Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer’s disease and 30 patients representing the three canonical syndromes of primary progressive aphasia , compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility.P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer’s disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals.We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients’ brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer’s disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications. et al. show that people with Alzheimer’s disease and progressive aphasia are impaired versus healthy controls on a degraded speech comprehension task. Using voxel-based morphometry, they show that impaired task performance correlates with atrophy of a fronto-temporal cortical network previously implicated in degraded speech processing.Jiang  This process, normally automatic and relatively effortless, is impaired in neurodegenerative disorders such as Alzheimer’s disease and the ‘language-led’ dementia syndromes of the primary progressive aphasia (PPA) spectrum.4–8Successful communication in the world at large depends on our ability to understand spoken messages under non-ideal listening conditions. In our daily lives, we are required to interpret speech that is acoustically degraded by a wide variety of different ways—we regularly conduct conversations over background noise, adapt to suboptimal telephone and video connections and interpret unfamiliar accents. The processing of such degraded speech signals presents the brain with a challenging computational problem, whereby acoustic signals (or ‘auditory objects’) of interest must be disambiguated from interfering (and changing) noise.10 While most studies addressing this linkage have focused on peripheral hearing function measured using the detection of pure tones,12 mounting evidence suggests that measures of central hearing (auditory brain) function and in particular, the comprehension of degraded speech signals, may be more pertinent.14 Large cohort studies have identified impaired comprehension of degraded messages as a harbinger of dementia.16 More specifically, Alzheimer’s disease has been shown to impact speech-in-noise perception17 and identification of dichotic digits.18–20 This is likely to reflect, at least in part, a generic impairment of auditory scene analysis in Alzheimer’s disease, affecting the parsing of non-verbal as well as verbal information and linked to degeneration of the core temporo-parietal ‘default mode’ network targeted by Alzheimer’s disease pathology.21–24Hearing impairment has recently been identified as a major risk factor for dementia and a driver of cognitive decline and disability.25–28 sinewave speech30 and noise-interrupted speech,31 suggesting that neurodegenerative pathologies impair the processing of degraded speech signals more generally. However, the neural mechanisms responsible, the types of speech degradation that are implicated in everyday listening and the effects of different neurodegenerative pathologies have not yet been fully clarified. There are several grounds on which the processing of degraded speech may be especially vulnerable to neurodegenerative pathologies.5 Neuroanatomically, the processing of degraded speech signals engages distributed neural networks in perisylvian, prefrontal and posterior temporo-parietal cortices: these same brain networks are targeted preferentially in PPA, particularly the non-fluent/agrammatic variant and logopenic variant syndromes.33 Computationally, the comprehension of degraded speech signals depends on precise, yet dynamic integration of information across neural circuitry35 and neurodegenerative pathologies are likely to blight these computations early and profoundly.Further, both Alzheimer’s disease and PPA syndromes impair comprehension of non-native accents,36 This procedure degrades the spectral content of the speech signal while preserving its overall longer range temporal structure. The level of intelligibility of the noise-vocoded speech signal can be controlled parametrically: fewer channels is equivalent to less spectral detail available, leading to less intelligible speech. Noise-vocoding simulates the acoustic characteristics of a cochlear implant, and noise-vocoded speech per se will not be encountered by most listeners in everyday life. However, among various alternative methods,5 noise-vocoding has certain attributes that make it attractive as a model paradigm to study the effects of disease on the processing of degraded speech more generally.One widely used technique for altering speech signals experimentally is noise-vocoding, whereby a speech signal is divided digitally into discrete frequency bands (‘channels’), each filled with white noise and modulated by the amplitude envelope of the original signal.36–42 As an exemplar of acoustic degradation based on reduction of spectral information, it is likely to capture auditory brain processes engaged by a variety of daily listening scenarios that require decoding of ‘noisy’ speech signals . In contrast to speech-in-noise techniques , noise-vocoding degrades the intrinsic features of the speech signal. It therefore opens a window on auditory perceptual and cognitive processes complementary to those engaged in processing sound scenes . Comprehension of noise-vocoded speech is likely to be more dependent on auditory object (phonemic) decoding than selective attention: indeed, perceptual and electrophysiological processing of noise-vocoded speech and acoustically degraded conspecific call sounds has been demonstrated in non-human primates,43–47 suggesting that noise-vocoding may engage a fundamental neural integrative mechanism for decoding vocal signals in primate auditory cortex. Further, noise-vocoding offers the substantial advantage of generating a quantifiable threshold for intelligibility of the degraded speech signal, based on the number of vocoding channels. This potentially allows for a more sensitive, graded and robust determination of deficit, enabling comparisons between diseases, tracking of disease evolution and potentially, assessing the impact of therapeutic interventions.Noise-vocoding has been widely studied and its behavioural and neuroanatomical correlates in the healthy human brain are fairly well established.48 This work showed that patients with nfvPPA rely more on cross-modal cues to disambiguate vocoded speech signals, and have inflexible predictive decoding mechanisms, instantiated in left inferior frontal cortex. However, noise-vocoding has not been exploited as a tool to compare degraded speech perception in different neurodegenerative syndromes. More generally, the cognitive and neuroanatomical mechanisms that mediate the processing of degraded speech and their clinical relevance in this disease spectrum remain poorly defined.Noise-vocoding has been previously applied in a joint behavioural and magnetoencephalographic (MEG) study of non-fluent/agrammatic variant PPA (nfvPPA), to assess the brain mechanisms that mediate comprehension of degraded speech in the context of relatively focal cerebral atrophy.48 and other degraded speech stimuli (e.g. speech-in-noise16 and sinewave speech29) in Alzheimer’s disease and PPA patients, we hypothesized that both Alzheimer’s disease and PPA patients would have elevated thresholds for comprehending noise-vocoded speech compared with healthy controls, and that this deficit would be more severe in nfvPPA and logopenic variant PPA (lvPPA) than in other neurodegenerative syndromes. We further hypothesized that elevated noise-vocoded intelligibility threshold (as an index of impaired comprehension of degraded speech) would be correlated over the combined patient cohort with regional grey matter atrophy in left posterior superior temporal, inferior parietal and inferior frontal cortices: a network of brain areas previously implicated in the processing of noise-vocoded speech in the healthy brain36–42 and targeted early and relatively selectively by neurodegenerative pathology in Alzheimer’s disease and PPA.49Here, using noise-vocoding, we evaluated the comprehension of acoustically degraded spoken messages in cohorts of patients with typical Alzheimer’s disease and with all major syndromes of PPA, referenced to healthy older listeners. We assessed how the understanding of noise-vocoded speech was related to other demographic and disease characteristics. We further assessed the structural neuroanatomical associations of the noise-vocoded speech intelligibility threshold in Alzheimer’s disease and PPA, using voxel-based morphometry (VBM) on patients’ brain magnetic resonance images. Based on available evidence with noise-vocoded51 No patients with pathogenic mutations were included.Nineteen patients with typical amnestic Alzheimer’s disease, eight patients with lvPPA, 10 patients with nfvPPA and 12 patients with semantic variant PPA (svPPA) were recruited via a specialist cognitive clinic. All patients fulfilled consensus clinical diagnostic criteria with compatible brain MRI profiles and had clinically mild-to-moderate disease.Twenty-five healthy older control participants with no history of neurological or psychiatric disorders were recruited from the Dementia Research Centre volunteer database. All participants had a comprehensive general neuropsychological assessment . None ha52Owing to the Covid-19 pandemic, some data for this study were collected remotely . We haveAll participants gave informed consent to take part in the study. Ethical approval was granted by the UCL-NHNN Joint Research Ethics Committees, in accordance with Declaration of Helsinki guidelines.https://uk.mathworks.com/) to generate acoustically altered stimuli with a prescribed level of degraded intelligibility  and 96 noise-vocoded with four stimuli for each number of channels, ranging from 1 to 24.The stimuli were administered binaurally in a quiet room via Audio-Technica ATH-M50X headphones at a comfortable fixed listening level (at least 70 dB). Data for 30 participants were collected remotely via video link during the Covid-19 pandemic .To familiarize the participants with the experimental procedure, they were first asked to repeat five three-digit numbers  that were spoken by the experimenter. Prior to presenting the experimental stimuli, participants were advised that the numbers they heard would vary in how difficult to understand they were, but that they should guess the number even if uncertain. Stimuli were presented in order of progressively decreasing channel number (intelligibility), first clear speech, then from 24 vocoding channels to one vocoding channel. On each experimental trial, the task was to repeat the number (or as many of the three digits as the participant could identify). Participants were allowed to write down the numbers they heard rather than speaking them if preferred; in scoring, we accepted the intended target digit as correct, even if imperfectly articulated. Responses were recorded for offline analysis. During the experiment, no feedback about performance was given and no time limits were imposed.Data were analysed in MATLAB® (vR2019b) and in R® (v4). For continuous demographic and neuropsychological data, participant groups were compared using ANOVA and Kruskal-Wallis tests ; group categorical data were compared using Fisher’s exact tests. Performance profiles in seven healthy control participants who performed the experiment both in person and subsequently remotely were very similar, justifying combining participants tested in person and remotely in the main analysis . An alph53 Individual participant and group mean psychometric curves were created for each diagnostic group using the MATLAB psignifit package. This package employs beta-binomial models that account for overdispersion of the fitted psychometric function, due (for example) to wide variation among individual patients.53 For each function, we report the following parameters: the binaural noise-vocoded speech intelligibility threshold (the number of vocoding channels at which 50% identification of noise-vocoded numbers was achieved); the slope of the function at the threshold point; lambda ; gamma ; and eta (a measure of overdispersion).Identification of noise-vocoded spoken numbers was scored according to the number of digits correct for each three-digit number . As three digits were presented on every trial, this scoring effectively yielded a total of 12 (4 × 3) data-points for each vocoding channel number, for each participant. As the perceptual effect of noise-vocoding scales is exponential , we applied a logarithmic (base 2) transformation to the data. The resulting data were then modelled using a Weibull sigmoid, a widely used function for fitting logarithmically scaled data.As the data were not normally distributed, we used non-parametric Kruskal Wallis tests to analyse psychometric parameters. Where the omnibus test was significant, we conducted Dunn’s tests to conduct pairwise comparisons between participant groups. We assessed the relationship of noise-vocoded speech intelligibility threshold to forward digit span over the whole patient cohort, using Spearman’s correlation; here, digit span provides a metric of each patient’s overall ability to repeat  natural spoken numbers. We further used Spearman’s correlation to assess, over the combined patient cohort, the relationship of intelligibility threshold to general demographic  and clinical  variables, executive performance [Wechsler Abbreviated Scale of Intelligence (WASI) Matrices] and measures of auditory perceptual function -3 subtest) .55Finally, receiver operating characteristic (ROC) curves were derived to assess the overall diagnostic utility of noise-vocoded speech comprehension in distinguishing each patient group from healthy controls. The binary classifier used was the 50% speech intelligibility threshold obtained from each psychometric function. The area under the ROC curve (AUC) was calculated for each syndromic group using parametric estimates in the pROC R package.1-weighted sagittal 3D magnetization prepared rapid gradient echo (MPRAGE) sequence , with dimensions 256 mm × 256 mm × 208 mm and voxel size 1.1 mm × 1.1 mm × 1.1 mm.Volumetric brain magnetic resonance images were acquired for 25 patients in a 3 T Siemens Prisma MRI scanner, using a 32-channel phased array head coil and following a Thttp://www.fil.ion.ucl.ac.uk/spm/software/spm12/) and the DARTEL toolbox with default parameters running under MATLAB R2014b. Images were smoothed using a 6-mm full-width at half-maximum (FWHM) Gaussian kernel. To control for individual differences in total (pre-morbid) brain size, total intracranial volume was calculated for each participant by summing white matter, grey matter and CSF volumes post-segmentation.56 An explicit brain mask was created using an automatic mask-creation strategy designed previously.57 A study-specific mean brain template image upon which to overlay statistical parametric maps was created by warping all patients’ native-space whole-brain images to the final DARTEL template and using the ImCalc function to generate an average of these images.For the VBM analysis, patients’ brain images were first preprocessed and normalized to MNI space using SPM12 software (P < 0.001) and assessed at peak-level significance threshold P < 0.05, after family-wise error (FWE) correction for multiple voxel-wise comparisons within five separate predefined regions of interest, specified during the design of the study, and based on previously published work on degraded speech perception in the healthy brain and in neurodegenerative disease: these regions, which together constitute a distributed neural network processing degraded speech signals, comprised left planum temporale,39 left angular gyrus,40–42 left anterior superior temporal gyrus,59 left inferior frontal gyrus 58 and left cingulate gyrus.60 Anatomical volumes were derived from Oxford-Harvard cortical maps61 and are shown in We assessed grey matter associations of noise-vocoded speech intelligibility threshold over the combined patient cohort. Voxel-wise grey matter intensity was modelled as a function of performance threshold in a multiple regression design, incorporating age, total intracranial volume and diagnostic group membership as covariates. Statistical parametric maps were generated using an initial cluster-defining threshold , with the Alzheimer’s disease , lvPPA  and nfvPPA  PPA groups being older on average than the svPPA group. Patient groups did not differ in mean symptom duration (P = 0.09) but did differ in MMSE score . In post hoc pairwise group comparisons versus healthy controls, mean intelligibility threshold was significantly elevated in all patient groups: in the lvPPA , nfvPPA , Alzheimer’s disease  and svPPA  groups. Comparing patient groups, intelligibility threshold was significantly elevated in the Alzheimer’s disease  and lvPPA  groups compared with the svPPA group. There was no significant effect of diagnostic group on the slope of the psychometric function (P = 0.347). There was a significant main effect of diagnostic group on the lapse rate, lambda . In post hoc pairwise group comparisons versus healthy controls, there was a significantly higher lapse rate (more errors made at maximum performance) in all patient groups: in the lvPPA , Alzheimer’s disease , nfvPPA , and svPPA  groups. There were no significant differences between patient groups for lapse rate. There was a significant main effect of diagnostic group on the guess rate, gamma . In post hoc pairwise group comparisons, there was a significantly higher gamma rate (i.e. more correct answers made at minimum performance) in the healthy control group than any patient groups (P < 0.05). There was no significant effect of diagnostic group on eta (overdispersion of the data) of the psychometric function (P = 0.118). Group effect sizes , phonological discrimination in clear speech , age  or symptom duration . Intelligibility threshold in the patient cohort was significantly correlated with WASI Matrices score , MMSE score  and forward digit span    . Lapse r= 0.018) .65), discrimination was ‘excellent’ for the lvPPA group , Alzheimer’s disease group  and nfvPPA group  and ‘fair’ for the svPPA group .Analysis of ROC curves revealed that noise-vocoded speech intelligibility threshold discriminated all patient groups well from healthy controls. Based on AUC values .Across the combined patient cohort, intelligibility threshold was significantly negatively associated with regional grey matter volume (i.e. associated with grey matter atrophy) in left planum temporale, left angular gyrus and anterior cingulate gyrus  speech is impaired in patients with Alzheimer’s disease and PPA syndromes relative to healthy older listeners, and further, stratifies syndromes: impairment was most severe in lvPPA and nfvPPA, and significantly more severe in Alzheimer’s disease than in svPPA. Intelligibility threshold for noise-vocoded speech did not correlate with measures of pure tone detection or phoneme discrimination in clear speech, suggesting that the deficit does not simply reflect a problem with peripheral hearing or elementary speech perception. Individual noise-vocoded speech intelligibility threshold varied widely within the Alzheimer’s disease, lvPPA and nfvPPA groups. Our findings suggest that elevation in noise-vocoded speech intelligibility threshold in these dementia syndromes captures a central auditory impairment potentially relevant to difficulties in diverse everyday listening situations requiring the decoding of acoustically altered speech signals.66 Planum temporale is likely to play a fundamental role in the deconvolution of complex sound patterns and engagement of neural representations corresponding to phonemes and other auditory objects.67 Angular gyrus mediates the disambiguation of speech signals in challenging listening environments, working memory for speech signals and transcoding of auditory inputs for motor responses, including orienting and repetition.67–70 Both regions are targeted in Alzheimer’s disease, lvPPA and nfvPPA71–74 and have been particularly implicated in the pathogenesis of impaired speech perception in these diseases.75 The anterior cingulate cortex operates in concert with these more posterior cortical hubs to decode spoken messages under challenging listening conditions,60 with a more general role in cognitive control and in allocating attentional resources to salient stimuli.77 Reduced activation of the anterior cingulate cortex during tracking of information in degraded speech signals has been demonstrated in nfvPPA and svPPA.33Neuroanatomically, impaired noise-vocoded speech comprehension across dementia syndromes was underpinned by atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus. This cortical network has been shown to be critical for processing speech signals under a range of noisy, daily listening conditions.2 Noise-vocoding fundamentally reduces the availability of acoustic cues that define phonemes as auditory objects: impaired recognition of these degraded auditory objects could in principle result from deficient encoding of acoustic features, damaged object–level representations  or impaired top-down, predictive disambiguation based on stored knowledge about speech signal characteristics. In Alzheimer’s disease and lvPPA, a core deficit of object-level representations has been demonstrated neuropsychologically and electrophysiologically using other procedures that alter acoustic detail in phonemes and non-verbal sounds79; it is therefore plausible that an analogous apperceptive deficit may have impacted the recognition of noise-vocoded phonemes in the Alzheimer’s disease and lvPPA groups here. In nfvPPA, one previous MEG study of noise-vocoded speech perception has foregrounded the role of inflexible top-down predictive decoding mechanisms , instantiated in frontal cortex.48 However, this is a clinically, neuroanatomically and neuropathologically diverse syndrome, and involvement of posterior superior temporal cortex engaged in early auditory pattern analysis may constitute a ‘second hit’ to phoneme recognition.81 In svPPA, the elevated noise-vocoded intelligibility threshold is a priori more likely to reflect reduced activation of semantic mechanisms engaged in the predictive disambiguation of degraded speech signals; and indeed, comprehension of other kinds of acoustically degraded speech signals by patients with svPPA has previously been shown to be sensitive to semantic predictability and to engage anterior cingulate cortex.33These neuroanatomical considerations suggest that the mechanisms of impaired noise-vocoded speech intelligibility are likely to differ between neurodegenerative syndromes, in keeping with the dissociable processes involved in phoneme recognition.83 As working memory demands did not vary across trials and number of vocoding channels, the principal driver of intelligibility threshold is likely to have been the level of acoustic alteration in the speech signal. On the other hand, all patient groups showed an increased lapse rate (i.e. errors unrelated to the stimulus level53) at higher vocoding channel numbers . This echoes previous work demonstrating that active listening can be abnormal in lvPPA and nfvPPA even for clear speech and other sounds in quiet.84 As lapse rate was also correlated with digit span, this suggests that reduced working memory may influence performance at the upper asymptote, potentially interacting with top-down mechanisms engaged in the predictive processing of speech.48 Indeed, frontal processes are likely to play a broader role in the disambiguation of degraded speech signals, including the allocation of attentional and executive resources85 and according with the observed correlation here between noise-vocoded speech intelligibility threshold and WASI Matrices score. Taken together, the present findings corroborate the profiles of deficit previously documented in Alzheimer’s disease and PPA syndromes for comprehension of sinewave speech and phonemic restoration in noise-interrupted speech.31Increasing intelligibility threshold was correlated with digit span over the combined patient cohort. This suggests that verbal working memory limitations may be integrally related to impaired processing of degraded speech, consistent with previous work highlighting the role of working memory in speech perception, particularly in older adults.65 However, the smaller sample size does need to be taken into consideration for the ROC analysis. Additionally, the noise-vocoded intelligibility threshold was correlated with overall disease severity (MMSE score) in the patient cohort. These findings build on a growing body of work suggesting that markers of ‘central’ hearing (auditory cognition) may sensitively signal the functional integrity of cortical regions that are vulnerable to Alzheimer’s disease and other neurodegenerative pathologies.16 The results of this study could further motivate the development of tailored strategies to help manage hearing difficulties experienced by people with dementia in various daily-life contexts and environments.Our findings further suggest that markers of noise-vocoded speech comprehension may have diagnostic and biomarker potential. The ROC analysis on the noise-vocoded intelligibility threshold measure  suggests30) and/or by perceptual learning, as in healthy listeners.86–88 Using another kind of speech degradation (sinewave transformation), we have previously shown that pharmacological and perceptual learning effects may operate in Alzheimer’s disease and PPA syndromes.30 To establish how noise-vocoded speech perception and its modulatory factors relate to neural circuit integrity in Alzheimer’s disease PPA, functional neuroimaging using techniques such as functional MRI and MEG will be required to capture dynamic network connectivity engaged by these processes and the neural mechanisms that represent and decode vocoded speech sounds. Furthermore, whilst a direct comparison across sensory modalities was beyond the scope of the present study, the perceptual processing deficit presented here in the auditory domain may extend to other sensory domains, such as vision.89 It would be of particular interest to assess whether cross-modal sensory cues can be used to help disambiguate degraded speech signals in patients with Alzheimer’s disease and PPA.This study has limitations that suggest directions for further work. Our noise-vocoding paradigm (based on a step-wise linear progression through channel numbers) was not optimally efficient; an adaptive staircase procedure would reduce testing time and allow individual thresholds to be captured without administering uninformative trials at higher channel numbers. It would be relevant to assess to what extent patients’ comprehension of noise-vocoded speech can be modulated: pharmacologically  will likely entail multicentre collaboration. Besides corroborating the present group findings, assessment of larger cohorts would allow characterization of the sources of the wide individual variation within diagnostic groups. There is also a need for prospective, longitudinal studies—both to assess how markers of degraded speech perception relate to disease course and to determine how early such markers may signal underlying neurodegenerative pathology. Auditory measures based on degraded speech comprehension would be well suited to future digital applications and potentially to large-scale screening of populations at risk of incident Alzheimer’s disease, as well as outcome measures in clinical trials of pharmacotherapies and non-pharmacological interventions.90 while degraded speech performance may have better predictive value in patients with dementia.91 There would be considerable clinical value in a quantifiable index of degraded speech perception that could serve as a proxy and predictor of daily life hearing function and disability in major dementias: comprehension of noise-vocoded speech is a promising candidate.The key next step, however, will be to establish how well measures of degraded speech comprehension, not solely noise-vocoding but also other ethologically relevant adverse speech listening tests, correlate with daily-life hearing and communication in Alzheimer’s disease and other neurodegenerative diseases—using both currently standardized symptom questionnaires and bespoke instruments developed to capture functional hearing disability in dementia. We have previously shown that pure tone audiometry alone is a poor predictor of everyday hearingThe link between hearing impairment and dementia continues to be debated but presents a major opportunity for earlier diagnosis and intervention. Our findings suggest that the perception of degraded (noise-vocoded) speech quantifies central hearing functions beyond sound detection in dementia and stratifies major dementia syndromes. This central hearing index may constitute a proxy for the communication difficulties experienced by patients with Alzheimer’s disease and PPA under challenging listening conditions in daily life. We hope that this work will motivate further studies to define the diagnostic and therapeutic scope of central hearing measures based on degraded speech perception in these diseases.awad163_Supplementary_DataClick here for additional data file.


Amiodarone is a potent antiarrhythmic medication used to treat life-threatening ventricular arrhythmias; however, its well-established adverse effect is a thyroid disorder. Amiodarone-induced thyroiditis (AIT), a clinical entity involving two types with different etiopathology and treatment approaches, may occur at the beginning or even several years after amiodarone treatment discontinuation. The toxicity profile of amiodarone becomes especially important in young patients with lifelong cardiac disorders, which are often refractory to other antiarrhythmic drugs. Herein, we report the first case of non-sustained ventricular tachycardia (NSVT), an unusual presentation of type II AIT, in a young male patient who was previously diagnosed with left ventricular cardiomyopathy with excessive trabeculation.99mTc-2-methoxyisobutylisonitrile (sestamibi) revealed decreased thyroid uptake; hence, prednisone was introduced for treatment. Clear improvements in both biochemical and electrocardiographic parameters were observed after immunomodulatory treatment of type II AIT in this young patient with cardiomyopathy and excessive trabeculation.A 36-year-old male non-athlete presented with tiredness during regular follow-up. Continuous electrocardiographic monitoring (cECG) revealed NSVT, whereas echocardiography and cardiac magnetic resonance imaging detected discrete structural and functional changes that could not fully explain the observed cECG report. Conversely, an unmeasurably low thyrotropin level on admission and previous exposure to amiodarone pointed the diagnostic pathway in the direction of the thyroid gland. Elevated free thyroxine and undetectable autoantibody titers with unremarkable sonographic findings raised clinical suspicion of type II AIT. Scintigraphic imaging with Treatment of reversible causes of cardiac rhythm abnormalities such as type II AIT should be considered before choosing other treatment modalities, particularly in patients with structural cardiac disorders. The importance of a multidisciplinary approach in complex cases such as the one reported, thus, cannot be emphasized enough. The ins99mTc-sestamibi thyroid uptake on scintigraphy and absent vascularity on color flow Doppler ultrasound suggest the diagnosis of type II AIT, detectable radioiodine uptake, increased vascularity, and elevated serum levels of autoantibodies directed towards thyroid peroxidase, thyroglobulin and/or thyrotropin receptor are typically found in patients with type I AIT  occurs in patients with a prominent increase in thyroid hormone production, as a consequence of an underlying thyroid condition such as latent Graves' disease or multinodular goiter. Conversely, the direct cytotoxic effect of amiodarone in patients with no underlying thyroid disorder leads to the destructive phenotype of type II AIT with increased release of thyroid hormones. Although mixed types of AIT may be observed, the distinction between type I and type II is the crucial step in the management of these patients because of the difference in the therapeutic approach consisting of thyroid suppressant or corticosteroid medications, respectively . While dpe I AIT –7. Reseape I AIT .Regardless of the type, AIT is associated with increased mortality independent of thyroid hormone levels and age but is strongly associated with severe left ventricular dysfunction . Few cas2.A 36-year-old male non-athlete presented with tiredness and a slight limitation of physical activity during regular follow-up for a structural cardiac disorder. The diagnosis of cardiomyopathy with excessive trabeculation , or accoOn admission, echocardiography and cardiac magnetic resonance imaging were performed to determine the presence of structural deterioration that could be attributed to the observed dysrhythmic changes. Recently performed coronary angiography with no evidence of stenosis or atherosclerosis excluded the ischemic etiology of NSVT. Transthoracic echocardiography using Vivid E95 Cardiac Ultrasound  revealed a degenerative aortic and mitral valve with normal overture and kinetics maintained, respectively. Myocardial thickness was normal, but global hypokinesia was described while the interventricular septum and the inferoposterior wall of the myocardium showed decreased contractility. The global ejection fraction of the left ventricle was estimated to be 45%. Additionally, transmitral diastolic flow with a biphasic pattern of abnormal LV relaxation (I/IV grade LV diastolic dysfunction) was noted. Cine cardiac magnetic resonance (CMR) steady-state free precession sequences showed a dilated left ventricle with septum hypo-dyskinesia and an ejection fraction of 48%, as well as excessive trabeculation in segments 13, 15, and 16, and a part of segments 7 and 10 with a non-compact to compact myocardium (NC/C) ratio higher than 2.3 in end-diastole . In the Pathological non-compaction, distinguished by an NC/C ratio higher than 2.3 in diastole, was the main morphological criterion used for the validation of LVNC two years before the current admission . The lef99mTc-sestamibi showed decreased thyroid uptake  and undetectable titers of thyroid-stimulating immunoglobulin, thyroid peroxidase, and thyroglobulin antibodies raised the clinical suspicion of type II AIT in a patient with previous exposure to amiodarone. Neck ultrasound was unremarkable, and color flow Doppler sonography did not show increased thyroid vascularity. Moreover, scintigraphic imaging after intravenous injection of 375 MBq d uptake . These fPatient-reported adherence to treatment was adequate and no adverse or unanticipated events were reported. After only a week of corticosteroid treatment, TSH was 0.01 mIU/L and free thyroxine level dropped to 26 pmol/L . After 22.1.“When I got admitted to the hospital, I was afraid. I did not know what caused that feeling of tiredness, but I was relieved once the doctors found the correct diagnosis. They explained everything to me, and I was very satisfied with the care during the hospital stay. Now, I am living a bit more cautiously, and I know my limitations. I understand how important it is to take my medications every day and attend regular follow-ups. At this point, I do not have any fears but know where to seek help if it changes. I would be happy to help other doctors learn from my case.”3.Excessive trabeculation of the left ventricle is a rare ventricular phenotype, affecting between 0.05% and 0.25% of the population, routinely quantified by cardiac imaging techniques, including CMR and echocardiography . The abnThe potent antiarrhythmic action of amiodarone tends to outweigh the risks of its toxicity, which was first described more than half a century ago , 22. AmiThe challenging path to the correct diagnosis and treatment of patients with AIT has been extensively studied and described in the literature –8. HowevTreatment of reversible causes of cardiac rhythm abnormalities such as type II AIT should be considered before choosing other treatment modalities, particularly in patients with structural cardiac disorders. The importance of a multidisciplinary approach in complex cases such as the one reported thus cannot be emphasized enough.


Autophagy is a cellular self-degradation process which plays an important role in cellular homeostasis by eliminating malfunctioning proteins and damaged organelles favoring cellular regeneration . In cancRecent advances in the modern field of nanotechnology make possible to counteract human diseases with effective bioactive compounds, overcoming the obstacles of traditional drugs such as biodistribution, biocompatibility and degradation or stability . InteresThis Research Topic gathers original research and review papers on novel drugs in cancer treatments based on autophagy modulation as well as the application of novel nanomedicines capable of modulating autophagy, and/or new discoveries in autophagy-related signaling pathways in cancer. The 9 accepted articles consist of 5 Original Research articles, 3 Reviews and 1 Brief Research article. Overall, these studies demonstrate that inhibition or enhancement of the autophagy pathway may serve as an effective tool to counteract cancer.Wang et al. and Chavda et al. focused on the therapeutic effects and mechanisms of plant-derived natural products as well as combination therapy on cancer disease. The authors discussed the tumor suppressor role of several natural compounds in autophagy modulation and the recent strategies of their encapsulation to generate effective nano-delivery tools for targeted therapies in cancer. The translational potential of such nanoformulations in the clinic is also discussed. This review aims to elicit the interest of the community for developing anticancer strategies in both cellular and animal models, with high efficacy and low side effects.In the last years, many herbal medicines and bioactive natural products have been explored for their antitumoral efficacy through modulation of key cellular signaling routes involving autophagy . In thisNazir et al. described the synthesis of 3-O-prenyl glycyrrhetinic acid (NPC-402), a derivative of glycyrrhetinic acid, and reported its cytotoxic activity in melanoma in in vitro and in vivo models. They showed that NPC-402 induces endoplasmic reticulum stress-mediated autophagy through modulation of an ERK/AKT signaling pathway in melanoma cells and reduces the tumor size and weight without any toxic side effects in C57BL/6J mice. Since methods to encapsulate NPC-402 in nanoformulations have been previously described -1H-indole-2-carbohydrazide (IHZ-1/ZJQ-24), a novel indole hydrazide derivative with bioactive proprieties for the management of liver cancer, has been evaluated. The authors showed that treatment with IHZ-1 in HCC cell lines increases the generation of intracellular reactive oxygen species (ROS) and induces autophagy through the activation of a ROS/JNK pathway. Interestingly, an indole hydrazide derivative has been encapsulated in different types of nanomaterials, such as hydrogels, pH-controlled biopolymers, or metal oxide nanoparticles, for their efficient delivery in cancer cells  has been explored for liver cancer treatment. In this regard, Hassan et al. showed that ZnO-NS synthesized by the Sol-gel method induced strong cytotoxic stress, ROS accumulation and lipid peroxidation in HuH7 cell line. They also reported lipid droplets accumulation and alterations in mitochondria leading to cell death. On the other side, the biochemical and mechanical proprieties of tumor microenvironment may affect drug distribution and release at the tumor site. To overcome this barrier, Yeow et al. produced a recombinant fusion protein consisting in tumor necrosis factor-α (TNF-α) and CSG peptide (CSGRRSSKC) to deplete extracellular matrix in liver cancer generated in mice models. This treatment was able to enhance an intra-tumoral accumulation of iron-oxide nanoparticles (IO-NPs) as determined by magnetic resonance imaging analysis. Since IO-NPs have been extensively studied as autophagy modulators in cancer therapy (escribed . Despiteer cells –11. Pacler cells –14. Xie  therapy , 16 this® and Abraxane® have already been used for breast cancer treatment as adjuvant therapy with favorable clinical outcomes (Gharoonpour et al. summarizes the advantages and disadvantages of nanoparticles-based therapy in breast cancer through autophagy modulation. The authors thoroughly discuss the translational potential of several nanoformulations combined with traditional chemotherapy, and the different phases of clinical trials involving nanomedicine that have been set up for breast cancer treatment. Moreover, Zhang et al. explored the therapeutic potential of chitosan/alginate nanoparticles for co-delivery of anti-autophagy drugs doxorubicin and hydroxychloroquine in breast cancer cells. This nanodelivery system was able to efficiently encapsulate these anti-autophagy drugs and allow their pH-sensitive release in the tumoral site.Breast cancer is the most common cancer that affect women worldwide. Despite significant progress, breast cancer remains the tumor with the highest mortality. Autophagy plays an important role during breast cancer genesis and progression participating in many phenotypic traits such as migration, invasion, and therapy resistance . Nanomedoutcomes . The revHence, the importance of the knowledge of the regulatory mechanisms of autophagy, along with the potential opportunities presented by newly emerging nanocarriers and nanomaterials suitable for bypassing developed cellular resistance, makes this topic particularly interesting. We believe that these advances will inspire basic and clinical scientists working in related fields to further investigate molecular mechanisms and to perform translational studies.MCor wrote the original draft and revised the manuscript. The other authors revised the manuscript and provided valuable suggestions. All authors listed have approved this manuscript for publication.


In recent years, innovative multiparty eye tracking setups have been introduced to synchronouslycapture eye movements of multiple individuals engaged in computer-mediated collaboration.Despite its great potential for studying cognitive processes within groups, themethod was primarily used as an interactive tool to enable and evaluate shared gaze visualizationsin remote interaction. We conducted a systematic literature review to provide acomprehensive overview of what to consider when using multiparty eye tracking as a diagnosticmethod in experiments and how to process the collected data to compute and analyzegroup-level metrics. By synthesizing our findings in an integrative conceptual framework,we identified fundamental requirements for a meaningful implementation. In addition, wederived several implications for future research, as multiparty eye tracking was mainly usedto study the correlation between joint attention and task performance in dyadic interaction.We found multidimensional recurrence quantification analysis, a novel method to quantifygroup-level dynamics in physiological data, to be a promising procedure for addressingsome of the highlighted research gaps. In particular, the computation method enables scholarsto investigate more complex cognitive processes within larger groups, as it scales up tomultiple data streams. In synchronous collaboration, defined as working together in real-time toachieve a common goal, our visual perception plays an important role inunderstanding the characteristics and constraints of a task and thesocial context in which it is embedded ; 15. FurDuring the last decade, novel eye tracking technologies have beenintroduced and leveraged to capture interdependent visual behaviorbetween individuals by implementing two eye trackers synchronously. This duDue to the global pandemic and worldwide confinements, virtualmeetings have been established as an efficient alternative toface-to-face communication. Therefore, understanding the characteristicsof social interaction in remote settings is more important than ever.Dual eye tracking is a promising methodology to investigateinterdependent cognitive processes between individuals incomputer-mediated collaboration. For instance, Jermann et al. observedRecently, a comprehensive overview of multiparty eye tracking setupsfor the study of social interaction has been provided by Valtakari etal. . HoweverIn order to address the outlined research gap, we conducted asystematic literature review following the guidelines by Kitchenham andCharters . AccordiThe development of the search strategy started with an initialexploration on Google Scholar by applying the following terms: “eyetracking” AND “collaboration”. After reviewing a sample of relevantpapers and according keywords, we defined a first version of the searchstring and specified it by several iterations. The final search stringconsisted of three parts see .The first part covered the most frequently used terms for indicatingeye tracking experiments. Furthermore, we included common keywordsrelating to a multiparty eye tracking setup as the second part. Thethird part limited the search to the context of collaboration. Ourinitial investigation highlighted that several studies referred tocollaboration as joint problem solving. Therefore, we also included thisterm. Furthermore, we decided not to add another part to the searchstring that limits the scope to studies explicitly referring to a remotesetting. However, computer-mediated communication was defined as aninclusion criterion. To collect all relevant literature, the next stepwas to compare various electronic databases by checking whether thepreviously identified sample of highly relevant papers could be found inthem. As a result, a combination of Scopus, Web of Science, ACM DigitalLibrary and EBSCOhost was selected to be appropriate for executing thesearch. We chose them to cover different research domains as it is aninterdisciplinary topic.In a further step, we defined the inclusion and exclusion criteria tobe followed when reviewing and selecting literature for data extractionsee .According to the scope of this article, only eye tracking studieswere selected. Due to the specific focus on collaboration, the firstcriterion was further specified to the synchronous tracking of at leasttwo participants’ eye movements. Furthermore, the experimental task hadto be characterized by a common objective and thus had to include sometype of collaborative activity as well as a measurable outcome variable,such as team performance. To address the specific context ofcomputer-mediated collaboration, only studies that featured remoteinteraction by providing individual and visually separated systems wereincluded. Finally, studies primarily concerned with the evaluation ofshared gaze visualizations based on multiparty eye tracking approacheswere excluded, since related findings are already covered by D’Angelo& Schneider  and do nIn the conducting phase, we executed the search strategy by applyingthe final search string to the selected databases. First, title andabstract of the identified literature were scanned following the definedselection criteria. Next, this procedure was repeated reviewing fulltexts. Finally, in an attempt to capture the entirety of relevantliterature, a forward and backward search was performed on GoogleScholar by checking the references of remaining studies and reviewingall articles that cited them. By carefully analyzing the final sample ofpapers, relevant aspects for answering the research question weredefined iteratively. The extracted data was tabulated accordingly toreport findings in a structured way see . FinallyIn this section, we first present the results of the review processin order to illustrate how the final sample of relevant literature wasacquired. In a subsequent step, the conceptual framework is introducedand described in detail by referring to the identified dimensions.The execution of the search strategy resulted in 1665 initial hits. 1529 irrelevant studies were excluded byscanning title and abstract. Next, another 114 were excluded byreviewing full texts. The forward and backward search performed with theremaining 22 studies resulted in another 3 hits. Thus, the final sampleof literature consisted of 25 relevant studies see .The integrative conceptual framework was developed by analyzing theextracted data and categorizing the identified aspects following abottom-up procedure see . RelevanDimension 1: Task & Context. Based on the particular activitiesperformed by collaborators, most tasks could be assigned to either acomputer-supported cooperative work-  or computer-supportedcollaborative learning-related context . The remaining taskswere labelled as artificial (12%).CSCW related tasks included software design activities referred to ascollaborative programming (28%) and cooperative decision-making taskscharacterized by the coordination on multiple attributes (24%). Forinstance, errors in a presented software code had to be discovered andmarked in a programming task . One of Dimension 2: Remote Interaction. Most studies investigated behaviorin dyadic interaction (92%). Only two studies tracked eye movements ofup to three participants simultaneously (8%). Furthermore, the abilityto interact with the tasks interface differed between the eye-trackedparticipants in eight studies, as they were assigned either an operatoror helper role (32%). In the other studies, all participants couldinteract with the interface equally using manual input devices (68%).Furthermore, the richness of the social interaction was determined bythe provided communication medium, ranging from simple chats (24%) toaudio- (64%) and mixed-media videoconferences (12%).Dimension 3: Data Collection. According to the focus oncomputer-mediated collaboration, only desktop-mounted eye trackers wereused in the studies. These were either screen-based devices integratedinto monitors (68%) or standalone devices set up next to the screen(32%). Moreover, most studies not only captured participants’ eyemovements (44%), but also other communication signals, such as speechand body language by recording audio (40%) and video logs (16%).Dimension 4: Data Processing. The computation methods used in theexamined studies were based on either the position or duration of gazepoints (92%). Two studies performed additional calculations with pupilsize data 8%; ; 33. In Dimension 5: Group-Level Metrics. Most studies performed thegroup-level computation methods to quantify joint attention (76%). Twostudies additionally operationalized the extent of joint mental effort(8%) by calculating a group’s cognitive load based on synchronized pupilsize data ; 33. VrzBy conducting the systematic literature review, we identifiedrelevant aspects that need to be considered when synchronously capturingand analyzing eye movements of multiple participants engaged incomputer-mediated collaboration. In this section, methodologicaldifferences in the usage of diagnostic multiparty eye tracking as wellas implications for future research avenues are critically discussedalong the conceptual framework.Despite adhering to the guidelines by Kitchenham and Charters ,the outIn order to investigate eye movements and gaze patterns ofcollaborating participants within a corresponding visual space, userinterfaces were shared in real time, contained a synchronized area, orwere duplicated within dyads ; 30;37.Furthermore, the ecological validity of the activities performeddiffered greatly between tasks. Gaze patterns identified in asynchronized visual search task, such as the change blindness taskintroduced by Tchanou et al. , might nWhen investigating visual behavior in virtual settings, certainproperties of the remote interaction context need to be considered.First, the number of involved participants determines the interaction’scomplexity . For insMoreover, participants were assigned either an operator or helperrole in nine studies. This creates an imbalance between collaborators asonly one is able to actively manipulate the tasks interface. As aresult, the validity of comparisons within a dyad is questionable asattentional processes related to the eye movements differed. Forexample, Belenky et al.  introducFurthermore, the richness of the computer-mediated communicationdiffered between studies as the degree of synchronization betweenparticipants and the presence of verbal and nonverbal cues wasdetermined by the communication medium featured .Chats, Eye movements of the participants have to be tracked synchronously tocapture interdependent dynamics of visual behavior. Although thisrequirement was already addressed by the inclusion criteria of thisreview, we identified considerable differences in the practicalimplementation of multiparty eye tracking. Recent studies usedstandalone desktop-mounted eye trackers instead of screen-based systems.This increases the area of application and makes it possible tointegrate eye tracking into more naturalistic settings. Furthermore,some studies used chin rests in order to prevent head movements andlimit a participant’s field of view to the screen ; 29. AltIn addition, most studies also collected audio and video logs inorder to investigate the relationship between gaze and othercommunication signals. Predominantly, the association between eyemovements and speech was analyzed as referring expressions can beprecursors of joint visual attention ; 25; 30As previously mentioned, studies followed a similar processingprocedure that included the division of the interface into smallersegments, the calculation of each participant’s individual metrics andfinally the specific computation method to quantify group-level eyemovement metrics.Cross Recurrence Quantification Analysis (CRQA). The majority ofstudies used CRQA to identify the degree of convergence between twoparticipants’ gaze locations over time. In order to identify recurrentstates between two temporal streams of eye movement data, the individualtime series of each participant’s fixations are initially cut into equalintervals . Next, each interval is assigned theAOI that contained the majority of gaze points during the selectedduration. Finally, the recurrence rate between two participants isquantified by calculating the proportion of converging AOIs along thesegmented time series see .The procedure can be repeated for any time lag between both datastreams by shifting the segmented series of one participant in time.This is an essential aspect, as gaze is typically not visuallytransmitted in computer-mediated interaction and thus, might notconverge in real time, but after a short period of time . For insMultidimensional Recurrence Quantification Analysis (MdRQA).Recently, Vrzakova et al.  performeThus, MdRQA can be used to investigate more complex processes betweenindividuals by operationalizing constructs of interest based on certainAOI compositions . Sharma et al.  developeIn a subsequent step, the similarity between two participants’ gazepatterns is computed by calculating either the scalar product or thereverse function of the proportionality vectors correlation matrix; 28. As Compared to recurrence analysis, the computation method is easier toperform as it requires fewer procedural steps. However, the conceptualdifferences between gaze convergence and gaze similarity have to beconsidered when investigating collaborative patterns incomputer-mediated collaboration. In contrast to CRQA, the exact order offixation locations along a time series is not taken into account. Thus,spatio-temporal dynamics of collaborative gaze could only beinvestigated by conducting recurrence analysis ; 36.Alternative Approaches. Sharma et al.  introducThe segmentation method should be considered when comparing episodesof visual behavior characterized by different degrees of couplingbetween participants. However, the proposed operationalization ofconvergence based on the range of fixated AOIs might be misleading,because the extent to which gaze spatially matched between participantswas not taken into account . The defFurthermore, Cherubini et al.  developeOverall, four distinct eye-based multiparty constructs wereoperationalized: joint attention, mutual gaze, gaze aversion, and jointmental effort. As calculated from spatial gaze data ,the first three constructs represent interdependent attentionalprocesses between collaborating individuals. Together, they are known asthe core dynamics of social gaze see ; 11; 26.Rather than examining the extent of visual coupling based on spatialgaze data, two studies measured the similarity in cognitive load betweenteam members, defined as joint mental effort. Cognitive load describesthe extent of cognitive resources expended while processing a task. In contJoint Attention. Examined studies almost exclusively quantified jointattention defined as visual coupling in terms of either gazeconvergence, similarity or overlap ;31. In Mutual Gaze & Gaze Aversion. The two social gaze dynamics thatoccur directly between individuals  – GRK2739/1 – Project Nr. 447089431 – Research TrainingGroup: KD²School – Designing Adaptive Systems for EconomicDecisions.


Firefighters wearing shorts and short sleeves absorbed higher amounts of certain compounds , and the PPE designed with enhanced interface control features appeared to provide more protection from some compounds. These results suggest that firefighters can dermally absorb VOCs and naphthalene that penetrate the PPE ensemble.Firefighters are at an increased risk of cancer due to their occupational exposure to combustion byproducts, especially when those compounds penetrate the firefighter personal protective equipment (PPE) ensemble. This has led to questions about the impact of base layers  under PPE ensembles. This study asked 23 firefighters to perform firefighting activities while wearing one of three different PPE ensembles with varying degrees of protection. Additionally, half of the firefighters unzipped their jackets after the scenario while the other half kept their jackets zipped for five additional minutes. Several volatile organic compound (VOC) and naphthalene air concentrations outside and inside of hoods, turnout jackets, and turnout pants were evaluated; biological  samples were also collected. VOCs and naphthalene penetrated the three sampling areas . Significant ( Over the past few decades, several studies have demonstrated through air samples that structural fires produce hazardous volatile organic compounds (VOCs) including benzene, toluene, acrolein, styrene, and polycyclic aromatic hydrocarbons (PAHs) like naphthalene ,2,3, somSome studies have found that firefighters have an increased risk for certain types of cancer ,13,14. DHistorically, firefighting personal protective equipment (PPE) was designed with the primary function of providing protection from thermal hazards while also providing protection against abrasion and body fluids. In recent years, as the exposure risks have been identified, PPE manufacturers have developed new designs for the firefighting PPE ensemble  aimed at reducing exposure to combustion byproducts. Some recent studies have shown that, while combustion byproducts can still permeate or penetrate the traditional firefighter turnout jacket design, the current bunker gear is moderately effective at reducing exposures to chemicals like PAHs—many of which will exist primarily as particulate . AdditioWhile the relative reduction in PAH exposure is encouraging, more recent studies have found that more volatile chemicals like benzene penetrate through and/or around turnout jackets worn by firefighters, often reaching levels close to those reported outside the jackets . It is rThe permeation or penetration of chemicals like benzene through the firefighter PPE ensemble increases the likelihood of dermal absorption. Mayer et al. 2022) found that benzene exhaled breath concentrations increased significantly post-fire compared to pre-fire for firefighters wearing SCBA and PPE ensembles that included traditional knit hoods or newer particulate-blocking hoods . VOCs li found thSome have hypothesized that wearing base layer shorts instead of base layer long pants under turnout pants may reduce heat stress for firefighters responding to fires in a warm environment, as is common in certain parts of the United States . AdditioThis study was performed at the University of Illinois Fire Service Institute (IFSI) with collaboration from the National Institute for Occupational Safety and Health (NIOSH) and Firefighter Safety Research Institute (FSRI) of UL Research Institutes. Institutional Review Board (IRB) approval was obtained from the University of Illinois at Urbana-Champaign and CDC/NIOSH.Participants were recruited through a local and statewide network of firefighters. Twenty-three firefighters, 21 men and two women, participated in three standard training scenarios. Participants ranged in age from 18–42 and the participants’ median body mass index (BMI) was 30.2 (range = 20.3–39.6). Firefighters were cleared by their department, fit-tested for SCBA, and took a pre-screening questionnaire. Firefighters with known underlying cardiac or gastrointestinal conditions, who were pregnant, or used tobacco were excluded from participating in the study.Using a repeated measures design, firefighters completed three separate but identical training scenarios in a FES that permitted standard exposure over a period of three days, wearing a different PPE configuration on each day. Twenty-two of the 23 firefighters participated in all three scenarios, while one firefighter participated in two scenarios. Up to six firefighters (three firefighters per chamber) per scenario performed simulated fireground operations in the FES. The fuel package and simulated firefighting activities for all scenarios were uniform and conducted utilizing the FES. All PPE was brand-new at the beginning of the study.Standard, commercially available NFPA 1971-compliant PPE with cotton short-sleeve shirt and shorts base layer (SS) and knit hood,Standard, commercially available NFPA 1971-compliant PPE with cotton long-sleeve shirt and long pants base layer and knit hood (SL), andInterface control PPE  and tightened interface between particulate-blocking hood and jacket, jacket and gloves, and boots and pants)) with cotton long-sleeve shirt and long pants base layer and particulate-blocking hood OL; .Firefighters were provided three PPE and base layer configurations, which were fitted based on their chest and waist sizes. The three configurations included:The SS configuration and SL configuration were compared to evaluate differences in exposure based on base layer (short sleeve shirts and shorts vs. long sleeve shirts and pants), and the SS and SL configurations were compared against the OL configuration to characterize differences in the interface PPE design (standard PPE vs. the interface control PPE). Comparisons are made between the three configurations in the subsequent analyses.The FES has been described in detail previously ,25. BrieTo begin each training scenario, a road flare was ignited and placed in the center of the sofa, loading doors were immediately closed, resulting in the only existing leakage paths in the combustion chamber for ventilation. After ignition, the fire was allowed to ventilate for 6 min prior to fire suppression from a water hose. Timing of activities and sofa ignition were coordinated to mimic conditions of realistic firefighting operations . An expeFollowing each scenario, half of the firefighters quickly unzipped their jacket immediately after exiting the structure. All firefighters were then transported to the data collection area and the other half of the firefighters kept their jacket zipped (for approximately 5 min) until they doffed their PPE at the data collection area (unzip vs. zip).Personal air sampling was similar to our previous study . BrieflyTo assess the magnitude of VOCs and naphthalene inside protective hoods and turnout pants, thermal desorption (TD) passive air samplers  were attached inside the PPE, but above firefighters’ base layers on the neck (inside hood samples) and on pants/shorts (inside pants samples). For each scenario, samplers were attached inside the PPE for one SL configuration, one SS configuration, and two OL configurations. TD passive field blanks were also collected for each scenario. Following each scenario, as firefighters doffed their PPE, TD samplers were capped as quickly as possible and stored in a refrigerator until analysis. Samples were desorbed and analyzed for VOCs and naphthalene following EPA TO-17 . Passiven = 128). Eight samples were removed from analyses (six because of the incorrect sampling location on firefighters wearing the OL configuration and two because of lab error). Additionally, one firefighter provided breath samples before and after only two scenarios. Both pre and post samples were collected outside in a tent. Post-exposure breath samples were collected as soon as operationally feasible following doffing of gear and SCBA. Firefighters were instructed to inhale deeply and then forcefully exhale their breath into the BioVOC™ twice which resulted in 258 mL of breath per sample. The breath sample was pushed into Markes TD tubes  and stored in a refrigerator. One field blank was collected for each collection period. Breath samples were analyzed for VOCs  [Breath samples were collected using the BioVOC™ , from firefighters before and immediately after doffing gear following each fire scenario n = 1. Eight sn = 68), 3-h post scenario (n = 68), and 6-h post scenario (n = 35). Firefighters were encouraged to hydrate throughout the scenarios, including after the scenario. Participants were provided sterile 120-mL specimen collection cups, instructed to wash their hands, and provide a clean-catch sample. Samples were aliquoted into tubes and stored at −70 °C pending PAH metabolite quantification and at −80 °C for those pending cotinine and creatinine measurements. Urine specific gravity was measured immediately following sample collection using a hand-held refractometer . VOC metabolite analysis was performed using ultrahigh performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) with some modification to the specific analytes of interest outlined in a published procedure [® 2000 analytical platform . After enzymatic hydrolysis of conjugated PAH metabolites in 100 µL urine, the target metabolites were quantified by online solid phase extraction coupled with high performance liquid chromatography-isotope dilution tandem mass spectrometry [Firefighters provided spot urine samples pre-firefighting , number of sample concentrations below LOD, mean, median, and range) are reported for air concentrations, stratified by firefighting PPE ensemble (configurations), sampling location, and zip status . The samA mixed model with individual firefighter as a random effect was utilized to account for statistical correlation among repeated measures from the same firefighter . Univarip-value = 0.026).p-values = 0.003 and < 0.001, respectively). This appeared to be largely driven by the detection frequency for inside gear samples, as the majority of the stratified sample results for the OL condition had a detection frequency under 25%. In fact, naphthalene was only detected in 5 out of 54 samples collected while firefighters were wearing the OL PPE, compared to 33 out of 49 when firefighters were wearing the SL PPE configuration.Naphthalene WPFs were higher for the turnout jacket and turnout pants compared to the hoods for the standard PPE (SS and SL), but not for the experimental PPE that included a particulate-blocking hood and measures to control leakage at ensemble interfaces (OL). However, the WPFs were much higher for naphthalene , indicating a higher level of protection from this compound. When we compared naphthalene concentrations by PPE configuration, the GM concentration for OL was significantly lower than for SS and SL  (< 0.001) . The chap-value < 0.05), but no significant differences were found between SS and SL. Additionally, firefighters wearing the SS configuration had a significantly higher change from pre- to 3-h post-fire for 1-NAP compared to the OL configuration . Lastly, firefighters wearing the SS configuration had a significantly higher change from pre- to 3-h post-fire for MUCA compared to SL . We found no differences in urinary metabolites by zip status.p-values < 0.001)  for all but the outside SL gear benzene concentrations and their relationship to the change in PhMA urinary concentrations.Regression analyses results  demonstrated positive associations between outside turnout gear benzene air concentrations and PhMA concentration differences from pre-fire to 3-h post-fire, and between inside turnout jackets benzene air concentrations and PhMA concentration differences from pre- to 3-h post-fire (both < 0.001) . After sThis study evaluated how well three turnout gear PPE and base layer configurations protected firefighters from the ingress of VOCs and naphthalene. Additionally, this study evaluated the effectiveness of quickly unzipping the firefighter turnout jacket post-fire to reduce the exposure to VOCs and naphthalene that may be trapped inside the PPE ensemble after a fire response. Our results suggest that VOCs  and naphthalene can permeate or penetrate all three PPE configurations, and that firefighters absorb these compounds that penetrate the PPE ensemble.Overall, benzene air concentrations from this study  were lower but within the same order of magnitude as benzene concentrations from our previous study that had firefighters conducting similar scenarios in the same FES with the same fuel load  . Nearly When we stratified by sample location, the data suggest that hoods provide less protection from benzene, toluene, styrene, and naphthalene compared to pants, followed by jackets. Benzene WPFs calculated from samples taken inside the hood were below 1, indicating no protection from benzene. This is not altogether surprising given that the hood is one of the weaker aspects of the PPE ensemble from an exposure reduction perspective . This isAlthough jackets and, to a lesser extent pants, appeared to protect the firefighter from VOCs and naphthalene better than hoods, ingress still occurred. However, quickly unzipping the jacket post-fire did appear to moderately reduce benzene air concentrations. By contrast, firefighters who kept their jacket zipped until doffing their PPE ensemble (about a five-minute difference) saw protection factors that were closer to results reported in our previous study for benzene . StyreneWhen we compared the PPE and base layer configurations, we expected to see lower VOC concentrations inside the gear for firefighters wearing the OL configuration compared to the other two configurations (SS and SL). Overall, the results were mixed and no significant differences were found between the PPE configurations for benzene and toluene. However, WPFs for styrene were consistently higher for the OL configuration compared to the SL configuration. The difference between PPE configurations was even more stark for naphthalene, as the WPF for the OL configuration was significantly higher than both SS and SL configuration. These results are consistent with our previous work which found the PPE ensemble to be better at protecting from naphthalene compared to benzene and toluene . The parBenzene exhaled breath concentrations increased significantly from pre- to post-fire, regardless of zip status or PPE configuration. This result is similar to our previous studies ,11 that Toluene exhaled breath concentrations also increased significantly from pre- to post-fire. Our previous manuscript  found toMedian values of several other urinary metabolites increased significantly from pre-fire to 3-h and 6-h post-fire, including metabolites of benzene (MUCA and PhMA), styrene/ethylbenzene (MADA and PhGA), xylene (2MHA), acrylonitrile (2CyEMA), crotonaldehyde (3HMPMA), and naphthalene (1-NAP and 2-NAP). This is the first time, to our knowledge, that metabolites of acrylonitrile and crotonaldehyde  ,41 have We also compared our results to the NHANES general population concentrations for smokers and non-smokers. The majority of the metabolites were below the 95th percentile for non-smokers, though 2CyEMA (acrylonitrile metabolite) median 3- and 6-h concentrations were above this threshold . Comparisons were also made to applicable BEIs, and several MUCA (benzene metabolite) pre and 6-h post-fire samples were above the BEI (500 µg/g creatinine). However, sorbic acid found in preserved food can contribute to MUCA concentrations . This, cWhen we stratified urinary concentrations by zip status, we found no statistically significant differences in urinary concentrations were found between firefighters who unzipped their jackets quickly after the fire and those who kept their jackets zipped (for approximately 5 more mins) until they doffed their entire gear. Though the results were not significant, MUCA and PhMA 3-h post-fire median concentrations were lower for firefighters who unzipped their jackets compared to those who kept them zipped .−2, and 4.5 × 10−2, 2.1 × 10−2 cm/h), which suggest that absorption of these compounds is possible [−2 cm/h), so it is not surprising that we see larger differences between SS, SL and OL for 1-NAP [Lastly, we stratified urinary concentrations by PPE configuration for metabolites that had significant increases from pre- to 3-h and 6-h post-fire . Firefigpossible . Naphthaor 1-NAP . OverallThis study has some limitations to consider. Sample sizes for some of our stratifications for air samples were relatively small, so statistical power was somewhat limited in the comparisons. This also limited our ability to analyze potential interactions between PPE configurations and zip status. We also did not analyze air samples for a host of chemicals whose biomarkers were measured in urine . Some of these compounds  have been observed on the fire scene in the past, and future work could sample for the others  in addition to other common contaminants found on the fireground including synthetic compounds like flame retardants and phthalates. In addition, firefighters in this study showered within 10 min after doffing their gear, per best practices. Showering so quickly is not always possible. Exposures could have differed had the firefighters taken longer to shower and is another important factor to study in the future. Firefighting activities in the FES are designed to simulate typical firefighting work, but do not capture all possible firefighting activities and movements or chemicals and concentrations that may be released in all fire ground responses. Furthermore, while smoke exposure is relatively short, it is a relatively high concentration and ambient high-pressure environment, which will not simulate all firefighting situations, particularly for those working outside of a structure. Future studies could characterize exposures for firefighters responding to emergency fire responses to better understand how these exposures compare in duration and magnitude.p-value < 0.05) from pre-fire to 3-h and 6-h post-fire, including metabolites of benzene , styrene/ethylbenzene , xylene , acrylonitrile , and crotonaldehyde . This is the first manuscript to report significant increases from pre- to post-fire for urinary metabolites of acrylonitrile and crotonaldehyde. We also found an association between personal air benzene concentrations and the change in exhaled breath concentrations and PhMA urinary concentrations from pre- to post-fire. Overall, results from our study show that benzene, toluene, styrene, and naphthalene penetrate the sampling areas . Given that firefighters for this study breathed through SCBA throughout the entire response, it appears that dermal absorption is an important route of exposure for some of these combustion byproducts. PPE protection against compounds appears to increase with decreasing vapor pressure of the chemicals. The PPE designed with enhanced interface control features (OL) appeared to provide the most protection from the chemicals measured compared to those wearing traditional PPE (the SS and SL configuration), including a reduction in some of the urinary metabolites. However, the OL configuration is only an experimental ensemble at the present time and its use by the fire service should be balanced with the potential for increased heat stress and challenges donning and doffing the gear. Additionally, short sleeves and shorts under turnout gear (SS configuration) also appeared to impact exposure, as firefighters wearing this ensemble had higher post-fire urinary concentrations of some metabolites .Benzene, toluene, styrene, and naphthalene all penetrated the three sampling areas  for all three PPE configurations . However, quickly unzipping the firefighter turnout jacket appeared to lower chemical concentrations inside the jacket. Additionally, benzene and toluene exhaled breath concentrations increased from pre- to post-fire, regardless of PPE configuration. Several urinary metabolites of VOCs and naphthalene also increased significantly (