A growing body of literature has demonstrated that dementia and hearing loss are interrelated. Recent interest in dementia research has expanded to brain imaging analyses with auditory function. The aim of this study was to investigate the link between hearing ability, which was assessed using pure-tone audiometry, and the volume of brain regions, specifically the hippocampus, entorhinal cortex, Heschl’s gyrus, and total gray matter, using Freesurfer software and T1-weighted brain magnetic resonance imaging. The data for 2082 samples (age range = 40–89 years) were extracted from a population-based cohort of community dwellers. Hearing-impaired individuals showed significantly smaller hippocampal volumes compared with their non-hearing-impaired counterparts for all auditory frequency ranges. In addition, a correlational analysis showed a significant dose-response relationship for hearing ability and hippocampal volume after adjusting for potential confounding factors so that the more degraded the peripheral hearing was, the smaller the hippocampal volume was. This association was consistent through the auditory frequency range. The volume of the entorhinal cortex, right Heschl’s gyrus and total gray matter did not correlate with hearing level at any frequency. The volume of the left Heschl’s gyrus showed a significant relationship with the hearing levels for some auditory frequencies. The current results suggested that the presence of hearing loss after middle age could be a modifier of hippocampal atrophy. Recently, the number of studies investigating the interrelationship of dementia and hearing loss has increased rapidly. Systematic reviews and meta-analyses of the association between hearing loss and cognitive function, cognitive impairment, and dementia were successively published in 2017 . LoughreLancet  ranged from 40 to 79 years, with similar numbers of participants in each decade of age . The cohort design was dynamic, and new participants with ages in their 40s were recruited every year.The data analyzed in the present study were collected from the participants (age range = 40–89 years) at the sixth-wave examination (July 2008–July 2010) of the NILS-LSA because the three-dimensional MRI data (explained below) of the NILS-LSA were available after the sixth wave.The study protocol was approved by the Committee of Ethics of Human Research of the National Center for Geriatrics and Gerontology . Written informed consent was obtained from all participants. The details of the NILS-LSA have been described elsewhere .3 resolution, and 256 × 256 matrix).All MRI scans were performed on a MAGNETOM Trio 3T system . Three-dimensional T1 MRI scans were acquired using a volumetric T1-weighted magnetization-prepared rapid gradient-echo sequence  of the left-right summation of the hippocampus, the left-right summation of the entorhinal cortex, right and left transverse temporal gyri (Heschl’s gyri), and total GM were the dependent measures. To account for individual differences in head size and express in the unit of mm3, individual regional GM volume was normalized by dividing it by the estimated total intracranial volume and then multiplying by the mean estimated total intracranial volume of all subjects.FreeSurfer (version 5.3)eviously . In shoreviously  and perfeviously . If any Air conduction pure-tone thresholds were measured at octave intervals from 0.125 to 8 kHz in a sound-proof booth by trained examiners using a standardized protocol and a diagnostic audiometer . In the analysis, we used the hearing thresholds of the ear with the better hearing that was based on the PTA thresholds of the following frequency ranges: low frequency (average of 0.125 and 0.25 kHz: PTA low), speech range , and high frequency . Hearing impairment was defined in the analysis as PTA low, PTA speech, and PTA high scores over 25 dB, which indicates bilateral hearing loss.The participants completed a series of questionnaires before the examination. Years of education (years of school); smoking status (yes or no); and medical history of hypertension, hyperlipidemia, stroke, cardiac disease, and/or diabetes (yes or no) were recorded. Alcohol consumption in the previous year was assessed using a food frequency questionnaire . For the level of education in Japan, nine or less indicates elementary school or junior high school equivalent, 10–12 indicates high school or junior high school equivalent under the former Japanese educational system, 13–14 is comparable to higher vocational school or junior college, and 15 or more years is comparable to college or graduate college. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression Scale, and the cutoff value was set to 15/16 points.The statistical analyses were conducted using Statistical Analysis System (SAS) software .t-test was used to compare differences in the continuous variables between the two groups, and comparisons of categorical variables were done using the chi-square test. Unless otherwise noted, the values are expressed as mean ± standard deviation (SD). Comparison of the regional brain volumes based on the presence or absence of hearing impairment in the PTA low, PTA speech, and PTA high frequency ranges was made using Tukey-Kramer multiple comparison tests. During the multivariate approach, age; sex; smoking status; alcohol consumption; years of education; medical history of hypertension, hyperlipidemia, cardiac disease, and diabetes; and depressive symptoms were consistently used as adjustment variables.For the univariate analysis, a P values less than 0.05 were considered significant.Scatterplots were employed to illustrate an overview of the potential association between each region of brain volume and PTA speech. Single and multiple regressions (adjustments were made for the 10 aforementioned variables) were analyzed using the General Linear Model (GLM) procedure of the SAS software. In addition, the PROC REG procedure in SAS was performed to obtain standardized partial regression coefficients in the relationship between each PTA and regional brain volume. Each region of brain volume was set as the dependent variable with adjustments for the 10 aforementioned variables. The standardized partial regression coefficients of brain volume were calculated per decibel increase in the hearing thresholds for PTA low, PTA speech, and PTA high frequency ranges. Figure 1); therefore, 2082 samples were included in this study. Table 1 shows the demographic characteristics of the study population. The mean age of the subjects was 61.0 years (SD: 12.4), and 49.8% were male. According to the univariate analysis of the demographic profiles according to the category of hearing impairment for PTA low, PTA speech, and PTA high frequency ranges, significant differences between those with and without hearing impairments were observed in mean age, educational level, and comorbidity . For the percentage of male participants and smokers, the significance differed in each classification.The data for the 2302 participants were extracted from the sixth-wave examination of the NILS-LSA. Following the analysis preparation process, 220 subjects were excluded  reveal the relationships and results of the single and multiple regression analyses of the PTA speech range with the volumes of the hippocampus, the entorhinal cortex, right Heschl’s gyrus, left Heschl’s gyrus, and total GM. The correlational analysis with the single regression model showed that the PTA speech range inversely correlated with the hippocampal volume . Similarly, in the other regions, greater hearing impairments were associated with smaller brain volumes. In the multiple regression model, significance was still observed for the volumes of the hippocampus and left Heschl’s gyrus, even after adjusting for possible confounders.The results of the correlational analysis are shown on scatterplot diagrams to illustrate the relationships between each region of brain volume and the PTA. Only the diagrams for PTA speech are shown as a representative example. Table 3. Hippocampal volume had a significant relationship with hearing level, regardless of the frequency range. The standardized partial regression coefficients were -0.0509 for the PTA low range (p = 0.0193), -0.0758 for the PTA speech range (p = 0.0029), and -0.0917 for the PTA high range (p = 0.0011). The volumes of the entorhinal cortex, right Heschl’s gyrus and total GM did not show significant relationships with the hearing levels for all frequency ranges. The volume of the left Heschl’s gyrus showed a significant relationship with the hearing levels for the PTA speech and PTA high ranges. The values of the goodness-of-fits of the analytical model were highest for total GM volume  and second highest for hippocampal volume .The results of the multiple regression analysis of the associations between the hearing level of each frequency range and the volumes of multiple brain regions are presented in The present epidemiological study of over 2000 community dwellers aged 40 or older demonstrated that peripheral hearing ability assessed by pure-tone audiometry significantly correlated with hippocampal volume after adjusting for potential confounding factors. Hearing-impaired individuals showed significantly smaller hippocampal volumes compared with their non-hearing-impaired counterparts for all auditory frequency ranges. In addition, a correlational analysis showed a significant dose-response relationship for hearing ability and hippocampal volume. Throughout the auditory frequency range, the worse the hearing, the smaller the hippocampal volume. Total GM volume did not significantly correlate with hearing ability at any frequency range.Although the correlational analysis in the single regression model showed a significant inverse association of hearing threshold with the brain volume of each targeted region, the data might have resulted from confounding effects. Aging, in particular, influences the volumes and structures of the brain  and stroFew studies have examined the relationship between age-related hearing loss and brain morphology using MRI. The results of previous studies were not always consistent with our result. In the Baltimore Longitudinal Study of Aging, The present results of the multiple regression analysis showed that the volume of the left Heschl’s gyrus, but not the right Heschl’s gyrus, was significantly related to the hearing levels for the PTA speech and PTA high frequencies. Several hypotheses of how hearing loss is related to cognitive decline have been proposed . MultiplOne of these hypothetical mechanisms could explain the mutual relationship between degraded hearing and hippocampal atrophy. A common neuropathologic process that causes declines in both hearing and cognition might affect both cochlear and brain aging. Those potential common factors include oxidative stress, microcirculatory insufficiency, general physical decline and genetics. Reactive oxygen species play an important role for performing signaling functions in brain, and for auditory processing, therefore, the brain and the inner ear are susceptible to oxidative stress .Experimental studies have investigated the neurodegenerative process that has been observed in both the hippocampus and auditory system. Blast injury, which is a common etiology for sensorineural hearing loss and tinnitus , causes Because tauopathies and cochlear neurodegeneration share the common pathophysiological correlate of oxidative stress  have demTable 4). Although this evaluation was simple and preliminary, the results suggest significant links among hearing ability, hippocampal volume, and memory function. One can argue that the significant correlation between the SMMSE score and the PTA speech might be simply due to hearing difficulty in understanding the question. However, we consider it is not probable because most of the participants (1060 of 1070) obtained a full score (3/3) for the immediate recall task indicating they could hear and understand the question. In addition, the results did not change if we analyzed using these 1060 subjects.To assess the relevance among hearing ability, hippocampal volume, and cognitive functions, especially in memory domain, we supplementally conducted a subgroup analysis in 1070 subjects aged 60 and over who tested the Mini-Mental State Examination (MMSE). From the 30 items of the whole MMSE that address multiple cognitive domains, we extracted six items which are specifically related to memory function calculated by the following formula: . This subset score, named as a short form of MMSE (SMMSE), is considered to be efficient in screening dementia among older adults with a memory complaint , and havThe present study had several limitations. First, the results seen in the present cross-sectional analyses are not sufficient for debating if there is a cause-and-effect relationship between hippocampal volume and peripheral hearing. The present analytical cross-sectional studies are useful for establishing preliminary evidence for a link between the two, but interpretation requires caution regarding the potential association. Further analyses by longitudinal design will be required in order to show temporal precedence of the cause . Second, information on pathological biomarkers, such as amyloid-beta (Aβ) and tau, which are critical in Alzheimer’s disease and other types of dementing disorders, was not available. However, atrophy of the medial temporal lobe observed in the hearing-impaired individuals might be different from that seen in Alzheimer’s disease, because we found no relationship between hearing and the entorhinal cortex, which is known to be a region that shows prominently progressive atrophy in the early stages of Alzheimer’s disease .Third, iEven considering the above limitations, the impact of hearing on hippocampal atrophy among Japanese community dwellers is noteworthy. The common link among hearing ability, hippocampal volume, and cognitive function and whether auditory corrections cause longitudinal changes on brain volume should be further investigated.In conclusion, we examined the relationship between hearing ability and regional brain tissue volume, specifically focusing on the volumes of the hippocampus, Heschl’s gyrus, and total GM, which was obtained by MRI in the samples of over 2000 community dwellers aged 40 and older. More degraded peripheral hearing that was assessed by pure-tone audiometry was significantly correlated with smaller hippocampal volume after adjusting for potential confounding factors, and the association was consistent through the auditory frequency ranges. The current results suggested that the presence of hearing loss after middle age could be a modifier of hippocampal atrophy.YU, YN, and AN drafting the manuscript, and taking responsibility for the accuracy of the data analysis. YU, YN, SS, CT, RO, FA, and HSh contribution to collecting data and statistical analyses. YN, TK, KI, and AN taking responsibility for brain MRI volume measurements and analyses. HSh and FA contribution to study concept and design of NILS-LSA. HSu and MS advice for interpretation of results. YU, SS, RO, and HSh: obtaining funding. All the authors contributed to the interpretation of the data and approved the final version of the manuscript before submission and will approve the final version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


EYA4 is a member of the vertebrate eya gene family of transcriptional activators and plays several roles in both embryonic and inner ear development. The majority of EYA4 gene mutations are associated with autosomal dominant non-syndromic hearing loss (DFNA10). In addition, some mutations in this gene cause autosomal dominant syndromic hearing loss with dilated cardiomyopathy. EYA4 is a rare cause of sensorineural hearing loss, and only a limited number of papers regarding mutations in this gene have been published. Thus, detailed clinical features remain unclear.EYA4 pathogenic variant. Pure-tone audiometry revealed bilateral, nearly symmetric, moderate sensorineural hearing loss in the low and middle frequencies. Minor abnormalities were observed on the patient’s electrocardiogram and echocardiography without any apparent symptoms. Next-generation sequencing is effective in elucidating the etiology of hearing loss, and the present findings suggested the possible phenotypic expansion of deafness caused by EYA4 gene mutations.We conducted next-generation sequencing of a Japanese individual with progressive sensorineural hearing loss and identified an  To date, ~180 non-syndromic hereditary sensory hearing loss loci and more than 100 corresponding genes have been identifiedEYA4 is a member of the vertebrate eya gene family of transcriptional activators that interact with other proteins, such as the sine oculis homeobox (SIX)  protein family, to ensure normal embryologic development2. Moreover, EYA4 also plays several roles in the mature inner ear system3. The majority of EYA4 gene mutations are associated with autosomal dominant non-syndromic hearing loss (DFNA10) (OMIM:# 601316)6. In addition, some mutations in this gene cause autosomal dominant syndromic hearing loss with dilated cardiomyopathy (OMIM:# 605362)7. EYA4 is a rare causative gene of sensorineural hearing loss and only a limited number of papers regarding mutations in this gene have been published. Thus, the complete picture with regard to the clinical features associated with these gene mutations remains unclear.EYA4 pathogenic variant was identified.Remarkable recent advances in molecular genetics technology, particularly in the clinical applications of next-generation sequencing technology, have made it easier to identify disease-causing genes in a relatively short period and at low cost. Here, we report a Japanese individual with progressive sensorineural hearing loss (SNHL) in whom an A 43-year-old Japanese male from a non-inbred family presented to our hospital to clarify the cause of his hearing loss. His maternal grandmother, mother, maternal uncle, and sister also have late-onset hearing loss (after acquisition of language) Fig. . The proThe patient’s hearing loss was first noticed during a checkup at age 26. He began wearing a hearing aid at age 36. Further deterioration in his hearing was recognized subjectively at 40 years of age due to loud noises associated with his work as a carpenter. At the age of 41, his tinnitus and hearing loss further worsened after exposure to loud firework explosions. No noticeable effects were observed upon treatment with various medications, including steroids. Clinically, he has no accompanying disease or disorder, but abnormalities in his electrocardiograms have been observed since his second decade of life.Pure-tone audiometry revealed bilateral, nearly symmetric, moderate SNHL with hearing loss in the low and middle frequencies. The hearing loss was progressive, and an audiogram at age 43 showed hearing loss at all frequencies with a flat pattern Fig. . He has 8, no mutations were observed upon examination of 46 known mutations in 13 deafness genes. Secondary screening using comprehensive next-generation sequencing analysis for 63 genes reported to cause hearing impairment was performed as described previously9.There was insufficient power in the kindreds to perform linkage studies, and we could not obtain consent from any of his family members. Thus, molecular diagnosis was performed using genomic DNA extracted from the peripheral blood of the proband alone. In the primary screening using the Invader assayEYA4:NM_004100.4:c.1177 C > T:p.Q393X (in exon13) (hg19:chr6:g.133804239 C > T) was identified in the eyes absent 4 gene  in this patient. This result was confirmed by Sanger sequencing. This variation was previously reported as a pathogenic variant in a non-syndromic SNHL Korean pedigree10. This variant was absent in the 1,000 Genomes Project; 6,500 Exome Variant Server; 333 healthy controls in the Shinshu University Project; Human Genetic Variation Database and 2KJPN for the Japanese population databases; and the 1,000 controls of Iowa University. Only one case carrying this variant was present in the Exome Aggregation Consortium database . According to the pathogenicity classification based on the Association College of Medical Genetics (ACMG)11, we regard the p.Q393X variant as “pathogenic”.As a result of this genetic analysis, a heterozygous variation EYA4 mutations present with non-syndromic SNHL, but some also experience dilated cardiomyopathy and heart failure accompanied by SNHL7. We, therefore, performed a detailed cardiac examination to confirm whether the patient had a non-syndromic phenotype. His electrocardiogram revealed an abnormal Q wave at V1 and V2 , and eight are located in the variable region of the EYA4 transcripts. The affected individual in this study carrying p.Q393X showed a similar progression of hearing deterioration to that observed in DFNA10 patients15. Further, the audiometric configuration of the previously reported Korean SNHL pedigree with the same mutation resembles that of the patient in this study10. It is therefore possible that both a mutational hot spot and founder effect are involved.Allele variants in EYA4 gene mutations is a rare associated symptom. However, it should be noted that some cardiac abnormalities  were detected by echocardiography in three of nine cases with EYA4 mutations6. In terms of gene expression, EYA4 is expressed in the heart and the inner ear16. Normal cardiac gene expression is sensitive to the concentration of EYA4-SIX complexes;5 therefore, a partial EYA4 deficiency may induce small cardiac abnormalities despite a clinically normal status. Even in asymptomatic patients, it is possible to avoid overlooking potential cardiac degradation leading to more serious conditions, such as heart failure, by cardiac examination. The present data suggest that EYA4-associated hearing loss possibly exhibits an extensive spectrum of conditions ranging from minor abnormalities showing clinically normal heart function to dilated cardiomyopathy. It is hypothesized that the susceptibility to cardiomyopathy may be determined by the mutational position on the EYA4 transcripts;6 however, no information of any genotype–phenotype correlation is currently available. Any such correlation will become clearer as data are accumulated in the future.The dilated cardiomyopathy caused by EYA4 mutations.Next-generation sequencing is an effective strategy for elucidating the etiology of hearing loss with high genetic heterogeneity, and our findings will provide a basis for further exploration of the pathological mechanisms and appropriate counseling for patients with EYA4 gene mutation. Minor abnormalities were observed on the patient’s electrocardiogram and echocardiography without any apparent symptoms. The present findings suggested the possible phenotypic expansion of deafness caused by EYA4 gene mutations.In this paper, we report a Japanese patient with progressive sensorineural hearing loss carrying a rare autosomal dominant


Studies have demonstrated the benefits of low frequency residual hearing in music perception and for psychoacoustic abilities of adult cochlear implant (CI) users, but less is known about these effects in the pediatric group. Understanding the contribution of combined electric and acoustic stimulation in this group can help to gain a better perspective on decisions regarding bilateral implantation. We evaluated the performance of six unilaterally implanted children between 9 and 13 years of age with contralateral residual hearing using the Clinical Assessment of Music Perception (CAMP), spectral ripple discrimination (SRD), and temporal modulation transfer function (TMTF) tests and compared findings with previous research. Our study sample performed similarly to normal hearing subjects in pitch direction discrimination (0.81 semitones) and performed well above typical CI users in melody recognition (43.37%). The performance difference was less in timbre recognition (48.61%), SRD (1.47 ripple/octave), and TMTF for four modulation frequencies. These findings suggest that the combination of low frequency acoustic hearing with the broader frequency range of electric hearing can help to increase clinical CI benefit in pediatric users and decisions regarding second-side implantation should consider these factors. Profoundly deaf patients can receive cochlear implants (CIs) and the advantages of electrical stimulation in restoring hearing capacity and speech understanding are well known. However, music perception and speech perception in noise are still generally poor in CI recipients without residual acoustic hearing, due to spectrotemporal limitations of electrical stimulation . CombiniN = 50) implanted with shorter electrode arrays performed similarly to normal hearing subjects in a pitch perception task using complex tones and the average score was 1.1 semitones. Conventional CI users tested in related studies have scores around three semitones. Melody perception was 65.9% and almost three times better than in conventional CI users. Timbre recognition was also better, but the difference was limited with Hybrid users scoring 56.6% and conventional CI users scoring 42.5%. The authors concluded that Hybrid CI users maintain music perception abilities postoperatively better than typically observed with conventional CIs.The benefits of combined acoustic and electric hearing are especially significant in music perception . GfellerTo determine whether the preserved acoustic cues contribute to superior performance, Speech and musical sounds contain multiple frequency and timing cues that vary in a complex manner. Both normal hearing and CI systems need a detailed representation of acoustic signals in spectral and temporal domains to fully perceive such complex signals, but spectral and temporal sensitivity is limited in current implants as a result of biological and technological constraints. Since there is no US FDA approval for the Hybrid or EAS systems for individuals younger than 18 years of age, reported outcomes in this age group with preserved residual hearing after implantation are limited. Benefit of combined acoustic and electric hearing on music emotion judgment  and percGiven the apparent benefits of bimodal hearing, there is an ongoing debate over when bimodal hearing may have benefits over bilateral CIs . StudiesM = 10.6 years) of age participated in this study. Subjects spoke English as their native language and had limited formal music training. Six unilaterally implanted children between 9 and 13 years  with custom MATLAB programs and a sound field presentation level of 65 dB A. All stimuli were presented via a loudspeaker that was positioned at 0° azimuth and 0° elevation at a 1-m distance from the subjects.Clinical Assessment of Music Perception is a test of music perception that was specifically developed for CI users and a previously described testing procedure was employed for pitch, timbre, and melody subtests . Each teThe complex pitch direction discrimination (PDD) test was a two alternative forced choice procedure in which the subject identifies the synthesized tone with a higher pitch. Two buttons (1 and 2) were presented on a computer screen and subjects were instructed to select the button corresponding to the tone with the higher pitch. Three base frequencies  were used as a reference stimulus and in each tone pair the comparison stimulus interval was changed by the step size of one semitone. The initial pitch pair has an interval of 12 semitones and each correct response was followed by a smaller interval with incorrect responses followed by larger intervals. The discrimination threshold in semitones was estimated as the mean interval size for three base frequencies, each determined from the mean of the final six of eight reversals. A reversal at zero was automatically added by the test algorithm when the subjects answered correctly at a one semitone interval to create an accurate psychometric function.Twelve well-known melody clips were played three times in random order in the melody recognition subtest. Rhythmic cues were removed from the melodies and each note of each melody has the same length and time signature with identical tempo. All melodies played in notes with a duration of 500 ms in an 8 note pattern at a tempo of 60 beats per minute. Each melody was prerecorded as five versions with different intensities per note (±4 dB) and each time a different version was played randomly to avoid intensity cues. After listening to the melody, subjects were asked to identify the melody by selecting the title of the song from the closed set of names. Measured outcome was a total percent correct score calculated after 36 melody presentations.In timbre recognition, subjects were asked to identify a musical instrument from a closed set of names with the picture of the corresponding instrument. Eight instruments playing an identical five-note sequence were used and all instruments were recorded live with attempted identical phrasing. A total percent of instruments correctly identified was calculated after 24 presentations.The SRD test is an adaptive task and previously described stimuli and procedures were used . The stiThe temporal modulation transfer function (TMTF) test used in this study was adapted from t indicates time and x indicates multiplication, f(t) is the wideband Gaussian noise carrier, mi is the modulation index (modulation depth), fm is the modulation frequency, and y(t) is the resulting signal. To compensate the intensity increment for the SAM stimuli the modulated waveform was divided by a factor of 1 + (mi) threshold (MDT) for each modulation frequency, converging on 70.7%  for 262 Hz; 0.78 (±0.25) for 330 Hz; 0.67 (±0.20) for 391 Hz; and 0.81 (±0.16) semitones on average. The timbre recognition score of the subjects was 48.61% (±8.06) on average. Pediatric users of CIs without residual hearing in a previous study scored 34.09% (±13.15) on average . Adult COn the melody recognition subtest the subjects scored 43.37% (±19.49) on average and with that score our study sample performed almost four times better than the children from a previous study without residual hearing . In refeMean spectral ripple threshold of study subjects was 1.47 (±0.85) rpo. Pediatric and adult CI recipients and adult Hybrid CI recipients in previous studies have mean spectral ripple thresholds at 2.08 (±1.6), 2.10 (0.40) and 4.60 (±0.60) rpo, respectively .Temporal modulation detection thresholds in four modulation frequency are shown in This study demonstrates the benefit of low frequency residual hearing on music perception measurements in CI recipients. Such benefit was shown in previous studies with bimodal users , Hybrid The complex PDD performance of our study sample was very close to normal hearing subjects in previous studies  with valThe superior performance seen in music perception was not evident in SRD and TMTF measurements. The SRD test stimulus has a frequency range of 100–5000 Hz and the perception of high frequency information above 1000 Hz is critical for ripple detection. Effects of age and maturation were studied previously and it has been suggested that SRD matures at 7 years of age in CI recipients . This isOur sample size was small due to the specific nature of the CI recipients in this study. This limitation precludes detailed statistical analysis. It is believed, however, that the findings present valuable information to assist decisions on when to perform second-side implantation in older children with residual hearing.Our study sample performed similarly to normal hearing listeners in the PDD task and also performed substantially better on melody recognition than CI recipients without residual hearing in previous studies. Timbre recognition, SRD, and TMTF performances were similar to previous studies of implant recipients. These findings must have taken into account when deciding whether to proceed with second-side implants in children with residual hearing. CI recipients who perform similarly to normal hearing individuals in any behavioral measure is an important and atypical outcome measurement post implantation, hence preserving this ability should be a priority for clinicians.The datasets generated for this study are available on request to the corresponding author.This study was carried out in accordance with the recommendations of the Declaration of Helsinki with written informed consent from all subjects. The protocol was approved by the Seattle Children’s Hospital and the University of Washington Institutional Review Boards.MY conducted the tests and wrote the manuscript. MM evaluated the subjects. JR conceptualized the study, reviewed the data, and edited the manuscript.JR has served as a paid consultant to Cochlear Ltd., and Advanced Bionics Corporation, two manufacturers of cochlear implants. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hearing loss represents a major sensory impairment in humans with a strong impact on quality of life. The current standard of care for chronic sensorineural hearing loss is limited to hearing aids and implantable devices like cochlear implants. Treatments for acute hearing loss consist of systemic or intratympanic corticosteroids. Emerging therapies are being developed to prevent hearing loss or to restore it at the cellular level. Many challenges and questions remain as to the delivery of these therapeutics into the inner ear. Scientists, clinicians, and industry stakeholders should always consider the treatment burden from the patient’s perspective when designing new drug delivery approaches. This article highlights key issues to consider. Worldwide, 466 million individuals suffer from disabling hearing loss and untreated hearing loss is estimated to cost $750bn according to the World Health Organization (WHO) making it a major public health issue . HearingA recent review of emerging therapies by The success of these approaches will require the therapeutic to reach its site of action at the right dose, over the right time course and without causing unwanted side effects. Research into developing techniques to efficiently deliver therapeutics into the inner ear is therefore timely and of the upmost importance. It is also vital to consider what patients want and need from new treatments.The most desirable treatment from the patient’s perspective would be a drug taken orally with no adverse side effects. This will be particularly important for prophylactic treatments targeting age-related hearing loss that may require frequent dosing or for otoprotective drugs designed to be administered before exposure to noise. An oral tablet that can be self-administered would have minimal impact on everyday life and would be the ideal solution for prevention of noise-induced hearing loss amongst military personnel.Intravenous (IV) delivery of prophylactic treatments may be acceptable to patients if the frequency of dosing is low, for treating acute or sudden onset hearing loss where a patient may be actively seeking medical help, or is already under medical care if being treated with IV aminoglycosides or cisplatin. Regular dosing might require time off work and disruption to everyday life making such treatments less acceptable to patients.Although systemic delivery of therapeutics to the cochlea is most desirable it may not always be possible. Challenges can include unwanted side effects and, depending on the drug’s chemical properties and pharmacokinetics, insufficient amounts crossing the blood-labyrinth barrier and reaching the cochlea .Injection of a therapeutic through the tympanic membrane may overcome some of the challenges faced with systemic delivery of inner ear therapeutics. It may reduce the risk of unwanted side effects and increase the availability of the therapeutic at the side of action, particularly if used in conjunction with polymers to control drug release over a period of time. Although minimally invasive, patients are unlikely to tolerate repeated administration and may become uncompliant. This is because the procedure can be painful, requires patients to take time from their daily activities to visit a clinic and requires them to avoid water entering the ear while the tympanic membrane heals. This could become burdensome. This route of administration is therefore most suited to the treatment of acute forms of hearing loss or the delivery of therapeutics to trigger regeneration of hearing which may be associated with significant improvement in hearing and infrequent administration. Advances in technologies able to reduce the discomfort and pain associated with intratympanic injection could make this approach more acceptable in the future for frequent administration of therapeutics. One such example uses magnetic forces to drive iron nanoparticles that can be linked to a therapeutic into the middle ear and cochlea . It is cNot all therapeutics injected into the middle ear will reach the cochlea at the required concentration, and for cell and gene therapies direct delivery to cochlea via a cochleostomy maybe the only option. This approach requires surgery under a general anesthesia requiring patients to spend time in hospital and recovering from the surgery. Therefore this approach is unlikely to be acceptable to patients for treatments that need frequent administration or for those that provide only modest improvements in hearing. The approach is also associated with the risk of causing permanent damage to any residual hearing, so is unlikely be acceptable to patients with milder forms of hearing loss. The exception may be people with genetic forms of hearing loss that are predicted to lead to a rapid loss of hearing. Intracochlear administration is therefore most suited to the delivery of “single shot” treatments to restore hearing or correct a genetic fault. Some are considering implantable intracochlear drug delivery devices for regular drug infusions to the inner ear. This alternative could be adopted by patients provided the refill chamber is easily accessible without surgery and the time between refills is acceptable.Finally, cochlear implants are being designed to deliver drugs to the cochlea. Approaches include coating the electrode in biodegradable eluting polymers or cells to release factors that reduce trauma and promote spiral ganglion survival . These tA new generation of therapeutics is emerging. It is vital that the field develops safe and efficient methods to deliver these to the inner ear. Disruptive technologies requiring expertise from different fields  are needed. A collaborative and international effort promoting such multidisciplinary research recently emerged with the launch of the International Society of Inner Ear Therapeutics . This wiDepending on the nature of the treatment and expected outcome, different patient populations are likely to tolerate different levels of risk and invasiveness. It is therefore important to seek the target patient population’s view at the early stages of developing a therapeutic to ensure its planned method of delivery is acceptable.Both authors wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this article, a dynamical downscaling (DD) procedure is proposed to downscale tropical cyclones (TCs) from a general circulation model, with the goal of investigating inland intense precipitation from these storms in the future. This DD procedure is sequential as it is performed from the large scale to the small scale within a one-way nesting modeling framework with the Weather Research and Forecasting (WRF) model. Furthermore, it involves a two-step validation process to ensure that the model produces realistic TCs, both in terms of their general properties and in terms of their intense precipitation statistics. In addition, this procedure makes use of several algorithms such as for the detection and tracking of TCs, with the objective of automatizing the DD process as much as possible so that this approach could be used to downscale massively many climate projections with several sets of model options. The DD approach was applied to the Community Climate System Model (CCSM) version 4 using Representative Concentration Pathway (RCP) 4.5 during the period 2005–2100, and the resulting TCs and their intense precipitation were examined. General circulation models (GCMs) are useful tools to investigate future conditions on Earth. In particular, given the destructive potential of tropical cyclones (TCs), including their ability to produce intense precipitation (IP) that may in turn trigger disastrous floods, it is crucial to evaluate how these storms will evolve in a changing climate both in terms of their frequency and intensity. So far, mainly three approaches have been used to evaluate changes in TC properties due to climate change using GCMs.The first approach is to use predictors for the development of TCs, which relate the observed frequencies of tropical cyclogenesis to large-scale environmental factors ,2,3. Thihurricane-type vortices [The second approach consists of the direct use of GCM outputs to identify TCs. In order to be applicable, this approach requires a sufficient horizontal resolution to resolve TCs. However, due to the large computational cost associated with the run of a GCM, a compromise is generally looked for between the available computational power, the time available to perform the study, and the model resolution. In fact, in early studies, TCs were sometimes referred to as vortices  to emphavortices , who assAlthough significant improvements have been made since then in the resolution of TCs in GCMs, the wide majority of the studies thus far ,8 still dynamical downscaling (DD). DD allows to better resolve TCs since regional atmospheric models (RAMs) can be run with a finer resolution than GCMs. In the literature, DD has been used in several ways to study future TCs. Although the most intuitive DD approach would be to use a RAM to simulate to a finer resolution a storm present in the parent GCM, this approach has rarely been employed for TCs because, as mentioned previously, the TCs produced by a GCM may be poorly resolved and too weak. The most common alternative for the DD of TCs has been to use a large simulation outer domain, so that the RAM generates its own TCs. In particular, this approach has been used in a series of studies by Thomas R. Knutson and coworkers [A third approach for the investigation of the change of TC properties in the future is oworkers ,12,13,14pseudo-global warming dynamical downscaling (PGW-DD) method, which is the most common approach for the DD of TCs under future conditions to date. The PGW-DD method consists of altering the present conditions, which may be obtained from an atmospheric reanalysis or from observation, by a time-invariant 3-dimensional climate change perturbation. Such a perturbation is obtained from a GCM or multi-GCM ensemble by subtracting the average conditions at the beginning of the considered period  from the average conditions at the end of this period . This approach has the advantage of reducing the model bias contained in the initial and boundary conditions (IBCs) from the GCM. On the other hand, the PGW-DD method makes strong assumptions: since the governing equations are nonlinear, adding perturbation fields due to climate change to the present-day atmospheric fields may result in imbalances between nonlinear terms, such as the advection terms [However, Knutson et al. did not perform the direct DD of a GCM’s outputs. Indeed, they explained that GCMs have known biases which may distort the simulation of TCs. Instead, in these studies, they used a method usually referred to as the on terms .The resolution in the simulation outer domain should be fine enough to resolve TCs;The outer domain should be large enough for several reasons. First, for the simulation of Atlantic TCs, the region of formation of African easterly waves should be included in the outer domain because these waves play an important role in the formation of TCs. Second, if the outer domain is too small, it will be too closely coupled with the driving GCM, and consequently unable to capture upscale interactions. This can be all the more problematic if the GCM is biased;The presence of bias in the driving GCM may prevent the RAM from generating its own TCs. In this case, it is necessary to remove the bias from the IBCs. In particular, in their study, Done et al.  found thDespite the concerns raised by the proponents of the PGW-DD method, a few studies reported on the direct DD of GCM outputs using a large simulation outer domain. For example, Done et al.  used theThis article presents the results for the direct DD of CCSM version 4 (CCSM4) using Representative Concentration Pathway (RCP) 4.5 with the WRF model. More precisely, the article focuses on the simulation of IP from TCs during the 21st century. The RAM used in this study was the Weather Research and Forecasting (WRF) model  version parameterization refers to the method of replacing processes that are too small-scale or complex to be physically represented in the model by a simplified process. Associated with these parameterizations are various parameters used in the simplified processes. A scheme refers to a given formulation of a parameterization (https://en.wikipedia.org/wiki/Parametrization_(atmospheric_modeling); last accessed on 18 February 2019).The WRF model was selected among other available models for several reasons. First, it has been used extensively in recent studies for the simulation of TCs ,21,22,23For this study, the WRF model was run using 38 atmospheric model levels in the vertical direction with a pressure top of 50 mbar, a time step of 3 min, and the PSs of The GCM selected in this study was the Community Climate System Model version 4 (CCSM4). CCSM4 is a coupled climate model developed by NCAR to simulate the global climate system . The modhttps://www.earthsystemgrid.org/; last accessed on 18 February 2019) or from the archives of the German Climate Computing Center .GCMs, like CCSM4, are generally driven by Representative Concentration Pathways (RCPs), which are greenhouse gas concentration trajectories for the future ,26. Thes−2) . In thisExamination of CCSM4 data revealed that the GCM failed to produce a population of well-defined TCs. Indeed, TCs are too few and too weak, which is not surprising given the relatively coarse resolution of the model. This problem was tackled by using the DD alternative discussed in Perform the DD of CCSM4 with the WRF model at 45 km horizontal resolution with the domain shown in Examine the WRF model outputs from the previous step to assess whether the model generated a sufficiently large number of TCs, including a sufficiently large number of landfalling TCs for the study of IP over the eastern and southern U.S. in the future. If so, one can go to the next step. It is noted that since the focus of this study is on IP rather than TC climatology , it is less problematic if the number of TCs simulated by the WRF model is less or more than it should be. There should be, however, substantially more TCs in the WRF model outputs than in CCSM4, since the scarcity of TCs in CCSM4 was the main reason for adopting this DD alternative. If the model fails to produce enough TCs, additional work is required. For example, following the discussion in Examine the TCs in the WRF model outputs to assess whether their properties  are realistic. For example, did the model generate a population of TCs that is overall too strong, or too weak? If not, one can go to the next step. Otherwise, additional work is required, which again may involve trying to remove the bias from CCSM4 and run the WRF model with the unbiased IBCs;Perform DD to 15 km horizontal resolution of the TCs identified in Step 2;Perform DD to 5 km horizontal resolution of the results from Step 4;Validate the WRF model performance in simulating IP from TCs during the historical period (corresponding to 2005–2017 in this study). This step is necessary if one wants to confidently use the WRF model previsions of future IP from TCs.More precisely, the following line of actions was employed for the DD of CCSM4 with WRF:One-way nesting means that the nested domains are run separately and sequentially starting with the outer domain, which differs from a two-way nesting modeling framework for which the nested domains are run simultaneously and communicate with each other.The flowchart of these steps is given in TCs in the WRF model outputs at 45 km resolution were identified using detection and tracking algorithms (DTAs). Indeed, although TCs could have been identified manually by visual examination of the model outputs, using for example the plots of the sea-level pressure (SLP) field  or of the meridional surface wind speed (SWS) field (which exhibits a dipole at the location of a TC), using such algorithms has the advantage of significantly limiting the time of postprocessing, so that the DD approach presented in this article may be applied to many climate projections and/or combinations of the model options. In this study, DD was performed for only one climate projection (CCSM4 RCP 4.5) and one combination of the PSs . Yet, sehttp://www.mpimet.mpg.de/en/science/models/echam.html; last accessed on 18 February 2019) to investigate the influence of greenhouse warming on the climatology of TCs. In this algorithm, TCs are identified by using several physical and dynamical criteria. More specifically, several thresholds are used for different quantities such as the relative vorticity at 850 hPa. In the present study, two separate sets of criteria were adopted: a first set called high-threshold set which allowed the detection of intense TCs, and a second, less stringent set called low-threshold set which was used for the reconstruction of their tracks. Model grid points passing the criteria were then gathered into TCs based on a distance threshold. Next, TC tracks were reconstructed by matching TCs at a given time step with TCs at the adjacent time steps using a threshold on the TC speed. It is noted that, for this study, the objective of these algorithms was not to necessarily detect all TCs, but a sufficient number of these storms to allow the investigation of their IP properties during the 21st century. More precisely, the DTAs were designed to be loose enough to detect as many TCs as possible but conservative enough to limit unintended postprocessing work to remove manually spurious storms from the TC population. A more extensive description of these algorithms is provided in the The detection algorithm was adapted from Bengtsson et al. , who useThe DTAs were first applied to the Climate Forecast System Reanalysis (CFSR) for 2004–2017 in order to assess their performance. The DTAs were then applied to the WRF model outputs for the DD of CCSM4 to 45 km resolution. A total of 49 TCs were detected during the period 2005–2017, including 11 landfalling TCs. This is less than the number of TCs detected in CFSR (76 TCs were detected in CFSR during the period 2005–2017), but this still offers a large enough population of TCs to work with. In particular, there was, on average, almost one landfalling TC per year during the period 2005–2017 in the WRF model outputs. Besides, 393 TCs were detected during the period 2005–2100 including 64 landfalling TCs. The sufficiently large is that the number of landfalling TCs identified in the model outputs was large enough to compute statistics for IP from this ensemble of storms. More precisely, there should be a sufficiently large number of realizations of an inland precipitation depth (PD) field during the historical period (2005–2017 for this study) to assess whether the model is suitable for the simulation of IP from TCs. On the other hand, the number of landfalling TCs during the 21st century should be sufficiently large to allow computing such IP statistics for the future conditions. These aspects are further discussed in In The CPD and TCCHL were first computed for each TC and each time step during a TC’s lifetime by analyzing the radial profile of the SLP. Although the SLP field generally already exhibits a clear local minimum at the TC location, we went one step further and worked instead with a SLP perturbation field. This perturbation field was computed by subtracting from the original SLP field a mean SLP field obtained by averaging the SLP over all time steps during the hurricane seasons of 2005–2100. The advantage of this exercise is that the local depression at the TC location in the SLP perturbation field is even more well-defined than in the original SLP field.r is the distance from the TC CLSLP and Secondly, all the grid points within a distance of 2000 km from the TC’s center of low SLP (CLSLP) were identified and used to compute the radial profile of the SLP perturbation field by averaging this field azimuthally. An example is provided in Similar to the case of the SLP field, a mean SWS field was computed by taking the average over all time steps during the hurricane seasons of 2005–2100. This mean SWS field was then subtracted from the SWS field at the considered time step in order to obtain an SWS perturbation field. The advantage of working with this perturbation field is that it is generally free from strong background currents such as the trade winds, so that the circulation around the CLSLP is more axisymmetric than in the original field. In fact, we went one step further by calculating the mean SWS perturbation within a radius of TCCHL from the CLSLP and subtracted this mean value from the SWS perturbation field, so that the resulting field is even closer to being axisymmetric. These efforts were done in an attempt to separate the TC circulation from the background field to improve the estimation of the MTSWS and RMTSWS.Next, all the grid points located within a distance of 2×TCCHL from the CLSLP were identified and used to compute the radial profile of the tangential SWS by averaging the tangential SWS azimuthally. Examples of such radial profiles are provided in Finally, the TC depth was estimated using the vertical profile of the vertical vorticity above the CLSLP. It was defined as the height for which the vertical vorticity drops below a given threshold taken as 5% of the surface vertical vorticity.In order to assess the adequacy of the TCs produced by the WRF model, the aforementioned TC properties were calculated for each TC identified in the WRF model outputs at 45 km resolution and in CFSR, and their mean values were compared .For the comparison of TC properties to be legitimate, the spatial resolution of the data should be the same, or at least should be close. The horizontal resolution of the WRF model outputs is 45 km whereas it is 0.5 for CFSR. 0.5 of latitude is approximately equal to 55.5 km whereas the distance in kilometers corresponding to 0.5 of longitude varies with latitude. For example, at the equator, 0.5 of longitude is approximately equal to 55.6 km while at 40N it is about 42.5 km. Besides, CFSR uses 37 atmospheric vertical levels whereas the WRF model was run with 38 levels. As a result, in the region of investigation for this study, the horizontal and vertical resolutions of the WRF model outputs and of CFSR are similar, although resolution is slightly coarser for CFSR. It is consequently legitimate to compare the second and third columns of Given this potential explanation in terms of the model resolution, and the fact that the difference between the two datasets is relatively small, it was decided that the population of TCs produced by the WRF model is sufficiently realistic for the purpose of this study, which checks out the third step of the line of actions proposed in One of the issues in the choice of the intermediate and inner domains for the simulation of IP from TCs in the eastern and southern U.S. is the diversity of TC tracks and consequently of landfall locations. This aspect may be tackled in two ways: either by customizing the nested domains to each storm so that they fit the location and size of the PD field, or by taking large nested domains encompassing the whole eastern and southern U.S. The problem with the first approach is that it may be time consuming to set up the nested domains manually for every storm. On the other hand, the problem with the second approach is that the time of computation increases drastically with the model resolution, so that it may not be feasible to perform the DD of such a large region to a fine resolution.A compromise was chosen in this study. First, it was found that the computational effort associated with the DD with a large domain of each TC in the WRF model outputs at 45 km resolution to 15 km resolution remained reasonable, so that such a large intermediate domain was used for the first downscaling step to 15 km resolution. Besides, for a given TC, the intermediate-domain simulation start date was taken as the date for which this TC’s MTSWS was the largest as the storm was moving over the Atlantic Ocean.Secondly, as far as the inner domain is concerned, it was chosen to construct this domain case by case, according to the location and size of each TC’s PD field in the intermediate domain. Algorithms were developed for this purpose. Indeed, setting up the inner domain manually for each storm would be very time consuming, which goes against the aforementioned objective in this work of automatizing the DD procedure as much as possible. The algorithms for the determination of the inner-domain simulation start and end dates and for the construction of the inner domains based on the PD fields in the intermediate domain are detailed in the In a nutshell, in these algorithms, the inner-domain simulation start date is taken one day before the time of landfall whereas the inner-domain simulation end date is taken as the time for which a TC stops producing IP over the U.S. The inner domain is then constructed based on the PD field in the intermediate domain accumulated between the inner-domain simulation start and end dates. The simulation start and end dates in the intermediate and inner domains for the 64 landfalling TCs during the 21st century are given in In the previous section, the DD of North Atlantic TCs during the 21st century was performed to 15 and 5 km resolutions to simulate to a fine resolution the PD fields produced by these TCs in the eastern and southern U.S. However, in order to confidently and legitimately use the WRF model’s previsions of IP from TCs in the future, one must first verify that IP simulated during the historical period of 2005–2017 is realistic. This task corresponds to the last step of the line of actions proposed in intense precipitation (IP)? This notion is, in fact, very subjective. In the literature, many definitions have been used. For example, Kunkel et al. [First and foremost, what is l et al.  defined l et al. , an evenl et al. , which c• IP Metric 1: surface area of the PD field above a given threshold In Stevenson and Schumacher , an IP esurface area of the region where the PD field exceeds the PD threshold field. Still, IP Metric 1 remains equivalent to the metric used in Stevenson and Schumacher [t is time. The max operator suggests that the maximum value over the duration of the storm should be retained. For example, suppose that a storm lasts for 48 h, that one is interested in the 24-h PD, and that the precipitation data is provided with a 1-h time increment. In this case, there will be 25 realizations of a 24-h PD field within the 48-h time interval, and the maximum of these 25 realizations should be retained in the construction of the metric. In other words, IP Metric 1 gives the surface area of the region where the PD field is larger than the PD threshold field at the time when the storm is the most intense.It is noted that this quantification (number of grid points above a threshold) depends on the resolution of the precipitation dataset. Indeed, the finer the resolution is, the larger the number of grid points above the threshold is. As a result, in this study, IP Metric 1 was instead taken as the humacher  since it• IP Metric 2: weighted surface area of the PD field 2 slightly above the PD threshold field whereas the second storm produced a PD field with 200 km2 where the PD threshold field was greatly exceeded. According to IP Metric 1, the first storm is much more intense than the second. However, is such a conclusion legitimate?IP Metric 1 contains information regarding whether a PD field exceeded a given threshold. However, it cannot tell how much larger than the threshold the PD field was. For example, let us consider two storms: the first storm produced a PD field with 1000 kmIP Metric 2 is proposed to tackle the emphasized limitation of IP Metric 1. In this case, the PD field is normalized using the PD threshold field, and the resulting normalized PD field is then integrated over the domain of investigation. Mathematically, IP Metric 2 is given by:IP Metric 2 is clearly a generalization of IP Metric 1.• IP Metric 3: maximum PD over a size-predefined area IP Metrics 1 and 2 provide information on the intensity of precipitation at the spatial scale of the storm, which may be a very large region encompassing several states. As a result, they cannot quantify IP at a predefined scale. For example, in the context of Probable Maximum Precipitation  estimat2 in 72 h. More generally, instead of one value, one may consider the depth–duration curve for this specified area by looking at a range of time intervals. In fact, one may even go one step further and compute the depth–area–duration curves, in which case not just one, but a range of spatial scales are accounted for. However, the computation of the depth–area–duration curves can be difficult and computationally intensive.IP Metric 3 is given by the maximum PD that a TC spawned over an area of a given size in a given time interval. For example, this may be the maximum PD falling over an area of 2400 km• IP Metric 4: maximum normalized PD over a size-predefined area 2 in 72 h was, on average, three times larger than the threshold.IP Metric 4 is constructed in the same way as IP Metric 3, but it uses the normalized PD field instead of the original  PD field. As for IP Metric 2, the normalized PD field is obtained by dividing the PD field by the PD threshold field. Using the previous example, if IP Metric 4 is equal to 3.0, this means that, within the domain of investigation , the largest PD that fell over an area of 2400 kmWikipedia by checking if these tracks passed over the conterminous U.S. , whereas the dates and times of landfall and termination were obtained from the Tropical Cyclones Reports of the National Hurricane Center. The list of historical landfalling TCs during the period 2005–2017 is given in the In order to validate the WRF model performance in simulating IP from TCs, the four IP metrics were calculated during the period 2005–2017 for all landfalling TCs in the WRF model outputs, and for all historical landfalling TCs. Stage IV was used for the historical TCs in the calculation of the IP metrics. Historical landfalling TCs were determined by visual examination of TC tracks provided by the free online encyclopedia For each of the historical landfalling TCs, the region affected by the TC’s precipitation was then determined by using the algorithms for the construction of the simulation inner domain discussed in https://hdsc.nws.noaa.gov/hdsc/pfds; last accessed on 18 February 2019). A 72-h period was considered instead of the 24-h period used in Stevenson and Schumacher [The IP metrics were calculated using the NOAA Atlas 14 100-yr, 72-h PD threshold field  obtainedhumacher  because 2, IP Metrics 3 and 4 were calculated by using a square of side A simplified approach was used to compute IP Metrics 3 and 4. When looking for the maximum PD (IP Metric 3) or the maximum normalized PD (IP Metric 4) that fell over an area of a given size, all geometries for this area should be ideally considered. However, such an approach would be computationally very intensive. As a result, a square region was considered for the calculation of IP Metrics 3 and 4. More precisely, considering an area of size S km2. The reason for the choice of a region size of 2400 km2 is the following. The material presented in this article actually originates from the third chapter of a Ph.D. thesis [On the maximization of precipitation from tropical cyclones in the context of climate change. In 2, which explains why IP Metrics 3 and 4 are calculated based on a surface area of 2400 km2 in this article.IP Metrics 3 and 4 were calculated using a spatial scale of 2400 km. thesis  entitled2 were considered for the purpose of the WRF model validation. In the case of the WRF model outputs in the inner domains (5 km resolution), squares of sides 7 grid cells, 8 grid cells, 9 grid cells, 10 grid cells, 11 grid cells and 12 grid cells were used which correspond to surface areas of 1225 km2, 1600 km2, 2025 km2, 2500 km2, 3025 km2, and 3600 km2, respectively. In the case of Stage IV having a horizontal resolution of 4 km, squares of sides 9 grid cells, 10 grid cells, 11 grid cells, 12 grid cells, 13 grid cells, 14 grid cells and 15 grid cells were used which correspond to surface areas of 1296 km2, 1600 km2, 1936 km2, 2304 km2, 2704 km2, 3136 km2, and 3600 km2, respectively. Validation results are given in More precisely, several surface areas around 2400 kmAs far as IP Metric 2 is concerned, results are less satisfactory. Indeed, the mean and standard deviation of IP Metric 2 for the simulated precipitation are smaller than the mean and standard deviation of IP Metric 2 for the observed precipitation in both the aforementioned cases . This suggests that the WRF model tended to produce too compact PD fields in the DD of CCSM4 when using the PSs of Besides, Thus, the WRF model gave overall satisfactory performance in simulating IP during the historical period 2005–2017, despite a tendency to produce slightly too compact and too locally intense PD fields compared to the PD fields in Stage IV. It is noted that, in practice, to save time, DD should be first performed for the historical period only, and the future years be downscaled only after validation of the model performance in simulating both TC properties as in  and IP f2, which corresponds to a square having 10 grid cells per side for the searching region since the resolution of the WRF model outputs in the inner domains is 5 km (5 × 10 × 5 × 10 = 2500). A surface area of 2500 km2 is chosen here because this is the closest surface area to 2400 km2 that may be attained when using a square as a searching region for the construction of IP Metrics 3 and 4 given the inner-domain model resolution of 5 km. As explained previously, 2400 km2 is the surface area of the drainage basin of the city of Asheville, NC, which was taken as the target area for the application of a physically based storm transposition method to four historical and two future TCs in Mure-ravaud [In this subsection, the IP metrics are calculated for all landfalling TCs in the WRF model outputs during the 21st century using the 100-yr, 72-h PD threshold field of e-ravaud .Results are given in 2 region since it is the region size used for the construction of IP Metrics 3 and 4) may also increase, but more moderately.It is seen that IP is expected to increase by the end of the century according to all metrics, although the increase is significantly larger for IP Metrics 1 and 2 than for IP Metrics 3 and 4. More precisely, this increase is the most pronounced for the anomaly of the moving-average normalized IP Metric 2 which becomes positive early, for TC No. 24 (in 2031), and remains positive until the end of the century. The moving-average normalized IP Metric 1 shows little variations  until TC No. 46 (in 2064) for which its anomaly exceeds 0.05 and remains significantly positive until the end of the century where it reaches a value of 0.1. The anomalies of the moving-average normalized IP Metrics 3 and 4 never exceed 0.05 in absolute value. They tend to be positive at the end of the century although they take slightly negative values for TC No. 61 (in 2089). These results suggest that, towards the end of the century, TCs may produce significantly larger and more intense PD fields. At the same time, their local IP  than the local  IP (as measured by IP Metrics 3 and 4). It is noted that the tendencies found in this study, either in terms of TC properties or TC IP in the future, should be treated with caution. Indeed, DD was performed only for one climate projection and one set of the WRF model options. Many more simulations are needed to legitimately draw any solid conclusion on such tendencies.


Oligonychus afrasiaticus (McGregor) management, which could reduce toxicant dose and host killing time. Therefore, phytol and Beauveria bassiana in different proportions were evaluated to determine their effectiveness. Prior to ascertaining host mortality and defense mechanisms, we have recorded in vitro action of phytol using different concentrations  against B. bassiana suspension. In vitro compatibility assays revealed that growth parameters  of B. bassiana were least affected by the action of phytol at all tested concentrations. Biological Index of B. bassiana exhibited compatibility with phytol allowed us to conduct Joint toxicity bioassays in which phytol and spores mixed in different proportions in order to attain maximum treatment effect in terms of high mortality at low concentration under short time. Results revealed that joint-application exhibited both synergistic (treatments with higher proportions of phytol), and antagonistic interaction (treatments with higher proportions of spores) interactions. Biochemical mechanisms involved in host antioxidant and detoxification response were explored by quantifying their respective enzymatic activities. Lethality of different treatments induced different patterns of detoxification enzymes including glutathione S-transferase (GST) and acetylcholinesterase (AchE). Overall, the least potent treatments  established in the current study induced relatively higher GST and AchE activities. On the other hand, the most potent treatment (80% phytol:20% spores) at its maximum concentration exhibited negligible relative GST and AchE activities. Antioxidant enzyme activities of CAT and SOD measured in the current study showed moderate to complex interaction might because of toxin-pathogen remarkable synergy. This study suggested that joint application of phytol with B. bassiana spores have shown tremendous acaricidal potential and found to be promising new strategy for controlling old world date mites.Current study reveals the likelihood to use pathogen and toxin mutually as an effective and eco-friendly strategy for  Phoenix dactylifera L.) is the dominant component of the oasis ecosystem responsible for the opening of vast desert areas for human activities. The unique nutritional characteristics of date palm fruit, exceptional tolerance against drought, salinity and harsh temperature, religious, and social affiliation of date palm with Arab culture make it the most preferred palm species to be cultivated in the oasis ecosystem. The date palm is the major fruit crop of the Kingdom of Saudi Arabia harvested on 145,516 ha with production of 964,536 tonnes during the year 2016 [The date palm (Oligonychus afrasiaticus (McGregor) is a widespread species of spider mites infesting the fruits of date palm in Middle East , and Noi Arabia , Algeriai Arabia ). The in bunches . Fine dupearance . Such daaricides ,14,15,16aricides ,17. ThusO. afrasiaticus attained particular attention because of host specificity, persistence in target host population, numerous isolates and eco-friendly [Beauveria bassiana are well-known for their pathogenicity against different target pest species [O. afrasiaticus in response to invading fungal pathogen and/or toxicant.The incorporation of fungal pathogens into the Integrated Pest Management program of friendly . Entomop species ,20,21,22 species ,24,25,26 species . Consequ species ,29. In a species ,31. PrevO. afrasiaticus populations. In this regard, we have tested the toxicity of crude extracts of different plant species against O. afrasiaticus in our preliminary study . We found phytol the most toxic fraction isolated from the crude extract of Cucumis sativus against O. afrasiaticus. We undertook the current investigation to determine the feasibility of the joint action of spore suspension of B. bassiana with plant secondary metabolite, Phytol against the infestations of old world date mites. The integration of B. bassiana with phytol require multiple experimentation on different aspects (1) determining the pathogenicity of B. bassiana and toxicity of Phytol against old world date mites; (2) evaluating the spores viability, sporulation and vegetative growth in the presence of Phytol to know their compatibility; (3) utilizing the multiple concentrations of phytol and B. bassiana and their interaction to determine synergism among them; and (4) exploring the host detoxification and antioxidant defense mechanism in response to phytol and/or B. bassiana. Toxin-pathogen synergy experimentation will lay the foundation for the development of an eco-friendly alternative control strategy against the infestations of old world date mites.The quest for the isolation and development of plant based secondary metabolites is the screening of plant extracts for the control of B. bassiana B6903 in the presence of different doses of phytol revealed dose-dependent response. The vegetative growth of B. bassiana B6903 that ranged from 73 mm to 80 mm showed significant differences  among all tested doses of phytol , and sporulation  revealed non-significant effect in response to different doses of phytol as shown in B. bassiana B6903.The vegetative growth, sporulation, and percent germination of the spores of f phytol a. OveralB. bassiana B6903 calculated in terms of mortality varied significantly , time intervals , and their interaction  showed significant differences in mortality of old world date mites , concentrations , and their interaction  (Toxicity of phytol and pathogenicity of the spores of ficantly . Sole apte mites a. Spore  0.0001) b.50 value (1.62 mg/mL) compared with sole application of phytol (LC50 = 3.28 mg/mL) and spores (LC50 = 28.28 mg/mL). The high joint toxicity index (691) calculated based on their LC50 values designated this action as “synergistic” , concentrations , and their interaction  showed significant differences in mortality of old world date mites (50 of 2.83 mg/mL led to a synergistic action (joint toxicity = 246). Mortality response of old world date mites at different concentrations , time intervals , and their interaction  showed significant differences , and 40% phytol:60% spores (joint toxicity = 60) as shown in O. afrasiaticus fed on date palm leaf disks treated with 20% phytol:80% spores calculated at different concentrations , time intervals , and their interaction  imparted significant differences , concentrations , and their interaction  as shown in Concentration-mortality response bioassays with higher proportions of the spores of ferences c. SimilaF = 2591.27; df = 5, 120; p < 0.0001), concentrations , and their interaction . Overall, the least potent treatment (spores of B. bassiana B6903) established in the current study showed the highest activities of CAT. However, different concentrations of the most potent treatment (80% phytol:20% spores) could not induce CAT activities and remained significantly at the lowest level compared to other treatments  and superoxide dismutase (SOD). Ninety-six hours after exposure, CAT activities of old world date mites differed significantly among different treatments . Overall, spores and 20% phytol:80% spores treatment at all of their tested concentrations did not greatly induce SOD activities compared with the control.The most potent treatment (80% phytol:20% spores) at its high concentration, established in the current study tremendously induced the SOD activities of old world date mites . The intF = 3527.72; df = 5, 120; p < 0.0001), concentrations , and their interaction , showed significant differences in their GST activities  and Acetylcholinesterase (AchE). Old world date mites upon exposure with different treatments , concentrations , and their interaction . Overall, all the treatments at their lowest concentration showed their highest AchE activities  for old world date mites. In the past, numerous studies successfully reduced the toxicant dose and mortality time by combining spores of entomopathogenic fungi [B. bassiana. In this study reported here, we observed that the growth parameters of B. bassiana B6903 were least affected by the action of phytol at all tested concentrations. The Biological Index computed from vegetative growth, percent germination and sporulation of B. bassiana ascertained compatibility with phytol. These in vitro compatibility results corroborate “Joint Application” to ascertain maximum treatment effect in terms of high mortality at low concentration under short period against old world date mites.Screening the plant secondary metabolites as potential acaricide is much demanding study due to resistance development among these short life span and high reproductive potential mites. In this regard, we have specifically selected an eco-friendly compound, phytol that belongs to acyclic monounsaturated diterpene alcohol, which previously reported as antibacterial ,34,35, at LC50 3. mg/mL foic fungi ,41. PrioO. afrasiaticus with the use of phytol and entomopathogenic fungus B. bassiana in combinations was recorded in the current study. However, their combined application exhibited varying interactions such as Synergistic or Antagonistic. Among the four combinations, antagonistic response did occur at 20% phytol:80% Spores and 40% phytol:60% Spores with Joint toxicity co-efficient 29.6 and 60, respectively. Such interaction (Antagonistic) in these treatments might because of high proportion of B. bassiana spores. In addition, our results revealed that B. bassiana spores alone found to be the least pathogenic treatment and their combinations with lower phytol concentration was not enough for old world date mites to impart synergistic response. On the other hand, 60% phytol:40% Spores and 80% phytol:20% Spores combinations revealed synergistic interaction with Joint toxicity co-efficient 246 and 691, respectively  demonstrated the possible effectiveness of a joint application approach for the management of old world date mites. Numerous studies in the past have demonstrated similar mortality trends in their target pest species upon exposure with dual application methodology including fungal spores and pesticides. For instance, simultaneous application of the combination of chlorantraniliprole and Metarhizium anisopliae imparted both synergistic and antagonistic mortality response against Locusta migratoria (Meyen) [Beauveria bassiana with azadirachtin and flufenoxuron revealed synergistic interaction in case of B. bassiana with flufenoxuron. On the other hand, Beauveria bassiana with azadirachtin showed an additive effect against Tetranychus urticae Koch (Acari: Tetranychidae) [Interaction of entomopathogenic fungal spores with chemicals can have antagonistic, neutral or synergistic mortality response against target pest population ,42. Increctively . These f (Meyen) . Laboratychidae) . These f2●–), and hydrogen peroxide (H2O2). The built-in antioxidant defense mechanism protects the biological systems by regulating ROS production. However, stressful situations disproportionate the target host intrinsic antioxidants and ROS balance by eliciting oxidative stress [Oxidative metabolism, a dominant source of energy leads to the generation of reactive oxygen species (ROS) such as superoxide anion  is a serine hydrolase enzyme involved in the termination of nerve impulses by rapid hydrolysis of acetylcholine (neurotransmitter) . HoweverOligonychus afrasiaticus was maintained under controlled conditions  photoperiod).The bunches of date palm fruits infested with old world date mites were collected from Agricultural Research Station, Al-Ahsa 31982, Saudi Arabia . The population of Beauveria bassiana B6903 screened in the preliminary study (data not shown) procured from the USDA-ARS collection was used in this study against old world date mites. The isolate B6903 was grown on potato dextrose agar medium  in complete darkness at 25 ± 0.5 °C. The required spore suspension of B6903 was prepared by Neubauer hemocytometer  in Tween 80 (0.05%) .The highly virulent isolate of Cucumis sativus extract was selected in this study due to its toxicity against O. afrasiaticus determined in our preliminary study. Phytol was purchased from Sigma Aldrich, London, UK . The required concentrations of phytol were prepared using environmental friendly dimethyl sulfoxide (DMSO) solvent.Phytol, an important fraction of B. bassiana isolate B6903 was multiplied in Petri dishes (115 mm × 20 mm) provided with PDA in complete darkness at 25 ± 0.5 °C. The mature 21-day culture of B6903 was suspended in 0.05% Tween 80 to prepare 1 × 106 spores/mL suspension using Neubauer hemocytometer. The compatibility of spore suspension with tested plant secondary metabolite (phytol) was determined using different concentrations . Due to the hydrophobic nature of phytol, we used 1% DMSO to evenly solubilize the active ingredient. Spore compatibility with phytol was determined by the biological index (BI) by recording spore germination, vegetative growth, and sporulation [Pure culture of rulation .B. bassiana isolate B6903 in the presence of different concentrations of phytol was assessed by poison food technique [B. bassiana B6903 suspension at a concentration of 1 × 106 spores/mL was pipetted to the center of each Petri dish. The inoculated plates after sealing with Parafilm were incubated at 25 ± 0.5 °C in complete darkness. After 12-days of incubation, vegetative growth of each experimental unit was determined by measuring the five perpendicular radial lengths (mm) of fungal growth. On the other hand, sporulation of each treatment was calculated by cutting 15 mm diameter sporulation colony of B. bassiana B6903 with the help of a sterile cork borer. Each disk after agitation in glass beaker was vortexed to count the number of spores in 0.05% Tween 80 solution under the compound microscope using Neubauer hemocytometer. One-way ANOVA analysis was performed for vegetative growth and sporulation. Significant differences in vegetative growth and sporulation in response to different concentrations of phytol were determined by Fisher’s LSD test (α = 0.05) [Vegetative growth of echnique . In brie = 0.05) .B. bassiana B6903. Each phytol strength Petri dish was separately inoculated with 200 µL spore suspension (1 × 106 spores/mL) of B. bassiana B6903. In case of control, only 1% DMSO was incorporated into the PDA. Each experimental unit was incubated for 18 h at 25 ± 0.5 °C in complete darkness. Spores germination of B6903 in response to each tested concentration of phytol was determined by counting 100 spores from five different fields of vision under compound microscope. Seven replicates were prepared likewise for each concentration. The percent of spore germination data were analyzed by one way ANOVA. Significant differences in the percent of spore germination against different concentrations of phytol were determined by Fisher’s LSD test (α = 0.05) [Potato dextrose agar supplemented petri dishes (115 mm × 20 mm) prepared with different strength of phytol including 0.70, 1.40, 2.10, 2.80, and 3.50 mg/mL were prepared to determine their impact on the germination of spores of  = 0.05) .B. bassiana B6903 were categorized on the basis of the biological index [B. bassiana B6903 in response to phytol was calculated using the following formula:Toxicological impacts of phytol on the growth of al index . BI valuB. bassiana B6903 against old world date mites [O. afrasiaticus on each leaf-disk were recorded after 24 h until 16-day post-exposure. The cadavers of old world date mites were transferred under a laminar airflow cabinet onto wet filter paper to promote fungal growth in order to make sure the actual cause of mortality. Natural mortality factor from treatment mortality was corrected by Abbott’s formula [Leaf-dip bioassay already used against old world date mites with some modifications was used to determine the pathogenicity of  formula . Mortali formula .O. afrasiaticus by leaf-dip bioassays. Date palm leaf-disks were dipped in different concentrations of phytol . After drying and surrounding the leaf-disks edges with dampened cotton, 50 deutronymphs  of O. afrasiaticus mites were transferred on each treated leaf-disk by a fine brush under a microscope. Petri dishes (150 mm × 20 mm) were incubated at 25 ± 1 °C, 62.5 ± 12.5% RH, and 16:8 h (L:D) photoperiod. The control treatment was prepared by dipping the leaf disks in 1% DMSO. Each replicate comprised of three leaf-disks arranged in one Petri dish. Five replicates were prepared likewise for each treatment. Concentration mortality response of phytol against old world date mites was also repeated in next season. Mortality data were recorded after 24 h until 16-day post-exposure. In order to eliminate natural mortality, phytol treatment mortality data were corrected by Abbott’s formula [O. afrasiaticus was analyzed by repeated measures ANOVA and means by Fisher’s LSD test [The toxicity of phytol was evaluated against  formula . In addiLSD test .Beauveria bassiana B6903 was determined by combining them in different proportions , and their joint application in different proportions (g at 4 °C for 15 min. The supernatant of each sample was used for protein quantification by standard methodology [The activities of enzymes involved in host defense mechanism including detoxification (GST and AChE) and antioxidant (CAT and SOD) were calculated using standard methodologies provided by the manufacturer. Old world date mites treated by leaf-disk method with different concentrations of phytol , portions  were inchodology . The enzhodology .B. bassiana spores against old world date mites, O. afrasiaticus. The synergistic combination of fungal spore application with phytol exhibit an effective strategy for the management of old world date mites by lowering the dose of the toxin and pathogen. Additionally, this approach will assist the development of eco-friendly protection of date palm fruit in the context of IPM for long-term sustainable management of old world date mites.In conclusion, synergistic and antagonistic effects vary with the proportion of phytol in combination with


Cognitive scientists and philosophers recently have highlighted the value of thinking about people at risk of or living with dementia as intertwined parts of broader cognitive systems that involve their spouse, family, friends, or carers. By this view, we rely on people and things around us to “scaffold” mental processes such as memory. In the current study, we identified 39 long-married, older adult couples who are part of the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Ageing; all were cognitively healthy but half were subjective memory complainers. During two visits to their homes 1 week apart, we assessed husbands’ and wives’ cognitive performance across a range of everyday memory tasks working alone (Week 1) versus together (Week 2), including a Friends Task where they provided first and last names of their friends and acquaintances. As reported elsewhere, elderly couples recalled many more friends’ names working together compared to alone. Couples who remembered successfully together used well-developed, rich, sensitive, and dynamic communication strategies to boost each other’s recall. However, if one or both spouses self-reported mild-to-moderate or severe hearing difficulties , couples received less benefit from collaboration. Our findings imply that hearing loss may disrupt collaborative support structures that couples (and other intimate communicative partners) hone over decades together. We discuss the possibility that, cut off from the social world that scaffolds them, hearing loss may place older adults at greater risk of cognitive decline and dementia. Across a lifetime in intimate relationships involving joint memory and action, people form expert “remembering systems” that may have (much) later cognitive payoffs . IntimatHowever, studies of collaborative memory in stranger dyads do not capture well the high levels of shared knowledge developed over the course of a lifetime of shared experiences, and rarely consider the degree to which collaborative benefits may be more (or less) related to the type of information  to be remembered . Recent via joint collaborative remembering, and we in turn help to scaffold them . These individuals formed 39 male–female couples, who had been married for 13–65 years . Participants were a subset of those from the Australian Imaging Biomarkers and Lifestyle Study of Ageing  aged 68–90 years old  were interested and available to participate, and these were our participants for the current study.The AIBL Study was established in 2006 with 1,112 individuals recruited during the baseline phase. They underwent a screening interview, cognitive and mood assessments, and blood-based biomarker analyses, and completed health and lifestyle questionnaires. Approximately a quarter of the sample underwent brain imaging, including magnetic resonance imaging (MRI) and Pittsburgh compound B–positron emission tomography (PiB-PET). A clinical review panel considered all medical, psychiatric, neuropsychological, and health data and classified 768 as healthy controls, 133 as having mild cognitive impairment MCI; , and 211The Macquarie University Human Research Ethics Committee provided ethical approval for this research and the AIBL Management Committee approved access to their participants and the study design. Prior to the experimental sessions, all participants received and completed the Hearing Handicap Inventory for the Elderly – Screening Version HHIE-S; . The HHISD = 1.48) and a mean GDS-SF score of 1.08 (SD = 1.38).On the day of testing in Week 1, participants also completed the MMSE  and the Individual and collaborative sessions were conducted in participants’ homes, 1 week apart. Week 1 involved an individual recall session, while Week 2 involved a collaborative recall session. During each of the two sessions, participants completed a range of memory tasks that varied by type and degree of personal significance of the information recalled. Overall performance across these tasks is reported elsewhere . We focut-test revealed that couples recalled significantly more names of mutual friends together in Week 2  compared to their pooled individual or “nominal” recall in Week 1 ; a paired-samples t-test comparing these scores was significant, t(38) = 10.02, p < 0.001. Therefore, on average, couples showed collaborative facilitation on the Mutual Friends task, recalling 16.79 more names (SD = 10.46) when they remembered together compared to separately. However, underneath this group level performance, there was considerable variability in the degree of collaborative benefit achieved by each couple. We indexed individual differences in the outcomes of collaboration by assigning each couple a “collaborative benefit” score, which was the difference between the number of names couples recalled during collaboration and the combined number of names recalled by husbands and wives during their individual recall. While no couples showed inhibited recall during collaboration compared to their nominal performance, collaborative benefit scores ranged from 0 to 38 extra names. Whereas 25% of couples gained six or fewer extra names when they collaborated, 25% gained 24 or more extra names. In other words, whereas some couples collaborated very successfully, others gained little or no benefit in terms of performance when collaborating with their spouse. Do hearing difficulties help to explain why?In the collaborative recall paradigm, the impact of recalling together is indexed by comparing collaborative output with the pooled, non-redundant output of individuals recalling alone. As reported in 2 = 5.37, p = 0.068. The increased hearing difficulties reported by men may reflect a greater willingness by men to report or the fact that, within couples, husbands  were slightly, but significantly, older than wives , t(38) = 5.08, p < 0.001. Indeed, we found significant age differences across participants in the different hearing classifications. A one-way analysis of variance (ANOVA) of hearing group on age was significant, F = 8.65, p < 0.001. Follow-up comparisons  suggested that each of the three hearing classifications differed from the others in age either marginally or significantly, with a pattern that hearing difficulties increased with age, all ps < 0.073 . .073 see .F = 1.02, p = 0.367, and neither was a chi-square analysis of the frequencies of subjective memory complainers in each group, χ2 = 1.38, p = 0.501. There was a marginal main effect suggesting increased depression symptomatology with increased severity of hearing difficulties, F = 2.94, p = 0.059, but across classifications, participants’ average GDS scores were well below the clinical cutoff of 6  = 0.88, p = 0.418 , (2) at least one spouse with mild hearing difficulties ; and (3) at least one spouse with severe hearing difficulties . We conducted a one-way ANOVA to compare collaborative benefit scores across these three groups. This analysis yielded a significant main effect of group, F = 3.57, p = 0.039, and a significant linear function, F = 7.14, p = 0.011. Follow up comparisons  indicated that couples in which at least one member reported severe hearing difficulties collaborated far less successfully  than couples in which neither member reported hearing difficulties , p = 0.034. The benefit scores for couples in which at least one member reported mild-to-moderate difficulties  fell in the middle and was not significantly different from the other two groups, ps > 0.21. The linear function suggests that collaborative benefit decreased as hearing difficulties within the couples increased.In Week 2, we explicitly instructed couples to “work together” to recall as many names as possible. Since we analyzed collaborative recall at the couple level, we classified couples into three groups to mirror our individual hearing classifications: (1) no hearing difficulties reported . This range suggests that it was relatively uncommon for both partners to report very high levels of hearing difficulties. Indeed, there were no cases in which both spouses reported severe hearing difficulties, only 3 (7.7%) cases in which one spouse reported significant difficulties and the other reported mild-to-moderate difficulties, and only 4 (10.3%) cases in which both spouses reported mild-to-moderate hearing difficulties. Instead, in 20 out of 39 cases (51.3%), one of the partners reported (mild-to-moderate or severe) hearing difficulties and the other reported no difficulties. In other words, many couples showed asymmetrical profiles with one spouse struggling to hear more than the other. Consistent with the linear relationship described above, couples’ combined hearing difficulty scores correlated negatively with their collaborative benefit scores, r = -0.34, p = 0.033 (two-tailed). Overall, our results suggest that greater hearing difficulties within couples’ “systems” reduced the success of their memory collaboration.To further examine this linear relationship between hearing difficulties and collaborative benefit within each couple, we added husbands’ and wives’ individual HHIE-S scores to create a measure of couple-level hearing difficulties. Higher additive scores indicate more reported hearing problems by the couples (possible range: 0–80). Couples’ additive scores ranged from 4 to 56 , one of the long-married couples who participated in this study. At the time of testing, Paul was 87 years old, Irene was 77 years old, and they had been married for 57 years. Paul’s HHIE-S score was 30, representing severe self-reported hearing difficulties, whereas Irene’s score was 6, representing no hearing difficulties . On the Mutual Friends task in Week 1, Paul recalled 9 names of mutual friends and acquaintances and Irene recalled 8 when they recalled individually with the experimenters. This gave them a total  score of 17 names at Week 1. When they worked together on this task 1 week later, they again recalled 17 names, experiencing no benefit from collaboration relative to remembering alone. This stands in contrast to the average collaborative benefit for all couples of nearly 17 names and the average collaborative benefit for couples without hearing difficulties of over 21 names (reported above).When we looked closely at Paul and Irene’s conversation during the Mutual Friends task . As is evident in the transcript above, self-report may not capture all cases or degrees of hearing loss. Whereas our measure of couple level hearing difficulties was relatively crude in simply adding spouses’ hearing scores, the impact of individual hearing loss within social systems such as long-married couples may be exponential rather than additive, emergent in combination with other factors, or buffered by still other factors , the Australian Code for the Responsible Conduct of Research (2007), and the Macquarie University Code for the Responsible Conduct of Research. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by Macquarie University’s Human Research Ethics Committee and the Management Committee of the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Study of Ageing.AB, CH, TM, and GS developed and designed the study. GS facilitated access to the AIBL participants. TM and AB led the conduct of the study and data collection assisted by CH and two research assistants. AB and PS led the statistical analysis assisted by CH and TM. AB and PS drafted the manuscript with contributions from CH and TM. All authors contributed to manuscript revision led by AB and CH, and read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.