The HA and BAHI groups showed statistically significant variances of T1 WM in noise . The HA and BAHI groups did not show statistically significant variances compared to T1. Our results suggest that hearing devices (HA and BAHI) in children with sensorineural UHL (SUHL) can improve WM capacity in noise. We speculate that bilateral hearing capacity might improve the quality of life of this population, especially during everyday activities where noise is present.Working memory (WM) function can be reduced in patients suffering from unilateral hearing loss (UHL) and can affect their academic performance. We aimed to compare the WM abilities of three categories of children with UHL: patients implanted with hearing aids (HAs), patients receiving a bone-anchored hearing implant (BAHI), and subjects who did not receive hearing devices. A randomized clinical study, in which 45 children (mean age: 9.5 years) were evaluated by pure tone audiometry (to identify the side and the severity of the UHL), was conducted in a tertiary referral center. Patients were simply randomized into three groups: (1) children without HAs (No-HA group), (2) patients with a  HA (HA group), and (3) children with a BAHI (BAHI group). Their working and short-term memories were studied in both noisy and silent conditions at the recruiting time  and 6 months after (T1) the treatment. Statistical analyses were performed to analyze the variances between T0 and T1 within each group and between the three groups. The No-HA group improved its T1 WM scores in silence ( The central auditory pathway is bilaterally stimulated by the ears due to crossing fibers, so a unilateral hearing function could modify sound perception . When boThe literature has shown that restoring bilateral hearing functions in children can improve speech perception , languagThere is only one study that analyzed the impact of bilateral hearing restoration on the memory performance of UHL children, only investigating patients exclusively treated by BAHI. Even today, there is very little information on the effect of different hearing aids on memory abilities. We therefore aimed to compare the effects of non-use vs. use of hearing aids (HA or BAHI) on memory performance in a sample of children suffering from UHL of varying severity.The study was conducted at the Cochlear Implantation Centre of the Santobono-Pausilipon Children’s Hospital in Naples  from January to September 2019, and it was performed according to Helsinki rules for human study. The protocol was approved by the internal review board (IRB) of the hospital, without issuing an authorization number in respect to national regulations for these types of studies. Before including the children in the study, all parents needed to sign a written consent, in which strengths and weaknesses of each treatment were discussed.SD: 2.8)] affected by congenital  sensorineural UHL (SUHL) that ranged from mild (26–40 dB) to severe (90 dB) and who presented a normal hearing threshold on the contralateral side were enrolled in the study  and 6 months after their first control (T1). They underwent a bilateral auditory pure tone test (PTA) at T0 in order to evaluate their hearing capacity and to confirm the presence and the side of the SUHL (details below) and then at T1. A Speech Perception Test (SPT) was also performed at T0 and T1 in all children.Three groups were defined: group 1 (control group) in which patients with SUHL were not treated with hearing aid (No-HA group), group 2 that included patients who were treated with hearing aid (HA), and group 3 in which patients’ SUHL was treated by a bone conduction system (BAHI group).The children were randomized by computer software to be assigned to one of the three groups and then to be treated as indicated by the relative group. The computer generated the random numbers that were used for the simple randomization. For a correct distribution in each group, the patients were separately randomized according to their HL severity; first, patients with mild SUHL were randomized, then the ones with more severe forms up to the ones with profound SUHL. Despite this initial randomization, we then revised the assignation of the children to one or another group to avoid undertreatment or overtreatment of SUHL, so we cannot define this study as a real randomized study.The randomization by different severities of SUHL was possible because the children had one ear with normal hearing threshold. Children with mild SUHL had an HL in the range in which BAHI could be an effective treatment.Patients in group 1 were untreated for speech rehab, while patients in groups 2 and 3 were trained by a speech therapist to optimize the use of their hearing aid. Patients with BAHI performed speech rehab once their prosthesis was osteointegrated. However, regardless of which group they were assigned to, all children underwent cognitive and learning rehabilitation.1 as hearing device. This digital device, specifically intended for children, is designed for treatment of sensorineural hearing loss (SNHL) in the severity range between 30 and 110 dB. The device covers a frequency range between 100 and 6,500 HZ, has an OSPL90 with maximum peak at 143 dB SPL and 135 dB SPL at 1,600 Hz, and allows a maximum of 83 dB at gain peak and 75 dB at 1,600 Hz. Its harmonic distortion at 70 dB SPL is 4% at 500 Hz, < 2% at 800 Hz, and < 2% at 1,600 Hz. The device entry noise level was 18 dB SPL omni and 32 dB SPL directional. Finally, it has an integrated receiver with a power of 2.4 GHz and is FM compatible. The hearing aids were used to compensate the hearing deficit. Hearing aids had to be worn all day from wake-up to bed time.All patients in group 2 used Xceed Play 1 BTE SP®2. The BAHA® was implanted percutaneously as previously described by Patients in group 3 were implanted with BAHAThe memory abilities were evaluated in all children at T0 before randomization both in silent and in noisy conditions (T0) and at T1–6 months after the hearing rehabilitation or the application of a hearing prosthesis. This 6-month follow-up was necessary to allow a correct osteointegration of the BAHI  and adequate speech rehab once the prosthesis was implanted. A memory evaluation included testing both the WM and the SM, as detailed below. All tests were conducted by a speech therapist and a psychologist together; both professionals had more than 10 years of experience in their respective field.The auditory tests were performed differently at T0 and T1. At T0, the patient was tested by earphones in a silent cabin. At T1, children were analyzed in free-field using speakers because they were wearing a hearing prosthesis. The T1 auditory test was performed with the patient seated in the center of the cabin where two speakers at 45° were placed one on each side of the patient. A pulse-tone was emitted by the speaker on the side of the ear that had to be tested while a white-noise sound (masquerading sound) was sent by an insert located on the opposite side. This procedure was performed bilaterally. The sound stimulation started from 10 dB, with increases of 10 dB and decreases of 5 dB, to confirm the sound perception. The impulse for each frequency tested  was sent to the studied ear three times, following the method described above. The masking signal (white noise range frequency 2–16 kHz) was sent at 50 dB and the testing signal at 20–30 dB on the ear in which we were evaluating the hearing threshold. Pure tone average (PTAv) was calculated by summing the results of pure tone audiometry (PTA) thresholds at 500, 1,000, and 2,000 Hz and dividing the total by 3.The test was performed in the same conditions as PTA. A list of simple words  was usedTests for Memory and Learning in Childhood. The memory test was standardized for children aged 5–11 years , the three groups did not present statistically significant differences in observation time; the variable “time” was not considered due to this reason. All WM scores  collected at T0 in noisy and in silent conditions and at T1 in the same conditions were compared using a one-way ANOVA test and by Holm−Bonferroni method. The same analysis was performed to compare SM scores at T0 and T1 in the three groups . We also analyzed the difference between T0 and T1 considering T1 as dependent variable by using a two-tailed SD: 3.8), HA 180.3 (SD: 3.4), and BAHI 180.6 (SD: 3.7).The time elapsed (days) between the first (T0) and the second (T1) follow-up in the three groups was: No-HA 180 (Group 1 (No-HA) included four patients with mild HL, five with moderate HL, three suffering from moderate to severe HL, and one with severe SUHL. In group 2 (HA), eight patients suffered from mild SUHL, five with a moderate form, two affected by moderate–severe SUHL and one with severe SUHL. In group 3 (BAHI), we observed three patients affected by mild SUHL, two with a moderate form, two with moderate–severe SUHL, and nine with severe SUHL.SD: 2.8)] suffered from right-sided SUHL, while 20 subjects were affected by left-sided SUHL . A statistically significant variance was identified between the WM scores in noise and silence at T0 in all three groups ; no statistically significant differences were identified between the groups at T0  or in noise (p < 0.01), but no statistically significant differences were observed in silence. A similar finding was observed in group 3  and silence (t-test: p = 0.01), but not statistically significant values in SM (t-test: p = 1). HA and BAHI groups presented statistically significant differences in the WM scores in noise, respectively p < 0.00001 and p < 0.00001. No statistically significant differences were observed in silence in HA (t-test: p = 0.09) and BAHI (t-test: p = 0.05) patients. SM values were not statistically significantly different in both groups (HA: t-test: p = 1 and BAHI: p = 1)  .Finally, no statistically significant variances were observed in the SM scores (T0 and T1) between right- and left-sided SUHL.Our study showed that the restoration of a bilateral hearing function in UHL subjects could improve WM functions, especially in noisy condition, and that this improvement was independent of the device used to rehab the auditory capacity, of the side affected by HL and of the severity of HL.These current results reinforce other recent observations , in whicThe analyses on T1 as dependent variable of T0 confirmed that HA and BAHI had improved the scores of WM in noise but not in silence and that the scores of SM remained substantially the same at the two follow-ups (T0-baseline and T1-6 months after baseline). Interesting data were that No-HA children statistically improved their WM scores in silence but not in noise; in the latter, we instead observed a statistically significant worsening of the WM capacities. We speculated that the difference observed in noise scores between the three groups could be related to three factors: (1) use of hearing device, (2) speech rehabilitation, and (3) cognitive and learning rehabilitation. In fact, in the No-HA group, the cognitive and learning rehab alone negatively impacted on the WM abilities in noise as shown by the statistically significant worsening of the scores that we observed.We also noted that, regardless of the severity of UHL, patients with hearing devices improved their PTA and SPT on comparing T0 and T1 ; this poAlthough both are very efficient in rehabilitating auditory functions, the hearing devices that we used in our study worked in different ways. The digital device improved the sound perception by increasing the volume of the incoming sound ; the BAHThe benefits achievable by bilateral hearing functions have already been described ; this reAlthough there is still some controversy on the use of hearing devices to support children with UHL —some autBased on our results, we suggest that a hearing device should always be used to avoid impairment of scholastic performance, regardless of the severity and the side of the HL.An important aspect to emphasize was the strong impact that speech rehabilitation had on maximizing the benefit of the hearing device. The speech therapist helped patients with hearing devices to focus their attention on what could be better perceived by wearing a prosthesis. This aspect was very helpful in better managing the distress related to wearing the device and improving patient compliance. The speech rehabilitation helped subjects to correctly focus their attention on the new external stimuli. The speech therapist not only increased the compliance of children in using the prosthesis, but she also supported parents in the management of this new situation, i.e., answering the questions related to the use of the device. The speech training was useful for children and parents/guardians. The latter, by understanding the efficacy of the prosthesis, strongly supported their children’s hearing aid compliance.The study presents some limitations. Firstly, the right-sided UHL group was slightly larger than the left-sided UHL group, and this may induce bias due to the unbalanced distribution of subjects. Secondly, the tests used to evaluate speech perception and memory functions were designed exclusively for Italian speakers, and other authors could obtain different results using other tests. In addition, we were focused on memory only and the attention of the patients could only be indirectly evaluated by looking at the results of the memory tests. Furthermore, we did not analyze if sound localization could impact on memory function, although we did not find differences comparing patients with hearing device on the right side with the ones in the left one. Additional studies investigating the effect of sound localization on memory function would be necessary.Our patients’ selection, in which we excluded patients affected by temporal bone abnormalities, might have determined a bias; in addition, the study has been performed on a small sample and other researchers might obtain different results studying a larger sample. In fact, our population of children could not reflect the broader universe of children with UHL.Another limitation, related to an ethical reason, was the slight unbalance between untreated patients (No-HA: 13 subjects) and patients treated with hearing aids (HA: 16 people and BAHI: 16 patients). Moreover, because of ethical and clinical reasons, group 3 (BAHI) included more patients with severe SUHL than the other two groups; in fact, restoration of an efficient hearing threshold was the main goal of this treatment. Finally, because of the use of a hearing device, auditory tests were differently performed at T0 (no hearing device) and T1 (wear hearing device), and this difference in tests might have an impact on the results of the study. However, this limitation is present in all studies of this type.via hearing aids/BAHI or hearing therapy should be suggested as the treatment of patients suffering from UHL, given that bilateral hearing stimulation may positively impact on the WM processes, especially in noisy conditions (Hearing restoration nditions . In factThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Santobono-Posilipon IRB. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.ADS contributed to the study design, analysis of data, interpretation of data, state of conclusion, supervision of the study, and article writing. AV contributed to the analysis of data, state of conclusion, and data collection and provided substantial contribution in article writing. VI contributed to the data collection and interpretation of data and provided supporting contribution in article writing. SG and ADL contributed to the data collection and data interpretation. VG and FL contributed to supporting data collection. GR contributed to criticism and provided supporting contribution in writing. All authors contributed to the article 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.


Hearing aid usage has been linked to improvements in cognition, communication, and socialization, but the extent to which it can affect the incidence and progression of dementia is unknown. Such research is vital given the high prevalence of dementia and hearing impairment in older adults, and the fact that both conditions often coexist. In this study, we examined for the first time the effect of the use of hearing aids on the conversion from mild cognitive impairment (MCI) to dementia and progression of dementia.We used a large referral‐based cohort of 2114 hearing‐impaired patients obtained from the National Alzheimer's Coordinating Center. Survival analyses using multivariable Cox proportional hazards regression model and weighted Cox regression model with censored data were performed to assess the effect of hearing aid use on the risk of conversion from MCI to dementia and risk of death in hearing‐impaired participants. Disease progression was assessed with Clinical Dementia Rating Sum of Boxes (CDR‐SB) scores. Three types of sensitivity analyses were performed to validate the robustness of the results.P = 0.004). The mean annual rate of change (standard deviation) in CDR‐SB scores for hearing aid users with MCI was 1.3 (1.45) points and significantly lower than for individuals not wearing hearing aids with a 1.7 (1.95) point increase in CDR‐SB per year (P = 0.02). No association between hearing aid use and risk of death was observed. Our findings were robust subject to sensitivity analyses.MCI participants that used hearing aids were at significantly lower risk of developing all‐cause dementia compared to those not using hearing aids (hazard ratio [HR] 0.73, 95% confidence interval [CI], 0.61 to 0.89; false discovery rate [FDR] Among hearing‐impaired adults, hearing aid use was independently associated with reduced dementia risk. The causality between hearing aid use and incident dementia should be further tested. We tested if the use of hearing aids is independently associated with a decreased risk of incident all‐cause dementia diagnosis for MCI patients and reduced risk of death in individuals with dementia. We also examined if the rate of cognitive decline is slower for hearing aid users when compared to those not using hearing aids.22.1We conducted a retrospective analysis of the demographic and clinical data obtained from the National Alzheimer's Coordinating Center (NACC).The analytic sample for this study included 2114 participants (age > 50) with hearing impairment who had UDS data in the NACC database available between 2005 and 2018  scores to assess a decline due to cognitive changes in six functional domains, namely: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.High prevalence of dementia and hearing impairment in older adults.Hearing aid (HA) use is associated with a lower risk of incident dementia.Slower cognitive decline in users than non‐users of HA with mild cognitive impairment.The relationship between hearing impairment and dementia should be further tested.Systematic Review: Hearing aid use in patients with hearing loss has been shown to improve auditory perception and communication, reduce cognitive load, and alleviate personal and social difficulties; however, no evidence has been presented to demonstrate whether such therapies can reduce the risk of conversion from mild cognitive impairment (MCI) to dementia and slow progression of dementia.Interpretation: Our results show that the use of hearing aids is independently associated with a decreased risk of incident all‐cause dementia diagnosis in individuals with MCI. Compared to hearing aid non‐users, participants with hearing aids experienced slower decline in cognitive abilities as indicated by the annual average rate of change in Clinical Dementia Rating Sum of Boxes score.Future directions: The causality between hearing aid use and the development and progression of dementia should be further tested in a randomized clinical trial.2.3The information on presence of hearing loss and use of hearing aids were extracted from the NACC‐UDS Physical Evaluation form.Information on hearing aid use was collected via self‐report using a single question: “Does the subject usually wear a hearing aid(s)?,” which provided possible responses of “yes’’ or “no.’’Accordingly, data from individuals identified with impaired hearing at every annual clinical evaluation, that consistently reported non‐use or use of hearing aids as well as functionally normal hearing when wearing hearing aids served as the sample for our study. The subject's hearing was characterized as functionally normal with a hearing aid if there was no evidence of reduced ability to do everyday activities such as listening to the radio/television or talking with family/friends.2.4t test.Baseline summary statistics are presented as proportions for categorical data and means with standard deviations (SD) for continuous variables. Unadjusted analyses for comparison of demographic and clinical features between individuals with hearing impairment that used and did not use hearing aids were performed with the Fisher's exact test and unpaired P = 0.7). The presence of non‐proportional hazards was observed in Group 2 (P = 0.001), with the proportional hazard assumption violated for age (P < 0.001) and CDR‐SB (P = 0.007) variables. Accordingly, we used the Cox proportional hazards regression model to model time to incident dementia for MCI patients (Group 1) and implemented weighted Cox regression accounting for time‐varying effects to determine the survival rate of individuals diagnosed with dementia (Group 2).P > 0.05).A Cox model with censored data was used to study time to incident dementia diagnosis for MCI patients (Group 1) and death for individuals diagnosed with dementia (Group 2).For each MCI individual in Group 1 and dementia participant in Group 2, time “zero’’ was defined as the date of the baseline evaluation. The diagnosis of MCI in Group 1 and dementia in Group 2 referred to the initial event while the endpoint event was considered the conversion to all‐cause dementia in Group 1 and the occurrence of death in Group 2 . Survival time was determined by the year. MCI‐nc subjects and dementia participants who did not die during the study follow‐up were censored at the last clinical assessment.P values (FDR P) < 0.05 were considered statistically significant.To avoid the inflation of false‐positive findings, the Benjamini‐Hochberg false discovery rate (FDR) procedure was used to adjust for multiple hypothesis‐testing.2.5To validate the robustness of the main findings, we performed three different sensitivity analyses: (1) propensity score matching to control for measured confounding, (2) the analysis for unmeasured confounding to assess the sensitivity of our main conclusions with respect to confounders not included in our study, and (3) the inverse probability of treatment weighting method to reduce selection bias within our study population.Propensity scores were generated for hearing aid status using multivariable logistic regression model and adjusting for baseline covariates, including age, sex, education, and CDR‐SB. The standardized mean difference between two patient groups, ie, patients with and without hearing aids, was then calculated for each covariate and compared before and after the matching process to determine covariate balance between the two groups.Sensitivity analysis for unmeasured confounding was conducted to measure the potential influence an unmeasured covariate might have on the HR estimates of the association between hearing aid use and: (1) incident dementia in Group 1; and (2) death in Group 2.The inverse probability of treatment weighting method was used to attenuate potential selection bias in the sampling and recruitment of NACC participants. Weights were derived from propensity score modeling of the probability of hearing aid use as a function of measured covariates using the generalized boosted model.33.1P = 0.01) and Group 2 (P = 0.02), with higher rates of hearing aid use in males. Hearing aid users with baseline MCI were significantly older than MCI individuals not using hearing aids (P  <  0.001). Age was comparable for users/non‐users of hearing aids in Group 2 (P = 0.32). Hearing aid users with dementia had more years of education completed (P < 0.001). The CDR‐SB score was significantly lower in both individuals with baseline MCI and dementia who used hearing aids .Baseline demographic and clinical characteristics of participants by hearing aid status are presented in Table 3.2During the study follow‐up, 497 MCI subjects in Group 1 developed dementia. The median time to incident dementia was 2 years for non–hearing aid users and 4 years for hearing aid users. The 5‐year overall survival rate, which is the percentage of participants that did not convert to dementia 5 years after the baseline MCI diagnosis, was 19% for non–hearing aid users and 33% for individuals using hearing aids.P < 0.001; Table P = 0.004).In the multivariable Cox proportional hazards regression model, the major risk factor for MCI‐to‐dementia conversion was the CDR‐SB score .The observed mean annual (SD) rate of change in CDR‐SB for non–hearing aid users with MCI was 1.7 (1.95) points per year and significantly higher than the average rate of change for hearing aid users of 1.3 (1.45) CDR‐SB points per year .In the weighted Cox regression model accounting for time‐varying effects, the relationship between the use of hearing aids and mortality risk was not statistically significant .The average (SD) annual rate of change in CDR‐SB score of 0.96 (1.02) for hearing aid users with dementia was not significantly different from the 0.94 (1.19) point increase in CDR‐SB score per year for individuals with dementia not using hearing aids . Again, we found that MCI individuals using hearing aids were at lower risk of developing dementia compared to non‐users of hearing aids  and no statistically significant association between hearing aid use and risk of death for dementia participants in Group 2  and no statistically significant relationship between the use of hearing aids and mortality risk in Group 2 including participants with dementia .A lack of improvement in hearing, when a hearing aid is used, may be an indicator of central auditory processing issues rather than a faulty device. As such, we performed additional analysis on a group of hearing aid users that included subjects who still experienced auditory difficulties when wearing a hearing aid  and outcome (incident dementia or death).It is also worth highlighting that the proportion of participants wearing hearing aids in the final groups was considerably higher than the prevalence of hearing aid use in the general population.Sex, socioeconomic factors, and cultural influences all play a role in the use of hearing aids. It may also be the case that unrecorded intrinsic factors that influence use of hearing aids, or lack thereof, play a significant role in the findings presented here. Indeed, severity of cognitive decline may influence acceptance, compliance, and correct usage of hearing aids. With incremental changes and decline in cognition, the capacity to comply with the use of hearing aids is likely to significantly diminish.Nevertheless, we implemented measures to account for the potential impact of confounding and selection bias in our study. Propensity score matching was applied to control for measured confounding; the analysis for residual confounding was implemented to assess the sensitivity of our main conclusions with respect to confounders not included in our study; and potential selection bias was addressed via the inverse probability of treatment weighting method. Our results remained robust under different assumptions.Finally, this study relies on self‐reported hearing loss, which is far less reliable than audiometric screening. The use of information on hearing impairment via self‐report prevents any adjustment for the effect of degree of hearing loss when investigating the impact of hearing aid usage on incidence and progression of dementia. It is also worth noting that even though ADRCs are anticipated to enter missing codes when they have reason to believe that the cognitive test is invalid, including if they are aware that the participant is unable to hear properly, we cannot exclude the possibility that hearing impairment, rather than cognitive function, impacted the ability to complete tasks on cognitive tests in participants with hearing loss who did not have hearing aids. Because verbal instructions that are used during cognitive testing depend significantly on hearing, hearing loss might have contributed to the overestimation of the level of cognitive impairment in some hearing‐impaired individuals.Irrespective of the limitations associated with the present analyses, the fact that significant benefit appears to be derived in delaying conversion of MCI to dementia with hearing aid use warrants further exploration. Properly designed clinical trials will definitively measure the potential benefit of hearing correction in those experiencing hearing loss.5Slower conversion from MCI to dementia in individuals using hearing aids suggests that effective identification and treatment of hearing loss may reduce the cumulative incidence of dementia. The competing risk of all‐cause mortality and dementia among those with MCI should be examined in future work. One of the findings reviewed above suggested that higher‐level cognitive processing involving memory in hearing‐impaired individuals might be compromised because of mental resources being reallocated to perception and away from storing information. We believe this hypothesis should be further tested to see if the use of hearing aids can make word identification less effortful and thus, allow for freeing resources for higher‐level processing that can in turn result in improvement in cognitive function. Furthermore, more research is needed to better understand the relationship among hearing impairment, changes in cognitive ability, and the role of hearing aids in preventing milder forms of cognitive impairment. Such knowledge may provide new and novel insights into prevention of cognitive decline. Most importantly, the magnitude and causality of the effect of hearing loss treatment on cognitive decline and incident dementia can only be established by conducting a well‐designed clinical trial.Public health campaigns are needed to demonstrate the scale and impact of hearing loss and increase awareness regarding effective prevention strategies, consequences of inaction, and potential benefits of timely audiological intervention.The authors declare that they have no competing interests.Supplementary informationClick here for additional data file.


Whether hearing impairment (HI) is associated with depressive symptoms remains disputed for older adults, in part due to varying definition employed, use of subjective hearing measures, or cross-sectional analysis. We studied 1936 men and women  enrolled in the prospective Health, Aging and Body Composition study Hearing thresholds at 500-4000 Hz were averaged to create a pure tone average (PTA) and HI was defined using clinical cutpoints in the better-hearing ear. Depression was measured using the Center for Epidemiologic Studies Depression Scale (CES-D) or the CES-D 10, a revised 10 question scale depending on visit. Linear mixed effects models with random intercepts and slopes were used to estimate difference in rates of change in depressive symptomatology by hearing status over nine years. Cox proportional hazard models were used to examine the association between HI and incident depression defined as change in CES-D score >=10 points. In models adjusted for demographic and clinical covariates, participants with HI demonstrated a higher baseline prevalence of depressive symptoms compared to those with normal hearing (20.7% vs. 8.4%).Rates of change did not differ by HI status. Participants with moderate or greater HI had an increased risk of 9-year incident depression  compared to participants with normal hearing. HI is associated with increased risk of incident depression and a greater overall prevalence of depression compared to normal hearing, underscoring the importance of further research on whether rehabilitative therapies can mitigate this association.


Glutaric aciduria type 1 (GA-1) is a rare disease connected with speech delay and neurological deficits. However, the audiological and otologic profiles of GA-1 have not yet been fully characterized. To our knowledge, this is the largest study of comprehensive audiological and otologic evaluation in patients with GA-1 to date.Thirteen patients diagnosed with GA-1 between January 1994 and December 2019 with audiological, radiological and genetic manifestations were retrospectively analyzed. Hearing tests were performed in all patients. MRI was performed for radiological evaluation.p = 0.0176). One patient had moderate sensorineural hearing loss and a past history of acute encephalopathic crisis. No usual causative gene mutations associated with hearing loss were found in these patients. MRI showed a normal vestibulocochlear apparatus and cochlear nerve. One patient with extensive injury of the basal ganglia on MRI after acute encephalopathic crisis was found to have moderate sensorineural hearing loss. Two patients with disability scores above 5 were found to have mild to moderate hearing impairment. No obvious correlation between macrocephaly and hearing loss was found.Hearing loss was found in 76.9% (10/13) of GA-1 patients, including slight hearing loss in 46.1% (6/13) of patients, mild hearing loss in 15.4% (2/13) of patients, and moderate hearing loss in 7.7% (1/13) of patients. Normal hearing thresholds were seen in 23% (3/13) of patients. Patients with intensive care unit (ICU) admission history showed significantly worse hearing than those without (29.17 ± 12.47 vs 13.56 ± 3.93 dB HL, 95% CI 2.92–24.70, A high prevalence of hearing impairment is found in GA-1 patients. Adequate audiological evaluation is essential for these patients, especially for those after encephalopathic crises or with ICU admission history. MRI often reveals a characteristic pattern of gray and white matter abnormalities and widened cerebrospinal fluid (CSF) spaces in GA-I. A recent study described that the severity of movement is related to extensive lesions of the putamen [l-carnitine. Mortality and morbidity are considerably reduced after proper treatment, and GA-I is therefore considered to be a treatable condition.As GA and 3-OH-GA are putatively neurotoxic, GA-1 is characterized by neurological impairment, macrocephaly, dystonia and seizure . Without putamen . Typical putamen , 9. Neur putamen . TreatmeMost children are found to have some degree of speech difficulty . Psychological functions including intelligence for assessment at the general level of development, motor functions and language have been suggested. GA-1 was reported to be associated with hearing loss in isolated case reports ; the spaGCDH gene mutation analysis. Of the 16 patients who were diagnosed with GA-1 at Veterans General Hospital, 13 patients underwent comprehensive otologic evaluation and audiological tests between September 1994 and December 2019. The demographic data of the patients were retrospectively collected from their medical records, including newborn hearing screening results, age at diagnosis of GA-1, occurrence of clinical encephalopathic crisis, disability score and length of follow-up. A history of intensive care unit (ICU) admission was also recorded.From January 2001 to November 2019, all patients diagnosed by newborn screening (NBS) underwent secondary confirmatory diagnosis by including quantitative analysis of GA and 3-OH-GA in urine and/or blood and GA-1 treatment was started immediately after diagnosis. The maintenance treatment consisted of carnitine and a low lysine diet supplemented with a GA-1 special formula. Parents were given instructions regarding emergency treatment. During intercurrent illness, catabolism needs to be prevented promptly by providing a high-energy intake. Patients were seen at our clinic every 3 months. T1-weighted and T2-weighted MRI, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps were arranged at the time of diagnosis, and new onset neurological symptoms were identified. Imaging data were not available for some patients because some parents were reluctant to subject asymptomatic children to MRI under sedation.Pure tone audiometry or conditioned behavioral audiometry (either reinforcement audiometry or conditioned play audiometry) was arranged for hearing assessment. A sound field test was conducted if the patient was not amenable to the headphone. Auditory brainstem response (ABR) was conducted for patients with poor auditory responsiveness resulting from any cognitive-related impairment. The audiological tests were conducted in a double-wall booth by an experienced audiologist. Air-conduction pure tone audiometry thresholds were tested at frequencies of 250, 500, 1000, 2000, 4000, and 8000 Hz. The pure tone average (PTA) was determined by calculating the threshold of frequencies at 500, 1000, 2000 and 4000 Hz. Our classification of the degree of hearing loss was based on calculating the PTA. There was no hearing loss if the PTA was less than 16 dB HL, 16–25 dB HL was slight hearing loss, 26–40 dB HL was mild hearing loss, 41–55 dB HL was moderate hearing loss, 56–70 dB HL was moderately severe hearing loss, 71–90 dB HL was severe hearing loss, and ≥ 91 dB HL was profound hearing loss in accordance with the American Speech Language Hearing Association guidelines , 12.Distortion product otoacoustic emissions (DPOAEs) were measured by using the Biologic Scout Sport PC-based diagnostic OAE system. The ratio of two primary tones, f2/f1, was fixed at 1.22, and moderate-level primary tones were used with L1 = 65 dB SPL and L2 = 55 dB SPL. The DPOAE measurements were over the frequency range 1–8 kHz and interpreted as present when the signal-to-noise ratio (SNR) exceeded 6 dB or more at the f2 frequency. DPOAE was interpreted by the SNR criterion. DPOAE criteria of 6-dB DPOAE/noise ratios or better determination of the presence of DPOAE and five frequencies were required to meet the criterion classified as normal hearing.SLC26A4, GJB2, GJB3 and mtDNA 1555 and 1494. First, we designed PCR primers for all candidate genes mentioned above by the online website tool Ion AmpliSeq™ Designer (Thermo Fisher). The expected sizes of all amplicons were set to 275 bps. A total amount of 10 ng of DNA from each individual was used to construct a sample library. All designed primers were mixed according to well-optimized proportions and used for multiplex PCR. After amplification, the reactants were purified and quantified by a Qubit fluorometer (Thermo Fisher). Proper amounts of reactants were subjected to second-stage library preparation, including adapter and barcode ligation to both ends of all amplicons, and size selection . The barcoding amplicons of each individual were analyzed by a Bioanalyzer system (Agilent) to ensure the sizes and quantities of the library products. The qualified libraries were subjected to sequencing reactions by “sequencing by synthesis” (SBS) technology on a MiSeq sequencer (Illumina). The sequencing kits with different sequencing throughputs were chosen according to the amounts of library. The average depth of the target regions was more than 200 ×. The data analysis, including quality control, reference sequence alignments, and variant annotations, was executed on the BaseSpace Sequence Hub webtool (Illumina).All of the patients underwent targeted sequencing of 4 common genes related to deafness in Taiwan, including The disability score, which is the summation of the scores for motor function, cognitive function and speech, giving a minimum of three and a maximum of nine, was developed and found to be significantly correlated with acute onset, dystonia and mortality . The dist tests for normally distributed data. Statistical significance was identified when p < 0.05. Calculations were performed using GraphPad Prism, Version 8 .The data are expressed as the mean, and descriptive statistics were also performed. Statistical analyses to compare the hearing thresholds of ICU admission, encephalopathic crisis, macroencephaly, and severe disability were performed using paired GCDH mutations. The mean age of treatment initiation was 8.9 days from birth . A total of 23.0% (3/13) of the patients experienced encephalopathic crisis and showed some degree of motor dysfunction.The demographic data of the patients included in the study are shown in Table p = 0.0176, Fig. p = 0.0506). No obvious correlation between macrocephaly and hearing loss was found (p = 0.977). No otological anomalies, such as atresia of the auricle or external ear canal, otitis media with effusion or any infection or inflammatory sources, were found in these patients. DPOAEs from 12 patients showed absent or partial loss in 62.5% (15/24) of ears (Table The hearing assessment was conducted with pure tone audiometry in 7 (53.8%) patients and sound field tests in 5 (38.5%) patients. The mean age at the first hearing test was 8.14 years old. The detailed audiometric data are shown in Table GCDH mutations in all enrolled patients. For the four deafness-related genes tested, including SLC26A4, GJB2, GJB3 and mtDNA 1555 and 1494, no pathological variants were found, indicating the origin of hearing loss from the pathological nature of GA-1.Genetic testing confirmed To explore the possible involvement of the auditory pathway, MRI investigations were evaluated in all thirteen patients. There was no vestibulocochlear malformation, atresia of the internal acoustic canal (< 4 mm), or absent or hypoplastic cochlear nerve in these patients. Furthermore, no lesions were noted along the central auditory pathway, including the cochlear nucleus (CN), superior olivary nucleus (SON), inferior colliculus (IC), medical geniculate body and auditory cortex. One of the patients (case 6) showed extensive putamen lesions on MRI Fig. a–c. An oGA-1 is a progressive disorder that typically appears normal at birth. However, patients may experience various degrees of permanent neurological sequelae, especially after encephalopathic crisis, including motor and cognitive dysfunctions and mental retardation. Newborn screening of GA-1 started in 2001 and has been publicly offered by the National Health Insurance system in Taiwan since 2006. Our previous data revealed that the incidence of GA-1 was 1 in 106,474, which is approximately the same worldwide and in the Taiwanese population . To our Gcdh−/− mice), demonstrated typical motor deficits and diffuse spongiform myelinopathy, but did not seem to show any hearing phenotypes [We found that a high percent of patients with GA-1 encountered slight to moderate sensorineural hearing loss in this study. The metabolite of GA-1 is neurotoxic, and accumulation in the central nervous system can cause severe neurological complications. The presence of 3-OH-GA in GA-1 patients may lead to increased vulnerability of endothelial structures and subsequent vascular dysfunction. The cochlea is the end organ fed solely by vessels of the labyrinthine artery, making it vulnerable to circulation causes . Like otenotypes . While hGJB2, SLC26A4, GJB3, and mitochondrial m.1555A > G, were included in our NGS panel. In terms of the allele frequency in the hearing-impaired population, these 4 mutations account for over 80% of the known deafness-associated mutations in Taiwan [We found that 75% of GA-1 patients had varying degrees of hearing loss in our study. The high prevalence of hearing loss was not reported previously. OAEs showed partial missing signals, indicating partial loss of function of the outer hair cells in the cochlea. It has been shown that over 50% of prelingual hearing loss has attributable genetic factors . To precn Taiwan . We did MRI offers the advantage of detecting causes of sensorineural hearing loss, including large vestibular aqueduct, inner ear anomaly, cochlear nerve deficiency and postinfection changes . In our The evolution of diffusion tensor imaging in MRI has led to the finding of an association between sensorineural hearing loss and white matter tract microstructure . Some exIn our study, hearing loss was found in 69.2% of patients, which is much higher than the global prevalence of pediatric hearing impairment (7.6–16.4% worldwide –39). HowSome risk factors have been reported to affect hearing performance, such as ICU admission, ototoxic drug use, genetic syndromes and recurrent middle ear infection , 46. In Although the results of the present study showed a high prevalence of hearing impairment among these children, there were several limitations, such as the nature of retrospective and cross-sectional observational studies, the small number of patients, and the use of a single medical facility. Therefore, data on other predisposing factors leading to hearing loss could not be fully collected, such as the use of ototoxic medications, noise exposure, infections during pregnancy and trauma. Furthermore, the origins of sensorineural hearing loss in patients with GA-1 also require further neuropathological and/or radiological studies. Nevertheless, this study provides the first evidence that children with GA-1 have a high prevalence of abnormal hearing performance, and further studies are needed to address rehabilitative and educational issues.Hearing loss is a common issue in patients with GA-1. Clinicians should consider the high prevalence of hearing loss in these patients, especially in patients with encephalopathic crisis or ICU admittance. Further studies are needed to investigate the nature of hearing impairment in GA-1.


Among middled-aged adults, are self-reported measures of hearing concordant with audiometry findings, and is potential discordance associated with age or lifestyle factors?In this cross-sectional study of 9666 participants in the English Longitudinal Study of Ageing, self-report measures of hearing had limited accuracy and were not sufficiently sensitive to detect hearing loss. Hearing loss went undetected by the self-reported measures.These findings may inform public health policies relevant to selection of appropriate and validated tools for detecting hearing problems among middle-aged and older adults. An effective and sustainable hearing loss (HL) screening strategy for the early detection of and intervention for HL in older adults is needed.To examine the concordance of self-reported measures of hearing difficulty with objective hearing data and the factors associated with the potential discordances among these measures across different population subgroups of a representative sample of people 50 years and older in England.This study was a cross-sectional analysis of wave 7 of the English Longitudinal Study of Ageing (ELSA), a large, population-based, prospective cohort study that provides a unique resource for exploring issues associated with aging in England in the 21st century. The full analytic cohort was composed of 9666 individuals participating in the ELSA wave 7, which collected information from June 1, 2014, to May 31, 2015. This study further analyzed a sample of 8529 adults 50 to 89 years of age who had an assessment of their hearing by self-reported measures, and consented to assessment by a qualified nurse via a hearing screening device, and did not have an ear infection or a cochlear implant. Bivariate analyses were performed from July 1 to December 30, 2018, and multivariate analysis from January 1 to June 30, 2019. Multiple logistic regression models examined factors associated with misclassification of hearing difficulties across several categories among those with objectively identified HL.The study examined whether age, marital status, retirement status, indicators of socioeconomic position, and lifestyle factors  were associated with the concordance between self-reported hearing problems and manual audiometry among older adults.Self-reported hearing measures, including hearing in background noise, compared with objective audiometric assessments.A total of 9666 study participants  provided responses regarding their hearing difficulties, hearing in noise, quality of care in hearing, and hearing aid recommendation in ELSA wave 7. Within the cohort, 684 individuals (30.2%) with objectively measured HL greater than 35 dB HL at 3.0 kHz went undetected by the self-report measure, whereas the new constructed categories for moderate and moderately severe or severe HL resulted in 9.3% increased sensitivity. Factors associated with misreporting hearing difficulties  were as follows: female sex , no educational qualifications , routine or manual occupation , tobacco consumption , alcohol intake above the low-risk-level guidelines , and lack of moderate physical activity . Age was largely associated with misreporting of moderately severe to severe HL; the odds were 5.75  higher for those 65 to 74 years of age and 7.08  higher for those 75 to 89 years of age to not report their hearing difficulties compared with those 50 to 64 years of age. In addition, socioeconomic indicators, such as educational level  and occupation , along with lifestyle factors, such as smoking  and alcohol intake above the low-risk-level guidelines , were factors associated with misreporting moderately severe or severe HL.The use of a screening measure for audiometric testing and a self-report measure is essential for accurately identifying older people with HL. The results of this study should be considered by HL researchers who analyze self-reported hearing data as a surrogate measurement of audiometric hearing to identify bias in their observed analytic research results. This cross-sectional study examines the concordance of self-reported measures of hearing difficulty with objective hearing data and the factors associated with the potential discordances among these measures in people 50 years and older in England. Evidence indicates a discordance between self-reported and objective measures of hearing because adults self-report HL according to their beliefs, which are influenced by a range of contextual factors.17 The full analytic cohort was composed of 9666 individuals participating in the wave 7 of ELSA, which collected information from June 1, 2014, to May 31, 2015. For the purpose of this cross-sectional analysis, we further analyzed a sample of 8529 adults 50 to 89 years of age who had an assessment of their hearing by self-reported measures, consented for assessment by a qualified nurse via a hearing screening device,18 and did not have an ear infection or a cochlear implant. All participants gave written informed consent at the recruitment wave to participate in ELSA and at each subsequent wave. All data were anonymized. Ethical approval was granted by the National Research and Ethics Committee.19 This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.We used data from ELSA, which is a large, population-based, prospective cohort study that provides a unique resource for exploring issues associated with aging in England in the 21st century.19 hearing difficulty is defined as having declared fair or poor hearing on a 5-point Likert scale  or finding it difficult to follow a conversation if there is background noise . The participants who positively answered the last question then answered in a separate question whether they had slight, moderate, or great difficulty in following a conversation if there is background noise. We used that response for a further classification of their hearing difficulty into categories, eliminating those who had indicated slight difficulty following a conversation if there is background noise to allow for a fair comparison with the categories of moderate and moderately severe or severe objectively measured HL  and afterwards another 3 pure high-frequency sounds at decreasing intensities at 3 kHz , testing for audibility for each sequence and per each ear. Participants indicated when they hear the sound by raising their finger.The objective measurement of hearing acuity was performed by the HearCheck Screener (Siemens), a handheld audiometric screening device.20The HearCheck Screener is an accurate tool in detecting HL when compared with pure-tone air conduction averages, which are designated as gold standard values. In cases of moderate or worse HL, the HearCheck Screener fulfills all the criteria of high sensitivity, high specificity, and high positive predictive values.21 Those with HL were further subdivided according to a categorization that has been previously used in the literature for the characterization of those assessed by the same audiometric screening device21 as follows: (1) moderate HL (tones heard at 75 dB HL and 55 dB HL but not at 35 dB HL) or (2) moderately severe or severe HL (tone heard or not at 75 dB HL and tones not heard at 55 dB HL and 35 dB HL).Hearing level was defined as greater than 35 dB HL at 3.0 kHz in the better-hearing ear because this is the level at which intervention for HL is definitely beneficial.We selected as indicators of socioeconomic position the highest educational attainment , tertiles of the self-reported occupation according to the National Statistics socioeconomic classification , and quintiles of the net household income and the total nonpension wealth (first quintile indicating the lowest and fifth quintile indicating the highest).22 We dichotomized marital status into currently married  or not . Retirement status was also dichotomized to being currently retired or not.We considered as covariates age, sex, and lifestyle factors  because these are key risk factors for HL among older adults.9 which examined the self-reported hearing difficulty in ELSA wave 2. There were no missing values in the hearing data of the final analytical sample, which was specifically chosen for the study to fulfill the criteria of completed assessment of hearing by self-reported measures, with given consent for assessment by pure-tone audiometry and without any ear infection or cochlear implant. Separate analyses were conducted for moderate and moderately severe or severe HL. Because some data were missing at random on many variables, we excluded records with missing data from our analyses, concluding that this would be unlikely to affect the validity of our findings.24Bivariate analyses were performed from July 1 to December 30, 2018, and multivariate analysis from January 1 to June 30, 2019. Descriptive statistical measures were reported on hearing difficulties, hearing in noise, quality of care in hearing, and hearing aid recommendation in ELSA wave 7. Participants’ self-reported and objectively measured HL (moderate and moderately severe or severe) was reported as absolute number (relative frequency). We fitted multiple logistic regression models to identify factors associated with the false-negative report of hearing difficulties in people with objectively identified HL. Age was categorized into 3 groups  to allow for a comparison with the study by Benova et al,P ≤ .05 was considered to be statistically significant. All data were analyzed using Stata, version 14 (StataCorp).For all models, odds ratios (ORs) and 95% CIs are presented. The performance of self-reported hearing difficulty with second stage pure-tone audiometry screening  was calculated, and the area under the receiver operating characteristic curve represents the accuracy of all models. We used the Hosmer-Lemeshow test as a postestimation tool, which demonstrates the goodness of fit of logistic regression models. A 2-tailed 25  provided responses regarding their hearing difficulties, hearing in noise, quality of care in hearing, and hearing aid recommendation in ELSA wave 725 . Within Examining the characteristics of the 2 separate categories  that the self-reported hearing difficulty was composed of, we found that not informing a health care professional was more common among those who reported difficulty in following conversations in the presence of background noise (1753 of 3424 [51.2%]) compared with those who had fair to poor self-reported hearing (691 of 2086 [33.1%]). Importantly, 1894 of the 3425 participants (55.3%) who had reported that they found it difficult to follow a conversation if there is background noise  and did not have hearing aids had reported that they have good, very good, or excellent hearing, which indicates that more than half of them had unacknowledged HL, with 718 of 1894 (37.9%) of them having moderate or great difficulty .Eliminating from the categories of self-reported hearing difficulties those that had indicated slight difficulty following a conversation if there is background noise , we had 2249 complete cases with hearing difficulty instead of the initial 3505. This sample size improved the classification accuracy substantially for those with self-reported hearing difficulty, resulting in 9.3% increased sensitivity (79.1%), which refers to the ability of the self-reported measure to correctly identify those with HL (true-positive results) . Under tThe multiple logistic regression models showed that demographic, socioeconomic, and lifestyle factors were associated with the inaccuracy in the self-identification of the objectively identified HL. Significant factors associated with total misreporting were female sex , no educational qualifications , routine or manual occupation , tobacco consumption , alcohol intake above the low-risk level guidelines , and lack of moderate physical activity .Age was largely associated with misreporting of moderately severe to severe HL; the odds were 5.75  higher for those 65 to 74 years of age and 7.08  for those 75 to 89 years of age to not report their hearing difficulties compared with those 50 to 64 years of age. In addition, socioeconomic indicators, such as education  and occupation , along with lifestyle factors, such as smoking  and alcohol intake above the low-risk level guidelines  were factors associated with misreporting moderately severe or severe HL.22 were largely associated with the inaccuracy of self-identification of hearing difficulties in those with objectively identified HL.In this study, we examined the validity of self-reported measures compared with HL as measured by the HearCheck Screener. We found that in a population-based sample of 8529 adults 50 to 89 years of age, nearly one-third of those had objectively identified HL that went undetected by the self-report measures. These findings suggest that the use of a screening measure for audiometric testing along with a self-report measure in epidemiologic studies and clinical practice is essential for accurately identifying older people with HL. Moreover, we found that female sex, older age, socioeconomic inequalities, and unhealthy lifestyle , which are recognized as key risk factors for HL among older adults,31 that have examined on a smaller scale the performance of self-reported hearing difficulties in combination with pure-tone audiometry among elderly individuals. However, to our knowledge, our study is the first vigorous examination of the validity of self-reported measures of hearing, including difficulties in background noise, with objective audiometric assessments in such a large and nationally representative cohort.Our findings are consistent with previous studies26 and Ferrite et al31 argued that self-reported hearing should not be considered representative in associations with functional outcomes. The study by Diao et al26 concluded that the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S) could be considered a reliable and valid screening tool. Professional organizations have suggested the use of HHIE-S in combination with pure-tone screening because HHIE-S is focused mainly on the assessment of the social and emotional aspects of HL on the individual (handicap) and not the self-reported hearing ability.26 The study by Ferrite et al31 focused on a small sample (n = 188) of a younger adult population (30-65 years of age) drawn from a population-based cohort study, which may reveal that different factors may affect the sensitivity and specificity of self-reported hearing measures in an older population.In general, all studies except for the studies by Diao et al28 who found that the agreement rates between subjective and objective hearing measures were lower among the older age group (≥60 years of age) and among women. This finding may reflect that people tend to undervalue the importance of hearing and consider its loss as an inevitable accompaniment of getting older22 and therefore adapt to HL over time,16 underestimating the magnitude of their HL.29The role of age and sex in the inaccuracy of the self-reported measures has also been highlighted by Kamil et al,28 and occupational groups subject to noise-induced HL.32 The role of income in the false-negative report of hearing difficulties may reflect financial barriers to the use of and access to hearing health care33 and the downgrade of HL as a health priority.26Regarding the role of socioeconomic position, our findings are consistent with previous studies that found that agreement rates between subjective and objective hearing measures were relatively lower among those of a lower educational attainment27 The underestimation of hearing difficulties poses a significant barrier to HL intervention, and the self-report measures should not be considered reliable measures of hearing acuity to influence the judgment for referral to secondary care.These findings have important public health implications and call for a revised assessment approach for HL in older adults; clinical research often relies on self-report measure of HL, but our findings indicate that this could not be regarded as a well-suited and accurate measure to identifying individuals with HL without the additional use of a screening measure for audiometric testing.13 In addition, unacknowledged HL constitutes a significant nonfinancial barrier. The existence of objective hearing measures is crucial, particularly for those belonging to high-risk groups that are most likely to remain unrecognized, such as people who face socioeconomic inequalities and adopt an unhealthy lifestyle, because these factors may affect the initiation of help-seeking and consequently the referral to ear specialists. Our findings address important conflicts in the literature, shedding light on the inconsistencies across studies regarding the association of HL with functional outcomes15 and may reflect attitudinal differences across different cultures and geographic variation in the acknowledgment of hearing difficulties.The help-seeking behavior for hearing difficulties starts with individuals’ self-diagnosis and initiation of contact with a health care professional in primary health care settings.15 However, the study also has significant limitations. First, the cross-sectional analyses did not allow for causal or temporal relationships among the factors associated with the inaccuracy of self-reported measures. In addition, questionnaires that contain few questions to assess hearing deficits may have validity.34 A relatively small proportion of participants who responded having good, very good, or excellent hearing were also using a hearing aid, which may have confounded their response. Finally, the comparison of self-reported measure to the results from the HearCheck Screener may contain information bias because the screening tool identified only those with HL greater than 35 dB HL at 3.0 kHz in the better-hearing ear, whereas the self-reported questions did not specify that criterion.The main strength of our study is that it provides the largest and most accurate evaluation of the discordance between objective and self-reported measures of HL today. Our study is also the first, to our knowledge, to address the association of lifestyle factors with the agreement rate, which had not been previously examined in the literature.15 and investigate sociospatial hearing health inequalities.Our study found that self-report measurement of HL had limited concordance with objective measures of HL. In light of these findings, the importance of an effective and sustainable HL screening strategy for the early detection and intervention for HL in older adults is reinforced. The lack of screening programs excludes the early detection and treatment of patients with gradually progressive HL, especially those with unacknowledged HL. These results should be considered by HL researchers who analyze self-reported hearing data as a surrogate measurement of audiometric hearing to identify bias in their observed analytic research results. Future research should examine the role of other environmental and personal factors in the agreement rate between self-reported and objective measures of hearing, for which little is known,


Nonsignificant associations were observed between the other five flavonoid subclasses and 10-year incidence of hearing loss. Our findings do not support the hypothesis that the intake of dietary flavonoids protect against long-term risk of hearing loss. The association with isoflavone intake needs to be confirmed by other population-based studies.Dietary flavonoids are vasoactive phytochemicals with promising anti-inflammatory properties. We aimed to assess the associations between baseline intakes of six commonly consumed flavonoid subclasses and 10-year incidence of age-related hearing loss. At baseline, 1691 participants aged 50+ years had information on dietary intakes and hearing status. Hearing loss was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz > 25 dB hearing level (HL). Dietary data were collected through a semi-quantitative food frequency questionnaire. The flavonoid content of foods was estimated using US databases. During the 10-year follow-up, 260 (31.6%) new cases of hearing loss (incident) were observed. After multivariable adjustment, participants in the fourth versus first quartile (reference group) of intake of dietary isoflavone had 36% lower risk of incident hearing loss after 10 years: odds ratios (OR) 0.64 ;  Age-related hearing loss is a decrease in hearing ability that occurs with age and is projected to be within the top 15 leading causes of the burden of disease by 2030 ,5. Age-rReactive oxygen metabolites and inflammatory processes may cause cochlear damage . TherefoHowever, to our best knowledge, no large prospective cohort study has assessed the temporal association between the intake of dietary flavonoids and age-related hearing loss. Therefore, we used a large, representative, population-based cohort to investigate longitudinal associations between six common flavonoid subclasses  and the 10-year incidence of hearing loss among adults aged 50+ years.The Blue Mountains Hearing Study (BMHS) is a survey of age-related hearing loss from 1997 to 2004 among participants of the Blue Mountains Eye Study (BMES) cohort as previously described . Briefly0.5-4KHz > 25 dB hearing level (HL) in the better of the two ears, i.e., bilateral hearing loss [We asked questions on family history of hearing loss and occupational noise exposure: ‘Have you ever worked in a noisy industry or noisy farm environment?’ Pure-tone audiometry was performed by audiologists in sound-treated booths, as previously described ,3,4,5. Wing loss .0.5-4KHz in the better ear of ≤25 dB HL at BMES-2 or BMES-3. Incident bilateral hearing loss was defined as a PTA0.5-4KHz >25 dB HL in the better ear at the 5- or 10-year follow-up examination among participants without hearing impairment.Risk of incident bilateral hearing loss during the 10 years (from BMES-2 to BMES-4) was considered among participants who had PTAA modified, 145-item, self-administered food frequency questionnaire (FFQ) was used to collect information on dietary intakes . The typFor each food, we assessed the intake of each individual flavonoid compound found in the food and determined the sum of measured flavonoids for each flavonoid class, as previously described . The flaSAS statistical software  version 9.4 was used for analyses. Associations between dietary flavonoid intakes (study factor) and 10-year incidence of age-related hearing loss (study outcome) were examined in discrete logistic regression models. Regression analysis first adjusted for age and sex and then for covariates that were found to be associated with incidence of age-related hearing loss in the BMHS cohort: Family history of hearing loss and exposure to noise at work . FindingThe Blue Mountains Eye and Hearing Studies were supported by the Australian National Health and Medical Research Council .Of the 2956 participants who had audiometric testing performed at BMES-2 , 1691 had complete information on dietary intakes. Of these 1691 baseline participants, 647 participants had bilateral hearing loss and were excluded from subsequent incidence analysis. Those who had hearing loss versus those who had normal hearing function at baseline were more likely to be male, older, and have a family history of hearing loss . Over thThe current study findings do not provide evidence that total flavonoid intake and the intakes of specific flavonoid subclasses influence the risk of age-related hearing loss. However, we observed a modest inverse association between the intakes of isoflavones and 10-year incidence of hearing loss, indicating a potential protective effect against the development of hearing loss.Although we demonstrated an association between a greater intake of dietary isoflavones and a lower risk of age-related hearing loss, we were unable to determine whether the observed association indicated a benefit of the isolated bioactive, per se, or whether it is a signal of the bioactives working together with the co-occurring phytochemicals within isoflavone-containing foods . We alsoNevertheless, we can posit a potential mechanism by which intake of isoflavones could protect against age-related hearing loss. For instance, isoflavones are considered to be ‘phytoestrogens’ with multiple potential cardioprotective benefits. They are structurally similar to estradiol and may reduce low-density lipoprotein cholesterol, induce nitric oxide production, and improve vascular reactivity ,32. ReceOverall, our results do not support a protective effect of most of the flavonoid classes against age-related hearing loss. The largely nonsignificant findings regarding total flavonoids and flavonoid subclasses could be due to the oral bioavailability of flavonoids being constrained by poor intrinsic transmembrane diffusion features . In addiThe strengths of our study include its representative sample of older adults with relatively high participation rates, minimizing selection bias. Furthermore, we used standardized, audiometric testing to measure hearing sensitivity and a validated food questionnaire to collect dietary information. Additionally, study participants were not aware of the study question and our dietary data were collected before detection of incident hearing loss, reducing indication bias arising from behavioral change after the hearing loss was diagnosed. However, this study is not without its limitations. First, flavonoid content of foods was solely estimated using US-based databases and, hence, this approach might have discounted any variation in the flavonoid content of Australian foods . We alsoIn summary, our study findings suggest that intakes of dietary flavonoid subclasses and compounds are unlikely to have a role in preserving healthy auditory function among older adults. However, we found that a higher intake of dietary isoflavones reduced the risk of incident hearing loss by over a third. Further large, prospective studies are now warranted to verify our findings and to establish whether aural benefits result from treatment with specific dietary flavonoids.


Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart. Heart development is a complex process which requires an interplay of different transcription factors, signaling pathways and morphological modifications . Mouse hThe formation of the heart is tightly controlled by a set of signal transduction pathways including the intracellular second messenger cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) . The intEleven PDEs have been described and they are defined by their cellular functions, catalytic properties, protein structure and affinity for cAMP and cGMP . Seven PConsidering these observations, the present study was carried out to further characterize the pattern of PDE expression in cardiac development at mRNA, protein and activity levels. This information will provide a useful tool to clarify the role of PDEs in the framework of the cardiac development and their potential role in cardiac diseases.Pde1, Pde2, Pde3, Pde4, Pde5, Pde8 and Pde9 were present in the heart of embryonic and fetal mice  cAMP or [3H] cGMP, and 0.1 μM [3H] cAMP for PDE1C detection. The reaction was stopped by adding 50 μL of 0.1 N HCl and then neutralized with 50 μL of 0.1 N NaOH in 0.1 M Tris–HCl pH 8.0. Subsequently, 25 μL of 2 mg/mL of 5′-nucleotidase  in 0.1M Tris–HCl pH 8.0 were added. Samples were gently mixed and incubated at 30 °C for 30 min to allow complete conversion of 5′-nucleotide to its corresponding nucleoside. Unhydrolyzed cyclic nucleotide and the corresponding nucleoside were separated by DEAE-Sephadex A-25 columns. The eluate was mixed with ULTIMA GOLD scintillation liquid (PerkinElmer) and counted on a Tri-Carb 2100TR Liquid Scintillation Counter .PDE activity was measured on the supernatant with the method described by Thompson and Appleman  in 60 mMTo evaluate the enzymatic specific activity of each PDEs, the specific inhibitors were added to the reaction mix at the following concentration: 10 μM milrinone (PDE3 inhibitor), 0.1 μM BAY 60-7550 (PDE2 inhibitor), 30 μM rolipram (PDE4 inhibitor), 0.1 μM sildenafil (PDE5 inhibitor) and 1 μM PF04449613 (PDE9 inhibitor). The percentage of each PDE was calculated comparing the difference between the total PDE activity and the residual PDE activity assayed in the presence of the specific inhibitor with respect to the total PDE activity fixed as 100%.p value of <0.05 was considered statistically significant; all data were presented as mean ± SD.The data obtained were statistically analyzed using the GraphPad Prism 5.0 . Comparison among groups was performed with the one-way ANOVA or two-way ANOVA and multiple comparisons by Tukey test. A


Tempo and Mode in Evolution is considered a classic of Synthesis-era biology, and Simpson often remarked on the influence of other major Synthesis figures – such as Ernst Mayr and Theodosius Dobzhansky – on his developing thought. Why, then, did paleontologists of the 1970s and 1980s – Stephen Jay Gould, Niles Eldredge, David M. Raup, Steven Stanley, and others – so frequently complain that paleontology remained marginalized within evolutionary biology? This essay considers three linked questions: first, were paleontologists genuinely welcomed into the Synthetic project during its initial stages? Second, was the initial promise of the role for paleontology realized during the decades between 1950 and 1980, when the Synthesis supposedly "hardened" to an "orthodoxy"? And third, did the period of organized dissent and opposition to this orthodoxy by paleontologists during the 1970s and 1980s bring about a long-delayed completion to the Modern Synthesis, or rather does it highlight the wider failure of any such unified Darwinian evolutionary consensus?In the received view of the history of the Modern Evolutionary Synthesis, paleontology was given a prominent role in evolutionary biology thanks to the significant influence of paleontologist George Gaylord Simpson on both the institutional and conceptual development of the Synthesis. Simpson's 1944  The received view among historians of science is that the three major “architects” of the Modern Evolutionary Synthesis in the 1940s were Ernst Mayr, Theodosius Dobzhansky, and George Gaylord Simpson. That is to say, the Synthesis was an endeavor inspired, respectively, by a systematist, a geneticist, and a paleontologist, and was a project devoted to uniting those three disciplines around common evolutionary questions. If this account is true, then this development represented a major boost for paleontology, which in the decades before the Synthesis occupied a decidedly marginal position with respect to evolutionary biology Sepkoski .Evolution: The Modern Synthesis, Julian Huxley wrote that “The time is ripe for a rapid advance in our understanding of evolution,” citing paleontology prominently among the several fields which had provided “new facts or new tools of research” . And, in his own “official” contribution to the early Synthesis, Tempo and Mode in Evolution  enjoyed wide popularity and approval from neo-Darwinian biologists and paleontologists, continued to play a major role in public dissemination of the Synthesis project over the next decade, including contributing a lengthy essay on “Evolution and the History of Life” to the University of Chicago Centennial celebration of Darwin in 1959 (Tax ed. The Evolutionary Synthesis (co-edited with William Provine), Mayr remarked that Simpson “was one of the most important architects of the synthesis” who “engineered the marriage of paleontology with genetics and more broadly with the rest of evolutionary biology”  he worked to create the Committee on Common Problems in Genetics and Paleontology, and in 1944 (after returning from war service), he inherited its chairmanship, leading the group to recognition by the AAAS in 1946 as the re-named Society for the Study of Evolution, with the journal gan Cain , p. 10.  Tax ed. . Two decGenetics and the Origin of Species (1937) had “most deeply influenced” his own theoretical understanding of evolution, and Simpson is widely credited with bringing an appreciation for modern population biology to paleontology.From this brief sketch, it would seem that paleontology was indeed a major contributor to the Modern Synthesis. Simpson himself maintained this view throughout his life, even claiming in an unpublished autobiographical sketch that he had coined the term “Synthetic Theory of Evolution” . He frequently remarked that Dobzhansky’s Tempo and Mode? Eldredge, for example, asserted that the consensus achieved by the Synthesis existed “only in the narrow sense.” Ultimately, he claims, what triumphed “was little more than hegemony achieved by a Fisherian population genetics view of the evolutionary process” that left little for paleontologists to contribute beyond mere documentation of history  as they do on intellectual or conceptual ones. The Modern Synthesis itself was, after all, as much a disciplinary engagement as it was a theoretical movement, and the question of paleontology’s role in any consensus achieved—a seat at the “high table” of evolutionary theory, as John Maynard Smith infamously put it—is part of a longer history of struggle for disciplinary autonomy and theoretical independence waged by paleontologists for more than a century.Tempo and Mode genuinely did inspire a new way of approaching evolutionary questions in paleontology. And make no mistake: prior to the 1940s, paleontology was a decidedly second-class discipline in the eyes of many Darwinian biologists. Take, for example, the dismissive tone of Thomas Hunt Morgan, who remarked in 1916 that:The geneticist says to the paleontologist, since you do not know, and from the nature of your case you can never know, whether your differences [in fossil series] are due to one change or to a thousand, you can not with certainty tell us anything about the hereditary units which have made the process of evolution possible. And without this knowledge there can be no understanding of the causes of evolution. Morgan , p. 27If one were to ask a paleontologist—even one as outspoken as Gould or Eldredge—whether paleontology was better or worse off as a theoretical, evolutionary discipline after 1944, he or she would have little hesitation in asserting that it was better off, by a wide margin. Much of the credit for this is due to Simpson, whose Evolution: The Modern Synthesis, Huxley quickly withdrew it only a few pages later, writing that “paleontology is of such a nature that its data by themselves cannot throw any light on genetics or selection…. All that paleontology can do… is to assert that, as regards the type of organisms which it studies, the evolutionary methods suggested by geneticists and evolutionists shall not contradict its data” , the roots of this attitude can be traced all the way back to Darwin, who, in The Origin of Species, famously commented:We have no right to expect to find in our geological formations, an infinite number of those fine transitional forms, which on my theory assuredly have connected all the past and present species of the same group into one long and branching chain of life…. [Rather] we ought only to look for a few links, some more closely, some more distantly related to each other; and these links, let them be ever so close, if found in different stages of the same formation, would, by most palæontologists, be ranked as distinct species.  synthesis and less exclusively along lines more nearly traditional in paleontology” , Simpson plotted curves estimating the longevity of particular taxonomic groups . These curves allowed him to estimate the mean evolutionary durations of particular taxa, revealing differences  as well as commonalities in patterns of evolutionary development. In particular, he noted that general patterns of survivorship tended to follow the same diminishing parabolic curve: despite different overall longevities, higher taxa tended to decline steeply at first, and then to persist with a few remaining groups for a lengthy period of time.Quantitative Zoology, which he co-authored with his wife Anne Roe, that attempted to teach basic statistical techniques to paleontologists and other students of natural history  and David Raup. But of broader importance was the methodology Simpson employed, which had an explicitly quantitative, modeling orientation. Simpson believed that one of the major reasons for paleontology’s second-class status was its lack of mathematical sophistication; indeed, he had addressed this issue in an earlier textbook,  Provine . It was Tempo and Mode—and the later Major Features of Evolution—was read by nearly every young paleobiologist between 1950 and 1980 and provided the crucial inspiration to attack big, evolutionary questions quantitatively. Later paleobiologists had the advantages of larger fossil databases to consult, more sophisticated (multivariate) statistical techniques, and, of course, digital computers. But Simpson was the unquestioned godfather of that later movement, and it is doubtful whether the revolution of the 1970s could have taken place without him.The importance of this approach for later studies in paleobiology during its “revolutionary” period in the 1970s and 1980s cannot be overstated: from the mid-1970s onwards, doing paleobiology meant studying patterns of diversification quantitatively. Simpson himself may not have achieved the striking results of his later followers (or even of his own colleagues like Newell), but in his day Simpson achieved a genuine synthesis of paleontology with evolutionary biology—in fact, it fairly begs it. One way of addressing it is to examine whether Simpson’s own views about evolution fit comfortably within the Synthetic “orthodoxy” preached by Mayr and Dobzhansky. In many ways they did: Simpson consistently insisted that a populational approach should dominate paleontology and asserted that macroevolution—that is, long-term patterns of evolutionary development—could be explained by neo-Darwinian microevolutionary genetic mechanisms of selection and drift. In one crucial regard, though, Tempo and Mode was at odds with the view of Mayr and Dobzhansky, who basically carried on Darwin’s assumption that major breaks in the fossil record were the artifact of an imperfect preservation process. As Simpson put it, “The development of discontinuities between species and genera, and sometimes between still higher categories, so regularly follows one sort of pattern that it is only reasonable to infer that this is normal and that sequences missing from the record would tend to follow much the same pattern…. [T]he face of the fossil record really does suggest normal discontinuity at all levels” , which characterizes most lineages, or else more quickly (tachytelic), which appears in a significant minority of cases. To explain the latter—where evolution proceeds very quickly leaving few intermediate stages in the fossil record—Simpson introduced what Gould has called “his most striking and original contribution”: quantum evolution Gould , p. 164.ion Mayr . Howeverion Mayr , p. 165.Tempo and Mode, it was virtually ignored in the revised 1953 Major Features of Evolution. Instead, Simpson now argued that “Phyletic splitting of lineages, including those from which higher categories up to the highest later develop, thus occurs by speciation at their bases…. The paleontological evidence cannot exclude the possibility of exceptions, but it confirms the conclusion in particular examples, and there is nothing in the record that requires or suggests exceptions”  and a vocal critic of paleobiological theorizing by people like Gould. One should bear in mind that not only had Gould been championing punctuated equilibria and other recent—and unorthodox—contributions by paleontologists as challenges to received evolutionary theory for more than a decade, but he had only a few years earlier published his infamous essay “Is a New and General Theory of Evolution Emerging?” In that piece Gould opined that despite being “beguiled” by the “unifying power” of the Synthesis as a student during the 1960s, he had been “watching it slowly unravel as a universal description of evolution ever since,” concluding that “if Mayr’s characterization of the synthetic theory is accurate, then that theory, as a general proposition, is effectively dead, despite its persistence as textbook orthodoxy” , Maynard Smith essentially agreed. “It might be supposed,” Maynard Smith began, “that the contribution [of paleontology to evolutionary theory] would be crucial, but, at least until recently, that has not been so.” As he explained,The palaeontologist G.G. Simpson was one of the main architects of the ‘modern synthesis’ that emerged in the 1940s, but his role was to show that the facts of palaeontology were consistent with the mechanisms of natural selection and geographical speciation proposed by the neonatologists , rather than to propose novel mechanisms of his own. Since that time, the attitude of population geneticists to any palaeontologist rash enough to offer a contribution to evolutionary theory has been to tell him to go away and find another fossil, and not to bother the grownups. . In a sense, I detect elements of all three sentiments in his piece. Maynard Smith’s enthusiasm for some developments in recent paleontology—especially mass extinction studies, which he cited as having “the greatest impact… on the way we see the mechanisms of evolution”—was clearly genuine and was shared by many biologists at the time. There is also a note of subtle condescension in the essay, in which praise is dispensed ambivalently , and the tone is decidedly one of a senior colleague addressing a junior one. But on one issue Maynard Smith seems to have been in complete agreement with Gould: that the Modern Synthesis, as a genuine synthesis of paleontology and genetics, was a failure.There are times when a historian should question his or her sources, and times when he or she should simply step back and let those sources have their say—and this is one of those times. Whether or not paleontology has since completed a delayed synthesis with evolutionary biology—and I suspect there are as many different opinions on that topic as there are paleontologists and evolutionary biologists—it seems fairly clear both from the historical record and from the mouths of the actors involved that whatever promise might have been extended in the 1940s was not achieved, at least until the mid-1980s or so. Mayr, writing both as an activist biologist during the Synthesis era and as a partisan historian several decades later, had a clear interest in characterizing the Synthesis as having been pluralistic and open in order to impose and celebrate his own distinctive view of what that synthesis should entail. Likewise, Gould and his compatriots in the 1970s and 1980s had conceptual and disciplinary motivations for arguing the reverse. In other words, there is no “right answer” to this question, but rather different perspectives that were conditioned by distinct disciplinary and theoretical agendas.The Structure of Evolutionary Theory  prominent public intellectuals with many scientific and popular accolades. Without a foil, however, punctuated equilibria had no teeth: indeed, one of the many criticisms of the theory that evolution proceeds through lengthy periods of morphological stasis, infrequently “punctuated” by bursts of rapid speciation, is that it was either unoriginal  or uncontroversial (for the stated reason that it did not require any novel evolutionary mechanisms) or both Cain . In facty Theory . Gould sy Theory .within geology and paleontology. By arguing that the Synthesis had failed or been incomplete, they were able to argue that their own sub-discipline—paleobiology—was the long hoped-for resolution to its ultimate completion. But, importantly, they could also make the case that completion of the Synthesis could not be accomplished within existing disciplinary structures—that is to say, with paleontologists isolated in museum or university geology departments, cut off from access to colleagues and resources in biology  , the Synthesis began with a more pluralistic outlook: “The original synthesists wanted to render all of evolution by known genetic mechanisms; but they tended to agnosticism about relative frequencies among the legitimate phenomena, notably on the issue of drift (and other random phenomena) vs. selection” (Gould Genetics), Wright (by downplaying the role of drift), and even himself . This meant, Gould argued, that paleontologists like Simpson were forced to drop more aggressive claims for the theoretical autonomy of paleontology, as evidenced by Simpson’s volte face concerning quantum evolution between Tempo and Mode and Major Features.In his final, n” Gould , p. 505.Unfinished Synthesis, in which he maintained that “the current version of the ‘modern synthesis’ remains so unmoved by the data of systematics, paleontology, and large-scale ecology that … we still have a theory of evolution that is not directly addressed to the actual events of the history of life”  affects another, how particular traits affect evolutionary rates, relative rates of evolution of different subclades in comparison with each other, whether the rate of evolution has decreased or increased through time, whether two subclades are evolving towards different evolutionary optima, how different traits relate to the likelihood of extinction, how population size has changed through time, whether there has been gene flow between particular species, when a species moved between land masses and the timings of accelerations and decelerations in trait evolution across clades and with respect to events such as climate changes or mass extinctions. Benton , p. 3Benton suggests a variety of reasons why the leading figures of the Paleobiological Revolution would have been resistant to phylogenetic approaches, but the essential point is that paleobiology, at least as it was understood in the 1980s, was out of step with the major new advances in biology .This may well be the case, and it is not my intention to try to settle the matter here. However, there are other reasons to believe that the intervention of paleobiologists during the revolutionary period was not decisive. As Michael Benton—a paleontologist long associated with the paleobiology movement who has spent his entire career in Britain —has argued, the Paleobiological Revolution, although a genuinely important episode, did not “set out the grounds within which modern palaeobiology operates,” because it mostly ignored the field of phylogenetic analysis Benton , p. 3. APrinciples of Paleontology, coauthored by Steven M. Stanley and David M. Raup , all but ignored phylogenetics in both editions , which has provided a framework for explaining how relatively large morphological changes can occur in geologically short intervals through modifications to developmental gene regulatory networks.In fact, some of the most exciting work in paleobiology in the past decade has involved the correlation of fossil evidence  with molecular data. The use of so-called “molecular clocks”  has greatly clarified our understanding of the origin and flourishing of multicellular life and, in particular, the puzzle of the so-called “Cambrian explosion,” in which most of the major animal phyla present today appear (from the fossil record) to have burst into existence over just a few million years some 500 million years ago. For example, phylogenetic estimates now suggest that, in fact, multicellular organisms probably evolved much earlier—perhaps 700 million years ago—and underwent a period of explosive diversification because of environmental conditions during the later Cambrian. One of the leading figures in this new approach has been the Smithsonian Institution paleobiologist Douglas Erwin , who explains, in an important coauthored paper on the Cambrian question, just how important phylogentic and other techniques have been:It goes without saying that many of these approaches—particularly molecular genetics and evo-devo—were unknown (or only dimly perceived) by the proponents of the Paleobiological Revolution.Rather, I think the Modern Synthesis is best understood as an event, coinciding roughly with the publication of a series of seminal books and papers between the 1930s and the early 1950s as well as a series of important disciplinary activities (like the founding of the Society for the Study of Evolution). In that context, it is fair to conclude that paleontology was an important part of the synthetic vision, but that this vision has been significantly eclipsed by subsequent events: the rise of computers as tools for phylogenetic and fossil diversity analysis, the molecular revolution, the Paleobiological Revolution of the 1970s and 1980s, the emergence of evo–devo and other major developments in geology (plate tectonics), ecology , and other fields. These events are self-contained phenomena, conditioned on contingent interactions in local contexts; there is no ultimate “core” we should seek for historically or philosophically to “Darwinism” or “The Modern Synthesis,” nor their final “completion.” From this perspective, paleontology’s role in evolutionary biology has continually evolved—as have other branches of evolutionary studies—and will surely continue to do so in the future in ways we historians cannot possibly predict from present conditions.