The primary objectives of this study were to evaluate the effect of hearing implant (HI) use on quality of life (QoL) and to determine which QoL measure(s) quantify QoL with greater sensitivity in users of different types of HIs. Participants were adult cochlear implant (CI), active middle ear implant (VIBRANT SOUNDBRIDGE (VSB)), or active transcutaneous bone conduction implant (the BONEBRIDGE (BB)) recipients. Generic QoL and disease-specific QoL were assessed at three intervals: pre-activation, 6 months of device use, and 12 months of device use. 169 participants completed the study . CI users’ QoL significantly increased from 0–6 m device use on both the generic- and the disease-specific measures. On some device-specific measures, their QoL also significantly increased between 6 and 12 m device use. VSB users’ QoL significantly increased between all tested intervals with the disease-specific measure but not the generic measure. BB users’ QoL significantly increased from 0–6 m device use on both the generic- and the disease-specific measures. In sum, HI users experienced significant postoperative increases in QoL within their first 12 m of device use, especially when disease-specific measures were used. Disease-specific QoL measures appeared to be more sensitive than their generic counterparts. The World Health Organization defines “health” as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity” . ConsequRegarding assessing the effects of hearing implant (HI) use, speech understanding has often been considered the primary outcome measure. HI recipients/users, therefore, routinely complete speech perception tests in sound booths or in similarly carefully controlled settings. While the results of these tests give invaluable information on users’ hearing ability, they do not convey the full benefit (or lack thereof) of HI use because carefully controlled environments do not mimic the actual lived experience with a HI. Thus, while gains in speech understanding may correlate with gains in QoL ,11, thisHI use can improve the QoL of a person with hearing loss ,16. ThusThe QoL benefit from HI use may depend upon the user’s severity of hearing loss, i.e., appropriately fit cochlear implant (CI) users with profound unaided hearing loss may derive more subjective benefit than hearing aid users with moderate hearing loss, despite having lower objective hearing levels . Thus, tThe secondary objectives were to assess if: (1) the results on disease-specific QoL tests correlate with those from generic QoL tests, (2) participants are satisfied with their received audio processor, (3) user satisfaction correlates with QoL scores, and (4) speech test outcomes correlate with the QoL results.To be enrolled in the study, potential participants had to have postlingual hearing loss, be at least 10 years old , have never used a HI, be willing and able to complete the study tasks, and give their informed consent.All participants became users of a CI, an active middle ear implant (VIBRANT SOUNDBRIDGE (VSB)), or an active transcutaneous bone conduction implant (the BONEBRIDGE (BB)). Based on their treatment, participants were allocated to one subgroup .All study sites are represented in the authors’ affiliations on the title page of this manuscript. Study sites were selected as per their long experience with HIs, state-of-the art facilities, and willingness and availability to participate.This study was of an exploratory nature. It was intended to enroll a minimum of 69 participants with a CI, 38 participants with a BB, and 38 participants with a VSB. The a-priori estimated sample sizes were based on following existing comparable data:t-test, a minimum sample size of 13 subjects was calculated for each CI indication group. CI participants: Arnoldner et al.  reportedVSB participants: Edfeldt et al.  reportedBB participants: no comparable data for BB users exist. As the indications for a VSB are quite similar to a BB, it was intended to also include 38 subjects.The three study intervals were: pre-activation, at 6 months of device use, and at 12 months of device use. Participants did not complete all tests at all intervals. Participants completed the questionnaires via paper and pencil. Clinical testing (speech tests and audiograms) was conducted as per the clinical routines at each center.Generic QoL was assessed in all participants via the HUI-3 at all three intervals . Scores 12) at all three intervals [12 consists of 12 items with a visual analogue scale between 0–10. It was used to measure hearing abilities across three subdomains: speech perception, spatial hearing, and general qualities of hearing. In this study, we analyzed the total score.Disease-specific QoL was assessed in all participants via the Speech, Spatial, and Qualities of Hearing Scale (short version with 12 items)  that can be split into the following nine subdomains: physical domain, basic sound perception, advanced sound perception, speech production, social domain, activity, social functioning, psychological functioning domain, and self-esteem. All 60 items in the NCIQ are answerable on a 5-point Likert scale. Before calculating final scores, the items were reversed if applicable and then transformed. Scores from each subdomain were calculated based on the average of these transformed values. A maximum of three missing answers  per subdomain was allowed . SubdomaParticipants assessed their own satisfaction with their audio processor at 6 months of device use and at 12 months of device use via the Audio Processor Satisfaction Questionnaire (APSQ) . The APSAt each of the two post-activation intervals, participants reported to their clinician how many hours per day they used their audio processor. Speech understanding was assessed at all intervals. Each clinic used the test(s) of their choice, as per their clinical routine.Data of participating study sites were pooled. The selection criteria set for this study allowed enrolling a homogeneous population within the context of a clinical routine, a real-life setting that allowed a non-biased pooling of the results. All study sites followed the same agreed-upon protocol to prevent a treatment-by-center interaction.Safety was evaluated via adverse event reports.Descriptive statistics were used to report patient’s demographic  and baseline characteristics . Descriptive statistics were also used to present questionnaire results and speech test outcomes.t-test, or the Wilcoxon signed-rank test was used to test for a significant improvement in QoL between two visits. Statistical significance was set to p ≤ 0.05. To avoid the Type I error rate because of multiple comparisons, the p-values were adjusted using the Holm–Bonferroni correction method. Missing data were treated as missing values. Statistical analyses were performed with IBM SPSS Statistics Version 24 . Inferential statistics were applied based on the formulated hypotheses for each of the three treatment groups. The Kolmogorov–Smirnov test was used to check for data distribution. General Linear Models for repeated measurements (RM ANOVAs) with time as factor were performed to test for a significant improvement in QoL over time. Depending on the data distribution, the Student’s A total of 169 of 171 enrolled participants completed the study. Two participants were withdrawn from analyses (one for not fulfilling the study criteria and one for not adhering to the major criteria of the study protocol). Of the 169 participants, 110 received a CI , 18 received a VSB , and 41 received a BB  see . n = 38, could be included. Choice of HI was based on indication. The choice of implant, array, and audio processor was related to availability and individual clinical preference. This explains why only 18 VSB recipients, rather than the planned The type of hearing loss varied for VSB and BB recipients. Amongst VSB recipients: eight participants had mixed hearing loss, five had sensorineural hearing loss, two had conductive hearing loss, and data were missing for three participants. Amongst BB recipients: 16 participants had mixed hearing loss, 13 had sensorineural hearing loss, 11 had conductive hearing loss, and data were missing for one participant. All CI recipients had sensorineural hearing loss.p < 0.001). For the BB group, scores improved significantly from pre-FF to 6 m (p = 0.031) and from pre-FF to 12 m (p = 0.018)  to 6 m, from pre-FF to 12 m, and over time  see .p < 0.001). For the VSB group, scores improved significantly from pre-FF to 6 m (p = 0.011), from pre-FF to 12 m (p = 0.002), from 6 m to 12 m (p = 0.030), and over time (p < 0.001). For the BB group, scores improved significantly form pre-FF to 6 m (p < 0.001), from pre-FF to 12 m (p < 0.001), and over time (p < 0.001)  see .p < 0.001). A significant improvement was found for basic sound perception from 6 m to 12 m (p = 0.002). Note, as this test is designed for CI users, only the CI group was assessed   see .Participants were asked at both post-activation visits about their average daily use. More than 90% of the CI subjects, more than 70% of the VSB subjects, and almost 60% of the BB subjects reported an average daily use of 9 h or more after 12 months of device use see .n = 19), 68.0% ±16.3% (29–96%) at 6 m (n = 35), and 66.8% ±21.2% (16–94%) at 12 m (n = 35); the pre-FF to 12 m gain was 41.6 percentage points. The Friedman test showed a significant improvement in speech performance over time for the CI group . Speech performance was collected according to clinical routine. The mean, the standard deviation (± SD), and the range of available speech test results in % correct and collapsed across sites were recorded. For CI users, speech performance was 25.2% ±23.0% (0–67%) at pre-FF  and from the 6 m visit to the 12 m visit aided with a CI . Additionally, we performed pairwise comparisons with the Wilcoxon signed-rank test that showed a significant improvement from the pre-fitting (FF) visit in the best-aided condition to the 6 m visit aided with a CI (n = 2), 87.5% (75 and 100%) at 6 m (n = 2), and 95% (range: 70–100%) at 12 m (n = 3); the pre-FF to 12 m gain was 70.8 percentage points. For BB users, one user scored 0 at pre-FF, and no users were tested at 6 m or 12 m. For VSB users, the median speech performance was 17.5% (0 and 35%) at pre-FF  was found for the CI group. No significant correlation between the two measures was found for the VSB or BB groups (HUI-3 and SSQ12).For this, objective data from the 12 m visit were used. A significant correlation between the HUI-3 score and the SSQ12 total score was significant by trend for the CI group (p = 0.040) and significant for the VSB group (p = 0.004). In CI users, a significant correlation between the APSQ total score and the NCIQ was reached in the Psychological Self-esteem subdomain (p = 0.002).For this, objective data from the 12 m visit were used. No significant correlation between the APSQ total score and the HUI-3 was found in any treatment group. The correlation between the APSQ total score and the SSQ12, and NCIQ) were found.Only data from CI users were considered because there were few speech test outcomes available for the other two groups. No significant correlations between speech test outcomes and the QoL measures  experienced pain or irritation, which was resolved by changing the magnet strength; one participant (SAMBA BB) experienced pain on the surgical side when wearing glasses, which was resolved by the participant changing his/her style of glasses; and one participant (SAMBA BB) experienced an internal device failure, which was resolved via explantation and reimplantation.Including QoL tests as part of the assessment battery of HI users has become common in the literature. Indeed, the role of QoL tests—and patient-reported outcomes in general—has increased so that they now play an important role in the decision making of regulatory bodies, health care payers, professionals, and users ,8,9,29. 12) and with a generic measure (HUI-3)  is not the average of the single-attribute scores, rather it is calculated by a special formula provided by the HUI-3 authors, which can result in a score below zero). The results show that HI use can have a significant impact on users’ generic and disease-specific QoL. The results from CI users (who have severe to profound hearing loss in at least one ear) suggest that, for high levels of hearing loss, device use leads to significant improvements in QoL when assessed with disease-specific measures (NCIQ and SSQThe changes in generic QoL (HUI-3) due to HI use in the CI group were relatively strong compared to the changes reported by the BB and VSB groups. A possible explanation for this could be the influence of the contralateral ear upon the user’s severity of hearing loss, i.e., appropriately fit CI users with profound unaided hearing loss may derive more subjective benefit than hearing aid users with moderate hearing loss, despite having low objective hearing levels . In the Improving the functionality of their implanted ear could substantially improve their QoL because it becomes their better hearing ear and the hearing in their contralateral ear is too poor to “fall back on”. In contrast, BB and VSB users were likely to have similar or even better hearing in their contralateral ear than in their implanted ear, even when best aided. Thus, the hearing benefit derived from device use would be less dramatic and, therefore, lead to smaller changes in QoL.12 scores (but not HUI-3 scores) increased from the second (6 months post-FF) to the third study visit (12 months post-FF). NCIQ scores also increased significantly during this time period but only for the “Basic sound perception” subdomain. This indicates that (1) CI users derive the bigger QoL benefit within 6 m of FF and that (2) the SSQ12 is more sensitive, likely due to its specificity, than the generic questionnaire. Interestingly, for the CI users, SSQ12  was sensitive enough to continue indicating a significant benefit, whereas the generic questionnaire was not. This could be interpreted as due to a change in quality of hearing and, potentially, in speech understanding.Importantly, compared to other generic QoL measures , the HUI-3 is more sensitive to changes in hearing; likely because the SF-36 and the EQ-5D both lack a specific hearing domain/subdomain assessment ,31, thus12 scores from the second to the third study visit (6 m to 12 m). Differences between these two HIs might contribute to this difference: the BB implant is screwed into the skull [This idea can be supported by the fact that the VSB but not the BB users showed a significant increase in the SSQhe skull , while the skull . This ca12. A possible result of these differences is that, for the BB, no changes in QoL are expected from the first fitting onwards. In contrast, VSB users may experience changes related to the healing and fitting process over a longer time. In turn, this may impact on hearing and secondarily on QoL. The mentioned factors could contribute to a change in quality of hearing and speech understanding, which, in turn, can be mirrored in the SSQCorrelational analyses between the different questionnaires used in the present study were very weak. Based on the results from this study and previously published studies, it seems recommendable to use a generic QoL measure ) and one disease-specific measurement. There are several studies that implemented this strategy and reported a high impact of using both measurements in participants with hearing loss ,35,36. 12 was very sensitive to changes during the first year after FF, while the NCIQ was less sensitive: significant changes could be detected only for one subdomain. The fact that the NCIQ detected the largest changes in disease-specific QoL early after CI switch-on is in line with the results of a previous study on CI users with SSD [12, which also contains several items on Quality of Hearing, was very sensitive to changes during the first year of HI use. If clinicians aim to investigate the change of QoL due to HI use in their patients, a generic QoL questionnaire can show large changes from before to after HI provision. It is important, however, to also consider that using the HUI-3 necessitates paying the questionnaire’s license fees. In the present study, the SSQwith SSD . In cont12 can better detect smaller changes in QoL or, rather, Quality of Hearing. Another advantage of using the SSQ12 is that it is much shorter than the NCIQ (12 items versus 60 items). Further, unlike the SSQ49/SSQ12, there is no short version of the NCIQ, and there is no proxy version that caretakers can take in the patients’ stead. This could be an issue for some candidates/recipients. Newer questionnaires, e.g., the ERSA [The AQOL-8D, a newer and (thus far) less-used generic QoL measure, also contains a dimension on senses, including hearing, and could be a promising free alternative . Using tthe ERSA  or the Cthe ERSA  may alsoDevice satisfaction, as measured with the APSQ, increased significantly during the first year of CI use. This is an interesting result because the average speech understanding results were similar for both follow-up visits. This first experience with the APSQ questionnaire in a longitudinal study suggests that this questionnaire can help clinicians evaluate user satisfaction with their device in everyday life throughout the first year of use. The APSQ could also be helpful for counselling of candidates and user rehabilitation; however, more data are needed before that can be stated with more confidence.Regarding speech understanding results and QoL results, their lack of correlation is in line with results of previously published studies ,14,38. TThis holistic view acknowledges that hearing loss has a broader impact on life than simply hearing and that small increases in hearing due to device use can have great benefits in a user’s life and vice versa. Thus, while speech-understanding scores are undoubtedly important, a full picture of the impact of HI use is incomplete unless users’ QoL and satisfaction with their HI are assessed before and after HI provision.The present study has certain limitations. First, the choice of intervals means that this study could not capture changes in QoL occurring before 6 months of use or after 12 months of use. Other published studies suggested that (1) a significant increase in QoL after HI treatment can be measured already after 3 months  and thatImprovements in QoL are an important result of HI use. The results of the present study showed that this improvement was significant within the first year of HI use, especially when evaluated using disease-specific measures. The significant increases in QoL did not correlate with increased speech perception. This finding highlights that real life benefits of HI use should not be extrapolated from in-clinic speech testing; instead, disease-specific measures are an important tool in assessing user benefit.


Lysosomal proteases play a crucial role in maintaining cell homeostasis. Human cathepsin D manages protein turnover degrading misfolded and aggregated proteins and favors apoptosis in the case of proteostasis disruption. However, when cathepsin D regulation is affected, it can contribute to numerous disorders. The down-regulation of human cathepsin D is associated with neurodegenerative disorders, such as neuronal ceroid lipofuscinosis. On the other hand, its excessive levels outside lysosomes and the cell membrane lead to tumor growth, migration, invasion and angiogenesis. Therefore, targeting cathepsin D could provide significant diagnostic benefits and new avenues of therapy. Herein, we provide a brief overview of cathepsin D structure, regulation, function, and its role in the progression of many diseases and the therapeutic potentialities of natural and synthetic inhibitors and activators of this protease. Their primary role is the disposal and the recycling of exhausted and deteriorated macromolecules and organelles, along with the digestion of alien structures supplied by endo- and phagocytosis . Lysosomme lumen . Cathepsme lumen . Most ofme lumen ,6,7,8. Tme lumen ,11,12,13CTSD) is located at the 11p15.5 region and contains 9 exons [The aspartic protease cathepsin D is the most abundant lysosomal protease . The hum 9 exons . The enc 9 exons . Once it 9 exons . This fi 9 exons   was shown to induce a progressive accumulation of undigested autophagic substrates and unfolded or oxidized protein aggregates within the lysosomes during aging. This phenomenon can cause lysosomal membrane damage, culminating in cathepsin leakage and consequent apoptosis, favoring neurodegeneration .CTSD gene are associated with different neurological defects [CTSD gene homozygous inactivation was reported to cause human congenital neuronal ceroid lipofuscinosis (NCL) with postnatal respiratory insufficiency, epilepsy, and death within hours to weeks after birth, due to neurological defects and absence of neuronal α-synuclein accumulation [CTSD gene heterozygous missense mutations is associated with childhood motor and visual disturbances, cerebral and cerebellar atrophy, as well as progressive psychomotor disability. NCL3, a group of rare recessive lysosomal storage diseases, is associated with mutations in 14 different genes, including CTSD [CLN5) c.A959G (p.Asn320Ser) correlates with Alzheimer’s disease occurrence [CLN5 c.A959G variant causes a defect in the transport of cathepsin D to the endolysosomal compartment, resulting in an increased pro-cathepsin D level and a reduced mature cathepsin D expression [Most neurodegenerative conditions can be distinguished in idiopathic (derived from unknown causes) and familial forms (linked to the gene mutation) . Familia defects . CTSD gemulation . Signifiing CTSD . The maicurrence . More prpression . MutatioIn line with these data, any misbalance in protein degradation processes, such as autophagy and lysosomal hydrolytic enzyme activity is linked to some age-associated neurodegenerative disorders ) . NPC is CTSD gene was associated with sporadic late-onset Alzheimer’s disease in the adult German, Iranian, and Ecuadorian populations [Some forms of cathepsin D deficiency could also predispose to late-onset Alzheimer’s disease and Parkinson’s disease . The polulations . Howeverulations . Alzheimulations . In suppulations . Anotherulations . Statistulations . TherefoThe unique role of cathepsin D in α-synuclein proteolysis, which accumulates in Parkinson’s disease, has been proven. Sulfated glycosaminoglycans, which hoard in substantia nigra of Parkinson’s disease patients along with α-synuclein, decrease the activity of cathepsin D . The defGBA1) are associated with Parkinson’s and Gaucher’s disease. Experiments on dopaminergic neurons and astrocytes carrying this mutation indicated excessive levels of α-synuclein released from neurons that are eventually endocytosed by astrocytes [ATP13A2 deficient zebrafish (Parkinson’s disease model) confirmed the reduced cathepsin D expression and showed lysosomal abnormalities, leading to the degeneration of dopaminergic neurons arguably caused by intracellular trafficking impairment [Mutations in the β-Glucocerebrosidase gene  were shown to increase cathepsin D activity at multiple concentrations after 24-h exposure . A highepression . This phpression . Experimpression . Chlorogpression . Specifi5Y cells . It was  neurons .There are multiple approaches to increase active cathepsin D in the cells. However, it is necessary to understand the kind of mechanism that caused the protease deprivation at first. There are also some risks associated with the modulation of this fragile balance that could favor the onset of other disorders.As mentioned earlier, Aβ aggregates can decrease the cathepsin D activity within the lysosomes. However, high exosomal levels of cathepsin D and LAMP1 together with low levels of the 70 kDa heat shock proteins were detected in the blood of patients with Alzheimer’s disease, suggesting a diagnostic role for this protease . In addiGlutaric acidemia type I (GA1) is a chronic progressive neurodegeneration caused by severe deficiency of glutaryl-CoA dehydrogenase activity, leading to glutaric acid and glutarylcarnitine accumulation . It was The plasma of maple syrup urine disease patients showed increased levels of cathepsin D compared to the control group . The autMost neurodegenerative disorders caused by cathepsin D imbalance are characterized by down-regulation of the protease. However, there is evidence that in pathological conditions it can increase extracellularly, while the lysosomal concentration of cathepsin D can decrease.Hyperglycemia can trigger cathepsin D release from the lysosomes by inducing lysosomal membrane permeabilization and ion release. Cathepsin D can remain active in non-acidic pH environments such as the cytosol. Altogether, this contributes to hyperglycemia-induced cardiomyocyte injury in patients with diabetic cardiomyopathy . These rThe data concerning the influence of excessive cathepsin D activity outside the lysosomes on the severity of diabetes are relatively scarce. Further investigation of the mechanisms of cathepsin D regulation in this disorder may reveal new approaches for anti-diabetic therapy. Nevertheless, accumulated data detail the connection between lysosomal protease release and a pathological condition.Increased extracellular levels of cathepsins are well-characterized for tumors, and cathepsin D is no exception. High levels of cathepsin D were observed in breast , ovarianProgesterone receptor isoforms A and B (PR-A and PR-B) ratio is used as a prognostic factor in breast cancer . Breast 2+-mediated lysosomal exocytosis in HCC [Liu et al. showed that tetrabromobisphenol A (TBBPA) could increase the extracellular and decrease the intracellular levels of cathepsins D and B in hepatocellular carcinoma (HCC) cell line, HepG2 . These rs in HCC . Increass in HCC . DetectiThe outcome of several studies claims that cathepsin D, together with cathepsin B, plays essential roles in the production of angiotensin peptides in glioblastoma cells bypassing the renin-angiotensin system . Basu etThe abundance of cathepsin D outside the lysosomes in malignant tumors makes it a convenient marker and a target for cancer treatment. Still, there must be targeted delivery of the inhibitors to prevent the onset of off-site disorders.Sophora flavescens down-regulated the expression of cathepsin D, inhibiting high mobility group protein 1/toll-like receptor 4/nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, resulting in the suppression of microglia-mediated neuroinflammation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-stimulated mouse model of Parkinson’s disease [Maclura pomifera, Maclura tinctoria, and Psidium guajava is claimed to be anti-oxidative and anti-inflammatory. Recently, it was shown to inhibit cathepsin D in kidneys of mice with chronic kidney damage [Most cathepsin are cysteine proteases so their inhibitors belong to the cystatin superfamily, including stefins, kininogens, thyropins, and serpins . However disease . Fucoida disease . Flavonoy damage . Molecul33 in cathepsin D. Furthermore, a group of scientists using a graph convolutional neural network (CNN) indicated that cathepsin D is an off-target ligand of some β-secretase 1 inhibitors [Some experiments demonstrated that a small-molecule inhibitor of β-secretase 1, aminothiazole-based compound LY2811376, inhibits cathepsin D activity as well . This pHhibitors . Anotherhibitors . It demohibitors . They wehibitors . Howeverhibitors .Peucedanum praeruptorum and U0126 synergistically inhibited cathepsin D expression through the extracellular signal-regulated kinase 1/2 signaling pathway in human non-small cell lung cancer cells [Streptomyces hygroscopicus combined with a recombinant analog of human milk protein lactaptin decreased cathepsin D activity with cytotoxic effects in MDA-MB-231 cell line (breast carcinoma) [Several studies indicated the effectiveness of combination therapy with natural and synthetic inhibitors. For instance, co-treatment with praeruptorin C from er cells . There ircinoma) .CTSD shRNA lentiviral vector transduction suppressed lipopolysaccharide-induced neuroinflammation by inhibiting NF-κB signaling pathway [P) RNA aptamer binding to PtdIns(3)P inhibited autophagy by hampering lysosomal acidification, which resulted in reduced cathepsin D activity [RNA-based compounds might represent another approach to inhibit cathepsin D. It was shown that cathepsin D knockdown via  pathway . This ph pathway . Phosphaactivity .Although some studies have shown that cathepsin inhibitors may be used as metastasis suppressors , others Cathepsin D is involved in autophagy, endocytosis, degradation of misfolded or mutated proteins, regulation of the activity of various polypeptides, enzymes and growth factors. Due to its numerous roles in metabolic processes, necessary for cell survival and death, it is crucial to maintain the level of cathepsin D activity within optimal limits.Decreased cathepsin D activity and/or levels have been observed in several neurodegenerative disorders . ReplaceLysosome membrane permeabilization also leads to excessive cathepsin D activity in the cytoplasm and extracellular space. This contributes to malignant tumor growth, metastasis and angiogenesis . The inhThere are still several functions of cathepsin D to investigate. For example, cathepsin D is involved in the development of disorders associated with diabetes or its involvement in redox response suggesting the potential use of this protease in anti-photoaging therapies . Therefo


Radical advancements in hearing technology in the last 30 years have offered some deaf and hard-of-hearing (DHH) children the adequate auditory access necessary to acquire spoken language with high-quality early intervention. However, meaningful achievement gaps in reading and spoken language persist despite the engineering marvel of modern hearing aids and cochlear implants. Moreover, there is enormous unexplained variability in spoken language and literacy outcomes. Aspects of signal processing in both hearing aids and cochlear implants are discussed as they relate to spoken language outcomes in preschool and school-age children. In suggesting areas for future research, a case is made for not only expanding the search for mechanisms of influence on outcomes outside of traditional device- and child-related factors, but also for framing the search within Biopsychosocial systems theories. This theoretical approach incorporates systems of risk factors across many levels, as well as the bidirectional and complex ways in which factors influence each other. The combination of sophisticated hearing technology and a fuller understanding of the complex environmental and biological factors that shape development will help maximize spoken language outcomes in DHH children and contribute to laying the groundwork for successful literacy and academic development. Certainly, there are educators nearing retirement who remember when young DHH children regularly wore body aids and there are mid-career educators who remember when DHH children wore large, analog, linear hearing aids as the standard, or even just one hearing aid, despite having bilateral hearing loss. Today, there are no children in US classrooms wearing body aids and very few wearing analog, linear hearing aids that dangle below their earlobes. Technology has come a long way not only in form, but also in function. While form certainly matters , radical advances in hearing technology has opened the door to the possibility of spoken language development for many  DHH children whose parents desire it.This review focuses on current-day hearing technology for children with permanent hearing loss, also known as sensorineural hearing loss. Typically, this type of hearing loss is due to damage to the cochlea but can also include damage to the auditory nerve and, occasionally, structures in the central auditory system. Sensorineural hearing loss not only results in reduced audibility, but also reduced spectral resolution , poor temporal processing (difficulty following changes in sound that occur over time), reduced binaural abilities (using both ears in tandem for locating where a sound originates in space and listening effectively in background noise), and loudness recruitment  . The comThe two primary types of hearing technology used by school-age children are hearing aids and cochlear implants. Hearing aids and cochlear implants each take fundamentally different approaches to delivering acoustic signals to the listener. Hearing aids amplify signals and transmit them to the listener’s ear canal, whereas cochlear implants convert the acoustic signal into pulses of electrical current that are emitted directly into the listener’s organ of hearing—their cochlea. The electrical pulses stimulate neural units from the auditory nerve along a portion of the cochlea. Those neural units then propagate information from the signal up the auditory pathway to the auditory cortex in the brain. The reason cochlear implants directly stimulate auditory nerve fibers is because they are intended to bypass irreparably damaged structures in the cochlea of listeners with severe-to-profound sensorineural hearing loss. In other words, cochlear implants are intended for listeners who do not benefit from hearing aids.2.There are many ways to classify hearing aids: by where they are worn on the body, by the type of amplifier they use, by the type of signal processing they employ, by their size, or even by a combination of these factors. For modern hearing aids, most are worn on or in the ear. There are implantable styles of hearing aids but many of them are not yet Food and Drug Administration (FDA)-approved for widespread use in young children, so we will concern ourselves with hearing aids that are worn on or in the ear, because they are the most commonly encountered ones today with children. Hearing aids that are custom fit to sit inside the ear canal or in the “bowl” of the ear around the entrance of the ear canal are not typically worn by children. There are several reasons for this: (1) children’s ears are constantly growing, particularly quickly when they are infants and toddlers, through to 8–10 years of age . This stAs mentioned earlier, most children are fit with standard BTEs . Some auBTEs  employ an amplifier . Amplifiers are either linear or nonlinear. At any given frequency, a linear amplifier amplifies an acoustic input by the same amount, regardless of the level of the input or what other sounds are present; a nonlinear amplifier varies the amount of amplification depending on the level of the input signal. Finally, most hearing aids use digital signal processing (much like a CD player or iPod) and many utilize wireless technology for certain applications. Digital signal processing takes a continuous electrical signal  and converts it to numerical values that occur at discrete moments in time. The virtue of this processing is that it allows the development and application of algorithms that can do mathematical manipulations of those numbers in ways that cannot be done with analog processing. In this way, digital signal processing has opened the door to many sophisticated processing algorithms for addressing problems that listeners with sensorineural hearing loss experience, such as problems listening in background noise.2.1.All hearing aids, regardless of type, contain the same basic parts:microphone or multiple microphones to convert the acoustic signal into an electrical signalA amplifier to differentially increase the power of the electrical signal across frequenciesAn receiver, which is like a small loudspeaker, to convert the electrical signal back into an acoustic signalA battery to provide power to the amplifierA 2.2.Likely, the area of hearing aid design of most interest to educators relates to how hearing aids address background noise. Background noise consists of any deleterious sound that interferes with the ability to hear and understand the signal of interest. Most background noise sources include heating, ventilation, and air conditioning (HVAC) systems, fluorescent lights, other children in the classroom, next-door classrooms and hallways, noise from the outdoors , chairs and desks sliding on the floors, and classroom pets. Background noise negatively affects spoken language processing e.g., -8) and a and a8])3.In BTE hearing aids the microphone(s) sits on the plastic case just above the ear, collects acoustic signals, and converts them into electrical signals. Hearing aid microphones can be omnidirectional, meaning that they collect signals equally 360 degrees in a plane around them, or directional, meaning that they suppress signals coming from a specific direction . The reason directionality might be employed is based on the assumption that the majority of the auditory signals of interest are thought to originate from in front of the listener . To the degree that this is in fact true, reducing the amount of sound coming from behind the listener  that gets processed by the hearing aid from the outset could provide an enhanced signal for the listener. Directional microphones improve the SNR by 2–3 dB . However4.Digital noise reduction encompasses a wide array of signal processing strategies intended to categorize what components of a signal are speech and what are noise, and to reduce the amount of gain the hearing aid provides when it detects primarily noise. The vast majority of research on digital noise reduction to date has been completed on adults. Those data suggest that digital noise reduction does not improve listeners’ spoken word recognition, nor does it hamper it, rather, it makes the listening experience more pleasant under high levels of noise . SimilaPerhaps the most promising work to date to address listening in noise has been carried out by Healy and Wang and their colleagues. They have developed a novel algorithm to cleverly segregate the speech signal of interest from background interfering speech (which is often the source of background noise) that has demonstrated significantly improved speech intelligibility for adults in laboratory settings . Tests 5.The primary goal of hearing aids is to restore audibility to DHH listeners. For the purpose of developing spoken language, restoring audibility is often described in reference to the speech signal: the goal is to make the long-term average spectrum of speech (LTASS) audible. Full access to the speech signal is the first of many steps in providing children the necessary input required to begin developing spoken language . PrescriStelmachowicz and colleagues’ work, as well as that of many other research teams, has been formative in our understanding of the role of speech audibility—the primary purpose of amplification—in spoken language development. All listeners need access to some degree of an audible signal in order to understand a speaker. However, children need a more audible signal—or a greater portion of the LTASS to be audible—than do adults, in order to maximize their spoken word recognition . This isPhonological development is markedly delayed in DHH children relative to hearing peers ,31. Dela6.A critical reader might ask, if high frequencies are so important for perception, why don’t hearing aid manufacturers increase the bandwidth of hearing aids beyond 5000 Hz? The simple answer is that there are technical limitations, an increased susceptibility to acoustic feedback, and limits on output that have restricted the ability of engineers to widen hearing aid bandwidths. A clever end-around to this problem, called “frequency lowering,” has been implemented in modern hearing aid technology. There are multiple approaches to frequency lowering, but generally, frequency lowering takes high-frequency acoustic information that is not typically accessible to the listener and spectrally lowers it down to a region that is audible. It has been estimated that frequency lowering is used on upwards of 80% of a common manufacturer’s pediatric fittings . Despite7.As discussed earlier, one of the consequences of sensorineural hearing loss is reduced dynamic range—or the ranges of intensities over which one is able to hear. A healthy ear has a dynamic range of approximately 120 dB, while the dynamic range of speech of an individual talker is about 30 dB. Across talkers, the dynamic range of speech is upwards of 60 dB. As sensorineural hearing loss sets in, soft sounds become inaudible and audible sounds reach maximum comfort levels faster than normal, and the dynamic range of hearing can start to encroach upon the dynamic range of the speech. In the case of severe-to-profound hearing loss, the dynamic range of speech can eclipse the dynamic range of hearing. In this case, the audiologist faces a dilemma: amplify soft sounds so that they are audible, while making loud sounds uncomfortably or painfully loud (resulting in the user not wearing the hearing aids), or amplify loud sounds to the point just below discomfort while sacrificing the ability to hear soft sounds ? This was the dilemma that audiologists faced when fitting linear hearing aids. Today, all modern hearing aids use a technology called “amplitude compression.” Amplitude compression is a non-linear approach to signal processing in which soft sounds are provided more amplification or gain than moderate-level sounds and certainly than loud sounds. Theoretically, this allows the audiologist the ability to give the listener access to the entire LTASS, while also making sure that all sounds are maintained at a comfortable volume. Because compression alters the original signal , it is r8.Hearing aid technology has changed dramatically in the last 30 years. Whereas this has made it feasible for many current DHH children to attain spoken language and academic achievements greater than the previous generation of DHH children , there r9.For children (and adults) whose degree of hearing loss is so severe that they do not benefit from hearing aids, cochlear implants offer an opportunity to receive access to sound. The phrase, “access to sound” was used intentionally because the development of spoken language does not generally occur automatically in children who receive cochlear implants. It is the product of years of aural (re-)habilitation, speech-language therapy, family dedication, and hard work on the part of the child, the family, and many professionals, including educators. Whereas aural (re-)habilitation should be a part of intervention for all DHH children, including those with hearing aids, aural (re-)habilitation is particularly critical for children with cochlear implants. They generally have sensorineural hearing loss that is severe-to-profound in degree, resulting in a period of time that they have not had adequate access to conversational speech, even that which is amplified by a hearing aid. Furthermore, the cochlear implant provides an entirely different signal than hearing aids. Thus, learning to listen to a new signal through an impaired auditory system generally requires an amount of training, effort, and time.9.1.Cochlear implant candidacy criteria are always evolving, are manufacturer-specific, and vary with candidate age, particular device, and whether the candidate has private insurance or is using Medicare. In general, the current pediatric audiological criteria for implantation according to the US Food and Drug Administration are as follows: 12- to 23-month-old infants must have bilateral, profound, sensorineural hearing loss and display little-to-no evidence of auditory development with appropriately fitted hearing aids; children ages two years and older must meet the same requirements except that their hearing loss can be severe in degree. For children who are too young to be tested with formal spoken word recognition tests, parental questionnaires that pose questions about auditory development are used. There is some evidence that infants implanted before 12 months of age develop better spoken language, but not better speech perception, than those implanted after 12 months of age e.g., ,51-54). -54. 51-5Depending on the age of the child, candidacy for cochlear implantation is determined with a team approach that at minimum typically includes audiology, speech-language pathology, and otolaryngology. Oftentimes, large teams also include developmental psychology, social work, and other professionals. From an audiological standpoint, the child will undergo a large battery of behavioral and physiological testing to confirm the degree, type, and configuration of hearing loss, a thorough hearing aid trial with hearing aids in which the fit has been verified, and a large, hierarchical battery of spoken language tests called the Pediatric Minimum Speech Test Battery ,58. SpeeSurgery is usually an outpatient procedure, lasting 2–3 h. It is minimally invasive, using a small, curved incision just behind the ear. Before the surgeon completes the procedure, most centers will confirm that the device is working by checking the integrity of the implanted electrodes and verifying the stimulation of the auditory nerve. Many surgeons will also obtain an X-ray or fluoroscopy of the internal device once it has been placed to ensure that it is indeed located where it is supposed to be inside of the cochlea. Cochlear implants themselves contain two major portions—an internal and an external portion. Only the internal portion is implanted inside the recipient’s head.9.2.9.2.1.The internal device of the cochlear implant looks different across manufacturers and across a single manufacturer’s different models, but they all contain the same basic components:magnet that helps keep the external device on the user’s headA internal receiver that receives radio frequency waves from the external component’s transmitter and converts it into electrical energyAn electrode array containing between 12–24 intracochlear electrodes, which deliver electrical pulses to auditory nerve fibers within the cochlea that are in close proximity to each electrodeA flexible 9.2.2.The external device of the cochlear implant  also looks different across manufacturers, as well as across the different types of processors within a single manufacturer. However, they all contain the same basic components:microphone to convert acoustic signals into an electrical signalsA sound processor that processes the electrical signal based on some logic regarding speech sound processingA transmitter that sends the signal across the skin on the head via radio frequency waves to the surgically implanted portion of the deviceA magnet that helps maintain the external device on the user’s headA 10.Cochlear implants work very differently from hearing aids. Whereas there is variability across manufacturers and across processing strategies regarding the specifics of how cochlear implants process acoustic signals and stimulate auditory nerve fibers, all cochlear implants do the same basic processing. After converting acoustic sound waves into electrical energy at the microphone, they all filter the electrical signal into contiguous frequency bands, amplitude compress the frequency bands, extract the envelopes of the filters, and modulate pulses from each electrode based on the extracted envelope. Importantly, the electrodes are located in physically distinct locations along the cochlea. Beginning at the cochlea and going all the way to the auditory cortex, the auditory system is organized in a “tonotopic” fashion, meaning that certain anatomical structures respond maximally to certain frequencies . In the Cochlear implants vary in how well they convey different cues in the speech spectrum to the listener. In general, they tend to be best at conveying speech cues that are conveyed well by temporal envelope cues, and are poorest at those that rely heavily on conveying fine frequency cues. The sounds that make up words—phonemes—can be classified into: manner of articulation, voicing, and place of articulation. Manner of articulation relies heavily on temporal envelope cues, whereas place of articulation (where in the mouth a sound is uttered) relies only on fine frequency cues . From a 10.1.For the first week following surgery, patients are instructed to undergo minimal activity. After 2–3 weeks, they visit the surgeon for a post-operative check to see how the incision site is healing and to evaluate general recovery. Approximately one month following surgery they visit the audiologist to receive the external portion of the device—this will be the first time they receive stimulation from the cochlear implant that allows them to perceive sound. One major reason for the delay is that the surgical site needs to heal and swelling needs to recede before the external magnet is placed on the head. During the visit in which they receive the external portion, the electrodes are “mapped,” meaning that the appropriate amount of current for each electrode is determined by the audiologist. This is a difficult process and one that is done both behaviorally and using physiological measurements. This will not be the child’s final MAP (a term that is used to describe the levels set on each electrode as a whole). The amount of current required to detect sound decreases over time, which will impact children’s MAPs ,61. MAPsCochlear implant processing has improved markedly since the first single-channel device was implanted in a child in the United States by William House, M.D. in 1980. All modern cochlear implants are multichannel devices. Current cochlear implants offer multiple types of processing strategies, which can provide differences in perception for individual users, but on average the processing strategies result in similar outcomes across cochlear implant recipients . Regard10.2.Spoken language outcomes in pediatric cochlear implant recipients are as variable as they can possibly be. For example, receptive and expressive language scores range from floor to ceiling in one of the largest studies to date of 188 children who received cochlear implants before age five years . These Factors that account for the variability in outcomes are nearly as diverse as the outcomes themselves. The most studied include: age at cochlear implantation, which also can be thought of as the length of auditory deprivation in many cases—in general, earlier implantation results in better language outcomes . The. The66])The vast majority of the literature on speech and language outcomes in children with cochlear implants uses standardized tests of spoken language. These tests have some advantages over non-standardized measures in that they allow the tester/researcher to compare the results to hearing children. Additionally, standardized spoken language tests are often used to determine if children receive services through the schools. These tests also have some disadvantages, though. They often do not test high-level language skills needed to develop deep peer relationships or to soar academically. Furthermore, they lack the ability to evaluate specific aspects of language development with which a particular child might struggle or specific aspects of language development particularly at-risk in children with hearing loss. Therefore, some investigators have argued that going beyond these standardized measures is important for quantifying their development across multiple domains of language , as wellDespite the ability to provide access to high-frequency cues not available in hearing aids, cochlear implants still lack the frequency resolution needed for perceiving fine frequency cues. Thus, children with cochlear implants display difficulties with morphological development, specifically those marking possessives, plurals, verb tense, and pronouns -96. AddiSpeech production of children with cochlear implants is also highly variable . Articul11.Similar to the outcomes in research on spoken language (and unsurprisingly), literacy outcomes in DHH children remain a significant area of risk despite recent efforts to emphasize literacy development and many changes in educational intervention . There aLiteracy development relies on many skills and experiences. However, the two key building blocks are general language abilities  and phonological knowledge to break down printed words into parts, sometimes called phonological coding and awareness . The rolEasterbrooks, Lederberg, Miller, Bergeron, and Connor , NittrouEvidence from both hearing  and DHH One method that has been effective in assisting DHH children in accessing the phonology of their auditory language and applying it to reading is an instruction method based in visual phonics -120. Thinot be reading-specific [Despite the strides that have been made in literacy research, significant unexplained variability and a large achievement gap remains for many DHH children. The majority of the data suggest that the language and literacy gaps are related to one another. That being said, some have argued that DHH children’s reading challenges might in fact specific . For exaspecific  have prospecific . Further12.This review of current hearing technology for DHH children and its influence on spoken language and literacy development has highlighted some gaps in knowledge. Below are some of the most pressing research needs to fill those holes:Investigations into why clinical and laboratory results are so discrepant regarding children’s match-to-target of their hearing aid fittings.not match the gain targets across frequency, meaning that the majority of children do not have optimal access to the LTASS [The first step in the marriage of hearing technology and spoken language development is making the LTASS fully audible. Access to high-quality auditory information is critical to spoken language development and an optimal hearing aid fitting that matches the prescribed gain target is step one in that process . Over hahe LTASS ,26. ThisThe effects of digital noise reduction on speech perception, spoken language development, and learning environments in children who use hearing aids.The consequences of frequency lowering to speech perception and spoken language development, and its links to literacy in children who use hearing aids.The achievement gap between DHH and hearing children and relatedly, identifying sources of individual differences in spoken language and literacy outcomes in DHH children.Literacy intervention investigations that take into account individual differences of DHH children.Expanding the search for factors that influence literacy achievement in DHH children outside of traditional language and phonological awareness measures.At this time, approximately half of the variability in outcomes of DHH children has been identified, leaving much of the remaining variability unexplained.Identifying other sources of individual differences could lead to novel interventions for DHH children and their families, which could contribute to narrowing, or ideally closing, the achievement gap in spoken language and literacy.13.Impressive advances in hearing technology have occurred in the last 30 years offering the opportunity for DHH children to have the adequate auditory access necessary to acquire spoken language with high-quality early intervention. While some children achieve outstanding spoken language and literacy outcomes, there remains a significant achievement gap between many DHH children and their hearing peers, even those who are identified early and receive appropriate early intervention with sophisticated technology. Addressing this achievement gap and identifying the sources of individual differences are two areas ripe for basic and translational research efforts. At present, we have a limited understanding of the development of DHH children in part because fields concerned with the development of DHH children have just begun to employ the widely-held view that human development is shaped by dynamic interactions between biology and environment . This li


Brain reserve is a topic of great interest to researchers in aging medicine field. Some individuals retain well-preserved cognitive function until they fulfill their lives despite significant brain pathology. One concept that explains this paradox is the reserve hypothesis, including brain reserve that assumes a virtual ability to mitigate the effects of neuropathological changes and reduce the effects on clinical symptoms flexibly and efficiently by making complete use of the cognitive and compensatory processes. One of the surrogate measures of reserve capacity is brain volume. Evidence that dementia and hearing loss are interrelated has been steadily accumulating, and age-related hearing loss is one of the most promising modifiable risk factors of dementia. Research focused on the imaging analysis of the aged brain relative to auditory function has been gradually increasing. Several morphological studies have been conducted to understand the relationship between hearing loss and brain volume. In this mini review, we provide a brief overview of the concept of brain reserve, followed by a small review of studies addressing brain morphology and hearing loss/hearing compensation, including the findings obtained from our previous study that hearing loss after middle age could affect hippocampal and primary auditory cortex atrophy. With the increase in aging population globally, dementia is a rapidly growing public health problem. While there is no fundamentally curative treatment, the proactive management of modifiable risk factors or resilience, which can delay the progression or slow down the onset of the disease, has become a focus of research in aging medicine field.The susceptibility to developing dementia varies greatly across individuals, and individual differences are still not well understood. Several concepts that account for “resilience” to aging and associated pathological changes have been the subject of numerous studies. Some individuals retain well-preserved cognitive function until they fulfill their lives despite significant brain pathology. One concept that explains this paradox is the reserve hypothesis that assumes a virtual ability to mitigate the effects of neuropathological changes and reduce the effects on clinical symptoms flexibly and efficiently by making complete use of the cognitive and compensatory processes. “Resilience” is a general term referring to multiple reserve-related processes, including the concepts of brain reserve, cognitive reserve, and brain maintenance. Their definitions were recently organized in a whitepaper published by the Reserve, Resilience and Protective Factors PIA Empirical Definitions and Conceptual Framework Workgroup under the auspices of the Alzheimer’s Association to develop a consensus . In the Since the 2017 report of the Lancet International Commission on Dementia Prevention, Intervention, and Care , in whicIn this mini review, we provide a brief overview of the concept of brain reserve, followed by a small review of studies addressing brain morphology and hearing loss/hearing compensation.The concept of brain reserve has been introduced to explain the fact that patients with Alzheimer’s disease (AD) who met the neuropathological criteria for AD with high brain volume generally have good clinical outcomes . KatzmanStern discerned brain reserve from cognitive reserve and refined the definition of brain reserve . Brain rBrain size is largely determined by biological and genetic backgrounds . AlthougThere is growing evidence of a link between structural brain findings and hearing loss with aging . VariousEven when limited to MRI-based studies, the main research targets are wide-ranging, such as the auditory cortex, including the primary auditory cortex, whole brain volume, GM, WM, and non-auditory cortex . Manno eFrom a survey of aged adults, several reports with cross-sectional or longitudinal analyses have been published from large-scale epidemiological studies in various countries. Although this was a narrative review and an objective systematic method of article extraction was not used, the literatures were hand-selected to be as recent as and as large a study population as possible, using the keywords brain volume, brain morphology, MRI, WM, GM, auditory, aged, aging, age-related hearing impairment, presbycusis, hearing, hearing loss, and so on. Representative studies with more than 100 participants that addressed the association between hearing loss and brain volume using MRI are listed in n = 126, age 56–86 years) . Individuals with hearing impairments exhibited accelerated volume declines in the whole brain and regions in the superior, middle, and inferior temporal gyri and parahippocampal gyrus of the right but not the left temporal lobe.The Baltimore Longitudinal Study of Aging (BLSA) analyzed brain volume measurements performed with semi-automated region-of interest (ROI) algorithms of individuals with normal hearing versus those with hearing impairment (speech-frequency pure tone average > 25 dB) followed for a mean of 6.4 years after the baseline scan (6 years) . The stuFrom a longitudinal analysis of the BLSA, an association between hearing and changes in WM microstructure has also been published . Three hIn the Rotterdam Study, a prospective cohort study ongoing since 1990 in the city of Rotterdam in the Netherlands comprising adults aged 45 years and older, the association between age-related hearing loss (ARHL) and morphological brain assessments has been investigated.In the Rotterdam Study, the relationship between brain morphology and central auditory speech processing, as assessed with the Digits-in-Noise task, as well as peripheral auditory function, was also investigated . RigtersThe speech recognition threshold and neuroimaging assessments  were analyzed by We published our results of analyzing the relationship between hearing ability assessed using pure-tone audiometry and the volume of brain regions, specifically focusing on the volumes of the hippocampus, Heschl’s gyrus, and total GM, using Freesurfer software and T1-weighted brain MRI in community dwellers in the National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA) . The datp < 0.01 hippocampus; p < 0.05, entorhinal cortex) displayed significantly accelerated atrophy in individuals with ARHL, although the baseline volume/thickness of these two regions was high in individuals with ARHL. ARHL was associated with high CSF levels of total tau (p < 0.001) or ptau181 (p < 0.05) at the baseline and fast elevation rates of these two types of biomarkers (p < 0.05).From the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, participants with ARHL were selected and analyzed cross-sectionally and longitudinally to explore how ARHL can influence cortical structure and several neurodegenerative biomarkers, such as the cerebrospinal fluid (CSF) β-amyloid (Aβ) and tau measurements, and brain Aβ load . AlthougThe regions that have been studied in relation to hearing loss using brain volume are quite diverse, and the results regarding their relationship are inconsistent. The causal relationship between hearing loss and increased risk of developing dementia is yet to be clarified, despite numerous epidemiological studies on the relationship between cognitive function and hearing loss. This may be another factor for a wide range of targets for researchers.There are a number of possible mechanisms for the relationship between hearing loss and dementia , and GriHearing aids are an effective strategy for auditory rehabilitation and are the primary choice in individuals with ARHL. According the World Health Organization Guideline “Risk Reduction of Cognitive Decline and Dementia,” there is currently insufficient evidence to recommend the use of hearing aids to reduce the risk of cognitive decline/dementia, but the use of hearing aids is important for correcting hearing loss in older adults for other benefits . The neuThere are no drug treatments that can cure AD or any other common type of dementia. Based on the recent evidence that neurogenesis in the human hippocampus likely persists throughout adulthood, and the fact that there are no significant adverse events associated with the use of hearing aids, hearing aid use in adults with ARHL is a promising option for maintaining cognitive function that deserves attention.YU, YN, RO, and SS contributed to the search and assessment of the available literature. YU mainly wrote the manuscript. MS, TY, TK, KI, and AN interpreted the results of previous studies. All authors approved the final version of the manuscript before submission.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.


In recent years, there has been increasing research interest in the correlation between hearing impairment and cognitive decline, two conditions that have demonstrated a strong association. Hearing loss appears as a risk factor for cognitive impairment, especially among certain populations, notably nursing home residents. Furthermore, hearing loss has been identified as a modifiable age-related condition linked to dementia, and it has been estimated that midlife hearing loss, if eliminated, might decrease the risk of dementia in the general population. Several mechanisms have been suggested to explain the pathologic connections between hearing loss and dementia; however, clear evidence is missing, and the common pathophysiological basis is still unclear. In this review, we discussed current knowledge about the relationship between hearing loss and dementia, and future perspectives in terms of the effects of hearing rehabilitation for early prevention of cognitive decline. Hearing loss and cognitive impairment are conditions with a significant incidence in the ageing population, in which they often coexist with mutual influences. Available evidence has shown that the risk of dementia is higher in patients with hearing loss compared to healthy controls ,2,3, andThis correlation between dementia and hearing loss emerged in the late 1980s, with a case-control study that found that cases of Alzheimer’s disease (AD) had twice the prevalence of hearing loss compared to controls, and a greater degree of hearing loss corresponded to a higher risk of developing severe cognitive decline .Additional investigations conducted in the following years confirmed this strong association. Lin et al. monitored with pure tone audiometry for 12 years over 600 older subjects with no diagnosis of dementia. The authors found that the presence of dementia was significantly higher in patients with hearing loss compared to people who had no hearing impairment . GallachARHL has been linked not just to cognitive impairment, but also to other conditions such as depression, falls and frailty ,14. DemeThe aim of this review is to highlight and discuss the close relationship between hearing loss and cognitive impairment and explore the known causal mechanisms; furthermore, this review examines the importance of preserving physiological hearing function and of promptly initiating the necessary hearing rehabilitation to prevent cognitive decline.The systematic review was performed following PRISMA .Two researchers independently conducted literature research on PubMed and Scopus. The search terms were: “hearing loss”, “dementia”, “cognitive decline”, “Alzheimer disease”, “hearing impairment”, “comorbidities”, “brain change”, “brain atrophy”, “auditory screening” and “hearing rehabilitation” as well as their possible combination.Only articles in the English language were considered. Any type of study  was included if discussed correlation/association between hearing loss (HL) and cognitive impairment; association/correlation between HL and AD; association/correlation among HL, cognitive impairment and systematic disease; description of common pathophysiological mechanism among HL and cognitive impairment, HL and AD, HL and cognitive impairment and AD; treatment of HL and effect on cognition/memory; treatment of HL and effect on cognitive impairment/AD outcomes. All review articles were also read in full. The related citation tool in PubMed was used to search further potential articles. References of all selected articles were also examined to identify additional relevant publications and ensure all applicable literature was included.Articles in French, Spanish, Chinese or other languages were excluded. Case report, short communication, letter, opinion, and editorial were excluded.After the removal of duplicates, 250 articles were identified. The title and abstract of each article were reviewed by the authors and the full-text article which contents corresponded to inclusion criteria were read in full by both researchers. Ninety-five articles containing the relevant info focused on answering the question about the impact of central/peripheral HL on CI and brain changes were used to prepare this systematic review.Hearing loss and cognitive impairment are widely diffused conditions in the ageing population. The burden of hearing loss is constantly growing for the increased exposure to loud sounds during lifetime and for the increase in life expectancy. Actually, the global number of people with hearing loss is estimated at 360 million by the World Health Organization (WHO) and this number is expected to double to 720 million by 2050 . In the Dementia is the greatest global challenge for health and social care in the 21st century. It occurs mainly in people older than 65 years and its incidence is also steadily rising because of increasing longevity ,19: currIt is therefore evident that both hearing loss and cognitive impairment are age-related conditions that often coexist, especially among certain groups of the population, notably nursing home residents .Hearing loss and cognitive impairment also have a huge economic impact. WHO estimates that untreated hearing loss poses an annual global cost of US$ 750 billion  and the Sensorineural hearing loss (SNHL) in the elderly is generally defined as age-related SNHL. Different mechanisms cause the auditory deterioration and, depending on the portion of the auditory pathways affected, can appear in different forms ,23.SNHL can be classified as peripheral in case of damage limited to the cochlea or to the cochlear nerve ; differeIn those cases, in which SNHL is caused by damage of the peripheral auditory pathways, three forms of presbycusis can be defined according to the structures involved.Sensory presbycusis results from the degeneration of the organ of Corti, in particular from the deterioration of outer hair cells starting from the basal turn of the cochlea (high frequencies) to the apex (low frequencies) [uencies) ,26.Neural presbycusis is referred traditionally to as the loss of spiral ganglia and to the damage of the cochlear nerve [ar nerve  with potar nerve . In thisar nerve . Speech ar nerve .Atrial or metabolic presbycusis results in hearing loss across the entire frequency range in the audiogram. It is caused by atrophy of the vascular stria, in which the loss of 30% or more of the tissue in the vascular stria causes a decrease in the hearing threshold [Finally Central SNHL is caused by the alteration of the superior auditory pathways . These structures can be affected by vascular damage ,32 that Brain atrophy is one of the links between cognitive decline, Mild Cognitive Impairment (MCI), Alzheimer’s Disease (AD) and hearing loss; in fact, all conditions cause atrophy of the brain .Cognitive decline is defined as the reduced cognitive function consequent to age , when thIn these conditions, memory (both working and short) progressively declines. In addition, psychological diseases can further impact memory function, and the elderly are more exposed to this problem .In this review, we refer to general cognitive decline (impairment), without a clear focus on MCI and AD.Today, hearing loss is considered as the most relevant modifiable risk factor for dementia, that, if eliminated, could reduce the risk of dementia by 9% . The youThe underlying causal mechanisms leading to the connection between these two conditions are not well understood, though several possible mechanisms have been suggested . GeneralSeveral theories have been proposed to explain the interactions and common pathophysiological mechanisms of cognitive decline and hearing impairment. They include increased cognitive load, changes in brain structure and function, common genetic and pathologic causes, and social disengagement.The cognitive load, which theory was developed in 1998 by psychologist John Sweller ,40, consNowadays, there is evidence that hearing impairment is associated with cerebral alterations. Specifically, magnetic resonance imaging studies demonstrate that hearing loss is correlated with reduced volume of the whole brain and of the primary auditory cerebral cortex in the temporal lobe ,38 Figu.The arterial spin labelling magnetic resonance imaging, instead, analyses cerebral perfusion in vivo and allows non-invasive investigation of brain perfusion changes. This technique revealed that perfusion within the bilateral primary auditory cortex in patients with hearing impairment is reduced, especially in the right lateral Heschl’s gyrus, a critical area for auditory processing and which is also involved in many other cognitive skills .Di Girolamo et al. investigated differences in sound stimulus processing and in connectivity of the primary auditory cortex in 131 patients affected by AD and in 36 normal subjects with brain PET/CT, finding reduced glucose consumption in brain areas 6, 7, 8, 39, whereas no differences were found in the primary auditory cortex .Chronic hearing impairment also induces less activation of the central auditory pathways, a dysfunction of the auditory–limbic pathway and atrophy of the frontal lobe  and of tIn parallel, hearing impairment is associated with an increase in stimuli coming from other sensory organs, such as the eyes. This can lead to a “compensatory” increase in volume in other areas, following cross-modal cortical reorganization, which reflects the brain’s ability to compensate for alterations/dysfunctions of other senses through neuroplasticity mechanisms. Essentially, the brain adapts to a loss by compensating through neuroplasticity mechanisms; however, this phenomenon can have a seriously detrimental effect on cognition. In fact, in people with hearing loss, the compensatory adaptation system significantly reduces the brain’s ability to process sounds, which in turn affects a person’s ability to understand speech and, even with mild hearing loss, the hearing areas of the brain become weaker. Successively, the areas of the brain that are necessary for higher-level thinking compensate for the weaker areas, essentially taking over for hearing and leaving them unavailable to do their primary job . This prSome researchers suggest that a common pathological condition might trigger both hearing loss and cognitive impairment: according to this hypothesis, both conditions are the results of a common neurodegenerative process in the aging brain ,51,52,53Both ARHL and cognitive impairment are multifactorial and heterogeneous, with several common risk factors, mainly vascular, such as atherosclerosis, smoking and diabetes, that increase the risk of cardiovascular disease and stroke ,59,60,61Social isolation might be another mechanism underlying the connections between hearing loss and cerebral alterations. In fact, social interactions are usually less satisfactory for individuals with hearing impairment because it is difficult for these patients to filter out a conversation from background noise. Communication difficulties associated with hearing loss can therefore encourage solitude, which is considered a risk factor for cognitive disorders, reduced cognitive stimulation, apathy and possibly depression , as showSocial isolation also promotes negative biological mechanisms, such as increased transcription of pro-inflammatory genes and, therefore, an increase in the general inflammatory status, which is a major risk factor for damage even to cerebral functions ,72.According to the National Institute on Deafness and Other Communication Disorders (NIDCD), patients with hearing loss averagely wait 7 years before seeking treatment. During this time, hearing loss may affect cognitive function leading to an irreversible decline; furthermore, hearing loss is often not detected and/or not treated in people with a diagnosed cognitive impairment .Conversely, performances on the cognitive tests that are used in the assessment of possible dementia are affected by various factors, including sensory impairment ,74. If aNICE guidelines on hearing loss recommend performing hearing evaluation for each patient with a clinical suspicion of cognitive impairment and should be repeated every two years in subjects with a diagnosis of dementia .Moreover, recent evidence has shown that also central auditory system dysfunction occurs in the prodromal or early stages of AD; its screening is recommended as a low-cost and effective means to identify precursors to AD pathology, especially in at-risk populations ,77,78.Central hearing loss is characterized by difficulty in making sense of speech against noise , not expCentral hearing loss appears to be commoner in mild cognitive impairment and AD than in age-matched controls : deficitGrowing evidence confirms that the treatment of hearing loss through hearing solutions is an effective solution to delay the onset of cognitive impairment and maintain a good cerebral function. Treating hearing loss in people with cognitive impairment may help improving communication, increasing quality of life, and reducing behavioral symptoms of dementia, with reduced stress for families and caregivers . It is bThe hearing aids are mostly used for treating hearing loss among people with cognitive impairment : they seOther interventions, such as hearing amplification devices and focused communication strategies, have been applied in both in-patient  and outpDifferent from conventional hearing aids, cochlear implants can restore hearing in patients with profound hearing loss . NeverthDespite promising results, studies on cochlear implants and cognition still have some important limitations. First, the long-term effects of cochlear implants on cognition are still unclear since most studies simply repeat neurocognitive tests at 6 and 12 months after implantation. Second, many of these studies did not have control groups, except that of Jayakody, comparing 16 implanted adults to 23 candidate adults waiting for surgery . Third, Available evidence confirms that hearing impairment is an independent and modifiable risk factor for cognitive decline. Our group already showed that hearing rehabilitation could positively impact the elderly brain function ; in factIn this perspective, it is essential to understand the mechanisms underlying the correlation between hearing and cognition, to prevent the onset of hearing disorders and, hence, of cognitive impairment. At the same time, it is equally essential to promptly recognize hearing loss; indeed, intervening to solve the problem means implementing a genuine therapy against cognitive decline with huge benefits for the individual person and society.


Proopiomelanocortin-positive amacrine cells (POMC ACs) were first discovered in adult mouse retinas in 2010; however, the development of POMC-ACs has not been studied. We bred POMC-EGFP mice to label POMC-positive cells and investigated the development of POMC neurons from embryonic to adult stages. We found that POMC neuron development is mainly divided into three stages: the embryonic stage, the closed-eye stage, and the open-eye stage. Each stage has unique characteristics. In the embryonic stage, POMC neurons appeared in the retina at about E13. There was a cell number developmental peak at E15, followed by a steep decline at E16. POMC neurons showed a large soma and increased spine numbers at the closed-eye stage, and two dendritic sublaminas formed in the inner plexiform layer (IPL). The appearance and increased soma size and dendrite numbers did not occur continuously in space. We found that the soma number was asymmetric between the superior and inferior retinas according to the developmental topographic map. Density peaked in the superior retina, which existed persistently in the retinal ganglion cell layer (GCL), but disappeared from the inner nuclear layer (INL) at about P6. At the same time, the soma distribution in the INL was the most regular. At the open-eye stage, the development of POMC neurons was nearly stable only with only an increase in the IPL width, which increased the soma–dendrite distance. The retina is a superb model for analyzing the circuitry development, structures, and functions of the nervous system. There is a similarity between the development of the retina and the cerebral cortex . The devBased on the type of inhibitory neurotransmitter ACs express, ACs are classified into four groups, including GABAergic ACs (43 types), glycinergic ACs (13 types), dual ACs (3 types), and nGnG ACs (4 types). Likewise, based on the neuropeptides they express, GABAergic ACs have been further classified into well-studied dopaminergic or tyrosine hydroxylase (TH) ACs, vasoactive intestinal peptide (VIP) ACs, and acetylcholinergic or choline acetyltransferase (AChT) ACs, and the newly discovered and poorly studied Proopiomelanocortin-positive amacrine cells (POMC ACs) .It has been reported that POMC-expressing cells exist in the anterior and intermediate lobes of the pituitary, arcuate nucleus (ARN), and nucleus of the solitary tract (NTS) in the rat brain . RetinalThe function of POMC in retinal physiology has been studied in adult animal models ; howeverad libitum. All mice were executed at about 2 p.m. All procedures were carried out following the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Tab of Animal Experimental Ethical Inspection of the First Affiliated Hospital, School of Medicine, Zhejiang University .POMC-EGFP mice  were purchased from the Jackson Laboratory, and they had more than 99% cellular colocalization of EGFP and POMC peptides . Mice weAt set timepoints, the mice were anesthetized with pentobarbitone , and myocardial perfusion was performed. The eyeballs were removed and fixed in 4% (w/v) paraformaldehyde in phosphate-buffered saline (PBS) for 2 h at 4°C. All the procedures were done under normal room light. The anterior part of the ocular globe, including the cornea, iris, and lens, was dissected under a microscope. The optic cup was suspended in 30% (w/v) sucrose solution. After dehydration, the optic cups were positioned in embedding medium  and frozen. We collected 15-μm-thick cryosections and air dried the slides at room temperature. Then the cryosections were washed with PBS for 10 min, dried, and blocked with confining liquid  for 1 h at room temperature in a humidity chamber. The sections were then dried, and the primary antibodies were added to the slides for 1 h at room temperature. The slides were washed with PBS three times (5 min each time) and then incubated with Alexa Fluor 488 or 546-conjugated secondary antibodies for 1 h at room temperature. After washing in PBS and drying, DAPI  was used to label the nuclei. The sections were then rinsed three times with PBS and mounted with 60% glycerine under coverslips. For retina whole mounts, retina tissues did not need dehydration, and the staining procedure was the same.The primary antibodies were anti-AP2 , anti-RBPMS , and anti-Iba-1 . The secondary antibodies were donkey anti-rabbit IgG  and donkey anti-mouse IgG .Retina whole-mount images (× 20) and × 20 retina section images were acquired with a virtual digital slice scanning system VS120 (6 slice system) fluorescence microscope . Retina whole-mount images [× 60 (oil)] were acquired with Nikon laser-scanning confocal microscope . Some × 20 retina section images were also taken with a confocal microscope .For × 60 cell single-soma analysis, we used the surface function of Imaris 9.0.1 to mask and obtain the volume, position, and ellipticity data. For × 60 cell single-spine analysis, we used the same function and obtained the volume and position data. We also adopted the spot function to obtain the spine number data. For × 20 section analysis, quantitation of the somas was performed using ImageJ (Fiji) software. For × 20 retina whole-mount analysis, we selected 30–40 areas for all quadrants in each retina to determine the cell density. We used the Imaris spot function to get the position of each cell, then used R  and R Studio to plot a pseudo color scatter density map. According to the density map, we selected a 500 × 500-μm area of the dense and spare part spots in each layer, then analyzed the nearest neighbor distances (NNDs), and drew the distribution histography with the python software (python 3.8 64-bit). We calculated the regularity index as the mean NND/SD (standard deviation) . Data weWe dissected the whole eye of E13, E14, E15, E16, E17, and P0 mouse pups (corresponding to around E19), sectioned it, and selected the sections that had the optic disc and optic nerve . From thFrom the enlarged section view , the denWe analyzed the cell number of the two layers of POMC and the GCL/INL ratio . The cel2  and suddenly dropped at E16 (∼244 cells/mm2). Afterward, it increased gradually. The cell density of both layers showed a peak from P4 to P12 and then decreased to the adult stage  and P6 (INL sparse part) and then decreased again . The GCLTo see the detailed difference between the dense and sparse part areas of the unevenly distributed retina at E13, E16, and P0–P2, we compared the dense and sparse part areas in the fluoroscopic images . At E13,To see the developmental detail between the soma and dendrites, we selected the densest part of each retina from E13 to P8 , and at 3), then decreased from P2 to P8 (479.37 ± 4.12 μm3), and then stayed stable from P8 to the adult stage (∼500–700 μm3). In the GCL, it decreased from P0 to P4 (68.64 ± 26.37 μm3), then increased and stayed stable from P6 to the adult stage (469.94 ± 9.15 μm3). We noticed that, surprisingly, the soma volume in both layers was slightly increased  at P28. For the soma morphology (3 for the INL and 30.44 ± 0.01 μm3 for the GCL) and in adults (24.29 ± 0.007 μm3 for the INL and 24.13 ± 0.016 μm3 for the GCL). The total spine volume in the sample area (0.045 mm2) of each retina was the same between the two layers at each time point  was costained with AP2 . AP2 is Our main discovery was that POMC neurons in the retina developed as early as E11 to E13. During development, the cell number, morphology, and distribution of POMC neurons changed. The POMC neuron development can be divided into three stages: the embryonic stage, closed-eye stage, and open-eye stage. During the embryonic stage, there was a dramatic change in the density and distribution of POMC-positive cells at E15-E16. Axon–dendrite trading off and taking turns occurred. During the closed-eye stage, the main difference was the increase in the number of neurons and dendrites, and the position of the density peak was different. Before P6, both the INL and GCL had a density peak in the superior retina. From P6 and onward, the GCL maintained the density peak in the superior retina, while the INL shifted the density peak to around the optic disc. In the open-eye stage, the soma–dendrite distance in the IPL increased, and regularity decreased. A summarizing schematic diagram is shown in Retinal cells have the same origin, and it is essential to discuss the fate determination and differentiation of these cells. The most accepted model is the multipotent progenitor cell competency and lineage tree differentiation model . The proInterestingly, we found that POMC starts expression at E10 ; however2; 2; Inconsistent with a previous report that suggested the number of ACs in the INL keep increasing from E12 to E17 based on immunofluorescent labeling , for theFrom E16 to P14, the distribution of soma number was uneven; especially, there was an asymmetric distribution between the superior and inferior retina. This asymmetric density persisted with the density peak in the superior retina from the embryonic stage to P0 . When ceIn addition to an asymmetric distribution, the distribution regularities in the dense and spare areas were also changeable . For theOur results also showed that cell development in the dense and sparse areas of the same retina were different . When moBefore eye opening, the increase in cell number was a broken line type. There was a slight decrease at P3 and P8 in the INL, whereas in the GCL, only P8 showed a decrease. A previous study has reported that between P3 and P8, many presumptive ACs die in the INL . After nFrom P4 to P6, there was soma expansion, which made the soma more ellipsoidal . MeanwhiWe calculated the total spine volume of each layer and found that they were similar . The GCLAfter eye opening, most POMC-ACs do not change both in number and distribution, until the adult stage. We found that the distance between the somas of the GCL and INLs increased slightly. The sublamellas formed at P2–P4, then the distance between S2 and S4 remained unchanged. We also found that the wideness of the IPL was due to the separation of somas and dendrites but not dendritic sublamellas . The rea2 for the INL, which was similar to that of VIP ACs .YZ, YS, and JF designed the research and edited the manuscript. XZ, XW, WP, and SW performed the research. XZ, XW, and RU analyzed the data. XZ wrote the first draft of the manuscript. RU wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Bacillus thuringiensis, Beauveria bassiana is the most studied biopesticide. After invading insect hosts, B. bassiana produces a variety of toxins, which are secondary metabolites such as beauvericin, bassianin, bassianolide, beauverolides, tenellin, oosporein, and oxalic acid. These toxins help B. bassiana to parasitize and kill the hosts. This review unequivocally considers beauveria toxins highly promising and summarizes their attack mechanism(s) on the host insect immune system. Genetic engineering strategies to improve toxin principles, genes, or virulent molecules of B. bassiana have also been discussed. Lastly, we discuss the future perspective of Beauveria toxin research, including newly discovered toxins.The long-term and excessive usage of pesticides is an enormous burden on the environment, which also increases pest resistance. To overcome this problem, research and application of entomopathogenic fungi, which are both environmentally friendly and cause lower resistance, have gained great momentum. Entomopathogenic fungi have a wide range of prospects. Apart from  Metarhizium anisopliae, Beauveria bassiana, and Bacillus thuringiensis are the most effective biological control agents against mosquito vectors , which is a more suitable research model, could also capture even the transient interaction with fungi toxins. In general, the host–fungus biological interactions are more prominent in the host insect and can be further magnified for research purposes .B. bassiana , and hyphae-produced specific infection structures (appressoria) that penetrate the host cell and proliferate . Extracet toxins . In addit toxins . Interest toxins . Oosporet toxins . It has t toxins .B. bassiana toxins. The insecticidal mechanisms involve several strategies, including the proliferation of virulence factors for continuous virulence, impeding the activation of the host immune system, disrupting the nerve conduction pathways, damaging the epidermis of the insect host to facilitate hyphae penetration, clogging of the spiracles the insect host, absorption of water and nutrients from the host body, and so on , cyclic peptides (beauverolides), and 2-pyridone tenellin  at the post-transcriptional level; and (3) It blocks the antimicrobial peptide cascade response  It inhibits the splitting of prophenoloxidase into polyphenol oxidase (PPO), which then hinders the activation of prophenoloxidase (PO); (2) It directly inhibits the expression of antifungal peptide gallerimycin  revealed several G protein-coupled receptors, protein kinases, and TFs that are similar to entomopathogen genes  (Bbsnf1 (Bbagt1 (a-glucoside transporter gene)  , Bbsnf1   , Bbmpd, d, Bbmtd , and BbC  screening the differentially expressed genes (DEGs) of B. bassiana before and after pathopoiesis  to screen for DEGs that affect virulence  scrgenicity , and (3)irulence . These tcreening  that canB. bassiana. In brief, heterologous transgenic expression and/or fusion protein technique(s) have been successfully applied to improve fungal toxicity. Cytolytic δ-endotoxin  and conidia tolerance to wet–heat stress (∼15%) and ultraviolet (∼46%) , a family of aminoacyl-tRNA synthetases, have a small N-terminal tRNA anticodon binding domain, a large C-terminal catalytic domain, and three conserved sequence motifs . The cytt (∼46%) . Importapidermis .B. thuringiensis  of the B. bassiana class I hydrophobin gene (hyd1) increased the insecticidal virulence by 9.8-fold , with intense insecticidal activity, were originally isolated from ngiensis . Vip3A sngiensis . Qin et nfection . Compare , which was isolated from the nization . It alsonization . Based onization .CDEP2, contains an open reading frame of 1,137 bp and can be translated into a 379-amino-acid protein (3.9 kDa) with an isoelectronic point of 8.21 . In another research, a scorpion neurotoxin peptide, aaIT, and the Pr1A were fused for a simultaneous and stable expression in B. bassiana strain 13 to improve the lethality of the original toxins. B. bassiana that expressed aaIT alone and those co-transformed with aaIT and Pr1A showed an LT50 of 4.5 days and 4.75 days, respectively, against Dendrolimus punctatus Walker. Compared to the wild-type strain (7.5 days), this was 40 and 36.7% reduction, respectively. Similarly, the LT50 against G. mellonella was 3.25 and 3.4 days, a decrease of 24.4 and 20.9%, respectively, compared to the wild type (4.3 days)  . These rB. bassiana suggests that it is not a monophyletic strain, and therefore further genome-wide phylogeny of B. bassiana is necessary  Increasing taxonomic complexity within the genus Beauveria has made the true taxonomic status of many commercial and experimental Beauveria strains uncertain; (2) A wide range of phenotypic characteristics have not yet been reported; and (3) Insects can develop resistance to B. bassiana by upregulating the expression of certain genes, such as P450s and epidermal protein genes. B. bassiana has evolved a series of effective virulence mechanisms involving the breach of the epidermal barrier and host insect immune attack systems, such as secretory epidermis-degradative enzymes, mechanical penetration, avoidance of being engulfed by phagocytes, and inhibition of the release of active immune substances (B. bassiana as a biopesticide, including a relatively long time to kill the target insect, effect on non-target invertebrates, allergies in humans, dependence on ambient temperature and humidity, growing insect resistance, and uncertain taxonomic status of the fungi. Fascinatingly, genetic engineering can specifically improve these deficiencies; however, most of these strategies have so far been restricted to the laboratory and need to be extensively popularized and applied.In pest control, the thropods . Althougbstances . HoweverThe discovery of new biocides or toxins is largely serendipitous or coincidental, but for now, improving the toxicity of fungus based on genetic engineering strategies may be the most appropriate option. Fungal secondary metabolites are also of additional concern. They not only affect the insecticidal process but also intervene with the host plant pathophysiology, as shown in numerous crop species . In addiB. bassiana may ensure human safety and provide an environment-friendly pest control strategy (in vitro insecticidal mechanism, insecticidal efficacy, effects on other non-target organisms, and increasing toxin production by in vitro synthesis, may be an effective way to ameliorate the development of insecticide resistance and improve insecticidal efficiency.Since the vertebrate and the invertebrate immune pathways are not the same, manipulating the insect immune system for fungal invasion and infection may be a desirable method. A natural insecticide such as strategy . BesidesHW and HP participated in writing–review and editing. WL and PC participated in visualization. MG participated in supervision and project administration. MG and PC participated in funding acquisition. All the authors have read and agreed to the published version 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.