An unsupervised artificial neural network (auto contractive map) was also used to detect and show, using graph analysis, the hidden connections between the explored variables. These findings may contribute to the formulation of mechanistic hypotheses about hearing damage due to co-exposure to noise and ototoxic solvents.This study is part of a project on early hearing dysfunction induced by combined exposure to volatile organic compounds (VOCs) and noise in occupational settings. In a previous study, 56 microRNAs were found differentially expressed in exposed workers compared to controls. Here, we analyze the statistical association of microRNA expression with audiometric hearing level (HL) and distortion product otoacoustic emission (DPOAE) level in that subset of differentially expressed microRNAs. The highest negative correlations were found; for HL, with miR-195-5p and miR-122-5p, and, for DPOAEs, with miR-92b-5p and miR-206. The homozygous ( The combined exposure to noise and ototoxic/neurotoxic substances in occupational settings represents a serious risk factor for the auditory function of workers. Noise-induced hearing loss is a well-known risk factor in occupational health, mainly related to hair cell damage in the basal region of the cochlea , 2. VOCs1 and f2, at several intermodulation distortion frequencies, and among them, the clinically most important is fDP = 2f1-f2. The 2f1-f2 distortion product is nonlinearly generated within a cochlear region  near the cochlear place, where the f2 frequency is resonant; therefore, the corresponding DPOAE provides an objective test of the cochlear functionality at frequency f2.The standard outcome variable for the evaluation of hearing dysfunction is the hearing level (HL) shift measured at a set of different frequencies by pure-tone audiometry. This outcome variable is clinically relevant as it integrates the adverse effects on the auditory system from the periphery to the auditory cortex. The HL is sensitive to the functionality of the cochlear receptor and, in particular, of the cochlear amplifier, identified with the outer hair cells (OHC) system, but it is also sensitive to the health status of the synapses and the whole retrocochlear auditory pathway. To distinguish the peripheral damage from the central one, distortion product otoacoustic emissions (DPOAEs) were also collected and analyzed. DPOAEs are acoustic signals generated in the cochlea as a nonlinear distortion response to acoustic stimuli, and measurable in the ear canal. Their level is strictly related to the effectiveness of the active feedback mechanism provided by the cochlear OHCs. Due to the cochlear nonlinearity, DPOAEs are evoked by two tones, fTo our knowledge, there are no previous studies regarding the association between microRNA expression and auditory variables in subjects professionally exposed to solvents. The data shown in this paper are part of a larger study aimed at assessing the early hearing dysfunction induced by the combined exposure to VOCs and noise in an occupational setting. In previous studies , 8, the MicroRNAs are short non-coding RNAs playing a role in the epigenetic regulation of gene expression, acting at a post-transcriptional level to modulate the protein-encoding genes , 13. MicThe subjects enrolled in this study are 17 male painters , aged from 21 to 54 years (average 39 years). Serum samples were collected in the framework of the routine tests requested by sanitary surveillance protocols. The analysis of biological samples was described in detail elsewhere  of a typical working day.All the VOC metabolites, mandelic acid (MA) and phenylglyoxylic acid (PGA), both metabolites of the ethylbenzene, methylhippuric acid , SPMA, S-phenylmercapturic acid , and S-benzyl mercapturic acid  were measured in the end shift urine matrix. Cotinine was also determined as a metabolite of nicotine.All values were divided by the concentration of urinary creatinine to normalize results for the dilution grade of urine , 19.The exposure dose to the different VOCs was expressed in terms of the concentration of the most specific metabolite multiplied by the exposure duration (in terms of years).The airborne concentration of the solvents in the mixture was monitored by means of Radiello samplers. The concentration of each VOC was correlated to its most specific urinary metabolite. As the workers wore full facepiece respirators during the entire work shift, biological monitoring was considered the most accurate method for assessing VOCs exposure. The urine samples were collected once per subject both before and after a work shift in June 2018.The extraction and reading of the microRNA matrix were performed by Qiagen Genomic Services. The next-generation sequencing (NGS) analysis of the microRNAs was performed on samples of human blood plasma (200 μl). The collected readings were subjected to quality control, unique molecular index-based correction (to remove PCR replicates), alignment, and downstream analysis.326Cys and the XRCC1 Arg399Gln gene polymorphisms were analyzed by Polymerase Chain Reaction (PCR) followed by restriction enzyme digestion , according to the methods described in a previous paper  method, were provided by QIAGEN. Genomic DNA was isolated from the whole blood of workers using the QiAmp DNA blood mini kit cat. N. 51306 . The hOGG1 Serus paper .1-f2 DPOAE complex spectra were recorded using chirp stimuli, with a constant primary frequency ratio r = f2/f1 = 1.22, stimulus levels (L1 and L2) =  dB FPL, in the range fDP = 1–4 kHz, with 20 Hz frequency resolution. The speed of the chirp stimuli was optimized to match the target frequency resolution of the analysis (20 Hz) to the temporal rate of change of the DPOAE frequency during the chirp. This way one can get a high-frequency resolution DPOAE spectrum in a relatively short time (3.75 s in this case). N=20 elementary DPOAE complex spectra were coherently averaged to increase the signal-to-noise ratio (SNR). Stimulus calibration in the ear canal of the forward pressure level (FPL) and evaluation of the emitted pressure level (EPL) of the DPOAE response was performed  = 1.564fDP.The hearing functionality was assessed by means of pure tone audiometry and high-resolution DPOAEs. All audiological measurements were performed in a quiet environment within the factory building, during a work break. The audiometric hearing level (HL), expressed in dB HL, was evaluated with steps of 5 dB at 11 frequencies in the 125–8,000 Hz range, using an Interacoustics AC40 audiometer, and the average level of the two ears was attributed to each subject. DPOAEs were measured using a dedicated acquisition system based on 24-bit NI-4461 PXI data acquisition boards, programmed in Labview 2015 , driving two ER-2 loudspeakers and recording the response of an ER10B+ low-noise microphone . High-resolution 2ferformed  was applerformed , and to Statistical analysis was performed using the SPSS/PC Statistical Software Package 25.0.  and the Statistical Software R .i-th gene in the j-th sample (with j representing the subject index) is described by a GLM  of the family of the Negative binomial distribution. The link function is a logarithmic one, relating the model coefficients to the log2 of the fold change between exposed and controls. A set of 56 genes with adjusted p-value ≤ 0.01 was selected in Sisto et al.  were studied to evaluate the association between the audiological variables and the microRNAs. Six and 11 models were studied, respectively, for the DPOAEs and the HL, in the different frequency bands. The mixed-effects models were chosen because the measurements in different frequency bands are obviously repeated measures on the same subject, treated as a random variable.The subjects were also separated into two groups  according to their average HL (with a dichotomous threshold level arbitrarily set at 29 dB HL) and, independently, according to their average DPOAE level (with a dichotomous threshold level arbitrarily set at 16 dB EPL). Two different dichotomous criteria may be reasonably applied, because the DPOAE and HL levels, although strongly (negatively) correlated to each other, are differently sensitive to, respectively, peripheral and overall hearing damage.n, starting from an initial space of dimension N, the components will be suitable linear combinations of n variables. For the sPLS-DA, an R package of the mixOmics library was used. Plotting both the cases and the microRNA in the 2-D space of the two main PLS components, it is possible to visually identify the microRNAs with a large component in the “direction” that best discriminates the two groups. The same sPLS-DA technique was applied to evaluate if the polymorphism of the investigated genes, hOGG1 and XRCC1, affects the susceptibility to hearing damage due to VOC exposure. For this purpose, the subjects were divided into two groups according to the hOGG1 and XRCC1 polymorphism. In the case of the hOGG1 polymorphism, the first group contains the wt variant, the second group contains both the mut and the het variants of the gene under investigation. In the case of the XRCC1, the first group contains both the wt and the mut variants, while the second group only contains the het variant. The reason for these different grouping criteria will be clarified later.The sparse partial least squares discriminant analysis (sPLS-DA) technique was applied to determine the combination of microRNA predictive variables maximizing the discrimination between the defined groups. If the maximum number of variables is set to The auto contractive map (AutoCM for short), an unsupervised artificial neural network, developed by Semeion , was appex, 8h, evaluated by means of personal phonometers, was 81.7 dB (A) on average for the roller painters and 87.2 dB (A) for the spray painters.The personal A-weighted daily noise exposure level L3) is shown in The VOCs exposure in terms of airborne concentration  and that including the mut and het variants of the hOGG1 polymorphism (red) are discriminated by the microRNA variables. Although this discrimination is not satisfactory from the point of view of sensitivity and specificity, the biplot of As shown in wt group, are the most significantly differentially expressed microRNAs correlated with HL in mut and het variants, as regards the risk of hearing impairment due to the exposure to VOCs, as also confirmed by the multivariate linear regressions using the hOGG1 polymorphism as a two-level factor, as shown in the last column of Note that the miR-885-3p and miR-122-5p, which point in the direction of the het variant in The microRNA variables also discriminate effectively against the XRCC1 variants, and In The negative correlation between the HL and miR-122-5p and that between the DPOAE level and miR-497-5p are well represented in The anti-correlation between the miR-497-5p and the DPOAEs is also evident in mut and het variants of the hOGG1 belong to the same tree of connections, so they were grouped together and compared to the wt. In the case of the XRCC1, the wt and mut belong to the same tree of connections. This graphical evidence was interpreted as suggesting that in this case the wt and mut variants are connected to each other, so they were grouped together and compared to the het variant.The MST Graph also motivated the choice of differently grouping the variants in the hOGG1 and XRCC1 cases. In the hOGG1 case, the In this study, statistically significant associations were found between audiological variables, i.e., HLs and DPOAE levels, and specific microRNAs that, in a previous study , had beeIn both cases, an increase in hearing impairment, i.e., a higher HL, is associated with a downregulation of the considered microRNAs. This circumstance seems to be coherent with the fact that the miR-122-5p and miR-195-5p were found downregulated in the exposed workers with respect to the controls. The statistical association between microRNA and HL is particularly strong in the low-mid frequency range, with no significant association between the aforementioned microRNAs and HL found at frequencies higher than 4,000 Hz. This is consistent with the observation that the hearing damage caused by solvents especially occurs in the low-medium frequency range. The microRNAs associated with DPOAEs are miR-206, miR-497-5p, and miR-92b-5p. In the case of miR-206, the decrease of the DPOAE amplitude, suggesting a reduction of the cochlear amplifier effectiveness, is associated with an upregulation of the microRNA. Similarly, miR-497-5p is significantly associated with the DPOAE in the band 1,830 Hz, while the DPOAE level is positively associated with miR-92b-5p. Several papers have shown the effect of miR-206 on the nervous system and neurological diseases, such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) . This mmut mutant genotype has been found statistically associated with noise-induced hearing loss. In the study mentioned above, a higher number of subjects have been found with the hOGG1 Cys/Cys genotype among noise-induced hearing loss workers compared to normal hearing workers, suggesting that the hOGG1 Cys/Cys genotype might be particularly susceptible to the risk of noise-induced hearing loss (Furthermore, different studies have demonstrated the relationship between genetic factors, including DNA synthesis-related genes, DNA repair pathways such as base excision repair, and individual susceptibility of workers exposed to industrial noise . Mutatioing loss . It was ing loss .mut and het hOGG1 genotypes may indeed contribute to the susceptibility to hearing damage of workers exposed to noise and ototoxicants. Such susceptible biomarkers are useful in the biomonitoring of the hearing impairment in workers simultaneously exposed to noise and ototoxic solvents. Further investigations and data analysis are needed, involving a larger number of workers compared to healthy controls.The results of this study suggest that the mut and het groups, with respect to the wt. These microRNAs are negatively correlated to the HL, suggesting that the mut and het variants are disadvantaged with respect to the wt.The statistical association of audiological variables with microRNA expression was studied, using different statistical analysis techniques. Both HLs, measured by pure tone audiometry, and DPOAE, an objective biomarker of the cochlear amplifier effectiveness, are significantly associated with microRNA expression levels. The HL shifts were found mainly associated with the downregulation of miR-122-5p and miR-195-5p. The DPOAE levels were found mainly associated with the miR-206, miR-497-5p, and miR-92b-5p. Only in the case of the miR-206, the reduced functionality of the cochlear amplifier was found associated with an upregulation of the microRNA, while in the case of the miR-497-5p and miR-92b-5p, the cochlear dysfunction is related to the downregulation of the microRNAs. The association between the microRNAs and the audiological variables was found significant in the low-mid frequency range. A significant association was found between the microRNAs and the polymorphisms of the hOGG1, responsible for coding enzymes involved in DNA repair. A set of microRNAs was found under-expressed in the This paper could give a contribution to the identification of microRNAs as specific biomarkers of susceptibility in the case of exposure to ototoxic and, more generally, neurotoxic substances. Monitoring these biomarkers could help understand mechanistically the toxicity effects on exposed workers, and design prevention strategies focused on these susceptibility indexes.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by ASUR Marche Prevention Department. The patients/participants provided their written informed consent to participate in this study.RS: conceptualization and data analysis and miRNA data analysis. GT, FS, LC, and RS: data collecting. RS, AM, GM, and SB: statistical data analysis. PB and GM: machine learning algorithms. PC and PC: polymorphisms analysis. RS, PC, and AM: manuscript writing. All the authors reviewed and approved the manuscript.This work was supported by Grant BRIC ID09 PAR 2019–2021 from the INAIL Research.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Dual-energy X-ray absorptiometry were used to evaluate fat mass (FM) and free-fat mass (FFM). Accuracy and mean bias were compared between the measured RMR and the prediction equations. A random training set  and a validation set  were used to develop a new prediction model. All the prediction equations underestimated RMR. The Cunningham equation obtained the largest mean deviation , followed by the Owen , Mifflin–St. Jeor , Harris–Benedict , and the WHO/FAO/UAU  equations. Our new proposed model includes sex, age, FM, and FFM and successfully predicted 73.5% of the explained variation, with a bias of 0.7% . This study demonstrates a large discrepancy between the common prediction equations and measured RMR and suggests a new accurate equation that includes both FM and FFM.Current prediction equations for resting metabolic rate (RMR) were validated in a relatively small sample with high-individual variance. This study determined the accuracy of five common RMR equations and proposed a novel prediction equation, including body composition. A total of 3001 participants (41 ± 13 years; BMI 28.5 ± 5.5 kg/m According to the World Health Organization (WHO), the global prevalence of overweight and obesity has nearly tripled over the last five decades, which is a significant public health concern . Body weThe Cunningham RMR prediction equation relies on fat-free mass (FFM) because of the strong correlation (r = 0.7) between FFM and RMR ,21,22. TTherefore, despite the wide use of the common equations, there remains a need to establish a novel prediction equation for RMR with a better fit at the individual level. The current study aimed to evaluate the common prediction equations on a large and diverse dataset and to develop a new prediction model that incorporates body composition parameters.2), and from different races, which represent well the general population in Israel. Participants were excluded from the study if they were lactating (n = 7), users of steroidal drugs (n = 18), or had undergone a surgical procedure that could affect body composition . Demographic parameters, including age and sex, were collected, as well as the medical history of bariatric surgery (n = 136), thyroid disorders (n = 46), or diabetes (n = 115) based on the clinical records. Furthermore, we classified the participants  based on self-reported previous weight loss attempts: never (n = 2109), one or two attempts (n = 625), or three or more attempts (n = 203). The study flow chart is shown in In this single-center cross-sectional observational study, 3001 participants attending a private nutrition clinic in the center of Israel were enrolled between October 2015 and October 2020. Study participants visited the clinic for nutrition consulting to improve their well-being, change lifestyle habits, or lose weight. Among the entire study population, 51.9% of the participants were male with a large range of BMI  while subjects were dressed in shorts and a T-shirt. A standard, wall-mounted stadiometer was used to measure the height (±0.1 cm) without shoes, and the BMI (kg/m2) was calculated accordingly. Neck and abdomen circumferences were measured (cm) with a flexible tape at the levels of laryngeal prominence and umbilicus, respectively.The same clinician conducted all the anthropometric measurements. While most participants (>95%) were tested on the same day, some conducted the metabolic and body composition assessments one week apart. Weight (±0.1 kg) was recorded on a digital scale , FM (kg), and FM (%), were measured using dual-energy X-ray absorptiometry  and analyzed using the integrated software . Participants were instructed to arrive at the clinic after at least a 4 h fast. Before the scan, participants were asked to remove all metal items. Each whole-body scan took ~7 min. Quality control calibration procedures were conducted on a spine phantom each morning.2 and VCO2)  between the estimated RMR of each equation and the experimentally measured RMR from our data. Lin’s concordance correlation was used to examine the concordance between the r2 and the linear equation of each estimated equation and the experimentally measured RMR values. The level of inter-method agreement was compared using Bland–Altman plots, with a 95% level of agreement for mean bias.The normality of the distribution of each continuous variable was assessed using histograms and QQ plots and by the Kolmogorov–Smirnov Test. Variables found to have non-normal distributions were subjected to traditional transformations: square root for left-tail distributions and log-normal transformation for right-tail distributions. Participant characteristics were presented as the mean ± SD for continuous variables and by prevalence for categorical and dichotomic variables. Student’s n = 2251) was assigned to a training set and 25% (n = 750) to a validation set. The two sets were matched in age, sex, BMI, and body composition  in the model, and according to the variance inflation factor (VIF).To develop a multivariable prediction model for RMR, the dataset was randomly split using the train_test_split function of the scikit-learn Python package. A random subset of 75% of the participants (position . The incn = 750), using Bland–Altman plots (with 95% level of agreement for mean bias), and using Lin’s concordance correlation. A good model fit was defined as having maximum mean absolute error ±200 kcal/24 h (~10%). Data were collected using Microsoft® Excel v.16.16.27 and analyzed using IBM® SPSS Statistics v.27.We validated our new model on the validation set (2 (range: 14.7–59 kg/m2), mean measured RMR was 1841 ± 365 kcal day−1, and 52% were females. As expected, compared to females, males had significantly higher RMR  and FFM , and lower FM . The largest category of subjects was overweight (35.1%), followed by obesity (32.8%), normal weight (32.3%), and underweight (0.9%). The measured RMR, FFM, and FM increased significantly with increases in BMI .Characteristics of the 3001 participants across sex are presented in −1, −16.6%; 95% LOA 1.9, −35.1). This was followed by the Owen equation , the Mifflin–St. Jeor equation , and the Harris–Benedict equation . The lowest mean deviation was obtained by the WHO/FAO/UAU equation . The explained variation (r2) ranges from 0.63 to 0.70, in the following order: Mifflin–St. Jeor > Harris–Benedict > WHO/FAO/UAU > Owen > Cunningham , height , and neck circumference , with the highest coefficient obtained with FFM . In addition, a high Pearson coefficient was obtained between FFM and height , neck circumference , and weight . These were not combined as RMR predictors in the model in order to avoid multicollinearity.Bland–Altman analysis presenting the bias and the 95% LOA of each of the common prediction equation is presented in nningham a,c,e,g. 2 value of 0.745.The two newly proposed models are presented in For males, RMR  = 775.8 − (age × 5) + (FFM × 20.5) + (FM × 7.7)For females, RMR  = 709 − (age × 5) + (FFM × 20.5) + (FM × 7.7)Model 2 includes an interaction variable of FFM × FM, which increases the explained variation by 0.001.For males, RMR  = 891.7 − (age × 5) + (FFM ×18.5) + (FM × 3.5) + (FFM × FM × 0.07)For females, RMR  = 824 − (age × 5) + (FFM × 20.5) + (FM × 7.7) + (FFM × FM × 0.07)p < 0.001). Male sex was related to an increase of 9% in predicted RMR (p < 0.001); each year of age was related to a decrease of 5 kcal day−1, and 1 kg of FFM contributed 20.5 kcal day−1 to the RMR, which is a three-fold increase over the value for FM kg . A sensitivity analysis for participants with thyroid disorders or following bariatric surgery revealed similar results in the accuracy of the model. Moreover, no significant change in the prediction accuracy or mean bias was found when the self-reported previous weight loss attempts were added to the model.In both models, the FFM predictor has the most significant contribution to RMR prediction . The mean deviation percentage of model 1 is −0.7% (p = 0.049), and no significant difference was found for the average deviation of model 2 and the measured RMR . The 95% level of agreement ranges from −18.6 to 19.7 for both proposed models.Next, we applied Bland–Altman analysis to the validation set to determine the mean bias and level of agreement of both models . The newTo our knowledge, the present investigation is the largest cross-sectional study to examine the accuracy of several common RMR prediction equations using body composition parameters, in addition to height, weight, sex, and age. As a result of the investigation, we propose a new prediction model for RMR. The known RMR prediction equations produced a large variation (−0.7% to −16.6%) in the mean bias with an explained variation of 0.63 to 0.70. In contrast, our new prediction equation, which includes both fat mass and fat-free mass, can successfully predict 73% of the explained variation of the measured RMR, with a mean bias of −0.7%.2, similar to the mean BMI among the USA (28.5 kg/m2) [2). In addition, the sample size we used to determine the accuracy of the common equations and to develop the new prediction model is larger than that used in any previous study. The Harris–Benedict equation was developed based on 239 Caucasian participants with normal body weight [Our findings demonstrate that the common prediction models underestimate experimentally measured RMR by −2.1 ± 12.4% to −16.1 ± 9.4%. While we appreciate that the population characteristics may influence the accuracy of a model, the characteristics of the 3001 Israeli participants comprising the study population employed are very similar to those of the general population. For example, the average BMI of the study participants was 28.5 kg/m5 kg/m2)  and sligy weight . Similar2 of 0.73 compared to the 0.63–0.71 range of explained variation obtained from the commonly used equations. Notably, an extensive systematic review of validated common equations revealed large deviations between the predicted and measured values of RMR, with both under- and overestimations, depending on the equation and the study population [The novel model proposed in this study exhibits higher accuracy with values of −0.6%; 0.55, and rpulation . The devpulation ; the devpulation ; and thepulation . FurtherIn this study, we found that combining demographic indices (age and sex) together with body composition indices increases the prediction accuracy and reduces the range of deviation. RMR prediction models based on body composition parameters have been previously proposed in the existing literature, but most are based on specific populations, e.g., women or athletes only ,24. The The model proposed in this study predicts 73% of the variation in RMR. Several factors influence RMR variation and may contribute to an increase in the explained variation. Several studies have shown that past calorie restriction attempts may lead to less-than-predicted RMR by losing muscle and respiring mass ,34,35,36The current study has several limitations. All the data were collected from a single clinic center in Israel, which might influence the ethnicity and socio-economic variety of the study Israeli population. However, our large sample size, with the representation of a wide age range, minimizes the potential selection bias in this study, as the study Israeli population has similar characteristics to the general population . The strengths of this study include DXA measurements of body composition and the use of a pre-defined protocol with the same metabolic cart for the RMR measurements for all participants. The suggested new prediction equation in this study relies on DXA measurement to assess body composition, a gold standard but expensive assessment rarely used in a clinical setting. While BIA is correlated with DXA measurements of body composition ,45, and In summary, by combining body composition indices and demographic parameters, we present a novel model with higher individual accuracy for predicting RMR. Based on the study findings, we believe that the proposed prediction model represents an important tool that can be used for frequent measurements in the general population with access to body composition assessment.


In this work, we apply the sequential processing (SqP) method to address the relatively low electron mobility in recent all-polymer solar cells  based on the polymerized small-molecule acceptor (PSMA). Compared to the blend-casting (BC) method, all-PSCs composed of PM6/PY-IT via the SqP method show boosted electron mobility and a more balanced charge carrier transport, which increases the FF of the SqP device and compensates for the short-circuit current loss, rendering comparable overall performance with the BC device. Through film-depth-dependent light absorption spectroscopy, we analyze the sub-layer absorption and exciton generation rate in the vertical direction of the device, and discuss the effect of the increased electron mobility on device performance, accordingly. As a promising green and renewable energy technology, thin-film organic solar cells (OSCs) have received worldwide interest and have developed quickly in recent decades due to their advantages, such as light weight, low cost, semitransparency, and flexibility ,4,5,6,7.With the synthesis of new materials and the exploration of new structures, all-polymer solar cells  consisting of p-type polymer donors and n-type polymer acceptors have attracted increased attention due to some of their distinctive features, such as enhanced electronic structure tunability, outstanding mechanical durability and stability, and excellent film-formation capability suitable for roll-to-roll manufacturing ,10,11. NTo optimize the BHJ morphology, sequential processing (SqP), also called layer-by--layer deposition, has been considered as an effective way to form a pseudo-bilayer configuration via two-step deposition of the donor and acceptor, sequentially, which is beneficial to enhance vertical phase separation and afford a purer donor/acceptor phase to accelerate the hole/electron transport ,24,25,26In this work, we present a sequentially processed all-PSC with PM6 as the electron donor and PY-IT, a PSMA, as the electron acceptor a. The naPolydithiophene))-alt-benzodithiophene-4,8-dione)] (PM6) was purchased from Solarmer Material Inc.  polythiadiazolothienothienopyrrolo thienothieno-indole-2,10-diyl)bis(methanylylidene))bis) dimalononitrile-co-2,5-thiophene (PY-IT) and poly (PNDIT-F3N) were purchased from eFlexPV Limited . Poly polystyrene sulfonate (PEDOT:PSS) (Clevios P VP 4083) was purchased from Heraeus Inc., Hanau, Germany. All the other reagents and chemicals were purchased from Sigma-Aldrich or Aladdin and used as received.Device fabrication. Solar cells were fabricated in a conventional device configuration of ITO/PEDOT:PSS/active layers/PNDIT-F3N/Ag. The ITO substrates were scrubbed by detergent and then sonicated with deionized water, acetone, and isopropanol, subsequently, and dried overnight in an oven. The glass substrates were treated with UV-Ozone for 30 min before use. PEDOT:PSS was spin-casted onto the ITO substrates at 5000 rpm for 30 s, and then dried at 120 °C for 10 min in air.The different kinds of devices used were as follows:−1 for all blends) or toluene , with 1-chloronaphthalene (1% vol) as an additive, and stirred overnight in a nitrogen-filled glove box. The chloroform blend solution was spin-casted at 2500 rpm for 30 s onto the PEDOT:PSS films, followed by a temperature annealing of 95 °C for 5 min. The 95 °C toluene blend solution was spin-casted at 2500 rpm for 30 s onto the PEDOT:PSS films, followed by a temperature annealing of 95 °C for 5 min.(1) For PM6:PY-IT (BC), the PM6:PY-IT blends (1:1.2 weight ratio) were dissolved in chloroform (the concentration of the donor was 7 mg mL−1), and the acceptor PY-IT was also dissolved in chloroform (the concentration of the donor was 9 mg mL−1) and 1-chloronaphthalene (2% vol) as an additive, and both solutions were stirred overnight in a nitrogen-filled glove box. The donor solution was spin-casted at 2500 rpm for 30 s onto the PEDOT:PSS films, and then the donor solution was spin-casted at 3000 rpm for 30 s onto the donor films, followed by a temperature annealing of 95 °C for 5 min.(2) For PM6/PY-IT (SqP), the PM6 was dissolved in chloroform (the concentration of the donor was 8 mg mL(3) For PM6/PY-IT (SqP-DTA), the thermal annealing at 90 °C for 5 min was carried out after the donor film was spin-casted, then the other steps were the same as outlined in (2).−1 was spin-coated onto the active layer at 2000 rpm for 30 s. Around 100 nm of Ag was evaporated under 1 × 10−4 Pa through a shadow mask, then the encapsulation was carried out.For all types of devices, methanol with a 0.5% vol. acetic acid blend solution of PNDIT-F3N at a concentration of 0.5 mg mLDevice characterization. The current density–voltage (J-V) curves of all encapsulated devices were measured using a Keithley 2400 Source Meter in air under AM 1.5G (100 mW cm−2) using a Newport solar simulator . The light intensity was calibrated using a standard Si diode . EQEs were measured using an Enlitech QE-S EQE system  equipped with a standard Si diode. Monochromatic light was generated from a Newport 300 W lamp source SCLC Measurements: The electron and hole mobilities were measured using the space-charge limited current (SCLC) method. The device architecture of the electron-only devices was ITO/ZnO/active layer/Ca/Ag, and that of the hole-only devices was ITO/MoOx/active layer/MoOx/Ag. The charge carrier mobilities were determined by fitting the dark current into the model of a single carrier SCLC according to the equation: J = 9ε0εrμV2/8d3, where J is the current density, d is the film thickness of the active layer, μ is the charge carrier mobility, εr is the relative dielectric constant of the transport medium, and ε0 is the permittivity of free space. V = Vapp − Vbi, where Vapp is the applied voltage and Vbi is the offset voltage. The carrier mobilities were calculated from the slope of the J~V2 curves.FTPS-EQE: FTPS measurements were conducted on the same devices used in J-V measurements using an integrated system (PECT-600) purchased from Enli Technology Co., Ltd. . The range of measurements was 500–1800 nm. The signal due to noise was cut out for all devices below 1.1–1.3 eV.Film-depth-dependent light absorption and composition distribution: Film-depth-dependent light absorption spectra were acquired by an in situ spectrometer   equipped with a soft plasma-ion source. The power-supply for generating the soft ionic source was 100 W, with input oxygen pressure ~ 10 Pa. The film surface is incrementally etched by the soft ion source, without damage to the materials underneath the surface, which is in situ monitored by a spectrometer. From the evolution of the spectra and the Beer-Lambert’s Law, film-depth-dependent absorption spectra were extracted.The composition distribution along the film-depth direction was obtained from the film-depth-dependent spectra. The exciton generation contour was numerically simulated upon inputting film-depth-dependent light absorption spectra into a modified optical transfer-matrix approach. The detailed experimental and numerical methods are available elsewhere ,32.The chemical structural formulas of PM6 and PY-IT are shown in J-V characteristic curves of all-PSCs based on BC, SqP, and SqP (DTA) systems. The corresponding specific device performance parameters are listed in JSC) of 23.70 mA·cm−2, a VOC of 0.937 V, and a fill factor (FF) of 67.7%. Considering those values of PM6:PY-IT (BC) as a benchmark, the PM6/PY-IT (SqP) exhibited a slightly lower JSC of 23.19 mA·cm−2, a nearly unchanged VOC (0.936 V), and a higher FF of 69.1%, and the PM6/PY-IT (SqP-DTA) showed a significantly lower JSC of 22.36 mA·cm−2, a more reduced FF (65.7%), and a decreased VOC (0.932 V), which led to the lowest PCE of 13.69% among the three. The result indicates that donor thermally annealed (DTA) is not ideal to tune BHJ morphology by SqP. The JSC differences for those film devices with the BC and SqP methods were also cross-checked with external quantum efficiency (EQE) measurements , PM6/PY-IT (SqP), and PM6/PY-IT (SqP-DTA) were 22.71, 22.18, and 22.04 mA·cm−2, respectively. The errors of JSC values between those calculated from the EQE and those measured from the J-V measurement were within 5%.ents see c. The reJSC on the light intensity (Plight). JSC and light intensity (JSC-Plight) curves, which are plotted on a logarithmic scale with a slope of S, as listed in S is to 1, the weaker the bimolecular recombination in the active layer. The bimolecular recombination of PM6/PY-IT (SqP-DTA) (S ≈ 0.979) was the highest, followed by PM6:PY-IT (BC) (S ≈ 0.981), and PM6/PY-IT (SqP) (S ≈ 0.998) with the lowest bimolecular recombination. This indicates that the SqP method can reduce the bimolecular recombination of the active layer when compared to BC, which is consistent with the trend of FFs of the corresponding devices.To understand the differences of charge recombination among devices based on different active layers, we first performed the dependence of nid) were calculated. When the ideality factor is approaching 1, the trap-assisted recombination is less, based on diode theory. Otherwise, more trap-assisted recombination makes the value become higher . We can obtain the ideality factors in the following two ways. The first is to calculate ideality factors  under different light intensities by I is the light intensity. The results are shown in nid,l values of PM6:PY-IT (BC), PM6/PY-IT (SqP), and PM6/PY-IT (SqP-DTA) were 1.248, 1.254, and 1.272, respectively. The nid,l values of PM6:PY-IT (BC) and PM6/PY-IT (SqP) were very close, lower than that of PM6/PY-IT (SqP-DTA), which indicates less trap-assisted recombination across the active layer of the SqP-based or BC-based device than that of the SqP-based device with extra thermal annealing (DTA). The second way is to fit the exponential region of the dark J-V curve, where the dark ideality factor  can be calculated by q, k, T, V, and J represent the fundamental charge, the Boltzmann constant, temperature, bias voltage, and dark current density, respectively. The dark J-V curves are plotted in nid,d values are listed alongside the series (Rs) and shunt resistance (Rsh) of the devices. The nid,d values of PM6:PY-IT (BC), PM6/PY-IT (SqP), and PM6/PY-IT (SqP-DTA) were 1.474, 1.449, and 1.496, respectively. The trend of nid,d of these three devices was almost consistent with that of nid,l, with SqP-DTA showing the highest ideality factor and thus the most trap-assisted recombination. These results imply that the SqP method without extra annealing can reduce not only bimolecular recombination, but also trap-assisted recombination, compared to BC.To examine trap-assisted recombination, ideality factors (The high-sensitivity EQE measurements were used here for probing trap states. The sub-gap EQEs were measured using Fourier-transform photocurrent spectroscopy (FTPS), and the spectra of the BC- and SqP-based devices are shown in J-V2 data of single-carrier devices to the space-charge limited current (SCLC) model. The results are presented in −4 and 2.3 × 10−4 cm2 V−1 s−1, respectively, which is consistent with its inferior photovoltaic performance since unbalanced carriers’ mobilities may result in severe bimolecular recombination to restrain the FF. PM6/PY-IT (SqP) with balanced mobilities for the hole and electron were tested to be 4.1 × 10−4 and 4.2 × 10−4 cm2 V−1 s−1, respectively, indicating that the SqP method may enhance the PM6/PY-IT phase purity to improve the carriers’ (hole and electron) transport pathway. For PM6/PY-IT (SqP-DTA), the obviously unbalanced mobilities for the hole and electron were 5.8 × 10−4 and 2.2 × 10−4 cm2 V−1 s−1, respectively, suggesting that extra thermal annealing for the underlayer donor PM6 (DTA) is likely to increase its crystallinity, which is favorable for hole transport, but it restrains the interpenetration between the acceptor and the donor, and finally leads to inferior photovoltaic performance.To deeply understand the relationship between charge transport property, vertical composite distribution, and device performance, the charge carrier mobilities of active layers processed by different methods were first measured by fitting the dark The vertical phase distributions of the donor and the acceptor and exciton generation across the thin film were explored through film-depth-dependent light absorption spectra (FLAS). The active layers were skimmed gradually by low-pressure plasma in a vacuum by precisely controlling the strength of the plasmas and the treatment time. Details are provided in the Experimental Section. Based on the absorption of the sublayers from the top to the bottom of an active layer, the vertical phase separation can be obtained as long as the absorption of the donor and acceptor can be distinguished. The film-depth-dependence light absorption spectra of PM6:PY-IT (BC) and PM6/PY-IT (SqP) have a thickness of 100 nm. The PM6 neat film possesses a strong absorption band at the long-wavelength region peak at 616 nm, while PY-IT strongly absorbs light at the short-wavelength region peak at 825 nm. The results are depicted in JSC in the active layer using the SqP method.The energy distributions of photons absorbed in a specific point per unit time in the active layer were calculated by E, and the result of exciton generation rate is shown in We prepared pure PM6 films and PM6:PY-IT blend films according to the same procedure used to fabricated devices. For DTA films, we took AFM images on the PM6 film before and after the extra thermal annealing step, and on the SqP blend films as well. The figure below is the new In conclusion, the two-step sequential processing has been successfully employed in the fabrication of all-PSCs based on a polymeric donor (PY-IT) and a polymeric acceptor (PM6), and it achieved PCEs of all-PSCs which were negligibly lower (15.15%) than the corresponding BC-based all-PSCs. Furthermore, by systematically comparing the similarities and differences between the devices prepared by the SqP method and the BC method with respect to their optical and electronic properties, together with the above-mentioned variation in BHJ morphology, we found that SqP presented greatly improved FF, reduced bimolecular recombination, and enhanced phase purity to increase the carrier mobility. The results imply that the SqP method is an effective approach to preciously control the morphology of photovoltaic materials and to fabricate high-performance all-PSCs, especially to realize industrial mass-production in the near future.


Research considers high frequency tonal audiometry as a tool for the early diagnosis of auditory alterations derived from etiological agents.to investigate possible differences in high frequency audiometry of individuals with normal hearing, based on the person who places the earphone.clinical and experimental study with 55 undergraduate students from a country side branch of the São Paulo State University, with normal hearing, underwent two tests each; for the first, the evaluator positioned the earphone on the participant; for the second one, the participant did it by him/herself. An AC40 audiometer calibrated to emit pure tone was used in the frequencies of 10, 12.5, and 16 kHz.The kappa(k) coefficient statistical analysis was used to verify the agreement between the two ways of earphone positioning of earphone, bearing a ≥0.70 kappa value as a criterion. Results attained for both ears were below this criterion, with k average of 0.50.results indicate a risk of compromising the exam reliability when the patient him/herself adjusts phone to his/her own ear.when performing audiometric assessment, this variable must be considered in order to attain reliable results. High frequency audiometric threshold studies are important because the first indicators of a disease that affects the inner ear is a drop in the 8.000HzUp to the 70's, this interest for audiologic evaluation focusing in the high frequencies was not so evident, having given the conclusions of other studies of the time that showed damages to the auditory system that could already be diagnosed early on by means of the conventional 8kHz frequencyThere are studies that have high frequencies tonal audiometry as a tool for the early diagnosis of hearing alterations caused by some etiological agents, such as aging, exposure to ototoxic agents, occupational noise, sequelae of otitis media, hearing monitoring in patients with hearing processing disorders, hearing impairment investigation in relatives of hearing impaired people of genetic originHigh frequency audiometry is a subjective hearing test, carried out in a soundproof booth, with earphones specially calibrated to emit extremely high sounds in the frequencies of 8,000 to 16,000Hz. There are audiometers able to generate pure tones of up to 20,000Hz, however there are no transducers able to emit tones above 16,000Hz, without distortions. It is considered an ideal exam to detect early phases of diseases that involve the auditory system and to monitor hearing risk status, such as cancer chemotherapy and the administration of potentially ototoxic drugs. Gender variability has been studiedConsidering hearing thresholds of up to 25dBHL (decibels Hearing Level) as normal hearing levels, we noticed an age-related progressive worsening in hearing acuity. Initially the impairment affects the frequency of 16kHz and, finally and with lesser intensity, the frequency of 10kHzThe difficulty in finding precise results led to the development of different assessment techniques. Notwithstanding, there are procedures that were created in order to solve this inter and intra-individual acoustic variability in the assessment of high frequencies that would not help in early diagnosis in clinical practice, when the assessments must rely on results and ease of application. For this reason, it is recommended to have special care in comparing findings in studies related to both normality and pathological stateIt is important to inspect the external acoustic meatus in order to rule out the possibility of wax obstruction or foreign bodies. Moreover, errors may occur during the auditory evaluation by air conduction in the frequency of 8kHz, because the presence of a stationary wave may influence the sound intensity presented. If this is seen, we advice repositioning the phone, since there is a possibility for improvement in the threshold reachedThis change in earphone positioning may alter the sound pressure level within the external acoustic meatus, varying according to sound frequency. In high frequencies there is some influence of the sound pressure level on the tympanic membrane, which also depends on the ear phone being well positionedEarphone positioning may impact the assessment precision because when ¼ of the wavelength gets closer to the external meatus length, resonances and stationary waves are created, in such a way as to alter the initial test signal. This happens frequently with sounds above 3kHz. Above 15kHz this phenomena happens when half of the wavelength produces resonances in the cross-sections of the external auditory canal. There is the possibility of variations of about 15-20dB resulting from the slightest changes in earphone positioning in the earIn clinical practice, it is possible to see a greater variability in tonal thresholds accruing from the collapse of the external acoustic meatus in the frequency of 4kHz, and most specially in the high frequenciesThe stationary wave pattern depends on the size of the outer ear, the middle ear impedance and sound source characteristics. A slight change in phone placement may also vary sound pressure on the tympanic membrane.Due to test variabilities, the phones should be calibrated for each individual being tested, at each session and may be carried out by placing a probe microphone in the external acoustic meatus, thus allowing sound pressure measurement near the tympanic membraneThus, it is necessary to investigate the behavior of these thresholds in normal hearing individuals and test reliability, from detection to hearing impairment monitoring, specially in sensorineural pathologies, that usually start on the high frequenciesSuch study aims at checking if there are differences concerning the assessment of high frequencies in normal hearing individuals due to earphone positioning carried out by the investigator and the individual being tested.This study is part of a greater project which investigates the audiologic characteristics of a group of students from an University in the country side of São Paulo State. In the present paper our goal is to compare the results of high frequency audiometric evaluation in normal hearing individuals with a change in ear phone position, when placed by the investigator and by the individual being tested.It is expected that the evidence attained may offer valuable information for our field of work in regards to obtaining more precise diagnostic procedures, thus contributing for an early diagnosis and proper evaluation of the individuals tested.Participants: 55 undergraduate students from an University in the country side of the State of São Paulo, with ages ranging between 18 and 25 years, with normal hearing.We used an AC40 audiometer, calibrated to emit a pure tone at the specific frequency level, free from distortions and noise, thus assuring proper acoustic patterns in order to guarantee result reliability. The assessment was carried out up to the frequency of 16kHz because this is the frequency threshold of the equipment used. In order to analyze the results we used the SAS - System for Windows V8 - statistical package.After the project was approved by the Research Ethics Committee (Protocol 185/05), we started collecting data. In order to select the participants in the study we carried out the conventional assessment involving patient interview, ear inspection, hearing threshold test, acoustic immittance and investigation of the stapedial reflexes. Only the participants with normal results in these tests were included in the high frequency audiometric assessment for this study. All the participants signed an informed consent form of their free will, according to Directive 196/96 from the Ministry of Health.We surveyed the frequencies of 10; 12.5 and 16kHz, being the latter equal to the upper frequency limit of the equipment used. In order to investigate audiometric thresholds for conductive hearing, we used the descending technique with 10dB intervals in each frequency, until the individual no longer responded to the sound. As of such intensity, the ascending technique was used at 5dB intervals until the individual could hear the sound again. The hearing threshold corresponds to a lower sound intensity heard by the individual being assessed in each frequency.Earphones were positioned by the investigators after briefly instructing the individuals on the task they should perform during the test. At the end of the threshold study in all the frequencies used, the individual herself removed and repositioned the earphone and a new threshold investigation was carried out in the frequencies of 10, 12.5 and 16kHz.Results attained in the frequencies of 10, 12.5 and 16kHz, with earphone being positioned by the investigator were compared to the results obtained in the same frequencies after the individuals repositioned the phones themselves.We controlled the variables related to test time and duration, room temperature, characteristics of that specific time of the day, and other variables that could harm results stability.For result analysis, we used the Kappa (k) statistics, which is an agreement measure used in nominal scales and allows us to see how much the observations differ from expectations, based on chance, thus showing the legitimacy of such interpretations. k statistics values vary from 0 to 1; 0 indicates that there is no agreement except for sheer luck, and 1 represents perfect agreementIn order to obtain the k coefficient, we have to first calculate the representative index of agreement expected for the case. After that, we calculate the observed variable agreement. With these two values, we then calculate the k value by means of dividing the difference between the observed agreement and the expected one, by the difference between the absolute agreement and the expected agreement by chance (the largest possible difference between the observed and the expected agreement)The k statistics magnitude is an agreement measure which is much more significant than its own statistical significanceThe k statistic standard error (SE) allows an estimate of its statistical significance and also its 95% confidence interval, calculated by the square root of the variable attained. Notwithstanding, the k value depends on the prevalence of the variable in question. A high prevalence results in a high level of agreement expected by chance, and this will result in a lower k value. On the other hand, a low prevalence variable will originate higher k valuesFor the present study we considered the Kappa coefficient above 0.70, substantial agreement, as a criterion. The confidence interval is of 95%, however the exact value of the estimate is between the minimum and maximum value in the range.Analyzing Results analysis attained through the left ear analysis in the frequencies of 10, 12,5 and 16kHz, shown on For all the frequencies tested, we noticed in both right and left ears, differences in attaining auditory thresholds with the change in earphone positioning based on who placed the earphone, being either the examiner or the subject.Such findings corroborate the results presented by Steffani et al.According to YonezakiAlthough these studies did not aim at assessing earphone positioning in high frequencies, they showed that phone positioning may impact audiologic assessment results. In a similar way, we observed in the present study that earphone placement by the examiner or by the examinee may impact high frequency audiologic assessment results.24.The agreement among the different measuring systems was considered to be low, with an average of 0.50. The measuring methods were considered different, because in all the cases the Kappa Statistical value was below 0.7, criterion deemed acceptable for this study. Even then, we may not state that there is no relation among the methods, because this average attained in the Kappa statistics is classified as moderate according to the literatureAccording to the analysis carried out, in all cases we noticed differences in hearing levels related to the person who placed the earphone. Thus, during an audiometric threshold investigation in the high frequencies, it is highly important to consider the interference of such variable when it is necessary to reposition the earphone in order to obtain reliable results.


Following the efforts of patient advocates, the World Health Organization published updated guidelines for management of multidrug-resistant tuberculosis in 2018 that advised against the routine use of ototoxic second-line injectable drugs . Although hearing loss is no longer considered an unavoidable harm for patients with multidrug-resistant tuberculosis, ototoxic medications continue to be used for several infectious and oncological disorders around the world. These drugs contribute to more than a half a million cases of hearing loss worldwide annually. Currently, there are no international standards for preventing and managing hearing loss associated with ototoxic medications. We present recent data on the prevention and management of hearing loss related to these drugs and highlight the variability in care across settings. More importantly, we aim to provide an evidence-based framework for evaluating, screening and preventing ototoxicity. Finally, we identify avenues for future research so that patients no longer have to choose between hearing loss and a disease cure. There remain significant gaps in our understanding about optimal screening and treatment of ototoxic hearing loss. Here we aim to inspire future international guidelines to address gaps in ototoxicity care and establish research agendas for eliminating ototoxic medications. The guidelines, updated in 2020, advised against the use of second-line injectable drugs, kanamycin and capreomycin, due to the increased risk of treatment failure, relapse and severe side-effects.,However, patients continue to receive ototoxic medications for certain infectious diseases, cancers and chronic health conditions . GloballStandardized guidance and research are needed, especially in low-resource settings, to detect and treat hearing loss from ototoxicity. Here, we propose an approach to early detection and management of ototoxic hearing loss, provide evidence-based treatment options and identify avenues for future research.Commonly used ototoxic drugs, and their incidence and mechanisms of ototoxicity are summarized in Pseudomonas aeruginosa commonly isolated in cystic fibrosis patients, tularaemia and multidrug-resistant urinary tract infections).Aminoglycosides are an injectable antibiotic class with a reported irreversible ototoxicity of 3–50%.Box 1Peru is a global leader in its efforts to combat multidrug-resistant tuberculosis. In 1994, a sampling study showed 12 out of 22 (54.4%) tested tuberculosis cases in Peru had antibiotic resistance.Up until 2018, Peru included ototoxic second-line injectable drugs in their recommended regimen. With newly published guidelines from the World Health OrganizationSecond-line injectable drugs are cheaper to purchase than some newer and repurposed drugs, although monitoring and managing toxicity caused by second-line injectable drugs is costly. Physicians’ fear of generating resistance to novel drug agents also limits the shift away from second-line injectable drugs. Many low- and middle-income countries face similar challenges. To decrease the use of ototoxic antibiotics, future research is needed to find novel antibiotic alternatives. For multidrug-resistant tuberculosis, the move away from ototoxic medications has been aided by the introduction of bedaquiline and delamanid, which are oral antibiotics with fewer associated side-effects. Parallel efforts are needed for other infectious diseases. Increasing multilateral organization support and government subsidies to low- and middle-income countries are key to accelerating this change.–,Vancomycin and macrolides are two other antibiotic classes that have been associated with reversible ototoxic hearing loss, although the reported incidence is much lower compared with aminoglycosides. Whether vancomycin is directly responsible for hearing loss is contested in the literature, given that many patients are concurrently receiving other ototoxic medications (such as aminoglycosides or diuretics).,,Platinum-based chemotherapies, such as cisplatin, have long been associated with irreversible hearing loss. Their mechanism for ototoxicity directly affects the stria vascularis, spiral ganglion cells and hair cells of the cochlea .Loop diuretics, salicylates and nonsteroidal anti-inflammatory drugs are all associated with reversible hearing loss, and their associated incidence of hearing loss is much lower compared with aminoglycosides and platinum-based chemotherapies. Loop diuretics are thought to act on the sodium, potassium and chloride cotransporter in the cochlea and on potassium levels in the endolymph. The mechanism by which salicylates and nonsteroidal anti-inflammatory drugs affect hearing is incompletely understood, but may be related to vasoconstriction with decreased blood supply to the stria vascularis of the cochlea. Approximately 7 per 1000 individuals and 11 per 1000 individuals experience ototoxicity while on diuretics and salicylates, respectively.,https://www.who.int/publications/journals/bulletin/). Given that the earliest stages of ototoxic hearing loss occur at high frequencies that patients may not be aware of, we believe that screening programmes should aim to provide standard screening over a set frequency range and at specific time intervals.Patients who receive ototoxic medications with irreversible effects (such as aminoglycosides or platinum-based chemotherapies) should be monitored closely with audiometry to assess hearing loss. Currently, there are no universal or even comparable standards or guidelines for monitoring for ototoxic hearing loss.,Our suggested screening protocol for early detection and management of ototoxic hearing loss in both high-income and low- and middle-income countries is based on expert guidance from the American Speech-Language-Hearing Association and American Academy of Audiology .43,45 WeHearing screening for ototoxic hearing loss should monitor frequencies between 250–8000 Hz, which span the frequencies for speech.If countries have the capacity to expand hearing screening beyond the standard frequencies for speech, monitoring of ultra-high frequency thresholds (> 8000 Hz) may improve early detection since high frequencies are the first affected in ototoxic hearing loss. Countries such as Portugal, South Africa and the United States of America already include ultra-high frequency screening in their ototoxicity screening protocols, although the upper limit of screened frequencies varies from 10 000 to 20 000 Hz . However,Using the earliest sign of hearing threshold shift as an indication to consider stopping the ototoxic agent is essential to minimizing drug ototoxicity.,––In practice, researchers – especially those from low- and middle-income countries – report difficulty in properly implementing screening protocols, and have identified gaps in audiological surveillance.,Therapeutic drug monitoring should also be integrated into clinical care to provide complementary information about plasma concentrations of ototoxic agents. This information can be used to titrate doses to achieve, and not exceed, the optimal plasma concentration. This technique could mitigate any dose-related aspects of ototoxic hearing loss and other associated side-effects such as balance function.For patients receiving ototoxic medications with reversible side-effects , patients need not be subjected to routine hearing screening unless they experience subjective changes in hearing, tinnitus or balance function. If patients experience any of these changes, referral for audiometric testing is appropriate. There may be a role for baseline audiograms in patients with prolonged or indefinite exposure to these medications. Future research is needed to determine what duration of time qualifies as prolonged drug exposure.Hearing aids and hearing assistive technology serve as the first-line treatment for ototoxicity-induced hearing loss.,Cochlear implants can improve hearing in certain patients with severe ototoxicity. Cochlear implants are indicated in individuals who have mild or severe hearing loss and poor word recognition.,Efforts to improve the feasibility of hearing screening, especially in low-resource settings, have been explored. Suggested protocols, which have yet to be validated, recommend focusing on the sensitive range for ototoxicity only and decreasing the screening frequency to monthly tests, and one test after treatment ends.,,The impact of ultra-high frequency hearing loss (> 8000 Hz) is unclear given that most sounds of daily life occur below this frequency. Future research should investigate whether hearing loss observed at these higher frequencies indicates degeneration at the lower frequencies important for speech, and whether the medication responsible should be stopped after detection of such ultra-high-frequency hearing loss. Before clinical recommendations are established, other methods with a higher sensitivity to detect hearing loss ‒ such as otoacoustic emissions and auditory brainstem testing ‒ require further validation in subjects receiving ototoxic drugs.,For irreversible ototoxic agents there should be a focus on finding alternative chemotherapies, as well as developing strategies to mitigate their consequences. Recent research efforts have investigated the use of otoprotectants such as thiosulfates, antioxidants or iron chelators  to neutralize reactive oxygen species and prevent hearing loss from aminoglycosides and platinum-based chemotherapies. There continues to be mixed evidence on whether these agents are effective.Hearing loss dramatically impacts quality of life across all age groups, and is associated with an increased burden of mental illness and dementia.At the population level, avoiding and treating hearing loss is an excellent investment. Overall, the cost of hearing loss to the health-care sector, for adults and children, is estimated to range from 67 billion to 107 billion United States dollars (US$).New treatment options and revised guidelines will protect millions of people from unnecessary exposure to drugs that cause irreversible hearing loss. In the case of tuberculosis, second-line injectable drugs should be used as a last resort and should be stopped if other medication options are available. When agents that result in irreversible hearing loss are the only option, evaluation and adoption of internationally recognized guidelines are needed, alongside additional research, to prevent, manage and treat this unfortunate adverse event.


Background: Accurate data on the prevalence of hearing impairment and severity across age and gender are paramount to formulate hearing health policies. Here, we sought to analyze audiometric data from a large group of age-diverse people in Japan, which has not been previously described in detail. Methods: We analyzed retrospective hearing threshold data of 23,860 participants  at 500, 1000, 2000, and 4000 Hz, and then classified them for hearing impairment severity according to the WHO Classification. Findings: There was a significant gender difference in median hearing thresholds, starting in 20-year-olds up to early 80-year-olds. Twenty-five percent of men in their late 50s had some level of HI, ~50% in their late 60s, and ~75% in their late 70s. For women, 25% had some level of HI in their early 60s, ~50% in their early 70s, and ~75% in their late 70s. For participants in their early 80s, 50% of either gender had moderate or more severe HI. Interpretation: Our results, derived from a large number of participants, provide basic information about the prevalence of hearing loss by age decade. Since people can expect to live longer than those in previous generations, our detailed data can inform national social systems responsible for hearing screening in making decisions about hearing-aid qualification, which may reduce barriers to older people’s independence, productivity, and quality of life. The Global Burden of Disease Study —which waAnother study estimated that, in 2019, the total global economic costs of failing to address hearing loss exceeded USD 981 billion . These cRecently, reports on early interventions addressing hearing loss have received increasing attention ,6, becauAccurate population data on the prevalence of hearing impairment and the rate of minor, moderate, and severe hearing loss across the age spectrum are very important if public health professionals are to formulate national policies about hearing-loss management. However, to date, there are only a few reports about these details ,16, mostIn our previous study, we built and analyzed the largest database to date of hearing thresholds and other audiometric data of Japanese people aged 10–90 years . These dIn the present study, we analyzed the entire dataset comprising 23,860 native Japanese-speaking participants, including a re-evaluation of participants’ data that were outliers. The subjects ranged in age from 10 to 99 years. We report the prevalence of hearing impairment and severity by age decade.We conducted a retrospective cross-sectional study of a broad age range of patients in Japan. A total of 30,147 patients and 69,222 associated pure-tone audiometry tests were available to be evaluated for inclusion. Audiometric data of some of these participants were presented in a previous report . To be eThis retrospective study was approved by the Tokyo Medical Center’s Institutional Review Board (IRB No. R20-087). Written informed consent was not obtained because of the study’s retrospective design and because it was impracticable. Included patients’ personal details and their data were de-identified.For the main analyses, we calculated the simple arithmetic mean hearing threshold, according to the method described in the WHO International Classification of Impairments, Disabilities, and Handicaps . BrieflyTo classify hearing loss severity, we graded hearing thresholds as described in the WHO International Classification of Impairments, Disabilities, and Handicaps . This grWe also measured and classified hearing loss according to methods outlined by Japanese law. In Japan, hearing loss is considered to be a public health issue; thus, Japan has enacted various laws and acts that take hearing into account. Those laws also describe methods for calculating and classifying hearing loss. For example, the Law for the Welfare of Physically Disabled Persons stipulates that hearing loss is to be assessed at 1000 Hz and that a weighted average is to be used to determine whether an individual qualifies for welfare support due to hearing impairment . On the p < 0.05 was considered statistically significant. GraphPad was also used to construct all graphs and visual depictions of data.We used the Shapiro–Wilk statistical test to assess whether the distribution was normal. As all parameters in our study were distributed non-normally, the Mann–Whitney test was used to evaluate differences. All statistical analyses were performed using GraphPad Prism 9.2.0 . The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.We identified 23,860 patients  who met The gender-specific distributions of average hearing thresholds are shown in The percentages of participants in the five WHO grades (Grades 0–4)  of heariA similar pattern of hearing loss severity was observed in female participants across the age spectrum, but the age onset appeared to be later for women. Twenty-five percent of women in their late 60s had some level of hearing impairment , while 50% of women in their early 70s and 75% in their late 70s had some level of hearing impairment . As with men, more than 50% of women had moderate or severe hearing loss in their early 80s. For women in their 90s, about 10% had a slight impairment (Grade 1).The results from using the methods for assessing hearing loss outlined by Japanese law are presented in Hearing impairment is a significant health burden globally , one thaIn the present study, the prevalence of hearing loss in patients visiting our clinic decreased from the second decade through to the fourth decade (10s to 30s years). As a majority of congenital or early-onset hearing loss can be detected by neonatal screening , patientIn each decade from the 20s to early 80s, the median hearing thresholds in men were significantly higher than in women. It is consistent with the past reports and was reported to be attributable to genetic and environmental factors ,25,26. AOne international health tracking survey on subjective hearing impairment and hearing-aid adoption showed that there was no difference in the prevalence of self-reported hearing loss rates between Europe  and JapaA leader in this approach is Singapore. In 2018, the Singapore government launched Project Silver Screen for citizens aged 60 and above, which screens for vision, oral, and hearing problems . HearingFor a relatively small nation as Singapore, the screening of all citizens aged 60 and above is reasonable, because its population is relatively small at 5.45 million . For couOur analysis has limitations. First, the study sample is based on retrospectively collected data from chart records of patients who underwent pure-tone audiometry for various reasons in the otolaryngology department at a major general hospital in Tokyo. Therefore, it might include some cases with hearing loss considered to be more severe than what is observed normally in a population of people not seeking medical attention. However, it is very difficult to evaluate thousands of people—from young people to the elderly—with high-quality pure-tone audiometry without any tendency. Therefore, our results can be considered to provide basic information about the prevalence of hearing loss by age bracket. Second, the data were collected over 20 years, and the analysis is a secondary analysis of data collected for a different purpose. Nonetheless, this is an effective means of research, as primary data collection is too costly or infeasible. Although our department has standard procedures for performing audiometric testing, we cannot be certain that the data might not have been collected systematically and that there might have been slight differences in data collection over the 20 years of audiometric testing.In conclusion, based on the results of the present study, population-wide hearing-loss screening initiatives should target those over 70 years old. This recommendation seems warranted since more than one-half of our subject population in these age groups had some level of hearing impairment. For more focused screening initiatives, the threshold for beginning routine screening should begin after age 80, since our present findings showed that more than one-half of those 80 years and older have moderate or severe hearing impairment. Public or social initiatives for hearing-loss screening should also direct individuals to where and how they can obtain more in-depth audiometric examination to promote hearing-aid adoption . Increas


The prevalence of activities of daily living (ADL) in patients with heart failure (HF) reported in current studies were inconsistent, ranging from 11.1 to 70.5%. The purpose of this study is to quantify the prevalence of ADL impairment in HF patients.Q and I2 values. Sensitivity analysis, subgroup analysis, and meta-regression were performed to investigate the sources of heterogeneity.PubMed, Embase, Cochrane, CINAHL, CNKI, SinoMed, VIP, and Wanfang databases were systematically searched for relevant studies . Cross-sectional, case-control, or cohort studies with detailed descriptions of overall ADL impairment in HF were included. Stata 16.0 was used for statistical analysis. Fixed-effect or random-effect model was adopted according to heterogeneity which was evaluated by Cochran’s I2 = 99.5%, P < 0.001). No possible sources of heterogeneity were found in subgroup analysis and meta-regression. Funnel plots and Egger’s test showed no publication bias (P = 0.595).A total of 12 studies with 15,795 HF patients were included in the meta-analysis, and the pooled prevalence of ADL impairment in patients with HF was 38.8% (95%CI: 28.2–49.3%; The prevalence of ADL impairment is relatively high in HF patients. Differences in the prevalence of ADL impairment in patients with HF may be influenced by country, region, and assessment time. We suggest that more researchers could focus on the changes of ADL impairment in HF patients during different disease periods in different regions and countries. Heart failure (HF) is a complex clinical syndrome characterized by deterioration of the heart and other systems such as the kidneys, liver, lungs, and muscles. It is estimated that 64.3 million people worldwide suffer from HF . The HF To allow a more rational allocation of medical resources, the prevalence of ADL impairment among patients with HF must be identified first. However, currently, investigations on this topic give a wide range of results. In a study from America (US), the ADL impairment prevalence was 11.1% . One stuThis systematic review and meta-analysis was based on the preferred report items in the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA 2020) guidelines.We searched four English databases  and four Chinese databases  for studies related to ADL impairment in patients with HF . We used the following search terms, adapted for each database when appropriate: ADL (“activities of daily living” or “ADL” or “Daily Living Activities” or “Chronic Limitation of Activity” or “ADL disability”) and HF  (the full list of search terms is provided in Inclusion criteria were: (1) Patients were diagnosed with HF; (2) The study included a detailed description of the assessment scale of ADL; (3) Complete baseline data of the total prevalence of ADL impairment was provided; (4) The study design was cross-sectional, case-control, or cohort; and (5) Research published in English or Chinese.Exclusion criteria were: (1) meeting abstract, case report, review, meta-analysis, letter, pilot study or qualitative study; or (2) duplicate studies and/or data .Two reviewers screened the literature separately according to the inclusion and exclusion criteria, and a third reviewer made a judgment if there were conflicts.Two investigators retrieved data from eligible studies independently, while a third investigator double-checked for accuracy. Data extracted included the first author, publication time, country, design, sample size, sex, age, type of patient, NYHA class III-V, LVEF, assessment scale, assessment time (Sources), and ADL impairment .Quality of the included studies was evaluated using the modified Newcastle-Ottawa Scale (M-NOS) . There aQ-value) and I2-value were used, with P < 0.05 or I2 > 50% indicating significant heterogeneity between studies. Fixed-effect model was performed to calculate the pooled prevalence of ADL impairment in patients with HF when there was no significant heterogeneity, and random-effect model was used otherwise. Subgroup analysis, sensitivity analysis and meta-regression analysis were undertaken to identify the sources of heterogeneity. Funnel plots and Egger’s test were conducted to evaluate publication bias.For statistical analysis, Stata 16.0 was employed. To examine heterogeneity, Cochran’s chi-square test   .Q = 3.25, P = 0.197). In the subgroup analysis of assessment scale, the prevalence was 49.0% (95%CI: 23.1–75.0%) by using BI, 32.1% (95%CI: 15.1–49.2%) by use other scale, and 35.2% (95%CI: 15.4–55.1%) by using KI . The prevalence of was 66.2% (95%CI: 58.7–73.6%) on admission. When discharged from the hospital, the prevalence was 33.8% (95%CI: 19.1–48.5%). When measured in the out-of-hospital setting, such as in a community setting or prior to hospital admission, the prevalence was 33.0% (95%CI: 23.6–42.5%) . In the assessment method subgroup analysis, the prevalence was 55.8% (95%CI: 27.0–84.6%) when the assessment was made by physical therapist, higher than 35.4% (95%CI: 23.9–46.7%) by self-report . However, none of the subgroups might be a source of heterogeneity , 38.3% (95%CI: 21.4–55.2%), and 30.0% (95%CI: 15.7–44.1%)   .t = 0.55, P = 0.595)  .This systematic review and meta-analysis included 12 studies with a total sample size of 15,795 HF patients. The pooled results showed that 38.8% of HF patients suffer from ADL impairment. As far as we know, this meta-analysis is the first to quantitative the prevalence of ADL impairment in patients with HF worldwide.P = 0.001). The prevalence of ADL impairment in Asian was 50.3%, which was the highest among the three regions. In our review, the highest prevalence of ADL impairment in Japanese HF patients was 58.2%. Firstly, Japan is the country with the fastest aging population in the world. The number of HF patients in Japan, especially the elderly, is increasing rapidly , followed by discharge 33.8%) and lowest in the out-of-hospital setting (33.0%). The higher ADL impairment prevalence in patients with HF in the acute setting  is reasonable. It can be explained by the presence of dyspnea, chest pain, and edema in the decompensated phase of HF patients . The HF .8% and lHowever, the present study also has the following limitations. First, more than half of the included studies were conducted in Europe and the US, and for some reason there is a lack of relevant studies on ADL impairment in HF patients in other countries. This made the consult potentially unrepresentative on global level. Considering the imbalance of health care resources in different regions, we suggest that more studies should be conducted in different regions to understand the overall situation. Second, due to limited data from the original study, quantitative assessment of ADL impairment was lacking, as well as subgroup analysis of some influencing factors associated with ADL impairment, such as LVEF, BMI, and age, was not performed. It is expected that future studies will provide more original data to explore the sources of inter-study heterogeneity from the above perspectives. Last, the assessment tool of ADL included in this review were based on subjective feedback of the patients, which may not be objective enough. We expect that future studies will use more objective tools to evaluate ADLs .The prevalence of ADL impairment in HF patients was 38.8%. Additionally, differences in the prevalence of ADL impairment in patients with HF may stem from country, region, and assessment time. We suggest that more researchers focus on the changes of ADL impairment in HF patients during different disease periods in different regions and countries.The original contributions presented in the study are included in the article/JL and YZ searched and checked the databases according to the inclusion and exclusion criteria, extracted the data, and assessed their quality. JL analyzed the data and wrote the draft of the manuscript. RY and MW gave advice on meta-analysis methodology and revised the manuscript. XS was the guarantors of this work and had full access to all the data in the study and took responsibility for its integrity and the accuracy of the data analysis. All authors contributed to reviewing read and approved the final 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Type 2 neurofibromatosis (NF2) is an autosomal dominant disease with a frequency of 0.5/100,000 inhabitants; it manifests mainly as bilateral vestibular schwannomas and bilateral profound hearing loss.Brainstem implants have been the main hearing rehabilitation method in these patients.The past decades have witnessed refinements in the results of surgeries for the treatment of vestibular schwannomas. The possibility of preserving the cochlear nerve in neurofibromatosis cases makes it feasible to fit cochlear implants for improved auditory rehabilitation.We present the results attained in a patients with neurofibromatosis in whom the neoplasm was removed and a cochlear implant was placed simultaneously. Based on a review of the literature, this is the first documented case of this procedure in Brazil.HC, a white male student aged 23 years, diagnosed with neurofibromatosis type 2, developed significant hearing loss to the right, which was associated with tumor growth in that side. The tumor was removed surgically in 2005, but the patient progressed to total hearing loss. In 2008, the patients noticed marked hearing loss to the left, diagnosed as profound hearing loss due to growth of the ipsilateral tumor .Figure 1Simultaneous surgery and brainstem implant were indicated. The patient did not want the brainstem implant, and it was agreed that if the cochlear nerve remained intact, a cochlear implant would be fitted.Translabyrinthine surgery was uneventful; the meningioma and the vestibular schwannoma were removed, and the facial and cochlear nerves were preserved; a cochlear implant was placed. Intraoperative neural telemetry confirmed consistent responses in all electrodes.The facial nerve remained functional.Imaging for control purposes demonstrated that the tumors had been adequately removed. After 6 months of cochlear implant use, the pure tone threshold was around 30 dB, monosyllable discrimination was 56%, and open set sentence discrimination was 100% (Treating patients with neurofibromatosis type 2 remains a difficult task. Fortunately, satisfactory results have currently been attained in the treatment of this disease, and patients have become more concerned with their quality of life. Approaches to restore hearing should always be taken into account when treating neurofibromatosis type 2, as bilateral profound hearing loss is an almost universal event in this condition. Brainstem implants have been the main choice for many years, and have yielded interesting but limited results in language discrimination.Finally, cochlear implants are safer than brainstem implants in terms of the eventual adverse effects of electrical stimulation; they are also less costly, and it is more practical to maintain its programming and electronic components. Furthermore, cochlear implants may be used in patients that live far from tertiary care or high complexity healthcare centers.Our case of a young patients with bilateral hearing loss that had already been operated, without hearing rehabilitation, benefited significantly from a cochlear implant fitter immediately after removing his second vestibular schwannoma, enjoying improved quality of life.Fitting a cochlear implant is an approach to be considered in the surgical planning of neurofibromatosis type 2 patients with bilateral schwannomas. This may be justified because of the superior auditory results that this technique provides compared to brainstem implants, as well as more safety and easier maintenance and programming.