ambient noise levels (MPANL) for ears not covered, but not the dB SPL levels corresponding to 0 dB HL between 2000-4000 Hz. In-ear noise measurements were repeatable over time. CONCLUSIONS: Reliable audiometry can be performed using a passive noise-attenuating hearing protector and in-ear noise measurements.

Web-Based, Interactive, Interest-Based Negotiation Training for Managing Conflict in Isolated Environments: Opportunistic Study With an e-Survey.

BACKGROUND: Effective negotiation in relationships is critical for successful long-duration space missions; inadequate conflict resolution has shown serious consequences. Less desirable forms of negotiation, including positional bargaining (eg, negotiating prices), can exacerbate conflicts. Traditional positional bargaining may work for simple, low-stakes transactions but does not prioritize ongoing relationships. High-stakes situations warrant interest-based negotiation, where parties with competing interests or goals collaborate in a mutually beneficial agreement. This is learnable but must be practiced. Refresher training during conflicts is important to prevent out-of-practice crew members from using less effective negotiation techniques. Training should be self-directed and not involve others because, on a space mission, the only other people available may be part of the conflict. OBJECTIVE: We aimed to develop and test an interactive module teaching principles and skills of interest-based negotiation in a way that users find acceptable, valuable for learning, and enjoyable. METHODS: Using a web-based, interactive-media approach, we scripted, filmed, and programmed an interest-based negotiation interactive training module. In the module, the program mentor introduces users to "The Circle of Value" approach to negotiation and highlights its key concepts through interactive scenarios requiring users to make selections at specific decision points. Each selection prompts feedback designed to reinforce a teaching point or highlight a particular negotiation technique. To evaluate the module, we sought populations experiencing isolation and confinement (an opportunistic design). This included 9 participants in isolated, confined environments in the Australian Antarctic Program and the Hawai'i Space Exploration Analog and Simulation Mars simulation, as well as a subset of people who self-identified as being isolated and confined during the COVID-19 pandemic. Feedback was collected from participants (n=54) through free-response answers and questionnaires with numerical scaling (0=strongly disagree to 4=strongly agree) at the end of the module. RESULTS: In total, 51 of 54 (94%) participants found the activity valuable for learning about conflict management (identified by those who selected either "somewhat agree" or "strongly agree"), including 100% of participants in the isolated and confined environment subset (mode=3). In total, 79% (128/162) of participant responses indicated that the module was realistic (mode=3), including 85% (23/27) of responses from participants in isolated and confined environments (mode=3). Most participants felt that this would be particularly valuable for new team members in an isolated, confined environment (46/54, 85% of all participants, mode 4; 7/9, 78% of the isolated and confined environment subset, mode 3) as well as veterans. CONCLUSIONS: This module offers a self-directed, consistent approach to interest-based negotiation training, which is well received by users. Although the data are limited due to the opportunistic study design, the module could be useful for individuals in isolated and confined environments and for anyone involved in high-stakes negotiations where sustaining relationships is essential.