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Ecological momentary assessment (EMA) is a way to evaluate experiences in everyday life. It is a powerful research tool but can be complex and challenging for beginners. Application of EMA in audiological research brings with it opportunities and challenges that differ from other research disciplines. This tutorial discusses important considerations when conducting EMA studies in hearing care. While more research is needed to develop specific guidelines for the various potential applications of EMA in hearing research, we hope this article can alert hearing researchers new to EMA to pitfalls when using EMA and help strengthen their study design. The current article elaborates study design details, such as choice of participants, representativeness of the study period for participants' lives, and balancing participant burden with data requirements. Mobile devices and sensors to collect objective data on the acoustic situation are reviewed alongside different possibilities for EMA setups ranging from online questionnaires paired with a timer to proprietary apps that also have access to parameters of a hearing device. In addition to considerations for survey design, a list of questionnaire items from previous studies is provided. For each item, an example and a list of references are given. EMA typically provides data sets that are rich but also challenging in that they are noisy, and there is often unequal amount of data between participants. After recommendations on how to check the data for compliance, reactivity, and careless responses, methods for statistical analysis on the individual level and on the group level are discussed including special methods for direct comparison of hearing device programs.

Objectives: When using ecological momentary assessment (EMA) to compare different hearing aid programs, it is usually assumed that for sufficiently long study durations similar situations will be experienced in both programs. However, conscious or subconscious adaptation of situations to one's hearing ability (e.g., asking a conversation partner to speak up, increasing TV volume)-which might be different across the time spent in different hearing aid programs-may challenge this assumption. In the present study, we investigated how test participants modify their acoustic environment and if these modifications depend on the hearing program., Design: Twenty-nine experienced hearing aid users were provided with hearing aids containing two hearing programs differing in directionality and noise reduction (NR). The hearing programs called NR-on and NR-off changed each day automatically. Over the course of 3 weeks, participants were asked to answer a questionnaire every time they encountered an acoustic situation they modified or would have liked to modify to improve the listening situation. Objective data on sound pressure level and classification of the acoustic situation were collected from the hearing aids. At the beginning of the study participants recollected modifications of the acoustic environments they typically do when using their own hearing aids and reported on the frequency of this behavior., Results: During the field trial, participants reported on average 2.3 situations per day that they modified or would have liked to modify. Modifications were usually performed quickly after the onset of the situation and significantly improved the pleasantness of the listening situation. While the number of the reported situations did not differ between the programs, modifications increasing the volume of the target signal and increasing the hearing aid volume were more frequent for the NR-on hearing program. Changes in the objective data at the time of the modification were consistent with the reported modifications. Further, the usage time as well as the distribution of the acoustic situations over the entire study period differed between the two hearing programs., Conclusions: The large improvement in pleasantness due to the modification might explain the generally positive ratings observed in EMA studies. Furthermore, the results found here suggest that caution is needed when comparing ratings of audiological attributes in EMA, because the different modification behavior across hearing programs may lead to an underestimation of hearing problems and reduced sensitivity when comparing two technologies., (Copyright © 2024 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.)

Background: Recently, we developed a hearing-related lifestyle questionnaire (HEARLI-Q) which asks respondents to rate their hearing aid (HA) satisfaction in 23 everyday listening situations. It is unknown how HA satisfaction on the retrospective HEARLI-Q scale compares to HA satisfaction measured on the same scale implemented in Ecological Momentary Assessments (EMA)., Purpose: To learn how retrospective (HEARLI-Q) and in-situ (EMA) assessments can complement each other., Research Design: An observational study., Study Sample: Twenty-one experienced HA users., Data Collection and Analysis: The participants first filled out the HEARLI-Q questionnaire, followed by a one-week EMA trial using their own hearing aids. HA satisfaction ratings were compared between the two questionnaires and the underlying drivers of discrepancies in HA satisfaction ratings were evaluated., Results: HA satisfaction scores were significantly higher in EMA for speech communication with one or several people. Hearing difficulty in these situations was rated higher in HEARLI-Q than in EMA, but occurrence of those difficult listening situations was also rated to be lower. When comparing only the situations that occur on daily or weekly basis, the two questionnaires had similar HA satisfaction ratings., Conclusions: Lower occurrence of difficult listening situations seems to be the key driver of discrepancies in HA satisfaction ratings between EMA and HEARLI-Q. The advantage of EMA is that it provides insight into an individual's day-to-day life and is not prone to memory bias. HEARLI-Q, on the other hand, can capture situations which occur infrequently or are inconvenient to report in the moment. Administering HEARLI-Q and EMA in combination could give a more holistic view of HA satisfaction., Competing Interests: All authors are employees of WS Audiology., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: In past Ecological Momentary Assessment (EMA) studies, hearing aid outcome ratings have often been close to ceiling., Methods: To analyze the underlying reasons for the very positive ratings, we conducted a study with 17 experienced hearing aid wearers who were fitted with study hearing aids. The acceptable noise level and the noise level where participants were unable to follow speech were measured. The participants then rated hearing aid satisfaction, speech understanding and listening effort for pre-defined SNRs between -10 and +20 dB SPL in the laboratory. These ratings were compared to ratings of a two-week EMA trial. Additionally, estimates of SNRs were collected from hearing aids during the EMA trial and we assessed whether the participants experienced those SNRs rated poorly in the laboratory in real life., Results: The results showed that for hearing aid satisfaction and speech understanding, the full rating scale was used in the laboratory, while the ratings in real life were strongly skewed towards the positive end of the scale. In the laboratory, SNRs where participants indicated they could not follow the narrator ("unable to follow" noise level) were rated clearly better than the lowest possible ratings. This indicates that very negative ratings may not be applicable in real-life testing. The lower part of the distribution of real-life SNR estimates was related to participants' individual "unable to follow" noise levels and the SNRs which were rated poorly in the laboratory made up less than 10% of the speech situations experienced in real life., Discussion: This indicates that people do not seem to frequently experience listening situations at SNRs where they are dissatisfied with their hearing aids and this could be the reason for the overly positive hearing aid outcome ratings in EMA studies. It remains unclear to what extent the scarcity of such situations is due lack of encounters or intentional avoidance., Competing Interests: NS-B and DL are full time employee of WS Audiology. JR was a working student and the research she did as part of her master thesis was funded by WS Audiology. She is now an employee of GN Hearing A/S., (© 2023 Schinkel-Bielefeld, Ritslev and Lelic.)

Background: CT scans are used in routine clinical practice for the diagnosis and treatment surveillance of non-small cell lung cancer (NSCLC). However, more sensitive methods are desirable. Liquid biopsy analyses of RNA and DNA can offer more sensitive diagnostic approaches. Cell-free RNA (cfRNA) has been described in several malignancies, but its clinical utility has not previously been explored., Methods: We evaluated the clinical utility of cfRNA for early detection and surveillance of tumor disease in a proof-of-concept study. Using real-time-droplet digital polymerase chain reaction we characterized a candidate transcript (MORF4L2) in plasma samples from 41 advanced stage, 38 early stage NSCLC and 39 healthy samples. We compared its diagnostic performance with tumor markers and evaluated its utility for disease monitoring., Results: MORF4L2 cfRNA was more abundant in patients than in healthy donors (p < 0.0001). Using the Youden index approach (cutoff value of 537 copies/ml was established) with a sensitivity of 0.73 (95% CI: 0.61-0.82) and a specificity of 0.87 (95% CI: 0.73-0.96). Positive and negative predictive values of 0.92 (95% CI: 0.83-0.95) and 0.59 (95% CI: 0.47-0.83) were achieved. Combination of cfRNA and Cyfra21-1 improved its predictive value from 89.5% to 94.7%. Low baseline MORF4L2 levels were associated with better overall survival (HR:0.25, 95% CI: 0.09-0.7, p = 0.009) and progression-free survival for patients treated with tyrosine kinase inhibitors (p = 0.011) and chemotherapy (p = 0.019). MORF4L2 profile between baseline and follow-up mirrored radiological response and tumor dynamics better than tumor markers. cfRNA transcripts allowed monitoring tumor dynamics in patients without tumor-reported genetic alterations., Conclusion: Our data support clinical utility of cfRNA for detection and surveillance of NSCLC. Further studies with larger cohorts are required., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility., Methods: We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays., Results: A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay ( meth cfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in meth cfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status., Conclusion: Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring., (Copyright © 2021. Published by Elsevier Inc.)

Background: We assessed the usefulness of circulating tumor DNA (ctDNA) pre- or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC)., Methods: Droplet digital PCR was used to measure absolute mutant V-Ki-ras2 Kirsten rat sarcoma viral oncogene ((mut)KRAS) ctDNA concentrations in 214 healthy controls (plasma and sera) and in 151 tissue-based mutKRAS positive patients with mCRC from the prospective multicenter phase 3 trial AIO KRK0207. Serial mutKRAS ctDNA was analyzed prior to and 2-3 weeks after first-line chemotherapy initiation with fluoropyrimidine, oxaliplatin, and bevacizumab in patients with mCRC and correlated with clinical parameters., Results: mut KRAS ctDNA was detected in 74.8% (113/151) of patients at baseline and in 59.6% (90/151) at follow-up. mutKRAS ctDNA at baseline and follow-up was associated with poor overall survival (OS) (hazard ratio [HR] =1.88, 95% confidence interval [CI] 1.20-2.95; HR = 2.15, 95% CI 1.47-3.15) and progression-free survival (PFS) (HR = 2.53, 95% CI 1.44-4.46; HR = 1.90, 95% CI 1.23-2.95), respectively. mutKRAS ctDNA clearance at follow-up conferred better disease control (P = 0.0075), better OS (log-rank P = 0.0018), and PFS (log-rank P = 0.0018). Measurable positive mutKRAS ctDNA at follow-up was the strongest and most significant independent prognostic factor on OS in multivariable analysis (HR = 2.31, 95% CI 1.40-3.25)., Conclusions: Serial analysis of circulating mutKRAS concentrations in mCRC has prognostic value. Post treatment mutKRAS concentrations 2 weeks after treatment initiation were associated with therapeutic response in multivariable analysis and may be an early response predictor in patients receiving first-line combination chemotherapy., Clinicaltrialsgov Identifier: NCT00973609., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background Ecological momentary assessment (EMA) is a method to evaluate hearing aids in everyday life that uses repeated smartphone-based questionnaires to assess a situation as it happens. Although being ecologically valid and avoiding memory bias, this method may be prone to selection biases due to questionnaires being skipped or the phone not being carried along in certain situations. Purpose This investigation analyzed which situations are underrepresented in questionnaire responses and physically measured objective EMA data (e.g., sound level), and how such underrepresentation may depend on different triggers. Method In an EMA study, 20 subjects with hearing impairment provided daily information on reasons for missed data, that is, skipped questionnaires or missing connections between their phone and hearing aids. Results Participants often deliberately did not bring the study phone to social situations or skipped questionnaires because they considered it inappropriate, for example, during church service or when engaging in conversation. They answered fewer questions in conversations with multiple partners and were more likely to postpone questionnaires when not in quiet environments. Conclusion Data for social situations will likely be underrepresented in EMA. However, these situations are particularly important for the evaluation of hearing aids, as individuals with hearing impairment often have difficulties communicating in noisy situations. Thus, it is vital to optimize the design of the study to find a balance between avoiding memory bias and enabling subjects to report retrospectively on situations where phone usage may be difficult. The implications for several applications of EMA are discussed. Supplemental Material https://doi.org/10.23641/asha.12746849.

Early detection of cancer holds high promise for reducing cancer-related mortality. Detection of circulating tumor-specific nucleic acids holds promise, but sensitivity and specificity issues remain with current technology. We studied cell-free RNA (cfRNA) in patients with non-small cell lung cancer (NSCLC; n = 56 stage IV, n = 39 stages I-III), pancreatic cancer (PDAC, n = 20 stage III), malignant melanoma (MM, n = 12 stage III-IV), urothelial bladder cancer (UBC, n = 22 stage II and IV), and 65 healthy controls by means of next generation sequencing (NGS) and real-time droplet digital PCR (RT-ddPCR). We identified 192 overlapping upregulated transcripts in NSCLC and PDAC by NGS, more than 90% of which were noncoding. Previously reported transcripts (e.g., HOTAIRM1) were identified. Plasma cfRNA transcript levels of POU6F2-AS2 discriminated NSCLC from healthy donors (AUC = 0.82 and 0.76 for stages IV and I-III, respectively) and significantly associated ( p = 0.017) with the established tumor marker Cyfra 21-1. cfRNA yield and POU6F2-AS transcript abundance discriminated PDAC patients from healthy donors (AUC = 1.0). POU6F2-AS2 transcript was significantly higher in MM ( p = 0.044). In summary, our findings support further validation of cfRNA detection by RT-ddPCR as a biomarker for early detection of solid cancers., Competing Interests: The authors declare no conflict of interest.

Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8 + T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.

Melanoma often recurs after a latency period of several years, presenting a T cell-edited phenotype that reflects a role for CD8(+) T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen-specific CD8(+) T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8(+) T cell-resistant, HLA class I-negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA class I loss in both metastases originated from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I haplotype-deficient lesion developed in year 3 of stage IV disease that acquired resistance toward dominant CD8(+) T-cell clonotypes targeting stage III tumor cells. At an early stage, melanoma cells showed a dedifferentiated c-Jun(high)/MITF(low) phenotype, possibly associated with immunosuppression, which contrasted with a c-Jun(low)/MITF(high) phenotype of T cell-edited tumor cells derived from late metastases. In summary, our work shows how tumor recurrences after long-term latency evolve toward T-cell resistance by independent genetic events, as a means for immune escape and immunotherapeutic resistance. Cancer Res; 76(15); 4347-58. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: CD8(+) T lymphocytes can kill autologous melanoma cells, but their activity is impaired when poorly immunogenic tumor phenotypes evolve in the course of disease progression. Here, we analyzed three consecutive melanoma lesions obtained within one year of developing stage IV disease for their recognition by autologous T cells., Experimental Design: One skin (Ma-Mel-48a) and two lymph node (Ma-Mel-48b, Ma-Mel-48c) metastases were analyzed for T-cell infiltration. Melanoma cell lines established from the respective lesions were characterized, determining the T-cell-stimulatory capacity, expression of surface molecules involved in T-cell activation, and specific genetic alterations affecting the tumor-T-cell interaction., Results: Metastases Ma-Mel-48a and Ma-Mel-48b, in contrast with Ma-Mel-48c, were infiltrated by T cells. The T-cell-stimulatory capacity was found to be strong for Ma-Mel-48a, lower for Ma-Mel-48b, and completely abrogated for Ma-Mel-48c cells. The latter proved to be HLA class I-negative due to an inactivating mutation in one allele of the beta-2-microglobulin (B2M) gene and concomitant loss of the other allele by a deletion on chromosome 15q. The same deletion was already present in Ma-Mel-48a and Ma-Mel-48b cells, pointing to an early acquired genetic event predisposing to development of β2m deficiency. Notably, the same chronology of genetic alterations was also observed in a second β2m-deficient melanoma model., Conclusion: Our study reveals a progressive loss in melanoma immunogenicity during the course of metastatic disease. The genetic evolvement of T-cell resistance suggests screening tumors for genetic alterations affecting immunogenicity could be clinically relevant in terms of predicting patient responses to T-cell-based immunotherapy., (©2014 American Association for Cancer Research.)

Activating mutations in the TERT promoter leading to increased telomerase expression were recently identified in cutaneous melanoma and subsequently in many other types of cancer. These mutations lead to increased telomerase expression, allowing cells to proliferate continuously without entering apoptosis or senescence. Atypical fibroxanthomas and pleomorphic dermal sarcomas are genetically poorly understood tumors developing in the skin of older patients. Known genetic events in these tumors are mutations in TP53 (atypical fibroxanthoma and pleomorphic dermal sarcoma) and RAS (pleomorphic dermal sarcoma) genes, often having a UV signature. We analyzed a cohort of 27 atypical fibroxanthomas and 34 pleomorphic dermal sarcomas for the presence of TERT promoter mutations by conventional Sanger sequencing. TERT promoter mutations were identified in 25 (93%) atypical fibroxanthomas and in 26 (76%) pleomorphic dermal sarcomas. Mutations were found to have a UV signature (C>T or CC>TT) and were largely identical to those detected in cutaneous melanoma. Our data show that TERT promoter mutations are the most frequent mutations in atypical fibroxanthomas and pleomorphic dermal sarcomas reported to date. The identified mutations confirm the pathogenetic role of UV exposure in both atypical fibroxanthomas and pleomorphic dermal sarcomas and suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis of these tumors.

Background: Melanoma is a deadly disease affecting people worldwide. Genetic studies have identified different melanoma subtypes characterized by specific recurrently mutated genes and led to the successful clinical introduction of targeted therapies. Hotspot mutations in SF3B1 were recently reported in uveal melanoma. Our aim was to see if these mutations also occur in cutaneous melanoma., Findings: We analyzed a cohort of 85 cutaneous melanoma including 22 superficial spreading, 24 acral-lentiginous, 36 nodular, and 3 lentigo-maligna melanomas. Exon 14 of SF3B1, containing the site of recurrent mutations described in uveal melanoma, was sequenced in all samples. Additionally, NRAS exon 1 and 2 and BRAF exon 15 were sequenced in all, KIT exons 9, 11, 13, 17, and 18 in 30 samples. High numbers of BRAF and NRAS mutations were identified with frequencies varying according to melanoma subtype. None of the samples were found to harbor a SF3B1 mutation., Conclusions: We conclude that recurrent mutations in codon 625 of SF3B1 as reported in uveal melanoma are not present in most types of cutaneous melanoma. This highlights the genetic differences between cutaneous and uveal melanoma and the need for subtype specific therapeutic approaches.

Intracellular studies have revealed the importance of cotuned excitatory and inhibitory inputs to neurons in auditory cortex, but typical spectrotemporal receptive field models of neuronal processing cannot account for this overlapping tuning. Here, we apply a new nonlinear modeling framework to extracellular data recorded from primary auditory cortex (A1) that enables us to explore how the interplay of excitation and inhibition contributes to the processing of complex natural sounds. The resulting description produces more accurate predictions of observed spike trains than the linear spectrotemporal model, and the properties of excitation and inhibition inferred by the model are furthermore consistent with previous intracellular observations. It can also describe several nonlinear properties of A1 that are not captured by linear models, including intensity tuning and selectivity to sound onsets and offsets. These results thus offer a broader picture of the computational role of excitation and inhibition in A1 and support the hypothesis that their interactions play an important role in the processing of natural auditory stimuli.

According to the seventh edition of the American Joint Committee on Cancer guidelines, the TNM staging category in thin cutaneous melanomas depends on the mitotic rate (MR). In this study, we analyze the interobserver agreement of the MR in a series of 92 thin cutaneous melanomas. Serial sections of the tumors were either stained with hematoxylin and eosin or immunohistochemically stained with pHH3, an antibody for phosphohistone H3, and analyzed by 4 observers. Determination of MR with pHH3 immunostaining resulted in higher sensitivity in counting mitosis for all observers. Moreover, interobserver agreement was higher with pHH3. Immunostaining with pHH3 is a sensitive method to detect mitosis in thin cutaneous melanomas, with good reproducibility of MR between independent observers. Further studies are needed to find out if higher sensitivity in the detection of mitosis by pHH3 immunostaining has additional prognostic relevance.

For processing and segmenting visual scenes, the brain is required to combine a multitude of features and sensory channels. It is neither known if these complex tasks involve optimal integration of information, nor according to which objectives computations might be performed. Here, we investigate if optimal inference can explain contour integration in human subjects. We performed experiments where observers detected contours of curvilinearly aligned edge configurations embedded into randomly oriented distractors. The key feature of our framework is to use a generative process for creating the contours, for which it is possible to derive a class of ideal detection models. This allowed us to compare human detection for contours with different statistical properties to the corresponding ideal detection models for the same stimuli. We then subjected the detection models to realistic constraints and required them to reproduce human decisions for every stimulus as well as possible. By independently varying the four model parameters, we identify a single detection model which quantitatively captures all correlations of human decision behaviour for more than 2000 stimuli from 42 contour ensembles with greatly varying statistical properties. This model reveals specific interactions between edges closely matching independent findings from physiology and psychophysics. These interactions imply a statistics of contours for which edge stimuli are indeed optimally integrated by the visual system, with the objective of inferring the presence of contours in cluttered scenes. The recurrent algorithm of our model makes testable predictions about the temporal dynamics of neuronal populations engaged in contour integration, and it suggests a strong directionality of the underlying functional anatomy.