Auditory deprivation in the form of deafness during development leads to lasting changes in central auditory system function. However, less is known about the effects of mild-to-moderate sensorineural hearing loss (MMHL) during development. Here, we used a longitudinal design to examine late auditory evoked responses and mismatch responses to nonspeech and speech sounds for children with MMHL. At Time 1, younger children with MMHL  showed age-appropriate mismatch negativities (MMNs) to sounds, but older children  did not. Six years later, we re-tested a subset of the younger (now older) children with MMHL (n = 13). Children who had shown significant MMNs at Time 1 showed MMNs that were reduced and, for nonspeech, absent at Time 2. Our findings demonstrate that even a mild-to-moderate hearing loss during early-to-mid childhood can lead to changes in the neural processing of sounds in late childhood/adolescence. The structure and function of the adult auditory system is dependent upon stimulation received during maturation . Animal Cortical event-related potentials (ERPs) have been used extensively to investigate the functional integrity of the auditory pathway in both normally hearing (NH) and hearing-impaired individuals  and 44 NH age-matched controls (NH group). Stimuli were presented at a constant intensity of 70 dB SPL, and children with MMHL were tested without their hearing aids in order to avoid stimulus alterations being introduced by the different hearing aid processors . In ordenonspeech), complex speech-like nonspeech (speech-like), and speech sounds (speech)), and three stimulus types  deviants, and small (difficult-to-detect) deviants; see To assess auditory cortical functioning in children with MMHL, we recorded the EEG from all children during a passive oddball paradigm for three stimulus conditions . t-tests) of the differential (standard minus deviant) wave amplitudes were performed to determine the latency period over which the waveforms were significantly different from zero (see Methods). Because adjacent points in the waveform are highly correlated, potentially leading to spurious significant values over short intervals, a response was considered present when p<0.01 (one-tailed) for >20 ms at adjacent time-points . To do so, point-to-point comparisons  been individually less likely to demonstrate MMNs to deviant sounds, (b) shown MMNs that were later or more variable in latency, or (c) shown MMNs that were reduced in amplitude, relative to their NH peers. To determine whether children in the MM-O subgroup were less likely to show an MMN to large deviants than NH children, presence or absence of a significant MMN or LDN was identified for each participant, for each condition (see Methods). Because MMRs are less reliable at the individual level, an adjusted value of p<0.05 (one-tailed) for >20 ms at adjacent time-points was used. Fs <1, both ps >0.10], or their two-way interaction .To determine whether the MM-O subgroup showed MMNs that were delayed in onset latency, a linear mixed-effects model was conducted to determine whether group, age band, condition, or their interactions predicted MMN latencies to large deviants. Only the main effect of condition was significant (χ(2)=39.69, p<0.001), with MMN onset earlier in the nonspeech condition than both the speech-like and speech conditions (both p<0.001), which did not differ from each other (p=0.863). To determine whether the MM-O subgroup showed greater variability in MMN onset latency, Levene’s tests for equality of variance were used. There were no significant differences in variance for group, age band , the MM-O subgroup had significantly smaller MMNs than the NH-O subgroup  . Linear mixed-effects models were then conducted to determine whether group, age band, condition, or their interactions predicted MMN or LDN amplitudes to large deviants see . For the71)] see . Differep = .051, respectively) but not smaller  in children with MMHL compared to NH controls. In contrast, N2 was significantly smaller  but not later in children with MMHL (p = .482), an effect that was greater in the speech-like (p<0.001) than both the nonspeech and speech conditions . Neither the amplitude or latency of the N1 differed between groups, where present (p>0.10). However, note that only around ¼ of children with MMHL showed an N1 or P2 response.Because children with MMHL were less likely to show LAERs and MMNs than their NH peers, we then asked whether these responses were normal for those children who did show them. To do so, we calculated the latencies and amplitudes of those components/responses that had been identified as present for each individual (see Methods and t(69.57)=−0.14, p=0.891, CI ], in the presence of significantly smaller MMNs for children in the MM-O subgroup relative to their NH-O peers . For the LDN, there were no differences between groups or age bands in the amplitude of the response where present (p>0.10). However, again, the LDN was only present in around ⅓ of children with MMHL.For those individuals who showed a significant MMN to large deviants, the group × age band interaction for MMN amplitude again just missed significance (p=0.055). Again, this was driven by the absence of a significant group difference for the Y subgroups . Conversely, the proportion of the MM-YO group showing a P2 increased between time-points .To assess changes in the development of LAER components with age, we compared the presence/absence of these components for the MM-YO subgroup at Time 2 to their younger selves (i.e. a subset of the MM-Y subgroup from Time 1). To assess longitudinal changes in the MMRs with age, we identified the periods of the 100–600 ms post-stimulus epoch where a significant MMN or LDN was observed for each subgroup, condition, and deviant type see . In the 2χ(1)=4.24, p=0.039]. Second, children in the MM-YO subgroup were less likely to show an MMN than children in the NH-O subgroup  but were not significantly different from those in the MM-O subgroup . Third, the MMN was significantly smaller (on average by 1.49 µV) for the MM-YO subgroup than for their younger selves (p=0.028). Finally, while MMN amplitude for the MM-YO subgroup did not differ significantly from that of the initial MM-O subgroup (p=0.957), it was significantly smaller than that observed for the NH-O subgroup from Time 1 (p<0.001).Developmental changes to the MMN following MMHL were investigated in four ways see , yieldinThis study investigated the effects of permanent, MMHL on the development of both the LAER and MMRs across mid- to late-childhood. Children with MMHL were less likely to show LAER components than their NH peers see also . MoreoveThe apparent absence of the MMN for older children with MMHL was somewhat surprising to us, hence our endeavour to replicate these findings in the form of the longitudinal follow-up. The fact that we partially did so, combined with consistent findings in the literature of reduced and delayed auditory MMNs in adults , but notadaptation in response to an ongoing stimulus (the standard), for older children with MMHL. This argument has been put forward previously, notably for N1 , inconsistent, or inadequate. In humans with MMHL, a period of auditory deprivation is likely, especially for those with mild SNHL, who are currently not routinely detected by newborn hearing screening programmes . Indeed,desynchronization of neural oscillations to deviants across delta, theta and alpha bands .Participants were recruited as part of a larger study, which entailed psychophysical and electrophysiological measures of auditory processing, as well as psychometric assessments of language and cognitive functioning see . The stuChildren with MMHL were approached via Hearing Services in Local Educational Authorities across Greater London and the South East of England. Inclusion criteria were: (a) a diagnosis of MMHL, defined as a BEPTA threshold of 21–40 dB HL (mild) or 41–70 dB HL (moderate) across octave frequencies 0.25–4 kHz , (b) beiChildren in the MM group were individually matched in age (±6 months) to NH children from schools in the same geographical location . In two instances, children from the MM group were matched to a single child from the NH group. No child in the NH group had a known history of hearing loss (including otitis media with effusion), educational difficulties, or speech and language problems (based on parent/guardian report). All achieved mean pure-tone-average (PTA) air-conduction thresholds of ≤20 dB HL, across octave frequencies 0.25–4 kHz in both ears, and obtained thresholds ≤ 25 dB HL at all octave frequencies from 0.25 to 8 kHz see . All achYounger (Y) children were aged 8–11 years, and Older (O) children were aged 12–16 years =3.02, p=0.086, 2η = 0.03] but had poorer BEPTA thresholds . However, the age at which children’s mothers’ left full-time education  just missed significance . Unexpectedly, the MM group also had marginally lower nonverbal IQ relative to NH controls . However, this was driven by the higher-than-expected nonverbal IQ of the NH group; The nonverbal IQ scores of the MM group were all within the normal range, and the mean T-score for this group  was higher than the normative mean =0.21, p=0.870, 2η = 0.00], nonverbal IQ , or BEPTA thresholds .In order to examine the developmental effects of MMHL on the LAER, MMN and LDN, both groups were further divided into two age bands based on a median split for the MM group (12.0 years), and roughly corresponding to known changes in the morphology of the LAER in children of this age range . Youngerears see . ParticiF=0.18, p=0.672, 2η = 0.00], worse-ear pure-tone-average (WEPTA) thresholds , or mean (both ears) PTA (MePTA) audiometric thresholds . Likewise, they did not differ in their age of detection of SNHL  or age at which hearing aids were first prescribed . However, a larger proportion of older than younger children did not have (n = 3 for MM-O subgroup) or did not wear (n = 2 for MM-O subgroup) hearing aids . Finally, children in the MM-Y subgroup had marginally but not significantly higher nonverbal IQ than those in the MM-O subgroup , but maternal education levels did not differ between groups .Because we found differences in the neural responses of our MM-Y and MM-O subgroups, we also examined whether these subgroups differed in their audiological, cognitive, or demographic profiles. Children in the MM-Y and MM-O subgroups did not differ from each other in their BEPTA thresholds, ; Owing to the time lag, the MM-YO subgroup was slightly older than both the MM-O and NH-O subgroups (on average by 1.4 years) . Age was therefore used as a covariate in the analyses for the longitudinal study. The MM-YO subgroup did not differ from the MM-O or NH-O subgroups in nonverbal IQ , or maternal education . The MM-YO subgroup also did not differ in their BEPTA, WEPTA, or MePTA audiometric thresholds relative to the MM-Y subgroup at Time 1 , but did differ from the MM-O subgroup  =0.01, p=0.975] age of hearing aid fitting , or in the proportion of children wearing hearing aids .Participant characteristics of the four subgroups  are presented in The experimental setup for stimulus presentation and EEG recording was identical to that used at Time 1, with two main differences. First, as the system was older, technical difficulties led to us to discard EEG activity recorded on the left mastoids. Therefore, data from the MM-YO subgroup was only re-referenced to the right mastoids. Second, some scalp channels appeared consistently faulty, hence increasing the noise floor at Time 2. Because the MMN typically displayed a fronto-central distribution for the cross-sectional study, we thus limited the artefact rejection to a threshold of ±100 µV criterion in either Cz or Fz. Data from the three other subgroups  were thus reprocessed using the same re-referencing and artefact rejection criterion as those applied to the MM-YO subgroup.2(12)=13.3, p=0.420; speech-like: χ2(12)=7.73, p=0.800; speech: χ2(12)=20.3, p=0.120].The numbers of rejected standard trials in each condition were compared between the MM-Y and MM-YO subgroups (i.e. within-subject) as an index of noise floor in the two studies. There was no significant difference in noise floor between studies in any of the three conditions [nonspeech: χ In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.eLife. Your article has been reviewed by three peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Barbara Shinn-Cunningham as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Dan H Sanes (Reviewer #2); David Moore (Reviewer #3).Thank you for submitting your article "Functional Brain Alterations Following Mild-to-Moderate Sensorineural Hearing Loss in Children" for consideration by The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.Summary:The purpose of this project was to investigate the neural processing of sounds across development in children with mild-to-moderate sensorineural hearing loss using EEG. This is particularly important because much of our knowledge to-date is based on either more severe forms of hearing deprivation and/or cross-sectional studies, so examining auditory responses longitudinally in children with mild-to-moderate hearing loss is an important feature. The results suggest children with mild-to-moderate hearing loss show changes in amplitude and latency in MMN components.Essential revisions:1) The potential influence of audiometric thresholds on the measures was not adequately addressed (this covers both the stimulus level and degree of hearing loss). Stimuli were delivered at the same level to all children, regardless of hearing loss, and participants who had hearing aids did not wear them. It is true that (putting aside the hearing aid issue for a moment) a constant level to all listeners reflects "real world" listening conditions. At the same time, it substantially weakens the claim about "brain alterations" if the brains are getting stimulated differently. That is, would the brains of older MMHL children produce control-like amplitudes if stimulated at a sufficient SPL? Or, perhaps easier to look at, would listeners with normal hearing produce smaller amplitudes if stimulated at a lower SPL? The critical question is whether the results represent a shift due to simply being at a different place along a stimulation curve, or a fundamental change in brain processing due to hearing impairment.2) Age is an important factor that was not adequately addressed. For example, if there were hearing changes with age (as might be expected in children with early onset mild-moderate hearing loss) these hearing changes could explain your findings. A clearer examining of how BEPTA shifts with age would be useful, but more helpful would be (a) plotting audiograms for each group and (b) considering information not contained in the BEPTA. Relatedly, what looks like rather parallel performance for the MMHL and NH groups in Figure 3 seems to contradict the idea that effects might be age-dependent. These are some specific examples of a broader need for more clarity on age effects and how these can be accounted for in the results and interpretation.3) The role of hearing aids needs to be better addressed in interpretation of the results, above the potential contribution to presentation level (point 1). For example, what was the duration of hearing aid use? And how consistently did they use their hearing aids? There is evidence that adolescents tend not to use their hearing aids , while in children up to age 7, increasing age predicts more consistent hearing aid use . It is therefore possible that the consistency of treatment that is being received for their hearing loss is also a defining difference between the two age bands in both the cross-sectional and the longitudinal components of this study.4) In some instances, the descriptions of results in the text did not clearly line up with the data displayed in the figures. For example, a sentence at the end of the Introduction "Despite showing age-appropriate MMNs at the time of Experiment 1, these children showed MMNs that were reduced or absent by Experiment 2." is not in accord with a sentence in the description of the results of Experiment 2 "In the Speech condition, a significant MMN remained in the MM-YO group." Perhaps some of the confusion comes from referring to different conditions in different contexts; however, there was an overall sense of a lack of clarity in the presentation of the results . Please clarify the results presentation and make sure the text descriptions clearly line up with results figures as presented.5) Duration of the analysis window. The analyses focus on the waveforms within the first 400 ms after stimulus onset, but there also appear to be potentially interesting group differences between the waveforms 400-600 ms post-stimulus-onset, particularly for the speech stimuli. Clearer justification for this choice  would be useful here.eLife Author Guide.6) Data and stimuli availability. Even in the absence of ethics approval for sharing personally identifiable information, summary measures should be shareable, as should stimuli used in the experiment. For example, age group, hearing status, and BEPTA figure prominently in the analyses. Similarly the latency and amplitude measures extracted from the raw data don't pose any risk of personal identification. Please see the policies section of the  Essential revisions:1) The potential influence of audiometric thresholds on the measures was not adequately addressed (this covers both the stimulus level and degree of hearing loss). Stimuli were delivered at the same level to all children, regardless of hearing loss, and participants who had hearing aids did not wear them. It is true that (putting aside the hearing aid issue for a moment) a constant level to all listeners reflects "real world" listening conditions. At the same time, it substantially weakens the claim about "brain alterations" if the brains are getting stimulated differently. That is, would the brains of older MMHL children produce control-like amplitudes if stimulated at a sufficient SPL? Or, perhaps easier to look at, would listeners with normal hearing produce smaller amplitudes if stimulated at a lower SPL? The critical question is whether the results represent a shift due to simply being at a different place along a stimulation curve, or a fundamental change in brain processing due to hearing impairment.This is an important question but unfortunately one that is very challenging to address. Sensorineural hearing loss (SNHL) affects not only the absolute hearing thresholds of affected individuals, but also their dynamic range. That is, many individuals with SNHL experience loudness recruitment for high intensity stimuli, meaning that listeners may not tolerate stimuli at intensities that are matched for sensation level (SL) with those of normally hearing (NH) listeners. Moreover, since the participants tested here were children, we were particularly keen to avoid causing further damage to the residual hearing they had. The result of this is that, in practice, it is very difficult to match the SL of stimuli experienced by children with MMHL to that experienced by NH controls.One potential way round this would have been to present NH children with lower-intensity stimuli that were matched for SL to those experienced by the MMHL group. However, this again is not straightforward, for three reasons. First, because BEPTA thresholds for children with MMHL range from 21-70 dB HL, there was no consistent SL for participants in the MMHL group. Second, because audiometric thresholds varied between ears for some children with MMHL, there was no consistent between-ear SL for participants in the MMHL group. Third, because audiometric thresholds varied across frequencies for participants in the MMHL, there was no consistent across-frequency SL for this group. The consequence of this was that in order to control for SL, we would have needed to match each individual child with MMHL to a NH child of the same age, and present the latter with stimuli that were shaped in intensity across frequencies and ears. It remains our view that this would have introduced too many moving parts to what was already a complex study.That said, in a more recent (as yet unpublished) study we have examined the effects of amplification on the MMN in children with MMHL. In this study, 18, 8-to-16 year-old children with MMHL, and 15 NH age-matched controls were tested. Electrophysiological measures were recorded in response to the same standard (probability: 90%) and large  deviant speech stimuli that were used in the current study. There were however a few methodological differences to the present study, the main one being that for children with MMHL, stimuli were presented both unamplified (70 dB SPL) and with a simulated, personalised amplification . NH children were only presented with the unamplified condition. Importantly, preliminary results from this study provide important insights regarding the interpretation of the study reported here. 2) Age is an important factor that was not adequately addressed. For example, if there were hearing changes with age (as might be expected in children with early onset mild-moderate hearing loss) these hearing changes could explain your findings. A clearer examining of how BEPTA shifts with age would be useful, but more helpful would be (a) plotting audiograms for each group and (b) considering information not contained in the BEPTA. Relatedly, what looks like rather parallel performance for the MMHL and NH groups in Figure 3 seems to contradict the idea that effects might be age-dependent. These are some specific examples of a broader need for more clarity on age effects and how these can be accounted for in the results and interpretation.We have made several changes to the manuscript which confirm that, for both studies, audiometric thresholds did not deteriorate with age for the MMHL group. Regarding the cross-sectional study, Figure 1 now shows audiometric thresholds (0.25-8 kHz for left and right ears) for children with MMHL compared to NH controls, plotted separately for the younger and older age bands. This illustrates that there were no differences in audiometric thresholds between younger and older children, whatever their group. We now also include statistics to that effect : Participants”, last paragraph) which report that the MM-O subgroup did not differ from the MM-Y subgroup in BEPTA thresholds, worse ear (WEPTA) thresholds, or mean PTA (MePTA) thresholds. Regarding the longitudinal study, audiometric thresholds for the MM-YO group at Time 1 and Time 2 are now reported in Figure 10—figure supplement 1 and Table 2, and statistical analyses in the last paragraph of the subsection “Longitudinal study (Time 2): Participants”. The MM-YO group did not differ in their BEPTA, WEPTA, or MePTA thresholds between Time 1 and Time 2.Upon performing these analyses, we also decided to see if the groups also differed on any other audiological measures that we had taken. For the cross-sectional study, the MM-Y and MM-O subgroups did not differ in their age of detection of SNHL, nor in the age at which they were first fitted with hearing aids (see Table 1 and the aforementioned paragraph). However, children in the MM-O subgroup were less likely to have or wear hearing aids (78%) than children in the MM-Y subgroup (100%). Note though that this difference does not apply in the case of the longitudinal study where children in the MM-YO group  were compared to themselves.Regarding what was Figure 3 in the original submission , as we report in the manuscript, we did not find an interaction between group and age on the latency or amplitude of any of the LAER components , where present . Nor did we see an interaction between group and age regarding the presence/absence of any of the LAER components (see “Children with MMHL show reduced presence of LAER components to sounds”). Rather, our findings suggest that any group × age interaction may be specific to the MMN; namely, that the MMN is (a) less likely to be present at the group level, and (b) where present, is likely to be smaller, in older children with MMHL compared to age-matched NH controls . Efforts have been taken to improve the clarity of the manuscript for this revision, particularly with regard to the Results section.3) The role of hearing aids needs to be better addressed in interpretation of the results, above the potential contribution to presentation level (point 1). For example, what was the duration of hearing aid use? And how consistently did they use their hearing aids? There is evidence that adolescents tend not to use their hearing aids , while in children up to age 7, increasing age predicts more consistent hearing aid use . It is therefore possible that the consistency of treatment that is being received for their hearing loss is also a defining difference between the two age bands in both the cross-sectional and the longitudinal components of this study.As outlined above, Table 1 now presents the mean age of detection of MMHL, the number of children who were fitted with hearing aids, and the mean age of aiding for those children with MMHL who wore hearing aids, for the Y and O subgroups. Regarding the consistency of hearing aid use in the MM groups, unfortunately we do not have much data on this as we were not able to access hearing aid logs, and parent report measures of hearing aid use have been shown to be unreliable :380-7). Nonetheless, there was some evidence for lower uptake of hearing aids in the MM-O subgroup at Time 1, in that three children in this group had not been prescribed with hearing aids, and two were refusing to wear their hearing aids. However, this may reflect a historical point in time; children in this subgroup were born before the UK national roll-out of the Universal Newborn Hearing Screening Programme. All of the children in the MM-Y subgroup at Time 1 had been prescribed with hearing aids, and all were wearing them at Time 2, although again, we do not know how consistently. We now include some discussion about this in the Discussion section .4) In some instances, the descriptions of results in the text did not clearly line up with the data displayed in the figures. For example, a sentence at the end of the Introduction "Despite showing age-appropriate MMNs at the time of Experiment 1, these children showed MMNs that were reduced or absent by Experiment 2." is not in accord with a sentence in the description of the results of Experiment 2 "In the Speech condition, a significant MMN remained in the MM-YO group." Perhaps some of the confusion comes from referring to different conditions in different contexts; however, there was an overall sense of a lack of clarity in the presentation of the results . Please clarify the results presentation and make sure the text descriptions clearly line up with results figures as presented.The Results section has now been substantially revised with a view to improving clarity. We have endeavoured to ensure that the main results of the study are conveyed clearly and that overall findings are not over-simplified .5) Duration of the analysis window. The analyses focus on the waveforms within the first 400 ms after stimulus onset, but there also appear to be potentially interesting group differences between the waveforms 400-600 ms post-stimulus-onset, particularly for the speech stimuli. Clearer justification for this choice  would be useful here.This is a good suggestion and something we had not noticed before as we had been focusing on the conventional time window for the MMN . Responses that occur after this time window are more typically considered to be akin to the late discriminatory negativity (LDN). We now include analyses of this response in the paper and associated discussions therein.6) Data and stimuli availability. Even in the absence of ethics approval for sharing personally identifiable information, summary measures should be shareable, as should stimuli used in the experiment. For example, age group, hearing status, and BEPTA figure prominently in the analyses. Similarly the latency and amplitude measures extracted from the raw data don't pose any risk of personal identification. Please see the policies section of the eLife Author Guide.https://github.com/acalcus/MMHL.git).We now provide the non-identifiable data, stimuli, and analysis scripts (see


Handgrip strength (HGS) and muscle mass are strong predictors for dependencyin Activities of Daily Living (ADL) and Instrumental Activities of Daily Living(IADL) in community dwelling older adults. Whether this also applies to olderhospitalized patients is yet unknown. We studied the association between HGS andmuscle mass with ADL and IADL dependency at admission and change of ADL and IADLdependency at three months after discharge in older hospitalized patients.Observational longitudinal inception cohort (EMPOWER) including 378 patientsaged 70 years and older.Four different clinical wards of a university teaching hospital, TheNetherlands.HGS and muscle mass were measured within 48 hours after admission using handdynamometry and Bio-electrical Impedance Analysis respectively. ADL dependency wasassessed using the Katz score (0-6 points) and IADL dependency using the Lawtonand Brody score (0-8 points) within 48 hours after admission and three monthsafter discharge.At admission, lower HGS was associated with ADL dependency in both males andfemales. Lower muscle mass was associated with ADL dependency in males. Lower HGSwas associated with IADL dependency, but only in males. Lower HGS at admission inmales was associated with an increase in ADL dependency three months afterdischarge.In hospitalized older patients, HGS is associated with ADL and IADL and musclemass measures with ADL in male patients only. HGS should be explored as predictivemarker for outcome of hospitalized older patients after discharge. Hospitalization rates among older adults account to more than one third ofhospital admissions . HospitaLow muscle strength and low muscle mass are diagnostic measures of sarcopeniaand are prevalent in up to 45% of acutely hospitalized patients aged 65 years orolder . In commThe aim of this study was to determine the association of muscle strength andmuscle mass at admission with 1) ADL and IADL dependency at admission and 2) changein ADL and IADL dependency from admission to three months after discharge inhospitalized older patients aged 70 years and older.The ‘Evaluation of Muscle parameters in a Prospective cohort of Older patientsat clinical Wards Exploring Relations with bed rest and malnutrition’ (EMPOWER)study is an observational, prospective inception cohort study. A total of 838subsequent hospitalized patients were screened for eligibility for inclusion fromApril 2015 to December 2015. Patients were included if they were aged 70 years andolder and admitted to one of four clinical wards  of the VU University MedicalCenter, Amsterdam, The Netherlands, a middle-sized teaching hospital. Patientswere excluded if they were terminally ill, had an expected length of stay in thehospital shorter than 24 hours, were admitted at another hospital and relocated tothe VU University Medical Center, were nursed in isolation rooms or were not ableto understand the Dutch language. The EMPOWER study included a total of 378patients. Patients were assessed within 48 hours after hospital admission,comprising assessment of patient characteristics, measurements of muscle strengthand muscle mass, and ADL and IADL dependency. ADL and IADL dependency wasre-assessed at three months after discharge using telephone calls as describedearlier . This stAt admission, the following items were assessed during an interview by anurse: living situation, use of walking aid, risk of malnutrition defined by theShort Nutritional Assessment Questionnaire (SNAQ) score using a score ≥2 out of 7points , risk ofThe following items were collected from medical records: age, sex,multimorbidity, polypharmacy, acute or elective admission and length of stay.Multimorbidity was defined as two or more of the following diseases:cerebrovascular accident/transient ischemic attack, chronic obstructive pulmonarydisease, hypertension, heart failure, chronic kidney disease, diabetes mellitus,malignancy, peripheral vascular disease, thyroid disease, Parkinson’s disease,arthrosis, rheumatoid arthritis and osteoporosis. Polypharmacy was defined as fiveor more medications .Weight was measured to the nearest 0.1 kilograms using a weighing chair.Self-reported weight was used when measurement of weight was impossible. Kneeheight was measured to the nearest 0.1 centimeter to estimate actual height to thenearest 1 cm using the Longitudinal Aging Study Amsterdam (LASA) formula. BMI wasHGS was measured using a hydraulic hand dynamometer . Measurements were performed according to instructionsrecommended by the American Society of Hand Therapists , i.e. paBody composition was measured using direct segmental multi-frequencybioelectrical impedance analysis (DSM-BIA) ,which is a validated and standardized method of estimating skeletal muscle masscompared to DXA . PatientADL dependency was assessed using the Katz score  ranging For longitudinal analysis, the change in ADL and IADL was defined as the scoreat follow-up assessment minus the score at admission (change in ADL and IADL);positive change ADL and IADL scores indicating a decrease in dependency andnegative change in ADL or IADL scores indicating an increase in dependency.Continuous variables were presented as mean with standard deviation (SD) ifnormally distributed and as median with interquartile range (IQR) if not normallydistributed.Cross-sectional analysis of the associations of HGS, SMM, SMM% and SMI(independent variables) with ADL and IADL dependency (dependent variables) atadmission were analyzed using binary logistic regression analysis . In model 1, analyses were adjusted for age. In model 2,analyses were additionally adjusted for multimorbidity and weight (kg) and height(m) (for HGS) or fat mass (kg) (for SMM and SMI) or weight (kg) (for SMM%).Longitudinal analyses of the association of HGS, SMM, SMM% and SMI with thechange in ADL and IADL scores were analyzed using linear regression analyses. Inmodel 1, analyses were adjusted for age and ADL or IADL score at admission. Inmodel 2, analyses were additionally adjusted for multimorbidity and weight (kg)and height (m) (for HGS) or fat mass (kg) (for SMM and SMI) or weight (kg) (forSMM%) .Statistical analyses were performed using the Statistical Package for theSocial Sciences, version 22 .P-values lower than 0.05 were considered statistically significant. P-values lowerthan 0.1 were considered a trend. In an observational prospective inception cohort study of hospitalized patientsaged 70 years and older lower hand grip strength (HGS) was associated with ADLdependency at admission. Muscle mass, i.e. relative and absolute skeletal musclemass and skeletal muscle mass index were associated with ADL at admission, but inmales only. Both lower HGS and relative skeletal mass were associated with anincrease of ADL dependency at three months after discharge, but only in males. OnlyHGS at admission was associated with IADL at admission and only in males.HGS was consistently associated with ADL dependency. HGS values in ourpopulation were similar to sarcopenic community dwelling subjects and acutelyhospitalized subjects , 29 and Associations of muscle measures with ADL dependency are in line with previousfindings in community dwelling older adults . Other studies have foundmuscle strength to be associated with both ADL and IADL . Our stuIn the present study, a significant decline three months after admission wasfound for the IADL scores, implying that IADL is more sensitive to change than basicADL activities after hospital discharge in older patients .In a previous cohort study of 492 older hospitalized subjects, 54% was found tobe independent in ADL before admission and 44% 3 months after admission. One thiEMPOWER is a large prospective inception cohort study of older adults admittedto various specialisms minimizing selection bias and ensuring diversity,representative for an older hospital population. Muscle mass parameters weremeasured by use of portable BIA devices, which is susceptible to hydration statewhich was as much as possible controlled for. Patients who were expected to bedischarged within 24 hours of admission were not included due to the short stay,which could have caused selection bias excluding the healthier patients. The usedADL and IADL scales have ceiling effects reducing sensitivity for changes andpotentially interfering with addressed associations. Muscle measures at hospital admission in older patients are related to ADLdependency at admission and change in ADL dependency three months after discharge,however, these associations are sex specific. Taken aforementioned findings intoaccount, HGS may be useful to predict outcome after hospital admission. Furtherresearch into trajectories of ADL dependency, before, during and afterhospitalization are required to further pinpoint risk factors, patients at risk andidentification and allocation of preventive measures.Conflict of Interest: None of the authorsreport a conflict of interest.Funding: This study was supported by theseventh framework program MYOAGE (HEALTH-2007-2.4.5-10); European Union’s Horizon2020 research and innovation programme (No 689238 and No 675003); and NutriciaResearch, Nutricia Advanced Medical Nutrition, The Netherlands.Ethical Standards: This study was reviewedand approved by the medical ethical committee of the VU University Medical Center,Amsterdam, The Netherlands. Informed consent was obtained from all includedpatients.


An astonishing 466 million people across the globe live with a disabling hearing loss, equating to 6.1% of the world's population , primariTo first understand the severity of the challenge of severe hearing loss in the aging population, and understand the necessity of appropriate treatment, it is important to explore the costly co-morbidities that are associated with it.According to the Lancet Commission, untreated hearing loss is the number one modifiable risk factor contributing to dementia, increasing an individual's risk of developing the condition by 9% . This trHearing loss has an impact on an individual's mental health and is also linked to the onset of depression. Social situations become more challenging through inhibited communication, leading to social withdrawal and isolation. This can further contribute to cognitive decline through depriving the brain of the stimulation it gets from social interactions , 5. CognFinally, the treatment and management of diabetes is hindered through hearing loss, impacting diabetes education through hindering communication between doctor and patient, making self-management of the condition more difficult .Considering the aforementioned co-morbidities and the fact that untreated hearing loss is also related to more frequent falls through reduced balance and restricted environment awareness, we can start to see how hearing loss might accelerate the deterioration of an individual's health and their progression into assisted living. Unfortunately, this can deprive people of the joy of their golden years, reduces independence, and often comes at significant financial costs. This makes hearing loss a significant public health challenge.Cochlear implantation has become a standard treatment for adults and children with bilateral severe to profound hearing loss, when powerful hearing aids no longer provide enough functional benefit toward speech understanding. Whilst surgically implanted, they can be recommended for even the oldest of adults. Numerous scientific studies have shown that hearing implants positively affect many factors. Older adults experience improved speech understanding, increased social contact, greater self-confidence, and an overall improvement in quality of life after implantation . MultiplHowever, as of December 2012, only a fraction of those who could benefit from Cochlear Implantation were reported to have received a CI: only 324,200 people world-wide. Across all regions, less than 10% of those with severe to profound hearing loss have been implanted , with alFirst, the low uptake of CI is in part due to the low number of suitable candidates presenting themselves for assessment. People have to be motivated enough to seek help for their hearing loss, and typically only do so when they are sufficiently concerned about its severity or that treatment on balance would be more beneficial than detrimental. With the older population specifically, this can be a barrier given that hearing loss can be viewed as a natural consequence of old age, by both the patient and professionals . ConcernThere is also a variance between those who are appropriate for CI and those who receive them, depending on the approach to hearing care across different countries. For example, in the United Kingdom, the first point of access for hearing care is the General Practitioner (GP) 83%), however in Germany for example, it is an Ear Nose and Throat (ENT) specialist (93%) (3%, howevFurthermore, studies reveal that there is a lack of awareness as to whether Cochlear Implantation is an option for the older population, despite the fact that the surgical complication rate is low even for older adults, if the patient's general state of health is good . This isFinally, an issue beyond awareness which cannot be excluded is the topic of payment. Global inequalities currently exist between high, low and middle income countries, in terms of how Cochlear Implants are reimbursed and funded. The cost of Cochlear Implants must not be a barrier to receiving treatment, and policy-makers must recognize access to hearing health as a human right.To conclude, hearing loss carries a heavy economic and social burden, which is only expected to increase as our global population continues to age. Hearing loss has a proven negative impact on an individual's overall health. If we do not provide access to appropriate treatment costly co-morbidities such as cognitive decline, depression and the mismanagement of diabetes will continue to deprive our older population of experiencing the full potential of their golden years, whilst placing huge financial costs on society. Cochlear Implantation is a cost-effective solution to alleviating the pressure of hearing loss on both individuals and global health systems and is appropriate for even older adults with low surgical complication rates. However, awareness amongst patients and professionals of Cochlear Implantation remains a key barrier to access for potential candidates, with alarmingly low rates of penetration. Hearing loss should not be viewed as a natural part of aging without a solution. To realize the full benefits of Cochlear Implantation, awareness of the CI must be raised amongst patients and professionals as well as policy-makers so that equitable reimbursement takes place across the globe.All authors contributed to the development of the opinion, the interpretation of existing public health policies related to hearing loss and the review of the final paper.PD is an employee of MED-EL GmbH, Innsbruck, Austria. PV receives grants to the institution from MED-EL and Cochlear. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pulmonary mucormycosis is a life‐threatening invasive fungal infection usually seen in the background of immunosuppression, haematological malignancies, or uncontrolled diabetes. Immunocompetent hosts can also be affected. Isolated endobronchial mucormycosis is rare with only a few cases reported in the literature. Here, we present a case of an endobronchial mass masquerading as a tumour that was later diagnosed as invasive mucormycosis by histopathological examination. Pulmonary mucormycosis is a serious opportunistic fungal infection that occurs most commonly in immunocompromised but also reported in an immunocompetent host 2) of 64.7 mm Hg and saturation of 94% in room air. Her chest X‐ray revealed a complete homogenous opacity on the left side  and grade 4 chronic kidney disease (creatinine of 3.2 mg/dL) presented to the clinic with a history of productive cough and dyspnoea of grade 4 Modified Medical Research Council scale for a period of one week. She had a history of high‐grade squamous intraepithelial lesion on her pap smear a year back for which she has not consulted further. Her physical examination revealed tachypnoea and grossly reduced breath sounds on the left side. Her blood gas analysis on admission showed respiratory alkalosis with partial pressure of Oxygen  Mucormycosis can present as five predominant forms: rhino‐cerebral, pulmonary, cutaneous, gastrointestinal, or disseminated Pulmonary mucormycosis presenting as an endobronchial lesion is rare. A recent analysis revealed that only 60 cases of mucormycosis involving larger airways have been reported in the literature so far Our patient had both uncontrolled diabetes and renal failure as comorbidities. She presented with an endobronchial mass that was radiologically evident with collapse consolidation of the left lung. Bronchoscopy showed a fleshy vascular growth mimicking a bronchial adenoma or bronchogenic carcinoma. Biopsy confirmed the diagnosis. A high index of suspicion is required for diagnosis.Appropriate written informed consent was obtained for publication of this case report and accompanying images.


MYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which ultimately requires cochlear implantation in early childhood. Recently, such variants have also been shown to possibly cause moderate-to-severe hearing loss. Herein, we also demonstrate that some MYO15A mutant alleles can cause postlingual onset of progressive partial deafness.Two multiplex Korean families (SB246 and SB224), manifesting postlingual, progressive, partial deafness in an autosomal recessive fashion, were recruited. Molecular genetics testing was performed in two different pipelines, in a parallel fashion, for the SB246 family: targeted exome sequencing (TES) of 129 known deafness genes from the proband and whole exome sequencing (WES) of all affected subjects. Only the former pipeline was performed for the SB224 family. Rigorous bioinformatics analyses encompassing structural variations were executed to investigate any causative variants.MYO15A. In the SB224 family, c.9790C > T (p.Q3264X) and c.10263C > G (p.I3421M) in the FERM domain were detected as candidate variants.In the SB246 family, two different molecular diagnostic pipelines provided exactly the same candidate variants: c.5504G > A (p.R1835H) in the motor domain and c.10245_10247delCTC (p.S3417del) in the FERM domain of MYO15A variants can cause postlingual onset of progressive partial deafness. The phenotypic spectrum of DFNB3 should be extended to include such partial deafness. The mechanism for a milder phenotype could be due to the milder pathogenic potential from hypomorphic alleles of MYO15A or the presence of modifier genes. This merits further investigation.Some recessive The online version of this article (10.1186/s12881-018-0541-9) contains supplementary material, which is available to authorized users. MYO15A, a causative gene of DFNB3 (OMIM 600316) [MYO15A pathogenic variant was about 2% [MYO15A pathogenic variant was reported in up to 9.9% of deafness cases in Turkey [MYO15A pathogenic variant was reported at a frequency of 2.1% in nonsyndromic autosomal recessive deafness, which was the fourth most common deafness gene in Korea, following SLC26A4, GJB2 and CDH23 [MYO15A pathogenic variants on hearing loss [MYO15A, includes the graded elongation and maintenance of stereocilia and actin-organization in the inner ear hair cells. These are both essential for normal auditory function. Therefore, MYO15A pathogenic variants were initially thought to induce congenital severe-to-profound hearing loss [MYO15A pathogenic variants varied depending on the affected domain. The variation of phenotypes according to the affected domain has been explained by the existence of two isoforms -- a class 1 isoform with the N-terminal domain, which is encoded by exon 2, and a class 2 isoform with no N-terminal domain [MYO15A [MYO15A pathogenic variants that reside in the regions shared by both isoforms are known to cause congenital or prelingual severe-to-profound hearing loss [The role of myosin XVA, which is encoded by ing loss –15. Howel domain , 17. Thel domain . The claMYO15A pathogenic variants, which had previously been thought to only cause profound hearing loss, may cause moderate-to-severe hearing loss [MYO15A pathogenic variants in the motor and FERM domains, which were expected to cause profound hearing loss. They showed postlingual onset of bilateral symmetrical, partial deafness with significant residual hearing at low frequencies. Based on these results, we suggest that MYO15A may be a causative gene responsible for the postlingual onset of progressive partial deafness, which in turn requires the expansion of the phenotypic spectrum of MYO15A pathogenic variants.Recently, Naz et al. reported that ing loss . We alsoAll procedures in this study were approved by the Institutional Review Boards of Seoul National University Hospital (IRBY-H-0905-041-281) and Institutional Review Boards of Seoul National University Bundang Hospital (IRB-B-1007-105-402). Written informed consent was obtained from all participants. Two multiplex Korean families (SB246 and SB224), with the segregation of postlingual, bilaterally symmetrical, partial hearing loss in an autosomal recessive fashion, were included in this study. The first family (SB246) was comprised of five individuals, three of whom participated in the study; the second family (SB224) was comprised of four individuals, all of whom participated. Two generations were included in each family  of 129 known deafness genes from the proband, followed by a segregation study using Sanger sequencing; the second pipeline was whole exome sequencing (WES) in the three affected subjects. In the SB224 family, TES of 129 known deafness genes was performed from the proband, followed by a segregation study using Sanger sequencing.http://152.99.75.168/KRGDB/menuPages/firstInfo.jsp). SNPs with allele frequency < 0.005 were chosen. Inheritance patterns were checked and SNPs that did not coincide with the autosomal recessive pattern were excluded. To predict the pathogenicity of each variant, SIFT, PolyPhen-2 analyses, and Pathogenic variantTaster were performed. Pathogenic variants are described in the context of the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines [http://genome.ucsc.edu/). The variants that were predicted as benign by silico prediction were excluded. The remaining SNPs were validated in other family members  by Sanger sequencing.TES and bioinformatics analyses were performed, as previously described –25. The idelines . The evoDNA samples from SB246–482, 483, and 484 were subjected to WES by Macrogen  , using SeqMan NGen, and the targeted variants were analyzed using ArrayStar software . Bioinformatics analyses were performed Fig. . After tMYO15A, survived the filtering steps in each family  and siblings SB246–483 and 484) of SB246–482, as well as in parents (SB224–593 and 594) and sibling (SB224–592) of SB224–437. Only two candidate variants from a single gene, ily Fig. . In the  and 484 ily Fig. . Moreoveily Fig. . FurtherMYO15A was related to hearing loss  in the SB246 family was performed in a parallel fashion. Following the basic filtering step, 1188 variants from 895 genes were selected as candidate pathogenic variants Fig. . The inh482 Fig. . The delOTOF and STRC, have been reported not to be fully covered by next generation sequencing [STRC and CATSPER2, which was reported to be an important molecular etiology of SNHL in Japan [MYO15A survived at the final filtering step of TES analyses; c.9790C > T was a nonsense variant causing truncation of the protein, and c.10263C > G has already been reported to be pathogenic. Therefore, it is most likely that hearing loss from SB224–437 was attributed to these two MYO15A variants. Sequentially, WES was not performed in SB224.Although TES of 129 genes in the deafness panel is an efficient and convenient tool for detecting known causative variants, pathogenic variants from a novel deafness gene may not be detected using only TES. To explore and minimize such a possibility, we performed genetic testing via two diagnostic pipelines, TES and WES, in a parallel fashion for the SB246 family. Filtering of candidate variants through these two pipelines indicated the same result, strongly supporting our molecular diagnosis. Moreover, certain genes, such as quencing . To overin Japan . In the MYO15A pathogenic variants, c.5504G > A (p.R1835H) and c.10245_10247delCTC (p.S3417del), in the SB246 family and c.9790C > T (p.Q3264X) and c.10263C > G (p.I3421M), in the SB224 family were the causative pathogenic variants of hearing loss. Among the four MYO15A pathogenic variants discovered here, c.5504G > A and c.9790C > T were novel variants; c.9790C > T was a nonsense pathogenic variant, and c.5504G > A resided in the motor domain. The motor domain is one of the most important domains in myosin XVA. Sequentially, it is reasonable to infer that variants in the motor domain may lead to profound hearing loss. c.10245_10247delCTC and c.10263C > G resided in the FERM domain; they have already been reported to cause congenital profound hearing loss [The conservation and pathogenicity prediction study also strengthened our hypothesis that ing loss –33. TherMYO15A, CDH23, and PTPRQ, have been reported to cause different types of hearing loss from those previously postulated in the literature [The establishment of genotype-phenotype correlation is one of the fundament goals of genetics, as it enables personalized and timely management of diseases, leading to great contribution to precision medicine. Personalized and timely auditory rehabilitation is crucial in hearing loss because there is a critical time window for auditory development and degeneration. Therefore, an establishment of genotype-phenotype correlation is a meaningful issue in hearing loss. Sequentially, genotype-phenotype correlations of several genes and their pathogenic variants have been investigated widely. However, genotype-phenotype correlations have generally been based on the observation of phenotypes, rather than prudent analysis of pathogenic mechanism. Previously established genotype-phenotype correlations could be modified. Recently, several genes, including terature , 31.MYO15A is one of the genes with a well-documented genotype-phenotype correlation. It has been reported that hearing loss phenotype related to MYO15A is different according to the affected domain. Specifically, pathogenic variants in the N-terminal domain of MYO15A have been suggested to be associated with residual hearing [MYO15A has greatly contributed to personalized and timely auditory rehabilitation. Recently, these previously established genotype-phenotype correlations appear to require an updated modification. Some MYO15A pathogenic variants affecting the domains other than the N-terminal, have shown to cause moderate-to-severe hearing loss, not profound hearing loss [MYO15A pathogenic variants, which were expected to cause congenital severe-to-profound hearing loss, but resulted in postlingual onset of progressive partial deafness with residual hearing at low frequencies. Indeed, SB224–437 carrying two MYO15A mutant alleles in this current study had a shallower angular insertion depth of 393°, by Flex 24 rather than by the longer Flex 28 electrode to minimize the shift in low frequency thresholds from this subject Additional file 2:Table S2. Depth of coverage of customized panel sequencing. The table enumerates the mean coverage of the targeted regions from customized panel sequencing sample calculated by mpileup of samtools. (DOCX 206 kb)Additional file 3:Table S3. Exome sequencing statistics. The table lists information of human genome reference (v19), customized panel and whole exome sequencing aligned reads from each patient estimated by CalculateHsMetrics of picard tool. (DOCX 29 kb)


We present a rare adult case of bilateral oval and round window atresia. Clinical and audiologic findings were suggestive of otosclerosis. High resolution CT Temporal bones showed unequivocal findings of bilateral oval and round window atresia. Atresia of these windows is a rare temporal bone anomaly. Presentation as an adult can confound the clinicians and warranting a closer look on the CT for atretic windows and subtle signs of otosclerosis in patients with conductive hearing loss. Isolated oval window atresia (OWA) is a rare middle ear temporal bone congenital anomaly. Multiple earlier reports have been surgical –3. OWA cThe oval window is a small oval-shaped normal bony defect or window designed for the stapes foot-plate at the medial wall of the middle ear opening into the vestibule . The latRound window atresia (RWA) is even more rare than OWA with few case reports –10. The We report here a rare case of an adult, clinically presenting as otosclerosis until HR CT T-Bone was performed showing bilateral both oval and round window atresia. This is an extremely rare case report  with uneA 30-year-old female was referred for hearing loss. She presented with long-standing bilateral hearing loss. On further enquiry, the patient mentioned of having hearing loss since childhood and has been regularly using hearing-aids. She did not have any significant history of ear infections or ear trauma. She denied any significant past medical, surgical or family history. Clinical assessment shows bilateral normal ear canals, both sides tympanic membranes were within normal limits.Hearing assessment performed in our department showed a conductive hearing loss in both ears. Bone conduction (BC) in both ears almost normal with a dip at 2 KHz frequency. Air conduction (AC) and air-bone gap was abnormal. There was a large air-bone gap of 60 dB (AC 88 dB and BC 28 dB) in the right ear while 62 dB (AC 92 dB and BC 30 dB) in the left ear . Speech Absence of round windows , arrows Absence of oval window  and kissing carotid canals  imaging mainly to confirm otosclerosis. CT showed the following findings on both the right and left temporal bones:The patient has normal speech development while currently her speech reception thresholds (SRT) are about 90 dB which is classified as profound hearing loss, this fact explains the progressive nature of this condition. Patient opted for hearing aids. Currently the patient is rehabilitated with high power hearing aids and coping well due to well preserved cochlea.We presented a rare adult case of bilateral oval and round window atresia presenting clinically as a case suggestive of otosclerosis. The case underscores the utility of HR CT T-Bone as a crucial preoperative aid in identification of atretic oval window as well as the rarer coexisting finding of round window atresia. This case will fall under Class 4 congenital middle ear anomalies.A classification system was developed by Teunissen and Cremers  to analyth–7th-week of development. The most important structure in this relationship is the facial nerve. Facial nerve along with lenticular process of the incus and stapes super-structure develop from the 2nd branchial arch. However, it is the contact of stapes which will incite the development of the oval window, which is derived from the otic capsule. Two theories have been proposed to explain OWA [The embryologic development of the oval window is closely related to the development of the second branchial arch structures in about 5lain OWA , 14: (a)lain OWA . The winlain OWA  includinPatients with OWA typically present at a younger age (unlike our case) with moderate to severe conductive hearing loss. The differential diagnosis can be broad mainly into middle ear acquired and congenital abnormalities and possibly inner ear anomalies. As the sound wave energy moves the ossicles-stapes footplate at the oval window, the round window membrane moves in an opposite phase to the movements of the oval window dissipating the sound energy. This mechanism allows the incompressible fluid in the cochlea to move causing movement of the basilar membrane which stimulates the inner ear hair cells that forms the basis of hearing. Bone conduction hearing involves direct stimulation of the cochlea which is housed firmly in the temporal bone . IsolateSimultaneous fixation of the round and the oval window leads to cancellation of their differential movements leading to a high degree of conductive hearing loss.The HR CT T-Bone is the modality of choice to diagnose OWA and RWA as well as an indispensable preoperative tool. CT will show absence of the oval shaped or rounded shaped niches on either axial, coronal or Pöschl view. Instead, there is obliteration of these windows by thick plates of the otic capsule.Axial images need to be assessed at three  levels of interest: (a) Round window level : showingIn cases of normal CT imaging, congenital stapes fixation (CSF) and otosclerosis need to be included in the differential diagnosis of the middle ear causes of conductive hearing loss. CSF can be confused with OWA. Patients with CSF have normal stapes on CT however, without the development of the annular ligament causing footplate ankylosis. Grade 1  otosclerosis usually have subtle finding of the ante-fenestral lucency  and can Management options in such rare cases are essentially limited to hearing aids for rehabilitation. Given the progressive nature of the clinical condition, our patient will need regular adjustment of the hearing aids. She is a suitable candidate for bone-conduction hearing aids which work on the principle of directly stimulating the cochlea bypassing the conductive pathway. Surgery for bone-conducting hearing aids  can be contemplated in such cases. Surgical correction for OWS itself can be difficult, as there are few landmarks for the vestibule, and the exposed facial nerve is at risk for injury. Sterkers et al.  describeth nerve. Our case is an extremely rare congenital anomaly of bilateral oval and round window atresia unmasked on the HR CT. There are few management options and usually sufficed to optimization of the hearing aids.In summary, the HR CT T-Bone is an essential tool in patients with bilateral conductive hearing loss. Apparent normal scan warrants careful and critical multiplanar evaluation of the ossicular continuity and fixation, presence of the oval and round windows, otosclerotic lucencies, and associated positioning of the tympanic 7


Compared with NF155− CIDP, CXCL8/IL‐8 and IL‐13 were significantly higher, and IL‐1β, IL‐1ra, and IL‐6 were lower, in NF155+ CIDP. CXCL8/IL‐8, IL‐13, CCL11/eotaxin, CXCL10/IP‐10, CCL3/MIP‐1α, CCL4/MIP‐1β, and TNF‐α levels were positively correlated with markedly elevated CSF protein, while IL‐13, CCL11/eotaxin, and IL‐17 levels were positively correlated with increased CSF cell counts. IL‐13, CXCL8/IL‐8, CCL4/MIP‐1β, CCL3/MIP‐1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155− CIDP had significantly increased IFN‐γ compared with NIND, and exhibited positive correlations of IFN‐γ, CXCL10/IP‐10, and CXCL8/IL‐8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155− CIDP were separable, and that IL‐4, IL‐10, and IL‐13 were the three most significant discriminators.CSF CXCL8/IL‐8, IL‐13, TNF‐α, CCL11/eotaxin, CCL2/MCP‐1, and IFN‐γ were significantly higher, while IL‐1β, IL‐1ra, and G‐CSF were lower, in NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti‐NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155 Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune‐mediated disease involving the peripheral nerves. Both cell‐mediated and humoral immunity are thought to play pathogenic roles in CIDP.+ CIDP) demonstrates distinctive features, including younger age at onset, higher frequencies of drop foot, sensory ataxia, and tremor, marked prolongation of distal and F wave latency, extremely high cerebrospinal fluid (CSF) protein amounts, and marked hypertrophy of nerve roots on magnetic resonance neurography.+ CIDP patients lack inflammation and onion bulb formation, with only subperineurial edema and minimal paranodal demyelination.+ CIDP, but not for anti‐NF155 antibody‐negative CIDP (NF155− CIDP).Anti‐NF155 antibodies found in a fraction of CIDP patients mainly belong to the immunoglobulin G (IgG)4 subclass.In vivo, IgG4 is monovalent and bispecific because of half molecular exchange, and does not internalize target antigens.human leukocyte antigen (HLA) class II alleles with NF155+ CIDP was reported in a European series,+ CIDP to elucidate the mechanism.IgG4 cannot activate complement because it does not bind C1q.+ CIDP and 36 NF155− CIDP patients were enrolled in the present study. None of the NF155+ or NF155− CIDP patients had anti‐NF186 or anti‐CNTN1 antibodies in sera. Among these patients, 44 were thoroughly examined in the Department of Neurology at Kyushu University Hospital between 01 January 2001 and 31 May 2018, while the other patients were referred to our department for an anti‐NF155 antibody assay between 1 November 2014 and 31 March 2018. All CIDP patients fulfilled the definite electrodiagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society for the diagnosis of CIDP,+ CIDP patient who showed no evoked potentials on nerve conduction studies. Clinical features of 11 NF155+ CIDP patients and biopsied sural nerve pathologies of 3 NF155+ CIDP patients showing subperineurial edema without inflammatory cell infiltrates were previously reported elsewhere.+ CIDP and 23 NF155− CIDP patients had received no treatment at the time of lumbar puncture (LP). Furthermore, two or more CSF samples at different time points were available in nine NF155+ CIDP patients. For controls, 28 other non‐inflammatory neurological disease (NIND) patients were enrolled, including 12 with amyotrophic lateral sclerosis, five with spondylosis, four with normal pressure hydrocephalus, three with spinocerebellar ataxia, and one each with metabolic neuropathy, hyperthyroidism, psychosomatic disorder, or cerebral venous malformations. The research protocols for the study were approved by the Kyushu University Ethics Committee. An opt‐out recruitment method was adopted.Thirty‐five consecutive IgG4 NF155+ and NF155− CIDP patients (Table g) at 4°C for 5 min, and the supernatants were stored at −80°C until analysis.CSF samples were obtained by non‐traumatic LP. None of the subjects for CSF analysis had any ongoing recent infection at the time of LP. The periods (disease durations) from onset of symptoms to CSF sample collection were comparable between NF155IgG and IgG4 anti‐NF155 antibodies as well as anti‐NF186 and anti‐CNTN1 antibodies in sera were measured by flow cytometry using human embryonic kidney 293 cell lines stably expressing human NF155, NF186, or CNTN1 as described previously.The concentrations of the following 28 cytokines/chemokines/growth factors Table  in the l+ CIDP, NF155− CIDP, and NIND patients. If the P < 0.05, Fisher’s exact probability test was used for comparisons between any two groups, followed by Bonferroni–Dunn’s correction. The Kruskal–Wallis test was performed to compare the levels of cytokines/chemokines/growth factors between three groups. If the P < 0.05, the Mann–Whitney U‐test was used for comparisons between any two groups, followed by Bonferroni–Dunn’s correction. The Wilcoxon signed‐rank test was performed to evaluate the longitudinal analysis according to treatment status. Spearman’s rank correlation coefficient was used for statistical analyses between cytokines/chemokines/growth factors and CSF protein amounts or cell counts. All of the above statistical analyses were performed with GraphPad Prism ver. 5.0 software . To separately analyze the correlations of CSF cytokines/chemokines in patients with NF155+ CIDP and NF155− CIDP, heatmaps were generated by the “gplots” package in R on the basis of Spearman’s rank correlation coefficient and cluster analysis. A canonical discriminant analysis (CDA) was performed by JMP Pro software .Cytokines/chemokines/growth factors with detection rates <30% were excluded from analysis as previously reported.+ CIDP, 36 NF155− CIDP, and 28 NIND patients are summarized in Table + CIDP patients than in NF155− CIDP patients (P = 0.0001). NF155+ CIDP patients showed a higher frequency of distal acquired demyelinating symmetric neuropathy (DADS) than NF155− CIDP patients (P = 0.0013), although more than half of NF155+ CIDP patients (57.1%) had typical CIDP. CSF protein amounts and cell counts were higher in NF155+ CIDP patients than in NF155− CIDP and NIND patients  .The demographic features of the 35 IgG4 NF155+ CIDP patients had higher levels of CXCL8/IL‐8 (P < 0.0001), IL‐13 (P < 0.0003), CCL11/eotaxin (P = 0.0210), CCL2/MCP‐1 (P = 0.0120), TNF‐α (P = 0.0042), and IFN‐γ (P < 0.0001) compared with NIND patients . IFN‐γ levels were also increased in NF155− CIDP patients compared with NIND patients (P = 0.0024). By contrast, NF155+ CIDP patients had lower levels of IL‐1β and IL‐1ra than NF155− CIDP and NIND patients . NF155+ CIDP patients had lower G‐CSF levels than NIND patients (P < 0.0001) and lower IL‐6 levels than NF155− CIDP patients (P = 0.0291). IL‐1ra and IL‐4 levels were lower in NF155− CIDP patients than in NIND patients . Even when only the pretreatment samples were evaluated, similar results were found , although CXCL8/IL‐8 levels tended toward a positive correlation with the scores   . Levels of IL‐13, CCL11/eotaxin, and IL‐17 also demonstrated positive correlations with CSF cell counts in NF155+ CIDP   , while the CXCL10/IP‐10, CXCL8/IL‐8, and IL‐1β levels did not differ between NF155− CIDP and NIND. Even when only the pretreatment samples were used, similar results were obtained  . Five patients    Fig. A. In NF142) Fig. B.+ CIDP showed three major clusters  or higher IL‐1β levels and those with lower than median IL‐1β levels. As a result, we found that the frequencies of typical CIDP and CSF protein levels were significantly higher in the low IL‐1β group than in the high IL‐1β group   Table . Sex rat+ CIDP were marked elevations of Th2‐ and Th1‐related cytokines. By contrast, NF155− CIDP showed a significant increase in IFN‐γ only and positive correlations of IFN‐γ and CXCL10/IP‐10 (chemokine downstream of IFN‐γ) with CSF protein amounts, suggesting a Th1 shift. Cluster analyses further supported distinct cytokine profiles between NF155+ and NF155− CIDP. Upregulation of cluster 3 cytokines, including IL‐13, CCL11/eotaxin, CCL2/MCP‐1, CCL3/MIP‐1α, CCL4/MIP‐1β, CXCL8/IL‐8, and CXCL10/IP‐10, was characteristic of NF155+ CIDP. Thus, we consider that co‐upregulation of Th2 and Th1 cytokines is a unique feature of NF155+ CIDP. An intrathecal Th1 shift has been proposed in CIDP, based on elevated levels of Th1‐related cytokines including IL‐12 and CXCL10/IP10 together with increased IFN‐γ+IL‐4−CD4+ T (Th1) cell percentages in CSF cells,+ CIDP comprises only a minority of total CIDP, the cytokine profile of total CIDP patients may have not reflected Th2 cytokine upregulation in NF155+ CIDP patients in previous studies.In this study, the characteristic features of IgG4 NF155+ and NF155− CIDP, suggesting a key role for these Th2 cytokines in NF155+ CIDP. Furthermore, the positive correlations of Th2 cytokines (IL‐13 and CCL11/eotaxin) with CSF cell counts and protein amounts and reduction of IL‐13 levels during longitudinal follow‐up after immunotherapy in NF155+ CIDP suggested the involvement of Th2 cells in spinal root inflammation, in addition to the induction of IgG4 autoantibodies. In Th2 inflammation, IL‐13 is a major effector cytokine, while CCL11/eotaxin exhibits potent chemotactic activity.IgG4 usually arises after chronic exposure to antigenic stimuli, and its physiological role is to compete with IgE and block its pathogenic effects in allergic responses.+ CIDP. The tendency toward positive correlations of CCL3/MIP‐1α and CXCL8/IL‐8 with Hughes functional grade scores may support an involvement of these chemokines in nerve damage, although further prospective evaluation of neurological impairment is required to confirm the correlations between CSF cytokine levels and disability. CXCL8/IL‐8 is secreted by a variety of cells including blood monocytes, fibroblasts, endothelial cells, and epithelial cells upon stimulation by various cytokines, leading to 10–100‐fold upregulation of CXCL8/IL‐8 expression.+ CIDP patients compared with NIND patients, also suggesting the potential involvement of Th1 cells. Because we found a small but significant increase in CSF cells in pretreated NF155+ CIDP patients, a more detailed analysis of CSF cytology, including helper T cells and eosinophils, is required to elucidate the effector mechanism of root inflammation.The decreases in CXCL8/IL‐8, CCL2/MCP‐1, CCL3/MIP‐1α, and CCL4/MIP‐1β, as downstream chemokines stimulated by IL‐13,+ CIDP patients compared with NF155− CIDP and NIND patients. Th2 cytokines such as IL‐13 were reported to decrease IL‐1β production,+ CIDP. Macrophage‐mediated demyelination, which is often seen in biopsied sural nerves of NF155− CIDP patients,+ CIDP patients.+ CIDP may be related to the absence of macrophage‐mediated demyelination. Even in NF155− CIDP patients, the low IL‐β subgroup showed higher frequencies of typical CIDP (nearly 90%) and higher CSF protein levels than the high IL‐β subgroup. Thus, in the low IL‐β subgroup preferentially presenting typical CIDP, a mechanism other than macrophage‐mediated demyelination could be operative. By contrast, a macrophage‐mediated mechanism may be operative in the high IL‐β subgroup. Although a decrease in IL‐1ra was common in both NF155+ and NF155− CIDP, the decrease was most marked in NF155+ CIDP. IL‐1ra is a representative anti‐inflammatory cytokine,+ CIDP patients may also contribute to severe spinal root inflammation.IL‐1β and IL‐1ra were significantly decreased in NF155+ CIDP patients including three biopsied cases and showed significant positive correlations with CSF protein levels in our study, these cytokines/chemokines and the immunocytes producing them may be directly or indirectly involved in BNB disruption.Biopsied sural nerves showed marked subperineurial edema, suggesting disruption of the blood–nerve barrier (BNB), although no onion bulb formation was observed.+ CIDP to IVIg has repeatedly been reported by us and others.+ CIDP may be explained by the lack of complement‐mediated inflammatory cascade and macrophage‐mediated demyelination in NF155+ CIDP, as shown by pathological studies of biopsied sural nerves.+ CIDP was recently reported in a small case series.+ CIDP. Indeed, combined immunotherapies, but not IVIg alone, decreased the concentrations of proinflammatory cytokines/chemokines, such as CXCL8/IL‐8, IL‐13, CCL3/MIP‐1α, and CCL4/MIP‐1β in CSF together with clinical improvement in our preliminary follow‐up study, suggesting that downregulation of intrathecal proinflammatory cytokines/chemokines is critical.Poor responsiveness of NF155+ CIDP is a rare disease, the present cases were collected from all over Japan. Thus, data and sample collection may not be uniform among the participating institutions, and only post‐treatment samples were available in some cases. Nevertheless, IgG4 NF155+ CIDP patients demonstrated relatively similar study results, and thus our preliminary CSF findings provide insights into its mechanism.This study had some limitations. First, we did not measure anti‐CASPR1 antibodies in our patients. However, because only one CIDP case with anti‐CASPR1 antibodies has been reported in the literature,HO, XZ, and JK designed and conceptualized the study, collected the data, analyzed the data, and drafted the manuscript. RY, YN, and TM collected data, analyzed the data, and drafted the manuscript. TF, AK, NM, KK, TM, YA, MK, SK, NI contributed to data collection, fidelity checking, data cleaning, and data interpretation.HO received a grant from JSPS KAKENHI (Grant No. 18K15454) and received honoraria from Japan Blood Products Organization and CSL Behring. XZ received financial support from the China Scholarship Council. RY received a grant from JSPS KAKENHI (Grant No. 16K09694). MK received honoraria from Teijin, Nihon Pharmaceutical and Japan Blood Products Organization. SK received grants from Ministry of Health, Labour and Welfare of Japan, the Japan Agency for Medical Research and Development (AMED) and Ministry of Education, Culture, Sports, Science and Technology of Japan, and received consultant fees, speaking fees and/or honoraria from Teijin, Japan Blood Product Organization and Nihon Pharmaceutical. YN received a grant and salary from Mitsubishi Tanabe Pharma, Bayer Yakuhin, Ltd., and Japan Blood Products Organization. TM received speaker honoraria payments from Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Company, and Biogen Japan. NI is supported by a grant from JSPS KAKENHI (Grant No. 18K07529), and received grant support from Mitsubishi Tanabe Pharma, Osoegawa Neurology Clinic, Bayer Yakuhin, Ltd., and Japan Blood Products Organization. JK is supported by grants from JSPS KAKENHI (Grant No. 16H02657), Health and Labour Sciences Research Grants on Intractable Diseases (H29‐Nanchitou (Nan)‐Ippan‐043), and grants from the Japan Agency for Medical Research and Development (AMED) under Grant Number JP17ek0109115 and JP18ek0109376, and received consultant fees, speaking fees and/or honoraria from Novartis Pharma, Mitsubishi Tanabe Pharma, Boehringer Ingelheim, Teijin Pharma, Takeda Pharmaceutical Company, Otsuka Pharmaceutical, Astellas Pharma, Pfizer Japan, and Eisai. TF, AM, NM, KK, TM and YA report no disclosures.Table S1. Detection rates of cytokines/chemokines/growth factors in CSF.Table S2. Comparisons of clinical and laboratory findings between anti‐NF155 antibody‐negative CIDP patients with high and low IL‐1β levels.Figure S1. CSF protein amounts, cell counts, and cytokine/chemokine/growth factor levels in untreated patients.Figure S2. Correlations of cytokine/chemokine levels with clinical severity and CSF protein amounts and cell counts in untreated patients.Figure S3. Comparisons of CSF cytokine/chemokine levels between untreated and treated patients.Click here for additional data file.


Tonic‐clonic seizures (TCS) lead to metabolic stress and changes in related blood markers. Such markers may indicate harmful conditions but can also help to identify TCS as a cause of transient loss of consciousness. In this study, we hypothesized that the alterations of circulating markers of metabolic stress depend on the clinical features of TCS.Ninety‐one adults undergoing video‐EEG monitoring participated in this prospective study. Electrolytes, renal parameters, creatine kinase (CK), prolactin (PRL), lactate, ammonia, glucose, and other parameters were measured at inclusion and different time points after TCS.A total of 39 TCS were recorded in 32 patients . Shortly after TCS, mean lactate, ammonia, and PRL levels were significantly increased 8.7‐fold, 2.6‐fold, and 5.1‐fold, respectively, with levels of more than twofold above the upper limits of the normal (ULN) in 90%, 71%, and 70% of the TCS and returned to baseline levels within 2 hours. Only postictal lactate levels were significantly correlated with the total duration of the tonic‐clonic phase. In contrast, CK elevations above the ULN were found in three TCS (~10%) only with a peak after 48 hours. Immediately after the TCS, hyperphosphatemia occurred in one third of the patients, whereas hypophosphatemia was observed in one third 2 hours later. TCS led to subtle but significant alterations of other electrolytes, creatinine, and uric acid, whereas glucose levels were moderately increased.Lactate is a robust metabolic marker of TCS with elevations found in ~90% of cases within 30 minutes after seizure termination, whereas ammonia rises in ~ 70%, similarly to PRL. Phosphate levels show an early increase and a decrease 2 hours after TCS in a third of patients. CK elevations are rare after video‐EEG‐documented TCS, challenging its value as a diagnostic marker. The occurrence and time course of metabolic markers after video‐EEG‐documented TCS were investigatedElevations of lactate were found in ~90% of TCS, ammonia and prolactin in ~70%, and CK in ~10%Metabolic stress markers, especially lactate, may be useful and complimentary to CK when assessing episodes with transient loss of consciousness due to TCS1Tonic‐clonic seizures (TCS), that is, generalized onset tonic‐clonic seizures (GTCS) and focal to bilateral tonic‐clonic seizures (FBTCS),Previous studies often investigated circulating blood markers with the goal to distinguish different causes of episodes of transient loss of consciousness (TLOC). Prolactin (PRL) and creatine kinase (CK) are the most widely used blood markers for purposes of differential diagnosis, with a specificity above 90%, but a lower sensitivity.In the present study, we particularly aimed at the investigation of metabolic consequences and pathophysiological aspects in the aftermaths of TCS. We hypothesized that the occurrence, extent, and time course of abnormally altered metabolic markers depend on the features of prior TCS. Therefore, we have prospectively investigated various blood biomarkers at different time points following documented TCS during video‐EEG monitoring.2Adult patients aged 18 years or older undergoing video‐EEG monitoring in the Department of Epileptology at the University Hospital Bonn for noninvasive presurgical evaluation or syndrome diagnosis and who had a history of previous TCS were asked to participate in this prospective clinical study. The study was approved by the local medical ethics committee (Ethikkommission der Medizinischen Fakultät der Rheinischen Friedrich‐Wilhelms‐Universität Bonn). Only patients who gave informed consent were participated in the study. We did not include patients with a TCS in the week before admission to the video‐EEG monitoring unit.The standard diagnostic procedure comprised cerebral 3 Tesla magnetic resonance imaging, neuropsychological testing, and continuous video‐EEG monitoring using noninvasive scalp EEG  or, in some cases invasive EEG  recordings (Micromed System). The clinical features of TCS  as well as the presence and duration of postictal generalized EEG suppression (PGES) were analyzed blinded to the results of the blood samples.Blood samples were collected at baseline  and at various time points after the TCS .® by Sarstedt®). Lithium‐heparin samples for ammonia were cooled at 4°C. Electrolytes were measured using indirect potentiometry. Creatinine, uric acid, blood urea nitrogen (BUN), glucose, lactate, and ammonia were measured by applying VIS photometry. Cystatin C was measured by immunnephelometry. All measurements were conducted on a Dimension Vista® System by Siemens Healthcare Diagnostics®. The laboratory measurements were performed at the Institute of Clinical Chemistry at the University Hospital Bonn which is located about 1 km from the Department of Epileptology. Because the mean time from blood sampling to arrival in the laboratory was 64 ± 18 minutes, the sensitive lithium‐heparin samples were cooled immediately after they were drawn. The baseline was drawn when video‐EEG monitoring started after admission 3 ± 2.2 days before the seizure. The first postictal blood sample was drawn 10 ± 8 minutes after the TCS, the second 2 ± 0.2 hours, the third one 6 ± 0.66 hours, the fourth one 23.8 ± 1.56 hours, and final one 46.7 ± 3.7 hours. An overview is provided in Table We used two serum samples, two EDTA samples, one lithium‐heparin sample, and one sodium‐fluoride sample  were performed with IBM33.1Blood samples of a total of 39 TCS in 32 patients were analyzed in this study. These included 6 GTCS from 6 patients and  33 FBTCS from 26 patients. The data on postictal cardiac blood markers in these patients were recently reported.3.2P = .062; Figure P < .0001, Figure At the group level, CK showed a trend to rise after 6 hours with mean CK elevations by 47% 48 hours after the TCS . For details, see Table P = .57) nor the time until the patients mental status recovered correlated with ammonia levels (P = .54).Lactate dramatically rose by 8.7‐fold immediately after TCS and decreased toward baseline levels after 2 hours . Most creatinine values remained in the normal range, but 8 (21.1%) patients fulfilled the criteria for "risk of renal injury" and 1 (2.6%) patient for "acute kidney injury," as described by the acute kidney injury network criteria (AKIN).Mean glucose levels were slightly increased by 14% shortly after TCS, mostly within the normal or mildly elevated range. The renal retention markers creatinine and cystatin c showed a transient but significant rise immediately after TCS  and elevated ammonia levels above the ULN (but below twice the ULN) were found in about 30% of the patients at baseline or more than 24 hours after the seizures. The blood samples were taken during daily clinical practice, so that the time of sample collection and the seizure was variable to some extent. However, analysis of variable collection and transport times did not reveal major effects on any blood marker apart of the trends in ammonia levels, strengthening the validity and conclusions of our study. Importantly, our study was not designed to assess the actual value of the investigated blood markers in the differential diagnosis of TLOC. Hence, we did not include other patient groups with psychogenic nonepileptic events, syncope, or physiological exercise.Investigations of laboratory markers are subject to inherent limitations, for example, due to circumstances of blood collection, transport, and storage of the samples. For instance, the ammonia levels showed a trend to correlate with the transport time to the laboratory . Since ammonia also quickly returns to baseline levels, it does not provide a wider diagnostic time window, which limits its use in the daily clinical practice.0%. SinceSerum lactate levels were elevated in ~90% of seizures and returned to baseline within 2 hours, indicating that shorter time windows are needed to use lactate as reliable biomarker of TCS. Orringer and colleagues showed a lactate reduction of 50% within the first postictal hour with a majority of patients still having elevated lactate at one hour.Recently, results of a retrospective ER study suggested hypophosphatemia as a potential marker of TCS in the differential diagnosis of TLOC4.5The most likely pathways leading to SUDEP are postictal respiratory depression, postictal arrhythmias, or a combination of both.R. Surges has received speaker fees or honorary for serving on the advisory board from Bial, Desitin, Eisai, LivaNova, Novartis, and UCB Pharma. CE Elger has received speaker fees from Eisai, Novartis, and UCB Pharma. RD Nass has received speaker fees from Eisai. The authors declare that there is no conflict of interest regarding the publication of this paper. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Click here for additional data file. Click here for additional data file. Click here for additional data file.