Agreement between methods was assessed by Bland–Altman analyses and each equation was assessed for accuracy by calculating the percentage of individuals predicted within ± 10 % of measured RMR. Slopes and intercepts of bias as a function of average RMR (mean of predicted and measured RMR) were calculated by regression analyses. Predictors of equation bias were investigated using univariate and multivariate linear regression. At group level, bias (the difference between predicted and measured RMR) was not different from zero only for Mifflin–St Jeor (0 (sd 153) kcal/d (0 (sd 640) kJ/d)) and Henry (8 (sd 163) kcal/d (33 (sd 682) kJ/d)) equations. Mifflin–St Jeor and Henry equations were most accurate at the individual level and predicted RMR within 10 % of measured RMR in 71 and 66 % of participants, respectively. For all equations, limits of agreement were wide, slopes of bias were negative, and intercepts of bias were positive and significantly (P < 0⋅05) different from zero. Increasing age, height and BMI were associated with underestimation of RMR, but collectively these variables explained only 15 % of the variance in estimation bias. Overall accuracy of equations for prediction of RMR is low at the individual level, particularly in women with low and high RMR. The Mifflin–St Jeor equation was the most accurate for this dataset, but prediction errors were still observed in about one-third of participants.Estimation of RMR using prediction equations is the basis for calculating energy requirements. In the present study, RMR was predicted by Harris–Benedict, Schofield, Henry, Mifflin–St Jeor and Owen equations and measured by indirect calorimetry in 125 healthy adult women of varying BMI (17–44 kg/m Despite known limitations, prediction equations offer a practical alternative to measuring RMR by indirect calorimetry since energy requirements can be calculated using routinely available measures such as weight, age, sex and height. Expense of indirect calorimetry equipment, requirement for trained personnel, and the time-consuming nature of RMR measurement prevent indirect calorimetry being routinely available in dietetic settings, though it is frequently used in research studies.Estimation of RMR using prediction equations is a fundamental part of clinical dietetic practice and is the basis for estimating daily energy requirements using the factorial method. FFM consists of multiple organs and tissues with varying metabolic rate. Despite comprising <6 % of total body weight, organs are the major drivers of RMR, with the brain, heart, kidneys and liver collectively accounting for 60–80 % and although skeletal muscle represents a greater proportion of FFM, its metabolic activity is lower,5. Since accurate measurement of FFM is not routinely available, RMR equations usually rely on body weight as the dominant predictor, and also consider age, sex and sometimes height. There are many factors influencing RMR and there is considerable individual variation even when adjusting for FFM, age and sex.RMR accounts for 60–70 % of total daily energy expenditure and fat-free mass (FFM) is the primary determinant of energy expended at rest. The equations of Schofield, Henry, Mifflin–St Jeor, Harris–Benedict and Owen,12 are all widely used. There have been several studies evaluating prediction equation accuracy over the years, including investigations in European–17 and US populations,18–20, but regular revalidation and updating of recommendations remain important due to changing demographics of modern populations, as well as changes in body composition. More specifically, in recent years the European Food Safety Authority recommended the Henry equation for predicting RMR in all European Union countries, and it is recommended for use by UK dietitians, yet its predictive accuracy still needs to be established within the current population, particularly within studies across BMI categories. The purpose of the present study was to evaluate the validity of several RMR prediction equations, by comparing RMR measured by indirect calorimetry with RMR predicted by equation, in a group of healthy women with varying BMI.Numerous published prediction equations are available to estimate RMR, with 248 different formulas being identified within the literature–29. Participants  were sedentary, non-smokers, not pregnant, not taking medication which could affect RMR and had maintained stable body weight for at least 2 months prior to study enrolment. They were asked to avoid exercise in the 24 h prior to testing. Only the baseline RMR values measured prior to participation in the interventions were considered for the present study. Four studies were approved by the College of Medical, Veterinary and Life Sciences of the University of Glasgow Ethics Committee–28, and the other by the West of Scotland NHS Ethics Committee. Studies were conducted in accordance with the Declaration of Helsinki, and all participants recruited provided written informed consent.The present study is a secondary analysis of data collected from healthy adult women across energy balance research studies performed in the Human Nutrition Unit at the University of Glasgow between 2008 and 20172) and carbon dioxide production (V˙CO2) every 30 s for the duration of the 20-min test period with participants lying in a supine position whilst fully awake. To ensure that steady-state conditions were obtained, data from the first 5 min were discarded and V˙O2 and V˙CO2 measured during the following 15-min period were required to have a CV ≤10 % to be accepted for the calculation of RMR, which was achieved using the following indirect calorimetry equations, with reference to Frayn:Participants reported to the metabolic investigation unit following a 12 h overnight fast. Height was measured to the nearest 0⋅1 cm using a stadiometer (Seca). Body weight was determined by bioelectrical impedance scales , and values obtained were incorporated within prediction equations for estimation of RMR. Participants rested for 20 min prior to RMR measurement, which took place in a thermoneutral environment between 07.00 and 10.00 hours to ensure that fasting periods were not extended for too long during daytime hours. Indirect calorimetry was conducted using a calibrated open-circuit ventilated hood system, Oxycon Pro (Jaeger GmbH) or Deltatrac Metabolic Monitor (Datex Engstrom). RMR was obtained in sixty-six subjects using Deltatrac and fifty-nine subjects using Oxycon Pro. Both devices were calibrated prior to the measurements and alcohol-burning validation tests were conducted weekly on Oxycon Pro during testing periods. The measurements involved recording the rate of oxygen consumption /0⋅57Rate of fat oxidation (g/min) = /0⋅3Rate of carbohydrate oxidation (g/min) =  =  + RMR  = RMR  × 1440 (min)Of the many prediction equations that have been published in the literature, those of Harris–Benedict, Henry, Mifflin–St Jeor, Owen and Schofield are amongst the most widely used, either currently or in the recent past. Therefore, these equations were used in the present study to predict RMR and compared against measured RMR by indirect calorimetry. The RMR equations, and the populations from which they were derived are described in t test. The 95 % limits of agreement were calculated as the mean of the two values, ± 1⋅96 sd. Root-mean-square error was calculated to show the sample standard deviation of differences between predicted and measured RMR. Agreement between predicted and measured values was assessed by Bland–Altman analyses. Slopes and intercepts of bias as a function of average RMR (mean of predicted and measured RMR) were calculated by regression analyses. At the individual level, RMR prediction was considered accurate if it was within ± 10 % of measured RMR, which is a standard approach for investigating accuracy of RMR prediction equations and in line with recommendations for conducting this type of research. When predicted RMR was <90 and >110 % of measured RMR, it was considered as an underestimation and an overestimation, respectively. Accuracy was calculated for the whole group and separately by BMI category: underweight, healthy weight, overweight and obesity. Predictors  of the bias were investigated using univariate and multivariate regression analysis. Results were considered statistically significant if P < 0⋅05. Data were analysed in Minitab 17 and MedCalc 17.2.Accuracy of the five prediction equations was assessed at both group and individual levels. Results are presented as mean values and standard deviations. At group level, bias (predicted – measured RMR) was assessed by one-sample sd 8⋅8) years (range 20–57 years), body weight 70⋅8 (range 41⋅0–120⋅9) kg and BMI 26⋅1(sd 6⋅6) kg/m2 (range 16⋅8–44⋅4 kg/m2). Combined overweight and obesity prevalence was 58 %.Descriptive data of the study participants are shown in Comparison of overall performance of the prediction equations is summarised in For each equation, the percentage of accurate RMR predictions was assessed for each BMI category separately and results are presented in R2 15 %). Thus, at least 85 % of the estimation bias was explained by other factors. In additional regression analyses, we found no difference in absolute and percentage prediction error between the Oxycon Pro and Deltatrac metabolic carts.Different methods for determining RMR are not likely to agree exactly, but whether differences in accuracy are likely to affect patient management is an important clinical consideration. In the present study conducted on healthy females with varying BMI, there was considerable room for improvement in the performance of each of the prediction equations at individual-level assessment, though good agreement between measured and predicted RMR was observed at group level using the Mifflin–St Jeor and Henry equations. Although our data suggest that the most accurate prediction of RMR can be expected from using the Mifflin–St Jeor equation, we note that in nearly one-third of participants predicted RMR was outwith 10 % of measured RMR. The wide limits of agreement and slopes and intercepts being different from zero in the regression from Bland–Altman analysis for Mifflin–St Jeor, and indeed for all equations, suggest that there was an asymmetrical relationship in the bias and that RMR prediction at individual level should be interpreted with caution and considered only as a starting point for planning dietary interventions. The findings of the present study also imply that in healthy women at the extremes of BMI (underweight/obesity), and therefore with relatively low or high measured RMR, the validity of prediction equations in general is particularly poor, with the one exception being when applying the Mifflin–St Jeor equation to women with obesity. This is of concern given that underweight and obesity are clinical situations where equations are frequently used in practice. Despite relatively poor accuracy at the individual level, the equations investigated in the present study can be expected to operate well at population level to assist governments in planning and monitoring nutrition programmes.,33. These findings imply that the Mifflin–St Jeor equation should not necessarily be restricted to women with obesity, since it was also as accurate as other equations for estimating RMR in underweight, healthy-weight and overweight women. It is perhaps not surprising that the Mifflin–St Jeor equation provided the most consistent accuracy across BMI categories since it was developed in a large sample of individuals with healthy weight, overweight and obesity. Although predicted RMR values do in part reflect the characteristics of the population they were derived from, and thus can lack specificity when applied to individuals different from the original population,35, our data suggest that population-specific factors play a relatively minor role in influencing prediction of RMR, and the Mifflin–St Jeor equation has demonstrated the best accuracy in several other studies using differing populations,20,36. The ± 10 % ‘rule’ for defining prediction accuracy is a pragmatic criterion which facilitates comparison between studies and is clinically relevant since chronic energy imbalances are likely to contribute to cases of malnutrition, or, conversely, to overweight and obesity. Due to the large number of confounding factors that exist, it is difficult to show clear links between adverse clinical outcomes and the selected cut-offs for under- and overfeeding (<90 or >110 % of energy requirements); however, respiratory and liver dysfunction, poor wound healing and infections, azotemia and renal failure, and total complication rate have been associated with under- and/or overfeeding in critically ill patients–42. Furthermore, prescription of higher (or lower) than intended energy deficits to people seeking to correct or ameliorate overweight and obesity-related complications are likely to result in poorer adherence and weight-loss outcomes.In this dataset, the Mifflin–St Jeor equation performed best in women with healthy weight, overweight and obesity, predicting RMR accurately in 73, 76 and 80 % of the participants, respectively. Our findings that Mifflin–St Jeor is the most accurate prediction equation, especially for women with obesity, is in line with evidence from systematic reviews which recommend the Mifflin–St Jeor equation for use in individuals with overweight and obesity, and also report a similar number of inaccurate predictions was influential in re-establishing the use of RMR rather than reported food consumption as the basis for estimating energy requirements, and was used to inform the development of dietary reference values for children and adults. The Schofield equations were widely used by dietitians in clinical practice until relatively recently, but key advisory groups now recommend using the Henry equation, as the older Schofield equation overestimates RMR–23. The newer Henry equation addressed some of the limitations of the Schofield equation by including data collected on greater numbers of people from tropical climates, and a large cohort of young, physically active Italian subjects were excluded who were found to have higher BMR per kg/body weight than other Caucasian groups. We found no difference between RMR measured by indirect calorimetry and predicted RMR using the Henry equation at group level and 66 % of predictions were within 10 % of measured RMR. Thus, the Henry equation predicts RMR more accurately than the Schofield, Harris–Benedict and Owen equations at group and individual levels, though overall the Mifflin–St Jeor equation is marginally more reliable than the Henry equation for prediction of RMR at the individual level. This is approximately agreeable with a study involving 239 US adults, which showed that the Henry equation predicted RMR accurately in 74 % of individuals, whilst the Mifflin–St Jeor equation provided accurate RMR predictions in 79 % of individuals; however, both equations performed poorer in a Dutch cohort.The work of Schofield and colleagues. This has implications for the lightest- and heaviest-weighing subjects in this sample, and therefore, is likely to affect those with low and high BMI. The number of underweight participants in this analysis was modest though prediction accuracy was low in underweight women for all equations, with the Harris–Benedict equation being particularly susceptible to error. Systematic overestimation of RMR was found in women with low RMR and thus most likely in those with low BMI, which would suggest that overestimation rather than underestimation of RMR can expected in underweight women. Although our findings should be interpreted with caution given the small numbers of underweight subjects, a study containing a larger underweight population showed even poorer prediction accuracy than in our dataset. This might be because fewer underweight individuals participated in the original development and validation of equations, or that anthropometric measurements and demographic characteristics are unable to predict the majority of variance in RMR measurements in this group.In the present analysis, all equations except Schofield demonstrated a tendency to systematically over- or underestimate RMR in individuals with relatively higher or lower RMR, which is in line with findings reported elsewhere, sympathetic nervous system activity, circadian and menstrual rhythms, thyroid function, ethnicity and genetic factors,52. These factors are also unable to be factored into prediction equations, and this underlies their inaccuracy at the individual level for a proportion of individuals.In the regression analyses, very little of the prediction error was explained by age, height or BMI. This may partly be explained by factors not investigated within this analysis which influence RMR, including body temperature,49. However, it should be appreciated that this evaluation was conducted in healthy women and overgeneralising to other populations should be avoided. Predictions of RMR and energy requirements of individuals incur errors using all equations, so careful monitoring of body-weight changes remains paramount to assess whether nutritional targets are being met. It has been reported that validity of RMR prediction equations can be influenced by the accuracy of the reference method , with some metabolic carts having insufficient accuracy and that RMR is not necessarily concordant between instruments. However, in the present study weekly alcohol burning tests, conducted on Oxycon Pro produced CV of ≤1⋅7 and Deltatrac is considered to exhibit the greatest accuracy of all metabolic carts. Furthermore, in regression analyses, accounting for the confounding effect of BMI and age, no difference was found in absolute or percentage prediction error between the two devices for obtaining RMR.A strength of the present study was that we had data available for large numbers of females across BMI categories, meaning we generalise findings to women though we make no assumptions regarding accuracy of these equations in males. Although all prediction equations have been derived from healthy populations, they are commonly applied in hospital settings where energy requirements of patients are altered by physiological stress imposed by disease state and factors such as surgery, infection, inflammation and changes in body composition. A further alternative might be to develop BMI-specific prediction equations, which were superior when compared with generic equations in a large German population, particularly in underweight individuals, with no additional benefit of including FFM in equation design. Incorporating additional, simple anthropometric variables  within prediction equations may also improve accuracy. More affordable hand-held calorimeters are becoming available and may provide a more accurate alternative to prediction equations, though others have reported that these machines have limited utility and traditional metabolic carts should remain the preferred method for estimating nutritional requirements where feasible.There are some limitations to this analysis. For reasons of feasibility and generalisability, we evaluated RMR prediction equations which used only routine anthropometric variables. Aggregate predictions of RMR, incorporating numerous equations, have been shown to significantly improve accuracy and reduce potential for selecting the worst-performing equation for an individualIn conclusion, the equation of Mifflin–St Jeor is the most reliable for predicting RMR, closely followed by the Henry equation, though clinically relevant errors can still be expected in about one-third of individuals, most commonly in individuals with obesity, or who are underweight. Although there is room for improvement, prediction equations do continue to provide convenient estimations of RMR and a starting point for estimating daily energy requirements and developing dietary interventions.


Few studies have examined factors associated with the timing of identification of hearing loss within a cohort of infants identified as deaf or hard of hearing (DHH) and what factors are associated with delayed identification. Minnesota Early Hearing Detection and Intervention (EHDI) personnel studied deidentified data from 729 infants with confirmed congenital hearing loss  born in Minnesota during 2012–2016. Differences in likelihood of delayed identification of congenital hearing loss (defined as not passing newborn hearing screening and age >3 months at the time of identification as DHH) based on multiple variables were analyzed. Overall, 222 (30.4%) infants identified as DHH had delayed identification. Multivariate regression showed that infants identified as DHH were significantly more likely to have delayed identification if they had 1) low birthweight, 2) public insurance, 3) a residence outside the metropolitan area, 4) a mother with a lower level of education, 5) a mother aged <25 years, or 6) a mother who was Hmong. Despite achievements of EHDI programs, disparities exist in timely identification of hearing loss. Using this information to develop public health initiatives that target certain populations could improve timely identification, reduce the risk for language delay, and enhance outcomes in children who are DHH.The institution of EHDI programs has substantially reduced the average age of identification of infants who are DHH  EHDI information system (EHDI-IS), which contains demographic, screening, diagnostic, and intervention data on children who have been identified as DHH. Data in EHDI-IS are obtained primarily from birth care providers and facilities, audiologists, public health nurses, and birth certificates via the Minnesota Office of Vital Records. The study population included 729 infants born in Minnesota during 2012–2016 who did not pass newborn hearing screening and were identified as DHH. Independent variables included location of residence and birth facility; maternal race/ethnicity, country of origin, age, and education level at the time of birth; primary language used in the home; birthweight; and infant’s health insurance status. If multiple maternal race categories were indicated on the birth certificate, the bridged race category derived by the Minnesota Office of Vital Records using the National Center for Health Statistics bridging methodology was used  were estimated for each independent variable using a modified Poisson regression model  had delayed identification of hearing loss . BivariaAfter adjusting for other variables, the characteristic most strongly associated with delayed identification of hearing loss was birth weight, specifically very low birthweight  or moderately low birth weight . Overall, 82% of infants born with VLBW and identified as DHH received the diagnosis at age >3 months. Infants born with VLBW were more than twice as likely to have delayed identification, and infants born with MLBW also were significantly more likely to have delayed identification compared with infants born with normal birth weight ; MLBW APR = 1.4; 1.0–1.8) (Table).Maternal age and education also were significantly associated with delayed identification of hearing loss. Only 16% of infants born to a mother with a college degree were identified late, compared with 36% of infants born to a mother with some college and 40% born to a mother with a high school diploma or less. Infants born to mothers who did not have a college degree were more likely to be identified late . Approximately one half of infants born to a mother aged <25 years had delayed identification, and they were more likely to be identified late compared with infants whose mother was aged 25–34 years  . For theSocioeconomic factors are well documented determinants of health, and several socioeconomic indicators in this study were associated with delayed identification of infants who are born DHH. More work is needed to understand the barriers to audiologic follow-up for persons with lower socioeconomic status. Partnering with birth and primary care providers to improve messaging about the need for follow-up after newborn hearing screening and improvements in scheduling follow-up appointments for further testing at the time the infant does not pass the screening have both been identified as promising practices that might have a positive effect  is another public health initiative with the potential to improve outcomes.The Joint Committee on Infant Hearing guidelines for Early Hearing Detection and Intervention recommends that all infants who have not passed newborn hearing screening should have diagnostic audiologic testing to identify hearing loss by age 3 months.Significant delays in diagnosis of hearing loss among Minnesota infants identified as deaf or hard of hearing (DHH) were associated with low birth weight, lower maternal education, maternal age <25 years, maternal Hmong ethnicity, residence outside the metropolitan area, and public health insurance use.Using this information to develop public health initiatives that target certain populations could improve timely identification, reduce the risk for language delay, and enhance outcomes in children who are DHH.


Background and Aim: Cytomegalovirus (CMV) is the main cause of congenital infection in developed countries leading to deafness but the burden of sensorineural hearing loss (SNHL) in asymptomatic children remains incompletely characterized. Aim of this study was to evaluate the long-term audiological outcome in this group of patients.Methods: Consecutive neonates with congenital CMV infection were followed from 2002 to 2018. Patients were considered asymptomatic if free from any clinical and instrumental impairment at referral and underwent serial clinical exams, audiological evaluations and CMV-PCR determinations.Results: A cohort of 258 children was analyzed and the disease onset was asymptomatic in 125 (48%) infants. Among these, we studied 102 patients with a follow-up longer than 1 year and a median observation period of 2.8 years (range: 1–10.3 years). No patient developed a stable delayed SNHL but only 14 (14%) presented a variable hearing impairment, seven of which bilateral. The unstable SNHL was mild in 12 infants and moderate in two. Patients with fluctuating SNHL had significantly higher urine viral load (p 0.002) and more often positive viremia (p 0.015) than babies with stable normal hearing.Conclusions: CMV infected, asymptomatic neonates have a low risk of transient SNHL later in infancy. Positive viremia and high urine viral load at onset are significant risk factors for delayed fluctuating SNHL. These data are relevant for an appropriate follow up plan of these patients. Cytomegalovirus (CMV) is the most common cause of congenital infection  and one This is a prospective study conducted at the Perinatal Infection Unit of the University Federico II of Naples, a tertiary care hospital with a dedicated multidisciplinary team. Inborn neonates born from 2002 to 2018 or referred to the Unit for maternal CMV seroconversion were considered eligible. Congenital infection was defined as viral DNA detection in urine by polymerase chain reaction assay within the first 3 weeks of life. Viral DNA detection in the blood and in urine was performed using an automated QIAsimphony SP platform performing all steps of the purification procedure and preparation for CMV DNA amplification, in combination with the Artus CMV QS-RGQ Kit on Rotor-Gene® Q system, accordingly to the manufacturer's instructions. Infants with no proof of CMV infection or with other congenital infections were excluded from the study. Clinical and instrumental evaluations are described in Cranial ultrasonography (US) was performed by an experienced neonatologist, who was blinded to the clinical data, using the Philips HD11 ultrasound imaging platform with an 8.5–12.4 MHz transducers (Microconvex and Phased Array transducers). Abnormal US was defined as presence of intracranial calcifications, ventriculomegaly, pseudocysts, or cerebellar lesions. Isolated candlestick lentriculostriated vasculopathy without other abnormalities was not considered as a sign of symptomatic cCMV infection . Head CTEnrolled patients underwent serial standard audiological evaluations to detect SNHL within the 1st month of life, every 3–6 months until the age of 3 years and then every 6–12 months later on. Hearing function was evaluated by TEOAE (transitory evoked otoacoustic emissions) at birth and by automatic ABR (auditory brainstem response) within the 1st month of life. In case of negative results, a click ABR and, according to the age of patient, pure tone audiometry and other specific tests, such as DPOAE (distortion product otoacoustic emissions), tympanometry, etc. were performed. Before 2007 the early audiological assessment was carried out in the 1st month of life through click ABR and tympanometry. Patients were examined more frequently in case of hearing loss, as established by the audiologist. In order to describe SNHL, the poorer hearing ear criterion was adopted as the most accurate to describe cCMV related damage.monolateral if it was present in one ear, or bilateral if it was present in both ears. A delayed-onset hearing loss was defined when detected after ≥1 assessments with normal hearing. Progressive hearing loss was defined as a worsening of the auditory threshold with 10 dB or more in successive assessments. Stable hearing loss was defined when there was no change between the first detection of SNHL and the last assessment. Improvement of hearing loss was defined when hearing thresholds improved with 10 dB or more. A fluctuating hearing loss was defined as an improvement of at least 10 dB after a previous worsening or a worsening after a previous improvement between consecutive assessments. Since middle ear disorders can cause transient conductive hearing loss, we excluded assessments with tympanometry type B routinely performed.SNHL was defined as air conduction thresholds >20 decibels (dB), in conjunction with normal bone conduction threshold and normal middle-ear function. Hearing loss was classified using the BIAP criteria , as repo3), hearing impairment, and abnormal findings on central nervous system (CNS) imaging evaluation. US and MRI scan, and CT in past years , chorioretinitis, hepatosplenomegaly, petechiae, elevated serum transaminase levels, cholestasis, thrombocytopenia  approved this study (protocol number 274/16).T-test or the Mann-Whitney U-tests for numerical variables and the Chi square test, or the Fisher exact test if appropriate, for categorical factors. Times to event variables were analyzed using the Kaplan Meier methods and compared between groups using the log-rank test. Univariate Cox regression models were used to estimate Hazard Ratio (HR) with the corresponding 95% Confidence Intervals (95% C.I.). All test were 2-tailed and p < 0.05 were considered statistically significant.All data analyses were performed using the statistical platform R (R Core Team 2018). Numerical variables were described using mean ± standard deviation (SD) or median with range  while categorical variables were summarized using absolute frequencies and percentages. Between-groups differences were, accordingly, assessed by the unpaired Out of a total of 326 patients referred to our Unit, 258 received a diagnosis of cCMV infection and 125 (48%) were classified as asymptomatic. One hundred two babies had a follow up longer than 1 year and met the inclusion criteria . Their gThe overall incidence of SNHL at onset in symptomatic patients was 64%: 29 monolateral cases (22%) and 56 bilateral ones (42%). According to our definition of asymptomatic cCMV infection, we had no hearing loss at onset in this group.p = 0.105]) nor considering the CMV blood load (p = 0.16) or in viruria (p = 0.333). A lumbar puncture was part of the standard initial evaluation of the asymptomatic neonate until December 2010. The evaluation of cerebrospinal fluid (CSF) was available for 42 asymptomatic and 84 symptomatic. No virus was detected in the former group while 13 symptomatic infants (15%) had a positive CMV in the CSF (p = 0.005). In the asymptomatic group, time to blood viral clearance was 104 days  in blood and 1,437 days  in urine. At the last observation 51 patients (51%) had no virus detectable in urine. Viral clearance in symptomatic babies depends on the antiviral therapy and is not reported here.Comparing symptomatic and asymptomatic patients according to the viral presence at onset, we found no statistical difference in viremia . In fact, we excluded assessments showing middle ear disorders causing transient conductive hearing loss. No asymptomatic infant developed a stable delayed hearing loss and 88 patients (86%) presented a normal hearing function at all audiological assessments. Only 14 patients (14%) presented a fluctuating hearing impairment that was bilateral in seven babies. Their transient dysfunction was classified as mild in 12 children and moderate first degree in the other two  as shown in In our cohort of 102 cCMV infected, purely asymptomatic infants, no one developed a stable SNHL after a mean follow up period of 3.3 years, with a median of 2.8 years. The quality of the result is strengthened by the investigation of babies free from hearing impairment shortly after birth, with an homogeneous clinical and instrumental follow-up period that included scrupulous search for middle-ear problems so that hearing fluctuations could not be due to transient, CMV-unrelated causes . Our datOur results, however, do not confirm previous observations were delayed SNHL seemed to be a relatively frequent event. Among the possible explanations, the precise definition of an asymptomatic, cCMV infected neonate is, probably, the most relevant.In an earlier report by Fowler et al. , the defIn a recent multicenter study, Lanzieri et al. classified as asymptomatic  also patRecently, Faure-Bardon et al.  showed tUnfortunately, we were unable to replicate their observation since details on maternal seroconversion during gestation were available in too few cases to draw reliable conclusions.In our series, the presence of CMV in the blood and its urinary load did not discriminate between symptomatic and asymptomatic infants. In the latter group, however, these two variables were significantly associated with a non-severe and transient hearing impairment. Whether the viral burden is a reliable SNHL predictor in infants with isolated hearing impairment or with frank cCMV symptoms at onset is currently debated –26. We sWe acknowledge that a longer average duration of our follow up would have strengthened our results. However, it has to be underlined that 18% of our cohort has a follow-up longer than 5 years.In conclusion, cCMV infected infants free from clinical symptoms and SNHL within the 1st month of life carry a very low risk of delayed hearing impairment. Our cohort identifies a stage of the interaction between the virus and the human neonate where a prolonged follow up program seems unnecessary.serena.salome@unina.it.The datasets for this study will not be made publicly available because it is confidential patient data. Any requests to access the datasets should be directed to Serena Salomè, The study was conducted in accordance with Helsinki Declaration as revised in 2013. The protocol was approved by the Ethics Committee of the Azienda Federico II (protocol number 274/16 of 2016). Parents of participants provided their written informed consent to participate in this study.SS designed the study, analyzed data, interpreted results, and drafted the article. AG, PD, LC, and GC contributed to the revision of draft and interpretation of data. CC and EC were involved in the acquisition of data. RM and EM performed and revised audiological outcomes. GP performed the virological analysis. PD analyzed data. FR conceived the study and revised the article critically for important intellectual content. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


ObjectiveIn this study, we aimed to assess the incidence of hearing loss in the pediatric population through otoacoustic emission (OAE) and brainstem evoked response audiometry (BERA) and to analyze the possible etiological factors responsible for it.Material and methodsA retrospective observational study was conducted in the Otolaryngology (ENT) and Gynecology and Obstetrics Departments at the Jinnah Postgraduate Medical Centre and National Institute of Child Health in Karachi, Pakistan between July 2019 and October 2019. The convenient sampling technique was used to select the patients. The final sample size consisting of newborns and children was 108. Initially, screening procedures were undertaken for newborns to detect permanent or fluctuating, bilateral or unilateral, and sensory or conductive hearing loss, averaging 30-40 dB or more in the frequency region, which indicated potential issues related to speech recognition . The screening of newborns involved the use of non-invasive, objective physiologic measures that included OAEs and/or auditory brainstem response (ABR). The children with hearing impairment then underwent BERA; thereafter, further investigations were performed to confirm the defects found on BERA testing.ResultsOf the 108 cases, 96 had normal hearing on OAE screening, and 12 were found to have hearing loss on the OAE test. Further testing was carried out on BERA for 12 cases that had been detected to have hearing loss on OAE, and BERA showed normal hearing for five cases whereas seven were found to have hearing loss. Of the seven patients with hearing loss on the BERA test, five were diagnosed with cochlear deafness, and two had retrocochlear deafness.ConclusionOur present study concludes that in order to avoid any hearing problems in infants, OAE hearing screening and diagnostic BERA screening programs should be carried out in all the hospitals of Pakistan to assess newborn hearing at an early age. Hearing function plays a substantial role in the growth of intellect as well as language-related abilities in humans. The effects of primary diagnoses and recovery of newborns having an impairment or loss of hearing are understated . As the The prevalence of sensorineural loss of hearing is estimated to be roughly about one to three per 1,000 newborn babies ,6. AmongPrograms for the screening of hearing among newborns have been proven to be the best and the most desirable method in detecting permanent congenital loss of hearing among them, which can help to initiate auditor rehabilitation prior to three years of age comprehensively. Thus, screening aids in the prevention of hearing deficiency or deafness as a secondary level of prevention, which is well accepted worldwide. It also helps in identifying those children with late diagnosis of hearing loss by implementing newborn screening programs for hearing loss throughout the globe . Three iSevere pre-lingual hearing impairment has drastic effects on language acquisition, communication, and intellectual, social, and emotional growth. Certainly, the evidence is emerging that even moderate hearing loss in very young children can be harmful -13. HearThis was a retrospective, observational study that was conducted in the ENT and the Gynecology and Obstetrics Departments at the Jinnah Postgraduate Medical Centre, and the National Institute of Child Health for a duration of three months, from July 2019 till October 2019. The convenient sampling technique was used for selecting patients. The final sample size of newborns and children was 108. Inclusion criteria were as follows: newborns and children of age up to five years of either gender, with the stipulation that newborns should have undergone screening for hearing prior to leaving the hospital or maternity ward; those with in utero infections ; gestational age of 37-42 weeks and birth weight of >1,500 g; family history of hearing impairment. Exclusion criteria included admissions to NICU, prematurity and birth weight below 1,500 g, presence of severe multiple anomalies rendering them incompatible with life, and untreated otitis externa, atresia, or stenosis of external ear canals of both ears.Initially, screening procedures were undertaken for newborns for detecting permanent or fluctuating, bilateral or unilateral, and sensory or conductive hearing loss: averaging 30-40 dB or more in the frequency region, which indicated potential issues related to speech recognition . The newborn screening involved the use of non-invasive, objective physiological measures including OAE and/or ABR.Children with hearing impairment then underwent BERA; thereafter, further investigations were done to confirm the defects detected on BERA testing. Collected data were analyzed with SPSS Statistics version 20  and presented in tables by calculating means and standard deviations for descriptive analysis.Among a total of 108 children selected for this study, 30 (27.77%) consisted of infants right after their births to those four months of age, 25 (23.15%) were aged from four months to one year, 21 (19.45%) were between one year to two years of age, 16 (14.82%) were two to three years old, 11 (10.19%) were three years or older, and five were over four years of age. The results of the OAE test showed that 96 (88.89%) passed and 12 failed (11.11%) (Table Out of the 96 patients (infants/children), the incidence of risk factor was found among 21, which entailed family history in one (4.76%), consanguinity in five (23.80%), hypoxia in two (9.52%), kernicterus in two (9.52%), maternal infections in three (14.29%), ototoxicity in two (9.52%), and low birth weight in six (28.57%) cases. Moreover, the children who failed the OAE test (n=12) and were further tested on BERA, and the results showed hearing loss in seven cases (58.33%). As for types of deafness, cochlear was found in five (71.43%) patients and retrocochlear was found in two (28.57%) patients. As to the degree of deafness in seven patients who had hearing loss, one had mild, two had moderate, and four had profound hearing loss , distortion-product otoacoustic emissions (DPOAEs), and BERA . They suVery few studies have been conducted in Pakistan on the auditory screening program in neonates . NeonataIn our study, 108 newborns and children were selected for OAE screening, with infants of ages ranging from immediately after birth to five years. Of these, 96 infants/children passed the test, whereas 12 were diagnosed with hearing loss. During the investigation, it was also revealed that the detection of unilateral hearing loss on OAE is very vital in diagnosing uncommon causes of unilateral deafness.Another study compared TEOAEs and DPOAEs and concluded that TEOAEs testing is easier to carry out and it is more trustworthy when compared to the DPOAEs test. According to this study, the specificity for TEOAEs was found to be 92%, which is fairly consistent with our study findings of 88.88% (96 passed) for OAE . One morThere are certain factors that might bring about delays in diagnosis and intervention in children with hearing loss in our society, including low literacy rate among parents, cultural considerations, doubts about the degree of hearing loss, uncertainty about the benefits of hearing amplification, attitudes towards wearing hearing aids, and cost and technical considerations .Our study reinforces the perception that like other developing countries, Pakistan should also implement neonatal screening programs for hearing in a cost-effective manner, which will help us to reduce the influence of hearing impairment on children's social, emotional, intellectual, and linguistic development.The current study indicated the importance of screening for hearing loss among neonates. Our study highlighted that BERA gives a perfect picture of hearing sensitivity. Thus, in all high-risk babies, BERA should be performed as a routine procedure to detect hearing impairment. Regular follow-ups should be done, and rehabilitative measures must be initiated as early as possible. Our present study concludes that in order to avoid any problem related to hearing function in infants, OAE hearing screening and diagnostic BERA screening programs should be carried out in all the hospitals of Pakistan to assess newborn hearing at an early age.


RB1). Despite recent progress in clinical outcomes of retinoblastoma, enucleation  remains a frequent treatment for retinoblastoma and the survival rate for metastatic retinoblastoma is just over 10%. Thus, there is a pressing clinical need to determine the factors responsible for tumor progression following RB1 inactivation in order to facilitate the development of new therapeutic strategies. Furthermore, the loss of pRB function contributes to a wide array of human cancers. A few years ago, we elucidated how tumors progress quickly following RB1 inactivation, showing that while the retinoblastoma genome is stable – with RB1 being the only known tumor suppressor gene mutated – multiple cancer pathways can be deregulated epigenetically [Although the role of the retinoblastoma protein (pRB) in cell cycle control has been extensively studied, druggable targets downstream of pRB remain to be identified. Retinoblastoma is the most common childhood intraocular malignancy caused by bi-allelic inactivation of the retinoblastoma gene RB. Despitenovo DNA methylation and stable gene silencing during cellular differentiation [RB1 inactivation could cause the epigenetic gene expression deregulation that results in tumorigenesis [HELLS gene is a direct target of E2F1 [HELLS  belongs to the SNF2 family of chromatin-remodeling ATPases. It remodels chromatin to allow accessibility of DNMT3A or DNMT3B to DNA in order to support de  of E2F1 ,6. Simil of E2F1 . The ost of E2F1 .Hells conditional knockout mouse models. Unlike previous reports showing impaired self-renewal and maintenance in neural progenitor cells during development [Hells-null retinal progenitor cells (RPCs) divide, undergo cell-fate specification, and give rise to normally laminated and fully functional retinae. In spite of the dispensable role of HELLS during retinal development, genetic ablation of Hells in a genetically engineered mouse model of retinoblastoma led to a drastic increase in survival and decrease in morbidity compared to littermate controls [Hells genetic ablation. Interestingly, loss of Hells did not alter proliferation in retinal progenitor cells – as reflected by the normal functioning Hells-null retina –, yet drastically reduced cellular proliferation in the RB-null retina (i.e. initiated cells). The observations in this study have a remarkable similarity with those on the E2F family. Activator E2Fs, particularly E2F1 and E2F3, control the transcription of genes required for DNA replication and proliferation of quiescent cells but are not required for normal progenitor division in several tissues, including the developing retina [Hells. Consequently, HELLS can act as a transcriptional co-activator of E2F3 , stimulating the expression of pro-proliferative genes  and retinoblastoma formation (Figure In our latest study, we examined the role of HELLS in normal retina development and tumorigenesis using novel elopment , our rescontrols . Intrigug retina . Howeverg retina ,11. ThusHells knockout mouse models of retinoblastoma make HELLS an interesting candidate for the treatment of retinoblastoma. HELLS is nonessential for retina development and its expression is absent in fully differentiated retina. These unique characteristics may open up a new avenue for the ocular delivery of HELLS inhibitors which holds potential in reducing tumor burden with low risk of retinal toxicities.Many limitations still exist when utilizing current methods for the treatment of retinoblastoma. The significant increase in survival observed in


Hearing and balance impairment are the most frequently reported features of infratentorial  superficial siderosis (iSS). There are few comprehensive descriptions of audiovestibular function in iSS and therefore limited understanding of the affected segment(s) of the audiovestibular pathway. In addition, monitoring disease progression and response to treatment is challenging and currently mainly guided by subjective patient reports and magnetic resonance imaging. To the best of our knowledge, there have been no previous reports assessing central auditory function in iSS. We describe such findings in a patient with iSS in an attempt to precisely localize the site of the audiovestibular dysfunction, determine its severity and functional impact. We confirm the presence of  auditory neuropathy and identify central auditory processing deficits, suggesting involvement of the central auditory pathway beyond the brainstem. We correlate the audiological and vestibular findings with self-report measures and the siderosis appearances on brain magnetic resonance images. Infratentorial  superficial siderosis (iSS) is a rare but increasingly recognized disabling neurological condition –3. It isClinically, iSS is characterized by a triad of hearing loss (most frequent symptom), imbalance (ataxia) and myelopathy. Hearing loss is usually described as high-frequency sensorineural, bilateral and often asymmetrical, ranging from mild-moderate to severe-profound , 3. It mWe report findings of central auditory dysfunction and bilateral  auditory neuropathy in a patient with iSS and correlate these with the self-report measures and the brain magnetic resonance images (MRI). To our knowledge this is the first case-study to report central auditory processing testing in iSS in combination with structural neuroimaging and self-reports.A 58 year-old male was referred with a radiologically confirmed diagnosis of iSS, likely from dural ectasia of the lumbosacral region. The patient reported a 4-year history of increasing difficulty hearing in noisy environments and a 3-year history of episodes of vertigo when standing or walking, a tendency to veer from the midline when walking and progressive imbalance when going uphill or on uneven surfaces. He had Marfan's syndrome, hypertension and was on warfarin for aortic valve replacement. There was no history of ear disease, noise exposure, head trauma, central nervous system tumors or surgery, and no family history of balance or hearing disorders.Otoscopy was normal bilaterally. There was left-sided primary position esotropia (present since childhood) and reduced upgaze and medial gaze eye movements, no nystagmus, normal smooth pursuit, saccades and finger-nose test. The patient had a broad-based gait, mild heel-shin dysmetria and was unable to perform tandem walk, Romberg's or Unterberger's-tests.Pure-tone audiometry, speech recognition tests, transient evoked otoacoustic emissions, and auditory brainstem responses were performed to assess auditory function up to the brainstem . Middle Table 1Results of auditory assessment and self-report audiovestibular measures.Auditory brainstem responses  demonstrated reproducible right waves I-V of degraded morphology, yet normal amplitude and latency and absent left responses. Absent left responses persisted on 6-month interval testing, with additional findings of poorly reproducible right waves I-V and poor wave I morphology, suggesting progressive right auditory nerve involvement.Measures of central auditory function included dichotic digits test,  frequency pattern test and Listening in Spatialized Noise-Sentences test. Dichotic digits test score was calculated as percent correct of sets of four digits presented simultaneously (two digits on each side). Frequency pattern test score was calculated as percent correct of the recognized sequences of three tone bursts of high and low frequency. The stimuli for both tests were presented at 50 dB SL (sensation-level) above the threshold level. Listening in Spatialized Noise-Sentences test scores were calculated by the software based on correct recognition of stimuli (sentences) presented simultaneously with competing sentences presented at 55 dB SPL (sound-pressure-level) of the same and different speaker-voice and at azimuth and 90 degrees to the stimuli sentences at a stimulus presentation level determined by the software. The scores were adjusted for mild peripheral hearing loss and were markedly low .Peripheral vestibular tests included cervical and ocular vestibular evoked myogenic potentials and video head impulse test, whereas videonystagmography was performed to distinguish between the peripheral and central vestibular involvement and to assess severity of the dysfunction . Video hThe patient completed validated hearing- and balance-specific questionnaires. Modified Amsterdam Inventory for Auditory Disability and Handicap (28 items) and Speech, Spatial and Qualities of Hearing Scale (49 items), were used to assess hearing difficulties attributable to everyday situations in five domains  , 12, andThe self-report measures scores were consistent with severe disability, except for normal Situational Vertigo Questionnaire score . Neuro-pThe brain and spine MRI were performed with MAGNETOM SKYRA 3T . Susceptibility weighted imaging sequences  identified appearances of haemosiderin deposits consistent with the radiological diagnostic criteria for iSS .Following the Siderosis Multidisciplinary Team meeting, the patient was commenced on Deferiprone, as there was no clear neurosurgical target for dural repair. The patient was aware of the risks associated with Deferiprone and the need for regular blood monitoring for neutropenia. He was referred for hearing therapy as a rehabilitative measure in view of central auditory deficits with near-normal peripheral auditory function, and for neuro-vestibular physiotherapy to address mixed  vestibular deficits. There were no adverse events, such as neutropenic sepsis. The treatment was suspended in view of COVID19 risks. He has a regular follow-up with Neurology, Neuro-otology and Hematology teams.A significant finding in this case report is the presence of central auditory processing deficits. It is important not only for diagnosis and understanding of the clinical spectrum of iSS but also for the potential approach to treatment.Central auditory involvement was indicated by the bilaterally reduced scores for frequency pattern and dichotic digits tests . These cOur case highlights the shortcomings of pure-tone audiometry as a single tool for hearing assessment. Marked hearing difficulties reported by our patient were not consistent with mildly elevated (likely age-related) thresholds , 25 as fOur findings also build on the previous reports of mixed vestibular involvement –10. ISS In a case-series of five patients with superficial siderosis, the superior vestibular nerve and utricle involvement were identified in all five cases . Three pAlthough the identified vestibulopathy may be associated with vestibular nerve involvement and sparing of saccule and utricle , 36, vesInvolvement of vestibulocochlear apparatus in iSS cannot be supported by the single report of temporal bone histology in a patient with superficial siderosis . The autCochlear aqueduct patency was proposed as a mechanism for hearing loss in iSS  which woEqually, it is important to consider hearing loss in the setting of Marfan's syndrome which has been described, albeit infrequently, as predominantly conductive, associated with otitis media, Eustachian tube dysfunction and cranio-facial abnormalities . SensoriThe MRI appearance of hypointense regions along the course of both vestibulocochlear nerves (slightly more marked on the left) was consistent with the clinical findings of asymmetrical auditory neuropathy and concurrent vestibulopathy . Severe Scores of dedicated self-report measures were consistent with the identified auditory and vestibular deficits . The totManagement of auditory processing disorder and ataxia in complex neurological patients requires individualized approach and is deficits- and needs-specific. Listening strategies, use of assistive listening devices, auditory training, hearing aids and cochlear implants (where fitting the criteria) should be considered. Reported outcomes of cochlear implantation in iSS patients are variable , 58 but There are several learning points in our case-study. We identified central auditory processing deficits in iSS, which correlate with the MRI findings and scores for self-report measures. Our case-study provides clear evidence of auditory and (concurrently) vestibular neuropathy, without confounding risk factors for end-organ involvement. It is possible that the anterograde progression of audiovestibular dysfunction may result in end-organ involvement. We highlight the need for comprehensive audiovestibular assessments in patients with neurodegenerative conditions to identify the site of lesion and provide patient- and deficit-specific management strategies.The limitations of this case-study are in its level/strength of evidence. Further dedicated prospective studies are needed to investigate whether the findings are patient-specific or are characteristic for iSS. Although there was stark asymmetry between right and left ocular vestibular evoked myogenic potentials, the results should be interpreted with caution in view of patient's restricted upgaze and previous reports of absent potentials in normal individuals .Patient's perspective: the patient's referral to our tertiary center, dedicated investigations and multidisciplinary input helped his understanding of the condition and of his symptoms. While he perceived little benefit from physiotherapy, with further gradual deterioration in balance, he reported benefit from management of his hearing deficits.There have been no previously documented central auditory function assessments for patients with iSS and correlation with the scores of self-report measures and MRI findings. Our case-study provides clear evidence of auditory and (concurrently) vestibular neuropathy, without confounding risk factors for end-organ involvement. It is possible that the end-organ involvement may be the result of anterograde progression of audiovestibular dysfunction. The importance of comprehensive audiovestibular assessments to identify the site of lesion in patients with neurodegenerative conditions is highlighted. Due to progressive, and possibly irreversible, nature and significant morbidity, it is necessary to determine the features that differentiate iSS-related and age-related hearing loss for timely diagnosis and to provide needs- and deficit-specific management strategies, with further efforts to halt disease progression by means of prompt surgical repair , 62, or The original contributions generated in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Formal written consent was sought from the patient prior to the write up and submission of the manuscript, including consent for the publication of any potentially identifiable images or data included in this article.NK wrote the manuscript. D-EB contributed to content and manuscript writing. DJW and PC reviewed the manuscript and provided comments. All authors reviewed the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the Netherlands, Youth Health Care services (YHC) have been carrying out neonatal hearing screening (NHS) in newborns since 2006. The aim of the NHS is to identify children with permanent hearing loss, so that intervention can be started before the age of 4 months. Early detection of hearing loss is important, as children who start intervention early have been shown to develop better. This article describes the structure and performance of the NHS carried out by the YHC, the quality of the program, and the timeliness of the start of intervention. Since its implementation, the NHS has been audited annually in order to monitor the program’s quality. Monitoring reports and data from the Dutch Foundation for the Deaf and Hard of Hearing Child were used in this study. For many years, results have shown the NHS to be a stable screening program of high quality. The participation rate is high, refer percentage low, and the timeliness of the program is continually improving. Although the timeliness of post screening diagnostics and intervention need most improvement as they do not always meet the target times, this has improved over recent years. In the Netherlands, the Youth Health Care services (YHC) have been performing neonatal hearing screening (NHS) in newborns since 2006 ,2. NHS hIn addition, the development of new screening apparatus has enabled newborns to be screened at home, meaning that identification methods of children with hearing loss have been undergoing a great change internationally. Most importantly, not only has detection itself been fundamentally changed by the introduction of NHS, but also hearing diagnostics, hearing rehabilitation, and the early intervention of children with hearing loss—and if we also include the rise and effect of early cochlear implantations, we can see that there has been an even more radical change. Moreover, the increased accessibility of early interventions for children with moderate hearing loss (40–60 dB) and developments in the quality of hearing aids have also contributed to the series of changes that have considerably increased the developmental opportunities of children with hearing loss.However, these changes have not evolved on their own—a lot of hard work has gone into accomplishing them. Possibly the most important factor in this process has been that since the introduction of NHS, the focus has consistently been on maintaining and improving the quality of the screening program, diagnostics, and intervention. The Dutch Institute for Public Health and the Environment’s Center for Population Screening (RIVM-CvB), directs the NHS on behalf of the Dutch Ministry of Health, Welfare and Sports. The underlying principle is that every population screening program should satisfy the public values of quality, accessibility, and affordability. To this effect, national guidelines, the organization of delivery, and quality requirements are laid down in a procedure manual . In turnA set of quality indicators has been created for the NHS, and each year the program is evaluated on behalf of RIVM-CvB. Since its implementation, this monitoring procedure has been carried out by The Netherlands Organization for Applied Scientific Research (TNO) . The maiThis article describes the structure and performance of the NHS delivered by YHC services, the quality of the program, and the timeliness of the start of intervention. The hearing screening carried out in NICUs falls outside the scope of this article as this is a standard part of NICU treatment delivered by the hospital.Two screening methods are used in the Netherlands: the otoacoustic emission (OAE) method, and the automated auditory brainstem response (A-ABR) method. Both methods have a high level of sensitivity and specificity.The OAE method measures sounds (emissions) that are produced by the outer hair cells in a well-functioning inner ear, during, and for a short time after, the processing of a sound . These eThe neonatal hearing screening test may be carried out in three stages, i.e., up to three separate screening sessions take place, as needed. Based on uniform and timely information, parents make an informed decision about their child’s participation in the program. At the first and second screening sessions, the OAE method is used. In most parts of the Netherlands, the first screening test is carried out by a member of the YHC staff at the same home visit as the heel prick test. In areas where midwives perform the heel prick test, the first screening test is done at a Well Baby Clinic at around three weeks after birth. If a satisfactory result for both ears is not obtained at the second OAE screening, then the third screening test is carried out by a regional coordinator using A-ABR. There is a 4–7 day period between each screening session. If, after the third screening, satisfactory results for both ears have not been obtained, the child is then referred to a SHC for further diagnostics. The screening procedure should be completed within 42 days of birth. Those children who are admitted to the hospital (but not to NICU) for a long period after birth, or children who have risk factors for auditory neuropathy syndrome disorders (ANSD) follow a separate NHS screening protocol. These children are screened with A-ABR screening in the first stage, because ANSD is not detected by OAE screening. This protocol is also carried out by YHC Staff.The quality of the NHS is closely monitored by a regional coordinator. A regional coordinator also manages the OAE screeners, organizes training, and coaches the screening teams. In the monitoring process, the regional coordinator makes use of a number of functions of the Central Administration System Neonatal Hearing Screening (CANG). See data collection for more information.At the SHC, diagnostic tests are performed in accordance with a uniform diagnostic protocol for neonates. In this protocol, the following diagnostic tests are stipulated: auditory brainstem response measurements, impedance testing, frequency specific otoacoustic emission measurements, and behavioral/observation audiometry.In the Netherlands there are 26 SHCs where neonatal diagnostics are carried out, which include both academic and regional centers. The aim is to have all diagnostic hearing testing completed within 92 days after birth. The results of the diagnostic tests are stored in the SHC’s electronic dossiers, and when parental permission has been obtained, also in the CANG.According to Dutch healthcare legislation, children with hearing loss of a minimum of 35–40 dB in the best ear are eligible for intervention by specialist centers for children with sensory handicaps. This is in accordance with the year 2000 position statement of the Joint Committee on Infant Hearing, which was used as a guideline for the screening program . AlthougChildren with unilateral hearing loss receive a follow-up at an SHC. Parents receive counselling from the SHC, and the child’s hearing loss is monitored in order to identify any deterioration over the years.The aim was to start the intervention within 4 months for children with bilateral hearing loss, whether it be an early intervention with hearing aids via an SHC, and/or an early intervention via a specialist center for people with sensory handicaps. The Netherlands has six early intervention centers that offer a range of services, including family counselling, courses for parents (including sign language courses), group intervention, and individual intervention . The results of the interventions were stored in (electronic) dossiers.The results of the screening for hearing testing were obtained from a report that evaluated its national implementation 2002–2006), and also from national monitoring reports 2008–2016) 002–2006,. The dat6 002–200The number of children with permanent bilateral hearing loss of a minimum of 40 dB detected annually, varies year by year . In 2015Of the hard of hearing children with bilateral hearing loss who had a loss of 40 dB or more in the best ear, and were born in 2014–2016, 94 were known to the NSDSK early intervention center. It is striking that a substantial percentage of these children had not been detected by the NHS. The average age at which children attended an intake appointment at the early intervention center was 6 months, with a very wide spread of 1.1 to 31 months. At the start of early intervention, the average age of the children was 6.6 months (1.4–32 months). See Where the age of starting an intervention is exceeded, there is often a clear reason for this. These were children in whom unilateral hearing loss was originally found, or in whom hearing loss of a temporary nature was suspected. After some time it became clear that these children required early intervention. The quality of the delivery of the NHS program is safeguarded at two levels—at screener level by the regional coordinator, and at national organizational level by the RIVM-CvB. If necessary, the regional coordinator gives feedback to the screeners. Each year, the RIVM-CvB sends national monitoring reports to all youth health services organizations and SHCs. A letter setting out the main results and key points for further attention is included in this. The YHC, the SHCs, and the institutes for early intervention each feel responsible for their own link in the NHS chain. They are open to discussing quality control and points for improvement. If the NHS has taught us anything about factors of success for screening programs, it is that continued focus, setting high standards, and working with specialized dedicated teams is crucial.Long-standing key points for improvement were around timely completion of diagnostic testing and the timely start of an intervention if necessary. After the introduction of the NHS, Leiden University Medical Center’s DECIBEL study reported on the ages at which children first received a hearing aid . Of all In 2008, 2010 and 2012, RIVM-CvB commissioned NSDSK to carry out an evaluation of the timeliness of the NHS program for fitting hearing aids in newborns in whom hearing loss had been detected. Their analyses showed that in 2012, the average age of fitting a hearing aid was 5.3 months, and 55% of all children diagnosed as having permanent hearing loss had hearing aids before the age of 4 months. In comparison with 2005, this was a considerable improvement—however, these analyses were based on relatively incomplete data from the feedback reports of the SHCs about the ages at which hearing aids were fitted. In 2017, the RIVM-CvB commissioned a study from the Platform for Audiological Clinical Testing of the Federation of Dutch Audiology Centers. They investigated the timeliness of hearing aid rehabilitation in children born in 2014. In addition, for the first time, timeliness was included in the early intervention program. An important factor of the study was that an intervention (hearing aids/family counselling) had been started with all children who had a hearing loss of 60 dB or more, at around the age of 4 months. Interventions were given later for children with less severe degrees of hearing loss. This was partially due to the fact that some parents had difficulty accepting the diagnosis. In addition, logistical factors of the SHCs and co-morbidity and/or illness in the children were found to play a role [However, the high quality of the NHS program in the Netherlands is not a reason to sit back and relax. In practice, continual adaptations are necessary and developments that could potentially influence the quality of the program which arise need to be addressed, as was the case with the introduction of new screening devices that required a new training program and instruction materials. A new European privacy law  was introduced in May 2018, thus making it necessary to adjust the program to meet the specific requirements of this law. One important point for the YHC is that the NHS does not guarantee lifelong good hearing. The OAE screening cannot detect hearing loss if the cause lies within the brain, which does occur occasionally. In addition, there are some cases where the hearing loss manifests itself after the screening has taken place, or where initially minor hearing loss progressively worsens over time. Thus, it is important that the YHC, parents, and others involved in the care of the child remain aware of the possibility of hearing loss developing after the neonatal period. The Dutch YHC guidelines on the early detection of hearing loss in children and young people (0–18 years) offers more guidance on this matter.The NHS program, carried out by the YHC, is a long-standing, stable screening program with a demonstrably high level of quality. Results have shown that participation levels were high, while refer percentages stayed low. Only 0.3% of screened children were referred for further testing, and 35–40% of them were proven to have unilateral or bilateral hearing loss of a minimum of 40 dB. Where timeliness is concerned, there is still room for improvement in both diagnostics and the start of intervention. The average age of children starting out in the early intervention program was 6.6 months (1.4–32 months). For children whose early intervention starting date with hearing aids was known, the average age at which they got a hearing aid was 4.5 months, and these averages are above the target of 4 months for starting rehabilitation.


Globally, about 50 million people were living with dementia in 2015, with this number projected to triple by 2050. With no cure or effective treatment currently insight, it is vital that factors are identified which will help prevent or delay both age-related and pathological cognitive decline and dementia. Observational data have suggested that hearing loss is a potentially modifiable risk factor for dementia, but no conclusive evidence from randomised controlled trials is currently available.The HearCog trial is a 24-month, randomised, controlled clinical trial aimed at determining whether a hearing loss intervention can delay or arrest the cognitive decline. We will randomise 180 older adults with hearing loss and mild cognitive impairment to a hearing aid or control group to determine if the fitting of hearing aids decreases the 12-month rate of cognitive decline compared with the control group. In addition, we will also determine if the expected clinical gains achieved after 12 months can be sustained over an additional 12 months and if losses experienced through the non-correction of hearing loss can be reversed with the fitting of hearing aids after 12 months.The trial will also explore the cost-effectiveness of the intervention compared to the control arm and the impact of hearing aids on anxiety, depression, physical health and quality of life. The results of this trial will clarify whether the systematic correction of hearing loss benefits cognition in older adults at risk of cognitive decline. We anticipate that our findings will have implications for clinical practice and health policy development.ANZCTR: 12618001278224), registered on 30.07.2018.Australian and New Zealand Clinical Trials Registry ( Hearing loss is the second highest cause of disability in the world, affecting 466 million people, with 90% of cases being due to age-related hearing loss (ARHL) . ARHL isCurrently, more than 50 million people are living with dementia, and this is projected to reach 75.63 million in 2030 and 135.46 million in 2050 . DevelopAustralian data from the Health In Men Study showed that in a sample of 37,898 older men, the hazard of dementia associated with hearing impairment was 1.69  . In addiOur trial aims to investigate whether the correction of hearing loss through the use of hearing aids (HAs) could decrease the 12-month rate of cognitive decline among older adults at risk of dementia.This trial will determine whether the correction of hearing loss through the use of hearing aids (HA) decreases the 12-month rate of cognitive decline among older adults at risk of dementia.We will also investigate whether the correction of hearing loss has a beneficial impact on memory and executive functions, anxiety and depressive symptoms, quality of life, physical health, and health-related costs over 12 months.We will explore whether the expected clinical gains achieved through the correction of hearing loss by 12 months can be sustained over an additional period of 12 months and if losses experienced through the non-correction of hearing loss can be reversed with the fitting of HAs after 12 months .Two-arm parallel randomised controlled trial.We will recruit 180 older adults with mild cognitive impairment and hearing loss. The trial will be conducted at the Ear Science Institute Australia (ESIA) based in the Perth and Bunbury metropolitan regions, Western Australia as well as the Western Australian Centre for Health & Ageing, Perth, Australia. Participants will be recruited from the ESIA hearing clinics, aged-care homes, and hospital memory clinics. In addition, we will place advertisements in the local media and primary care networks, inviting interested participants for screening. If the recruitment of participants is lower than predicted, we will use the electoral roll list to select a random list of people aged ≥70 years living the study areas: they will receive information about the study and an invitation to contact the research office for screening if they believe they may be potentially eligible . This approach has been used successfully in other studies.Be older adults aged 70 years or older (cognitive decline is more pronounced later in life).Have a Montreal Cognitive Assessment for the Hearing Impaired  (HFAHL) ≥ 40 dB as measured using air conduction pure-tone audiometry  ith ARHL .Be fluent English speakers.Participants will:Have impaired instrumental activities of daily living (IADL)  due to c> 70 dBHL, and open-set sentence scores in quiet in the worse ear < 65% and in the better ear < 85% or open set phoneme scores in quiet in the worse ear < 45% and in the better ear < 65% with optimised HA fitting  and Group 2 . A control group of 19 normal-hearing participants was also included. All participants completed hearing and a non-verbal cognitive assessment using the CANTAB test battery at baseline, 6 and 12 months. Hearing aids (HA) were fitted to Group 2 participants after the baseline assessment. Analysis of variance revealed that Group 2 participants (HA users) performed significantly better than Group 1 (non-HA users) on the delayed matching-to-sample (DMS) test of the CANTAB battery . We used G*Power software [In preparation of this trial, we conducted a pilot observational intervention study of two groups of hearing-impaired older adults: Group 1 [software  to deterThe computer-generated randomisation sequence will be stratified by the severity of the hearing loss (mild to moderate vs severe) based on the results of the hearing assessment. Each stratification block will be associated with a random sequence of numbers assigned to the intervention and control group in random permuted blocks of 6, 8 or 10. This sequence will be stored in a password-protected server housed at the University of Western Australia and will be managed by a biostatistician not involved in this project. Once a participant consents and is enrolled, s/he will be automatically ascribed a number and group membership (intervention or control).NOT: (i) discuss any aspects of the intervention during the assessments, (ii) wear their HAs during the assessment. Binaural hearing amplifiers will be used to facilitate the communication between participants and research staff during all assessment visits (including the 12 and 24-month visits).Due to the nature of the intervention, participants will know their group assignment, but research staff involved in the assessment of cognitive function, quality of life, mood and physical function will remain blind to treatment allocation. This will be achieved by directing participants to This will involve the development of a model to estimate the incremental cost-effectiveness of the intervention compared to the control. The analyses will be from the perspective of the health service and will be expressed as Quality-Adjusted Life Years gained. A particular focus of the economic evaluation will be a full assessment of the cost of delivering the intervention compared to that of the control group . Given the feasibility of obtaining health administrative data within the study time frame, we will use a validated patient cost questionnaire to obtain self-reported health care utilisation data . Whilst The second aspect will include the assessment of the effectiveness of the intervention – effectiveness of the intervention and control will be measured using the SF-12, which is widely used in economic evaluations.Incremental cost-effectiveness ratios will be calculated in terms of the incremental cost per sustained remission and the incremental cost per Quality-Adjusted Life Year (QALY) gained by the intervention. The QALY is a widely-used approach for estimating the quality of life benefits in economic evaluations. The values obtained from the SF-12 will be transformed into utility weights using the Short Form 6D algorithm  to formuAll analyses will follow CONSORT guidelines. We will use standard descriptive statistics to compare basic sociodemographic and clinical data across treatment arms. We will use multilevel mixed models to investigate changes in cognitive and other scale scores over time. Mixed models provide estimates that are “intention-to-treat’ and allow for the investigation of interactions between group and time effects, as well as for the adjustment of possible imbalances between the groups following the randomisation. We will use imputed chain equations if the loss to follow up exceeds 25%. All probability tests will be two-tailed.The current paper discusses the methodology for a randomised control trial that investigates whether hearing loss intervention using hearing aids could delay or arrest the cognitive decline in older adults with mild cognitive impairment. One of the strengths of this trial is that it follows CONSORT guidelines for the design of randomised controlled trials. The recruitment of participants with mild cognitive deficits was guided by our desire to test a population at risk of dementia (when prevention may be possible) and by the difficulties associated with the consenting of older adults with moderate to severe cognitive impairment. Besides, those with severe to profound hearing loss who meet the criteria for a cochlear implant will not benefit from HA amplification, hence, including them would potentially undermine the impact of HA amplification on cognitive functions, mental health and QoL. We acknowledge, however, that our study will focus on the cognitive decline rather than conversion to dementia. At this stage, this is a “proof of concept’ investigation, as a dementia prevention trial would require a substantially larger sample and follow up. The projected outcomes of the current study can immediately be translated to practice through audiology clinics and will be applicable across practices around the world. Findings can also be used to inform audiologists, general practitioners and other health-care providers. This will provide important information for older people about the use of hearing aids to prevent worsening cognitive impairment. In addition, consumer support will be requested in disseminating lay summaries/information to the community. If cognitive decline can be delayed or arrested, this would improve the quality of life of older adults who are at risk of developing dementia. It may also lower costs to the health-care and social support systems, by decreasing the needs for services and residential care placement. It would also significantly reduce the overall burden borne by the community.