Valeriana jatamansi is a high value perennial herb that grows at an altitude of 1000–3000 MASL in the Indian Himalayan Region and is used in the Ayurvedic, Unani and Chinese systems of medicine. The plant extracts and essential oil (EO) obtained from its roots are used in the pharmaceutical, aromatic and flavouring industries. On account of high global annual demand and lack of organized cultivation of this herb, it is mostly collected from the wild causing depletion of the natural populations and also leading to variable produce making it unsuitable for industrial use. Therefore, to promote its cultivation, it becomes imperative to develop varieties with uniformity. Significant variations have been reported in V. jatamansi populations in terms of underground biomass accumulation, essential oil and valepotriates indicating potential of genotypic variability for effective selection. The review focuses on the diversity and variations at inter- and intra-population levels for phenotypic traits, variations for different active constituents and scope of improvement through selective breeding in V. jatamansi. The species has cross-pollinated breeding behaviour on account of floral dimorphism and presents unique opportunities for development of homozygous progeny lines through controlled self/sib-pollination by applying the breeding methods described in the review for population improvement. The germplasm resources of unique and improved selections can be maintained clonally to ensure their true-to-type identity. This review article was framed in the year 2022 after thoroughly studying the literature from the year 1919–2022. The study focuses on the variations in V. jatamansi which could be used to maximize the production through various breeding techniques for biomass and yield of different active constituents to meet the requirements of pharmaceutical and aroma industries. MASLMeters Above Sea LevelRAPDRandom Amplified Polymorphic DNAISSRInter Simple Sequence RepeatsEOEssential oilMbpMegabase pairMTMetric Tongmgramcmcenti meterNAA1-Naphthaleneacetic acid2,4-D2,4-dichlorophenoxyacetic acidIBAIndol Butayric AcidMSMurashige and Skoog mediumBAP6-Benzylaminopurine1Valeriana jatamansi Jones  commonly known as Indian valerian or Tagar belongs to the family Caprifoliaceae . It is anaceae; . It is fanaceae;  mostly oanaceae; . While ianaceae; . It is uanaceae; . The plaanaceae; .Valeriana jatamansi draws a long history among the ancient and modern medicinal systems. Various ayurvedic formulations are prepared using the extracts of the species [V. jatamansi is reported to improve Alzheimer's disease, learning, memory and Parkinson's disease [V. jatamansi on the brain-gut axis in a mouse model in form of an anti-depressant has been reported by [V. jatamansi has been traded in high volumes of over 100 MT/year [ species  like ‘Di species . Roots a species , 10. The species . In case species . V. jata disease . Effect orted by , while aorted by . Recentlorted by , the efforted by . Traditiorted by . The acc MT/year , 19.V. jatamansi than in V. ciliata [V. jatamansi phytochemicals is being carried out [Valeriana jatamansi exhibits unique floral dimorphism which needs to be studied in detail to utilize it as a breeding tool in hybridization programs. Therefore, the present review analyses the diversity and variations among and within the natural populations of V. jatamansi for phenotypic traits, phytochemicals, the role of floral biology in pollination and breeding strategy for selective improvement.The type of habitat and altitudinal range mainly affects the genetic diversity of the crop . More ge ciliata . A large ciliata , 23, 24.ried out  but progV. jatamansi. The improved varieties can further be used beneficially for the aromatic and pharmaceutical industry.The review attempts to collect the scattered information on various breeding tools and associated chemical parameters which are lined up in this review article. The review aims to focus on breeding strategies that could be applied for the varietal development program in 2V. jatamansi and other related crops was collected online from various sources like Google Scholar, PubMed, Science.gov and Semantic Scholar. The literature from year 1919–2022 was collected and thoroughly studied during year 2022 to frame useful information from it. The information was then used for writing review article. The presented review contains 129 references, 4 tables and 6 figures.The literature on 3Valeriana has over 350 species worldwide [V. jatamansi is believed to have evolved recently [V. jatamansi is reported to be 3.01 Mbp [V. jatamansi. Polymorphism can be detected by using SSR markers and many alleles at a single locus can be identified by using microsatellites [The genus orldwide  of whichorldwide  and V. jrecently . Severalrecently . The gen3.01 Mbp . Varioustellites .Diversity is controlled by genetic conditions which directly affect the EO and valepotriates; moreover, maximum genetic diversity is found to be at lower altitudes and keeps on decreasing as the altitude increases , 36. Kumet al. [More variations were reported within a population and very less (7%) among populations whereas gene flow was observed in some of the populations studied . Populatet al.  studied 3.1Valeriana jatamansi is a perennial herb and its height varies in the field and natural conditions. The plant height in the western Himalayas varied among the female and hermaphrodite plants. Among the female plants, plant height was found to be 48.4–80 cm while 44.2–68.2 cm in the case of hermaphrodite flowers [et al. [et al. [ flowers . However flowers  reported flowers . Whereas [et al.  where fe [et al.  selectedV. jatamansi, base and cauline. Base leaves are found during the vegetative phase while cauline leaves are formed during the reproductive phase with the initiation of flowering buds when the flowering stalk develops. Pinnate venation is found in leaves with cordate or ovate shapes. Variable leaf margins are found in the leaves which may be entire, sinuate, serrate, dentate or wavy having acute leaf apex [Two types of leaves are found in eaf apex . There ieaf apex . Intereseaf apex , 45, 46.eaf apex .Valeriana jatamansi have leaves with five different types of lamina viz; oval, oval and reniform, deltoid, oval and oval-deltoid. Four different types of leaf apex viz; acute, obtuse, acuminate and acute-obtuse. Lamina base is mainly of three types; cordate, truncate with straight base and sagitate with overlapping base. Leaf margins are found to be of four types viz; entire, serrate, crenate-serrate and entire sinuate. Thakur et al [V. jatamansi developed through the progeny selection approach at CSIR-IHBT, Palampur  the number of leaves varied from 70-448 after two years of growth, while variations in leaf length and leaf width ranged from 4.8-16.1 cm was 4.2–14 cm  while for tetraploids it will be five allele combinations, viz., nulliplex (aaaa), simplex (Aaaa), duplex (AAaa), triplex (AAAa) and quadruplex (AAAA) , 65. AlsValeriana officinalis cytotypes were analysed and compared with available sequences from NCBI-GenBank [V. jatamansi.There is a high degree of polymorphism in internal transcribed spacer-region (ITS-region) sequences which can be used for genetic variability identification and are often used for genealogical studies. If there is a mutation that occurred in the tandem-like sequences of internal transcribed spacer-region through molecular approaches known as “concerted evolution” then this mutated sequence will replace all other tandem sequences or the mutated sequence will be eradicated . In allo-GenBank . In the -GenBank , 69. Suc3.4Valeriana jatamansi is a sciophytic, hydrophilic plant with shallow roots which can be cultivated in fertile humus-rich loamy soil with good drainage. Roots are shallow and readily absorb moisture from irrigation or rainfall. It can be propagated by seeds as well as clonally through splitting the rhizome, cuttings of apical buds and through micropropagation [V. jatamansi seeds was found to be 0.329 gm. Seeds start germinating after 7–10 days and should be transplanted when they attain the 5–7 leaf stage after 3 months [pagation , 55. Thepagation . The tes3 months . Seed-raV. jatamansi. Kaur et al. [et al. [V. jatamansi production by IBA, NAA, 2,4-D fortified Murashige and Skoog (MS) medium. Callus was induced from leaves on MS + 1.0–7.5 μM 2,4-D + 5.0 μM NAA and adventitious roots were formed by using 5.0 μM IBA, 5.0 μM NAA or 1.0–5.0 μM 2,4-D [in vitro propagation is costly as compared to vegetative propagation methods. Recently, a method of vegetative propagation has been developed by treating apical shoots with a 50 mg/L concentration of NAA hormone for 30 min [Clonal propagation of plants is done through the splitting of the rhizome into different parts. Genotypic variations were observed for the number of rhizomes after splitting (6–31) as well as size (5–16 cm) and weight of rhizomes (40–480 gm). However, low phenotypic variations were observed within the clonal lines. Various micropropagation techniques have also been developed for clonal propagation of r et al.  establis [et al.  developeμM 2,4-D . TreatinμM 2,4-D . Howeverr 30 min . By usin3.5V. jatamansi are of targeted interest [V. jatamansi has antioxidant and insecticidal properties while moderate neuroprotective effects and inhibitory activity on acetylcholinesterase were shown by iridoids and sesquiterpenoids [Valepotriatets from roots and rhizomes of interest , Iridoidinterest , 77 flavinterest , 79, 80,interest , tanninsinterest , sesquitinterest , 83, bakinterest , 84, pheinterest  and EO [interest . EOs areinterest , 90. EO rpenoids .3.5.1Iridoids , found i3.5.2Valeriana-epoxy-triesters), found in the family Valerianaceae, chemically belong to group iridoid glycosides and are important secondary metabolites which exhibit significant biological activities due to the presence of acyloxy group linkages. Roots, rhizomes or whole plants could be used for the extraction of valepotriates [Valepotriates . Gehlot et al. [V. jatamansi and found that a higher accumulation of valerenic acid (1525.14 μg/g) was in plant rhizomes whereas acetoxyvalerenic acid (543.91 μg/g) and hydroxyl valerenic acid (919.57 μg/g) was higher in adventitious roots. It was also found that the maximum fresh root biomass was with half-strength Schenk & Hildebrandt medium having 2% sucrose and 4.92 μM IBA. Shukla et al. [V. jatamansi from different locations in Jammu & Kashmir, India and found that the sample from Patnitop contain 0.38 mg/g and that from Sanasar contained 0.27 mg/g of valerenic acid. In a study conducted by Jugran et al [V. jatamansi from different locations of Shimla, Sirmaur, Chamba and Solan districts in Himachal Pradesh, India were analysed and maximum valepotriate content was found in the rhizome (3.41%), root (3.74%) and rootstock (3.57%) of plants from Dalhousie of Chamba district. The range of valepotriates varied from 2.05-3.41% in the case of rhizome, 2.18–3.74% in root and 2.11–3.57% for rootstock [Singh et al.  evaluated Mondal  studied t et al.  studied a et al.  analysedc acid 54.91 μg/g an et al . In a diootstock . It was ootstock  in diffe3.5.3V. jatamansi led to the identification of major compounds which are maaliol, patchouli alcohol, calarene/ß-gurjunene, seychellene, α-santalene [et al. [V. jatamansi of European origin while the main component in case of Nepalese and commercially available root material is patchouli alcohol. From the wild-grown population's variation in quantity and quality of EO was noticed, roots giving higher yield (0.35–0.43%) than rhizomes (0.05–0.08%); α-bulnesene, α-guaiene, bornyl acetate, 7-epi-α-selinene, γ-patchoulene and β-elemene being a major proportion in root oil while patchouli alcohol, maaliol, isovaleric acid and viridiflorol quantity was higher in rhizome oil [et al. [Studies on EO from rhizome and roots of antalene , 24. Othantalene . In the antalene . Unident [et al.  with idezome oil . The stu [et al.  revealed [et al. .et al. [He et al.  separateet al.  reportedet al. [V. jatamansi EO forming the largest fraction (about 62%). Studies based on EO exhibited wide variations reaching up to 65.04% of patchouli alcohol in the oil samples analysed [As revealed in the study by Gautam et al.  the esseanalysed , 55, 109analysed . Such vaIn the chemical diversity analysis by Thakur et al  it was f4Valeriana jatamansi is in high demand, both in the aromatic and pharmaceutical industry. To promote its organized cultivation, breeders should develop varieties with increased EO and valepotriates content. Since, EO content and valepotriates are found in roots and rhizome of V. jatamansi, high biomass of roots and rhizome constitutes an important breeding objective. The second important issue that needs to be addressed is uniformity of the produce. In both the cases of collections from the wild and open pollinated varieties, heterogeneous raw produce is a major limitation for aromatic and pharmaceutical industry, which is further compounded by the perennial life-cycle of the plant as it is mostly harvested after two years of transplantation [antation . Varietiantation  making r4.1V. jatamansi is a cross pollinated crop, so pollination control becomes the first and main step for achieving the breeding objectives. Self-pollination of plants bearing hermaphrodite flowers is possible through isolation/bagging at the onset of flowering and seeds have been successfully obtained through this method [Valeriana officinalis [Valeriana officinalis has minimal difference which eliminates the use of hot water treatment for emasculation [It is evident that s method . Cross-ps method . Hybridiicinalis . The temculation . The genculation .4.2V. jatamansi [A crop improvement program in a species is based on the diverse and variable genetic resources. Exploration is an integral activity of breeding programs followed by collecting genetic resources and unique germplasm lines can directly be developed as a variety/cultivar of that species. Wide range of phenotypic and chemical diversity is observed in germplasm collections of atamansi , 42, 55.Ex situ conservation is an important approach for conserving genetic resources in form of germplasm accessions. Ex situ conservation involves field gene bank of living plants of vegetatively propagated crops. Mukherjee et al. [ex situ conservation in V. jatamansi at high altitudes at four different locations to determine the survival rate and found that V. jatamansi has shown higher survival rate at higher altitude range 2000–3000 mean sea levels as compared to lower altitudes. As a backup, in vitro conservation of germplasm is also important to protect the unique genetic resources from risk of extinction in case of inclement weather conditions. Normah et al. [in vitro culture has offered disease-free multiplication of clonally propagated V. jatamansi. Sharma et al. [V. jatamansi in which shoot tips were conserved using a mixture of two cryoprotectants and observed that cryopreservation can be used for long term conservation of V. jatamansi and shoot tips were treated with Plant Vitrification Solution-2 at 0 °C for 110 min which showed greater shoot recovery as compared to others. In this way, germplasm of V. jatamansi has been conserved by encapsulation of somatic embryo, shoot tips and axillary buds.e et al.  studied h et al.  found tha et al.  studied 4.3V. jatamansi is available for the natural populations occurring in the wild. Heterogeneity of such populations on account of random out-crossing, perennial growth habit, age of plants in the same population and seasonal variations in the environment, makes it difficult to screen the plants at an early stage. Evaluation of the biomass yield in V. jatamansi plants was done by Karnwal et al. [V. jatamansi germplasm collections at CSIR-IHBT, Palampur , breeding line VJ-20-16 was identified having 480 gm of fresh underground biomass [V. jatamansi as it utilizes the heritable component of the phenotypic traits.Selection is an important tool which gives direction to the breeding program and effective selection depends on variability among the parental lines, selection intensity and heritability of the traits of interest. Most of the information pertaining to variability in l et al.  to identl et al.  also eva biomass . ResponsValeriana officinalis where, the contents are influenced by environmental conditions, plant development stage, processing strategies and genetic constitution as well [Valeriana officinalis and the plant stage in which it was obtained. It was found that EO of Valeriana officinalis increased in the vegetative phase and decreased with the formation of generative parts [Environmental variations affect the production of secondary metabolites and therefore, selection for quality traits may not be effective when the data is available for a particular season or location . Similar as well . A correve parts . The amove parts , 121, whve parts  discusse4.4V. jatamansi, there is a tendency towards natural cross-pollination (xenogamy). Accordingly, breeding methods for population improvement are applicable to Indian valerian. The simplest method for population improvement is mass-selection in which phenotypically superior plants are selected in the population, followed by seed production by random open pollination among the selected plants. This method does not involve progeny testing and is comparable to open pollinated variety. When selection of phenotypically superior plants is based on performance of their progeny lines (such as ear-to-row method) it is termed as mass selection with progeny test which provides higher level of selection efficiency to the breeding program.On account of unique floral dimorphism in 4.5V. jatamansi recurrent selection may help in increasing the underground mass as well as EO and valepotriate content.With a focus to utilize heterosis in cross-pollinated crops, recurrent selection schemes have been devised  to ensur4.6It is a type of recurrent selection in which a number of plants with desirable phenotype are selected and self-pollinated followed by raising of separate progeny rows from selfed seeds of selected plants. The progenies are inter-crossed in all possible combinations and equal amount of seeds from each cross is composited to produce the next generation. Population is subjected to more than one recurrent selection cycle to increase the frequency of desirable traits in the population.4.7V. jatamansi Indian valerian.In this scheme, progenies of selected plants are obtained by crossing selected plants to a tester parent with broad genetic base and also self-pollinated. This scheme is based on early testing method suggested by Jenkins  which in4.8The purpose of this method is to isolate potential lines from a population that combine well with a given inbred. It was first proposed by Hull  with foc4.9This method of improvement is applicable when improvement is sought in two different populations in their ability to combine with each other . In this4.10V. jatamansi, self-progenies obtained from a hermaphrodite plant are observed to segregate for pistillate and hermaphrodite flowers. Repeated selfing of hermaphrodite plants from elite populations in each generation may lead to development of inbreds, although this possibility is yet to be investigated regarding response of the plant species in terms of inbreeding depression. Alternatively, a parallelism may be drawn among plants with pistillate flowers and male sterile lines, while hermaphrodite siblings of pistillate plants (obtained from same self progenies) will serve as maintainer lines. In fact, repeated sib-mating will be required for the development of such inbreds in V. jatamansi while retaining a level of heterozygosity to avoid possible inbreeding depression. These inbreds will be plants with pistillate flowers and function as male sterile lines as is the case in hybrid varieties. Using this method, inbreds can be developed from diverse populations through generation advancement in isolation and inbreds so obtained may be maintained and multiplied through clonal propagation.Inbreds isolated from a particular population when crossed with inbreds from other population leads to expression of maximum heterosis in the hybrids. Specific combining ability of inbreds represents the non-additive component of gene action which is maximized when inbreds obtained from diverse populations are crossed. Repeated selfing is prerequisite for development of inbred lines. In Valeriana officinalis and it was found that values for negative and positive mid-parent heterosis (MPH), were different between the inbreds and characteristics [An investigation was carried out on four inbred lines (I3) that were crossed in eristics . ObservaValeriana officinalis, major cultivars are tetraploid. According to Stoskopf et al. [Valeriana officinalis and homozygosity in tetraploids is expected to be achieved after 21 generations of selfing. However, inbreeding depression occurs in Valeriana officinalis in the first inbred generation itself and further increases with each generation. The vitality indicating characteristics such as seed yield, plant height, time for full ground coverage are affected by inbreeding and it had been illustrated that further inbreeding after third generation are difficult to execute and lead to the production of inviable plant material [Valeriana jatamansi to inbreeding needs to be studied in detail to isolate inbred lines.In f et al.  identifymaterial . Respons4.11V. jatamansi variety with better root mass having increased valepotriate and EO content which could be produced using low cost seed raised plants. A synthetic variety can be developed by inter-crossing inbred lines derived through recurrent selection for general combining ability (utilizing additive and additive x additive components of heterosis) and also reciprocal recurrent selection  schemes. More than one inbred lines are tested for combining ability for producing synthetic variety and seed production of synthetic variety is obtained by random crossing among the inbred lines raised in a crossing block.There is a need to develop In case of composite varieties, seeds from several lines of similar phenotype are mixed and allowed to open pollinate. Unlike synthetic varieties composites are developed without testing them for their combining ability but composite varieties show significantly more heterosis than open pollinated varieties. The main objective of developing synthetic and composite varieties is to utilize the available heterosis on account of high degree of natural outcrossing and lack of pollination control system. Synthetic varieties have higher yield than open pollinated variety but lower yield than single and double cross hybrids.4.12A single-cross hybrid variety is developed by inter-crossing two inbred lines derived through recurrent selection for specific combining ability (utilizing dominance and dominance x dominance components of heterosis) as well as reciprocal recurrent selection  methods. In a single cross, inbreds (I) are crossed in the order IA x IB (where A and B represent origin of inbreds from diverse populations). Alternatively, double cross inbreds may also be developed involving four inbreds in the order (IA1 x IA2) X (IB1 x IB2) to maximize yields .4.13Valeriana officinalis plant through anther culture, but were unsuccessful. Reciprocal crosses of di, tetra and octoploid Valeriana officinalis resulted in triploid progeny in a cross involving octoploid (♀) x diploid (♂). This may be due to distorting effect during meiosis [V. jatamansi on response to anther culture and also hybridizations involving different ploidy levels to possibly yield haploids which may be utilized for production of doubled haploids through colchicine treatment to achieve chromosome doubling.Utilizing biotechnological approaches such as anther culture or chromosome elimination technique, haploid plants could be generated which can be used for production of doubled haploids through colchicine treatment. Doubled haploid lines are genetically 100% homozygous (inbreds) and can be readily utilized for development of hybrid varieties when they have a diverse origin. A protocol for doubled-haploidy breeding in a plant species shortens the breeding cycle to a single generation for developing homozygous plants. Certain attempts were made  for deve meiosis  leading 5Valeriana jatamansi is a high value medicinal plant species. The essential oil and valepotriates obtained from the plant have high demand in pharmaceutical and aromatic industry. Besides its major applications in pharmaceuticals, the essential oil has been reported with many biological activities . Indeed, the worldwide demand of high quality planting material of V. jatamansi is expected to increase in the near future. Therefore, to meet the growing demand, both quality and quantity plantation material of V. jatamansi is urgently required. To fulfil this goal, V. jatamansi varieties with desired traits like higher root biomass, high oil content, uniform produce and early maturity are required to meet the specific demand of the industries. This review presents information about phenotypic and phytochemical variations in V. jatamansi germplasm which were successfully utilized for initial improvement of yield and quality through progeny and clonal selection approaches. Further improvements are envisaged through various breeding schemes aimed at population improvement and utilization of both the additive and dominance components of variation in the reconstituted populations developed through breeding.V. jatamansi in the form of underground biomass, essential oil content and maturity of the crop among different clonal lines, indicating significant genotypic variability for the traits. These variations can be utilized for making effective selections for the desired traits. Also, there is a need to maintain the genetic identity of phenotypically and chemically characterized lines clonally. High response of the species to clonal propagation is an added advantage and can be applied for maintaining the genetic purity of unique germplasm and conservation of diverse genetic resources in form of a field gene bank. Further, the recurrent selection strategies can be employed for development of novel varieties having higher root and rhizome biomass. Response to selections based on progeny test hold potential in improving the rootstock biomass of V. jatamansi as it utilizes the heritable component of the phenotypic traits.There are wide range of variations for the desired phenotypic traits of V. jatamansi on response to anther culture and also hybridizations involving different ploidy levels to possibly yield haploids which may be utilized for production of doubled haploids through colchicine treatment to achieve chromosome doubling.The cross-pollinated breeding behaviour of the species owing to floral dimorphism and development of selfed progenies of hermaphrodite plants obtained through controlled self-pollination presents a unique opportunity for applying the afore stated breeding methods for population improvement. The repeated selfing of hermaphrodite plants will lead to the formation of inbreds. These inbreds could be utilized for specific combining ability which could then be used for the development of hybrids. Investigations are yet to be made in Significant variations have been observed for quality aspects  based on season to season and different geographical location, signifying the role of environment on harvest quality. Moreover, right stage for the uprooting of plants need to be identified so as to produce best quality of essential oil. Selection procedures need to be devised in alignment with climatic factors during crop growth and harvesting time to ensure uniform quality of root biomass. The study aims to maximize the selection accuracy for development of breeding populations with improved biomass and higher yield of different active constituents to meet the requirements of pharmaceutical and aroma industries.All authors listed have significantly contributed to the development and the writing of this article.CSIR Aroma Mission - Phase III (HCP-0007).Funded by Data included in article/supplementary material/referenced in article.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Military veterans have high rates of noise‐induced hearing loss (NIHL) which is associated with more significant spiral ganglion neuronal loss. This study explores the relationship between NIHL and cochlear implant (CI) outcomes in veterans.Retrospective case series of veterans who underwent CI between 2019 and 2021.Veterans Health Administration hospital.AzBio Sentence Test, Consonant‐Nucleus‐Consonant (CNC) scores, and Speech, Spatial, and Qualities of Hearing Scale (SSQ) were measured pre‐ and postoperatively. Linear regression assessed relationships between outcomes and noise exposure history, etiology of hearing loss, duration of hearing loss, and Self‐Administered Gerocognitive Exam (SAGE) scores.p < .0001). Younger age, SAGE score ≥17, and shorter duration of amplification were associated with higher postoperative AzBio scores. Greater improvement in AzBio and CNC scores was associated with lower preoperative scores. Noise exposure was not associated with any difference in CI performance.Fifty‐two male veterans were implanted at an average (standard deviation) age of 75.0 (9.2) years without major complications. The average duration of hearing loss was 36.0 (18.4) years. The average time of hearing aid use was 21.2 (15.4) years. Noise exposure was reported in 51.3% of patients. Objectively, AzBio and CNC scores 6 months postoperatively showed significant improvement of 48% and 39%, respectively. Subjectively, average 6‐month SSQ scores showed significant improvement by 34 points (Despite high levels of noise exposure and advanced age, veterans derive substantial benefits from cochlear implantation. SAGE score ≥17 may be predictive of overall CI outcomes. Noise exposure does not impact CI outcomes.Level 4. Cochlear implants (CIs) provide substantial benefits to tens of thousands of Americans with hearing loss who have undergone implantation since the first single‐channel implantation in 1961 and the initial Food and Drug Administration approval of CIs in the 1980s.After approval from the Richard L. Roudebush VA Medical Center Institutional Review Board (IRB# 13588), records for patients receiving cochlear implantation at an urban VHA facility in a moderately sized metropolitan area from initiation of the program in May 2019 to May 2022 were retrospectively reviewed. Patient age at implantation, educational attainment, gender, laterality, and history of the prior implant were recorded. Additionally, etiology of hearing loss, duration of hearing loss, preoperative testing scores, type of implant and processor, and SAGE scores were recorded along with postoperative AzBio Sentence Test and Consonant‐Nucleus‐Consonant (CNC) scores at 2, 3, 6, and 12 months postoperatively. The SAGE test is “a brief self‐administered cognitive screening instrument to identify Mild Cognitive Impairment and early dementia” with a maximum score of 22.Statistical analysis was performed using SAS software (SAS Institute). Single‐predictor linear regression was used to assess the impact of “normal” SAGE scores , tinnitus, and noise exposure on changes in CNC and AzBio scores in implanted ears at 2, 3, 6, and 12 months postoperatively. Linear regression was also used to assess the effect of daily usage (hours per day) on change in CNC and AzBio scores. Multivariable linear regression was subsequently used to analyze the effect of SAGE scores and daily usage on patient CNC and AzBio scores at the time points mentioned above.TM Nucleus® implants with the CI522 implanted in 15 (25%) ears, the CI622 in 36 (61%) ears, and the CI624 in 8 (14%) ears. The type of electrode was not associated with a significant difference in CNC or AzBio outcomes at any time point. Seven patients received bilateral CIs. The left ear was implanted first in 5 (71%) of the bilaterally implanted patients. Six months after the respective operations, patients recorded a mean (SD) AzBio score of 80.0% (11.9%) in the initially implanted ear and 79.8% (2.1%) in the second implanted ear (p = .97). CNC scores 6 months postoperatively were 69.2% (7.0%) for initially implanted ear and 72.5% (7.5%) for subsequently implanted ear (p = .52). The average IOI‐CI score was 38.8 (4.0) 1 year postoperatively. Of 8 patients with SAGE score recorded 1 year postoperatively, only 1 patient with a “normal” sage score preoperatively recorded an abnormal SAGE score postoperatively.A total of 52 patients (59 ears) were implanted from the initiation of the CI program in May 2019 to May 2022. The average age at implantation was 75.0 (standard deviation [SD]: 9.2) years, while the median age was 75 years (interquartile range: 70‐80) while 50 (98%) of patients with recorded race were white (Table p < .0001).Single‐variable linear regression was used to assess AzBio and CNC score outcomes and improvement postoperatively at 2, 3, 6, and 12 months postoperatively. Factors associated with significantly better AzBio performance postoperatively were: younger age at 2, 3, 6, and 12 months, SAGE score ≥17 at 2, 3, and 6 months, tinnitus at 3 and 12 months, and duration of amplification and duration of hearing loss at 6 months (Table p = .79) from the civilian population despite having an older mean age (75 vs 62) and a much higher rate of noise exposure (51.3% vs 15.7%).Factors associated with a greater improvement in AzBio score were: younger age at 2 and 12 months, shorter duration of amplification at 2 months, duration of hearing loss at 6 months, and worse preoperative AzBio score at all time points Table . A shortCochlear implantation is highly effective in treating moderate‐to‐profound hearing loss in a sample of elderly male Veterans. CI enables patients to detect and understand sound and speech, therefore providing hearing‐impaired patients the ability to hear, communicate, and interact with the world around them. This study provides unique insight into hearing rehabilitation via cochlear implantation in a unique understudied population with a high proportion of reported noise‐induced hearing loss (NIHL) who receive care through the VHA.The VHA provides high‐quality health care to millions of veterans across the United States. A previous study demonstrated that veterans lived a median of 80 miles from the nearest VHA facility offering cochlear implantation and associated care.History of NIHL was also not predictive of CI outcomes among veterans. Although noise exposure has been associated with accelerated SGN cell death, likely due to loss of trophic support after hair cell death, patient outcomes are equivalent to those without a noise exposure history. This is consistent with prior research suggesting that SGN counts did not correlate with CI outcomes when the SGN counts were between 2800 to 25,000. However, counts <2800 were associated with poor CI outcomes.Factors that were predictive of better and/or more improved AzBio or CNC scores at various postoperative time points included “normal” SAGE cognition scores, younger age, and shorter duration of amplification. These findings are consistent with prior studies, which have previously demonstrated these relationships.Limitations to this study include limited duration of follow‐up due in part to the COVID‐19 pandemic, the recent establishment of the CI program resulting in the limited number of patients, and 1 location of a relatively homogenous population making generalizations to the overall population challenging. However, the majority of hearing improvement is seen in the first 3 to 6 months postoperatively.NIHL does not adversely impact CI outcomes in military veterans. As veterans are at risk of exposure to levels of acoustic trauma greater than almost any other population, NIHL is unlikely to adversely impact CI outcomes in any population. Consistent with previous literature, younger age, improved cognition, and shorter duration of hearing loss may improve CI outcomes in military veterans.Douglas J. Totten, study development and design, data collection, data analysis, manuscript composition; Abdul Saltagi, data collection, manuscript composition; Karen Libich, study development and design, data collection, manuscript composition; David B. Pisoni, study development and design, manuscript composition; Rick F. Nelson, study development and design, manuscript composition.None.None.


Mitochondrial diseases (MDs) are heterogeneous genetic disorders characterized by mitochondrial DNA (mtDNA) defects, involving tissues highly dependent on oxidative metabolism: the inner ear, brain, eye, skeletal muscle, and heart. We describe adult patients with genetically defined MDs, characterizing hearing function and neuroimaging results. We enrolled 34 patients  classified in four groups: MELAS, MIDD, PEO, and Encephalopathy/Polyneuropathy. Audiological evaluations included psychoacoustical tests (pure-tone and speech audiometry), electrophysiological tests , and Impedenzometry. Neuroimaging evaluations considered global MRI abnormalities or structural brain changes. In total, 19/34 patients carried the m.3243A > G mutation ; 11 had an mtDNA deletion ; 3 had nuclear genes associated with MDs (POLG1 and OPA1); and 1 patient had an mtDNA deletion without an identified nuclear gene defect (affected by PEO). Sensory neural, bilateral, and symmetrical hearing loss was present in 25 patients (73.5%) to different degrees: 9 mild, 9 moderate, 5 severe, and 2 profound. The severe/profound and mild hearing losses were associated with pantonal and high-frequency audiograms, respectively. Instead, moderate hearing losses were associated with both high-frequency (five cases) and pantonal (five cases) audiogram shapes. In addition, 21/25 patients showed a cochlear site of lesion (84%), and 4/25 (16%) showed a retrocochlear site. We found global MRI abnormalities or structural brain changes in 26/30 subjects (86.6%): 21 had white matter abnormalities, 15 had cortical atrophy, 10 had subcortical atrophy, 8 had basal nuclei involvement or cerebellar atrophy, 4 had stroke-like lesions or laminar necrosis, and 1 had cysts or vacuolated lesions. We concluded that genetic alterations are associated with different clinical presentations for both auditory function and neuroradiological findings. There is no fixed relationship between genotype and phenotype for the clinical conditions analyzed. In recent years, the knowledge of mitochondrial diseases (MDs) has greatly increased. MDs are complex disorders associated with an abnormal cellular respiratory chain and oxidative phosphorylation for adenosine triphosphate (ATP) synthesis.Their phenotypes can be different, ranging from a myopathy to multisystem diseases. The age of onset, severity, and clinical progression can also be highly variable.On the other hand, their genetic features can also vary. Genetic defects can be located in the mitochondrial DNA (mtDNA) or the nuclear genome (nDNA). Mitochondrial disorders due to mtDNA mutations follow a different inheritance than nuclear genes. Single mtDNA deletions can be sporadic, while other mtDNA point mutations can be inherited according to the rules of mitochondrial genetics  .MDs are the most common inherited neurometabolic disorders. Pathogenic variants of nuclear or mtDNA variants are estimated to affect 1 in 4300 individuals [In addition to the considerable phenotypic and genotypic variability, there is an important and variable genotype–phenotype relationship . This makes MD evaluation very complex and justifies the large number of syndromic presentations.Mitochondria are ubiquitous, which explains large variability typical of MDs showing different clinical characteristics. Tissues that are highly dependent on oxidative metabolism are most frequently involved, and the effects of mutations affecting the respiratory chain are often multisystemic. The involvement of the visual and auditory pathways, heart, central nervous system, and/or skeletal muscle is well known. Therefore, a mitochondrial disorder should be considered in the presence of myopathy with exercise intolerance, axonal neuropathy, eyelid ptosis, ophthalmoparesis, pigmentary retinopathy, optic neuropathy, sensorineural hearing loss, diabetes mellitus, hypertrophic cardiomyopathy, migraine, short stature, and cognitive impairment .In MDs, hearing impairment may be non-syndromic, as deafness is an isolated symptom, or associated with other disorders in syndromic hearing loss. Syndromic hearing loss includes Mitochondrial Encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); maternally inherited diabetes with deafness (MIDD); chronic progressive external ophthalmoplegia (CPEO); and Myoclonic Epilepsy with Ragged-Red Fibers (MERRF) ,3.The hearing impairment in these patients is quite variable. Deafness ranging from mild to profound can be found. The audiometric threshold pattern can involve only high frequencies or all frequencies. Moreover, deafness may more frequently be cochlear but may also be retrocochlear . Magnetic resonance imaging (MRI) represents a fundamental tool for the early diagnosis of MDs, including both conventional MRI imaging and functional imaging . Mitochondrial disorders exhibit a wide range of MRI findings, varying according to the clinical phenotype, stage of the disease, and patient age. Even if no single feature is diagnostic, three main MR patterns may be found. In the non-syndromic diseases of adult-hood, the MR pattern is commonly non-specific (pattern type I), characterized by a variable degree of brain atrophy and multifocal cerebral white matter involvement. Typical imaging findings may be found in patients with syndromic phenotypes, either as a specific pattern (type II) or as a leukodystrophy-like pattern (type III). The predominant findings of pattern type II include basal ganglia and brainstem nuclei involvement, along with cortical infarct-like involvement. Atrophy of a variable degree may also be present. Lastly, pattern type III shows the diffuse and symmetric involvement of cerebral deep white matter, progressing toward the subcortical regions. White matter rarefaction with the appearance of small cysts, along with ventricular enlargement, has also been documented within the affected areas. Some cases may also display infratentorial white matter involvement, either as signal alterations in brain-stem long tracts or in cerebellar white matter. In pattern type III, basal and brain stem nuclei are rarely affected .Maternally inherited diabetes and deafness (MIDD) is characterized by maternally transmitted diabetes and sensorineural deafness, while MELAS syndrome is a multi-organ disease with broad manifestations, including stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature . HearingCPEO phenotypes of are Kearns–Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (CPEO). The following triad defines KSS: onset before the age of 20, CPEO, and pigmentary retinopathy . PearsonFinally, MERRF is a rare mitochondrial disease with an early childhood or adult onset. It is a multisystem disorder characterized by myoclonus, generalized epilepsy, ataxia, weakness, exercise intolerance, and dementia. The most frequent clinical signs are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac arrhythmias, peripheral neuropathy, pigmentary retinopathy, optic neuropathy, diabetes mellitus, and lipomatosis . MERRF iThe aim of this article was to describe a cross-sectional cohort study of adult patients with genetically defined mitochondrial diseases based on the prevalence and characterization of hearing impairment and neuroimaging results.This was a retrospective observational study.Thirty-four adult patients  were recruited over a period of 17 months at the Neurological and ENT Clinics of the Fondazione Policlinico Universitario A. Gemelli, IRCCS. All subjects participated voluntarily and gave informed consent . We reviewed the clinical records of patients affected by specific mitochondrial diseases diagnosed using muscle biopsies performed during the initial investigations.The inclusion criterion was a proven mtDNA or nuclear DNA associated with an MD mutation. The exclusion criteria were known otological diseases or exposure to noise and other systemic and neurological diseases that can modify hearing function.All patients underwent a comprehensive audiological evaluation. We considered a single assessment of the auditory function. Patients were classified according to clinical features into four groups: MELAS, MIDD, PEO, and Encephalopathy/Polyneuropathy.The audiological evaluations included psychoacoustical tests (pure-tone audiometry and speech audiometry), electrophysiological tests (Auditory Brainstem Responses (ABRs)), and Impedenzometry (tympanometry and Acoustic Reflex Threshold (ART)). An experienced ENT doctor evaluated and interpreted the auditory function according to clinical standards. Pure-tone air conduction and bone conduction hearing tests were administered to all participants following standard procedures . The tests were performed in a sound-treated booth with environmental noise of less than 20 dB in order to detect the auditory threshold (Pure-Tone Average (PTA)) of the hearing level in decibels (dBHL). Evaluations of air conduction were obtained using headphones (Telephonics TDh4) for frequencies of 125, 250, 500, 1000, 2000, 4000, and 8000 Hz. Bone conduction was evaluated using a bone conductor for frequencies of 250, 500, 1000, 2000, and 4000 Hz. Hearing loss (HL) was present if the average threshold was a >20 dB hearing level (HL).The air conduction threshold, bone conduction threshold, and bone–air conduction difference were used to differentiate hearing loss: conductive hearing loss ; sensorineural hearing loss (SNHL) , and mixed hearing loss (bone conduction difference of  >10 dB HL). The severity of hearing loss was classified as follows: average thresholds ranging between 21 and 40 dB HL were considered mild hearing loss, thresholds of 41–70 dB HL were considered moderate, thresholds of 71–95 dB HL were considered severe, and thresholds >95 dB HL were considered profound. Speech audiometry was obtained using monosyllabic words, and the total number of correctly recognized words (as a percentage) was determined for different presentation levels (in dB HL). ABRs were recorded using a clinical audiological evoked potential recording device in order to investigate retrocochlear auditory neural processing up to the inferior colliculus. The EEG signal was amplified (100 K) and filtered with a bandpass between 10 and 3000 Hz. The stimulus was an alternating polarity click with a 0.1 ms duration, presented monaurally through earphones (Telephonics TDh4) at the supraliminal level. The total number of stimuli was between 500 and 2000. An analysis of brain stem responses was obtained by evaluating the absolute peak latencies of reproducible waves , as well as the intervals between the I-III, I-V, and III-V waves. The aim of the ABR test was to define a possible abnormal prolonged neural conductivity between different auditory generators. Tympanometry and the ART were assessed using a tympanometric system, inserting a pressurized probe into the patient’s ears. Tympanometry measured the response of the tympanic membrane to changes in pressure, and it was used to study the condition of the middle ear. The ART test was performed by eliciting the contraction of the stapedii muscles with sounds of different frequencies  with the intensity varying between 65 dB and 95 dB. Both the tympanometry and ART test were helpful in distinguishing between different types of hearing loss, which was useful in the differential diagnosis between cochlear and retrocochlear damage.MRI examinations were performed using a 1.5 T MR system  equipped with an eight-channel head coil for sensitivity encoding.The MRI exams included conventional anatomical sequences such as axial T2-fluid-attenuated inversion recovery (FLAIR), T2 fast spin echo (FSE), axial pre- and post-contrast T1 FSE, post-contrast 3D-fast spoiled gradient echo (FSPGR), susceptibility-weighted imaging (SWI), and diffusion-weighted imaging (DWI). Apparent diffusion coefficient (ADC) maps were automatically calculated from the diffusion data by the scanner software. The following imaging findings were considered: cerebellar atrophy; cerebral cortical and subcortical atrophy; symmetric signal changes in subcortical structures ; asymmetric signal changes in the cerebral cortex, such as stroke-like lesions and laminar necrosis; white matter abnormalities, including leukoencephalopathy; and cysts or vacuolated lesions. These elementary MRI abnormalities could be combined in various ways in a single patient, corresponding to the clinically recognized pathological patterns.MRI examinations were not performed for four patients for technical reasons (an inability to perform the examination).The audiological results obtained from the subjective and objective tests were then matched with the genetic data and the neuroradiological findings.The A-to-G point mutation at position 3243 in the mitochondrial genome (m.3243A > G) was found in 19 patients enrolled in this study  . In totaSensorineural hearing loss was present in 25/34 patients. The hearing loss was bilateral and symmetrical and ranged from subclinical to severe . The analysis of audiometric pattern showed that 11/25 hearing loss patients had an involvement of all frequencies (flat shape) while in 14/25 patients only high frequencies were involved (ski sloping). Severe or profound hearing loss was always associated with a flat shape type, while mild HL was associated with the ski-sloping one. In the nine patients with moderate hearing loss, we highlighted five ski-sloping curves and five flat shapes . On the Considering the electrophysiological data (ABR) and the Acoustic Reflex Threshold (ART), we identified cochlear or retrocochlear origins of deafness: 21 out of 25 patients showed a cochlear site of lesion and four out 25 retrocochlear . All patNeuroradiological evaluations were conducted on 30 patients. We observed global MRI abnormalities or structural brain changes in 26 out of 30 subjects. Twenty-one out of 26 cases exhibited white matter abnormalities, followed by cortical atrophy (15 subjects), subcortical atrophy (10 subjects), basal ganglia involvement (8 subjects), cerebellar atrophy (8 subjects), stroke-like lesions or laminar necrosis (4 subjects), and cysts or vacuolated lesions (1 patient). Stroke-like lesions affecting the parieto-occipital regions and laminar necrosis were characteristic findings of MELAS, predominant cerebral and/or cerebellar atrophy were observed in the PEO group, and white matter changes were core features of the leukoencephalopathy group, whereas nonspecific findings occasionally associated with basal nuclei involvement were observed in the MIDD group .MELAS group (six patients): The degree of hearing loss ranged from mild (two cases) to severe (only one case). Half of the cases were moderate. Half of the patients showed a flat audiometric pattern, and half showed a ski-sloping pattern. Only one patient had moderate retrocochlear deafness. All patients except one showed cortical atrophy and subcortical atrophy. Four subjects demonstrated stroke-like lesions and laminar necrosis; three had cerebellar atrophy, basal nuclei involvement, and white matter abnormalities; and only one patient had cysts or vacuolated lesions .MIDD group (twelve patients): Three subjects had normal hearing, three had mild ski-sloping hearing loss, four had moderate hearing loss (three of which had the ski-sloping type), and two had profound hearing loss. Three patients had moderate retrocochlear deafness. Four patients did not undergo neuroradiological evaluations , and only one patient had normal neuroimaging. In all seven remaining cases, we demonstrated the presence of white matter abnormalities. Cortical atrophy, basal nuclei involvement, and cerebellar atrophy were present in three cases .PEO group (fourteen patients): Nine patients showed cochlear deafness ranging from mild to severe . Of the two patients with moderate deafness, one showed a ski-sloping pattern and the other showed a flat curve. Three patients had normal neuroimaging evaluations. In the other patients (11 subjects), 9 showed white matter abnormalities, 6 showed cortical atrophy, 4 showed subcortical atrophy, and 2 showed cerebellar atrophy and basal nuclei involvement .Encephalopathy/Polyneuropathy (two patients): One patient affected by Encephalopathy had normal hearing, while the other one had mild cochlear deafness. Both patients showed white matter abnormalities on their MRI .In total, 17 patients out of 19 carrying the m.3243A > G mutation had hearing loss ranging from subclinical to severe with predominantly high-frequency involvement; 13 of these presented a cochlear site of lesion, and in the remaining 4 (23.5%) we identified central auditory pathway involvement .Eight out of eleven patients with single mtDNA deletion presented a sensorineural hear-ing loss, with cochlear function affected in all cases. Seven patients showed severe hearing loss, while three showed mild hearing loss. Only one patient had moderate deafness associated with a flat curve .Of the patients with nuclear genes associated with mitochondrial diseases (POLG1 and OPA1), only one patient with OPA1 affected by polyneuropathy showed mild cochlear hearing loss .The clinical data are summarized in Inner ear involvement in MDs has been extensively described in the literature, although the series reported are very often quite small. Our results confirmed that the hearing loss is related to several MDs, represented in all groups with varying degrees and shapes for different sites of injury. In particular, sensorineural hearing loss was present in all MELAS patients, and there was retrocochlear involvement in only one patient. Our findings are in partial agreement with the literature, showing that hearing loss is present in 30–81% of patients with MELAS syndrome, varying from mild loss to severe with both cochlear and retrocochlear origins ,14,15,16All patients of the MELAS group exhibited different MRI signal abnormalities, in-cluding white matter lesions , gray matter lesions , and parenchymal atrophy. However, the distinguishing feature was the occurrence of stroke-like lesions, as reported in the literature . These fGenetically, all subjects affected by MELAS had the DNA (mtDNA) point mutation m.3243A > G, which can therefore be correlated with a more serious disease. The m.3243A > G (A3243G) mutation is a point mutation at base pair number 3243 in mtDNA, resulting in an adenosine to guanine switch in the tRNA-leu (UUR) encoded by the MT-TL1 gene . The pheThe same genetic observations could be made in the MIDD group, which presented, in our series, the genetic profile of the MELAS group (m.3243A > G mutation) with quite variable clinical manifestations. In this group, we found 2 cases of deafness of a profound degree, 3 of retrocochlear origin, and only 3 of 12 (25%) with normal hearing. Also, in this group we highlighted a greater involvement of the high frequencies, in agreement with the literature , with thIn the neuroimaging, the MIDD group displayed non specific MRI findings. Specifically, three patients exhibited neuroradiological findings resembling those observed in the MELAS group, while four patients demonstrated only white matter abnormalities with varying configurations, extensions, and distributions. These abnormalities were characterized by increased T2 signals, indicating demyelination, gliosis, or axonal loss . Among tIn the PEO group, the genetic analysis demonstrated different changes: multiple mtDNA deletions in one subject, POLG1 involvement in another one, and single mtDNA deletions in the remaining subjects. In total, 5 out of 14 patients had normal hearing without any specific genetic pattern. In the PEO group, mild-to-moderate generalized cerebral and/or cerebellar atrophy, which varied in degree, was the only predominant neuroradiological finding. These changes were observed in eight cases and were sometimes accompanied by white matter lesions (WMLs). The presence of these findings represents a challenge in differentiating PEO from other syndromic phenotypes of mitochondrial disorders. Additionally, isolated cases of WMLs were identified in three subjects, while three other subjects exhibited normal MRI findings. Among the three subjects with normal neuroimaging, one had normal hearing. It is noteworthy that all of our patients exhibited a single mutation in the mitochondrial DNA (mtDNA). It can be assumed that the PEO group showed less severe neurological manifestations than the other groups, while four patients demonstrated severe cochlear hearing loss . Our audTherefore, considering our overall results, we can claim that different genetic alterations are associated with different clinical presentations. The genotype–phenotype relationship in mitochondrial disorders is complex, as previously observed: a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes ,25.The improvement of knowledge could be implemented by large multicenter studies, contributing to better patient categorization, which is useful to understand the natural history of mitochondrial disorders.A bias of this study is the lack of an applied correction factor for age (as recently performed by van Kempen ). HoweveMDs are pathological conditions with high genotypic and phenotypic variability.The associated hearing loss is usually bilateral but it can have different qualitative and quantitative characteristics. Deafness can be progressive, cochlear, or retrocochlear, with different shapes. MRI lacks the high sensitivity or specificity for diagnosing the syndromic forms of mitochondrial diseases, although certain disease types may exhibit more distinguishing brain imaging features or patterns. The other important symptoms and signs  related to the different syndromic diseases must also be well known in order to define a correct diagnosis. Achieving an accurate diagnosis and the effective management of these conditions requires a comprehensive diagnostic evaluation, which includes clinical assessment, genetic testing, and auditory investigations. Auditory dysfunction should alert physicians requiring confirmation of the diagnosis with genetic testing.Further studies on the mitochondrial mechanisms involved the inner ear are needed to better understand the true prevalence and expression of the hearing impairment in MDs.Finally, it will be important to establish the follow-up-times for patients with hearing loss in order to improve the understanding of different audiological phenotypes for both qualitative and quantitative outcomes.


Emergency laparotomy may be required in patients with inflammatory bowel disease (IBD). NELA is the largest prospectively maintained database of adult emergency laparotomies in England and Wales and includes clinical urgency of the cases. The impact of surgeon subspeciality on outcomes after emergency laparotomy for IBD is unclear. We have investigated this association, according to the degree of urgency in IBD emergency laparotomy, including the effect of minimally invasive surgery (MIS).Adults with IBD in the NELA database between 2013 and 2016 were included. Surgeon subspeciality was colorectal or non-colorectal. Urgencies are ‘Immediate’, ‘2–6 h’, ‘6–18 h’ and ’18–24 h’. Logistic regression was used to investigate in-patient mortality and post-operative length of stay (LOS).P = 0.025, LOS IRR 1.18 (CI 1.02–1.4) P = 0.025. This association was not seen in more urgent categories. Colorectal surgeons were more likely to use MIS, P < 0.001, and MIS was associated with decreased LOS in the least urgent cohort, P < 0.001, but not in the other urgencies.There was significantly reduced mortality and LOS in IBD patients who were operated on by a colorectal surgeon in the least urgent category of emergency laparotomies; Mortality adjusted OR 2.99 (CI 1.2–7.8) We found improved outcomes in the least urgent cohort of IBD emergency laparotomies when operated on by a colorectal surgeon in comparison to a non-colorectal general surgeon. In the most urgent cases, there was no benefit in the operation being performed by a colorectal surgeon. Further work on characterising IBD emergencies by urgency would be of value. Emergency laparotomy may be required in patients with inflammatory bowel disease (IBD). Many of these operations are performed out of normal working hours by the on-call general surgeon. UK surgical training demands that all trainees obtaining Certification of Completion of Training (CCT) in general surgery are able to manage an unselected surgical take and perform the necessary operations via either an open or minimally invasive approach . HoweverInflammatory bowel disease may present acutely to surgeons in a number of ways. Some, with perforation or peritonitis will require immediate emergency surgery. Others will require expedited surgery through lack of response to maximal medical therapy . UrgencyThe National Emergency Laparotomy Audit (NELA) prospectively collects patient level data for emergency laparotomy in England and Wales with a case ascertainment of approximately 80%. The primary goal of the audit is to improve patient outcomes through identification of patient and organisational risk factors. Some key outputs include increasing consultant presence in theatre, post-operative critical care support, and for patients with a pre-operative risk of death of greater than 5%. Since it was first commissioned in 2013, NELA has observed a decrease in mortality and post-operative length of stay. Among the data collected are specimen histology, speciality interest of the operating surgeon and clinical urgency of the case, as defined by POSSUM and NCEPOD .The aim of this study is to investigate the impact of surgeon subspeciality interest, timing of surgery and surgical approach on outcomes for patients who have urgent or emergency surgery for IBD. It is thought that surgeon’s elective speciality interest may have an influence on IBD emergency outcomes through peri-operative decision making in these often-complex patients, as well as through differential experience with surgery of the lower GI tract.NELA, approved under Sect. 251 of the NHS Act 2006 by the Confidential Advisory Group, is commissioned to collect data on, understand and improve the care of patients undergoing emergency laparotomy in England and Wales; this process is outlined in the NELA annual reports. For thiPatients were classified as having had an emergency laparotomy for inflammatory bowel disease if ulcerative colitis (UC) or Crohn’s disease (CD) was recorded in the histology domain of the NELA database. The primary procedure for that admission was the only one included in the analysis; planned or unplanned returns to theatre were not included to avoid increasing heterogeneity in the group. Complete data, including histology, was available between December 2013 and November 2016. After 2016, NELA no longer recorded histology and so data from 2017 to present has been excluded as the authors cannot be sure it accurately represents IBD. Patients with UC or CD were analysed grouped in a single cohort, here on referred to as ‘IBD’, and by specific IBD diagnosis.NELA records the general surgery speciality interest of the consultant surgeon responsible for the case. For the purpose of this study, these were grouped as colorectal and non-colorectal.The three cohorts; UC, CD and IBD (UC and CD combined) were analysed as groups divided by clinical urgency. NELA records clinical urgency categories as ‘18–24 h’, ‘6–18 h’, ‘2–6 h’, ‘ < 2 h’ and ‘immediate’ [Descriptive data are presented as median [interquartile range] and proportion (%) as appropriate. Logistic regression models were adjusted for a priori potential confounding variables. These included age, sex, ASA grade, cardiac and respiratory symptoms, ECG findings, systolic blood pressure, pulse rate, white cell count, creatinine, sodium, potassium, Glasgow coma score, high risk indication (perforation or ischaemia), anaemia (moderate or severe) and post-operative destination (ward versus higher level care) . We coulLinear continuous predictors were identified using the lowess command of logit-transformed outcomes and the Box–Tidwell test. Nonlinear covariates were added as factor variables in known risk categories as per the NELA risk score publication . This waWe identified 3744 cases of emergency laparotomy for IBD between December 2013 and November 2016 in England and Wales. The patient characteristics by operating surgeon speciality interest are displayed in Table P = 0.025). This is also true of the least urgent CD cases where the mortality for colorectal surgeons was 0.9% and non-colorectal surgeons was 4.1% . This increased mortality is not seen in more urgent cases of IBD, UC or CD cohorts . This difference is also seen in the least urgent UC cohort where the post-operative length of stay increases from 9.8 days for colorectal surgeons to 13.1 days for non-colorectal surgeons . We observed no difference in post-operative length of stay for the CD cohorts between colorectal and non-colorectal surgeons.There was an upward trend in post-operative length of stay in patients operated on by non-colorectal surgeons in comparison to colorectal surgeons in almost all cohorts. In IBD patients, this reached statistical significance in the least urgent cohort with a median post-operative length of stay for colorectal surgeons of 8.9 days in comparison to 10.1 days for non-colorectal surgeons , in UC 31.2% MIS when operated on by a colorectal surgeon in comparison to 8.5% when operated on by a non-colorectal general surgeon  and in CD 12.3% MIS when operated on by a colorectal surgeon in comparison to 5.6% when operated on by a non-colorectal general surgeon . When adjusting for confounding variables, there was no association between MIS and mortality. There was however a significant association between MIS and post-operative length of stay (LOS) in the least urgent IBD, UC and CD cases; For IBD, LOS after MIS was 7 days in comparison to LOS after open surgery of 9.8 days . In UC, LOS after MIS was 7.9 days in comparison to LOS after open surgery of 10.9 days . In CD, LOS after MIS was 6.1 days in comparison to LOS after open surgery of 8.9 days . This association between MIS and post-operative LOS was not seen in the more urgent cases  and had more extensive pre-operative optimisation. In this group, our data show a significant difference in outcome for patients operated on by a colorectal surgeon in comparison to a non-colorectal surgeon for both mortality and post-operative length of stay.It is possible that this reflects peri-operative decision making; colorectal surgeons are more likely to be part of the IBD MDT, have closer working relationships with luminal gastroenterology colleagues and more familiar with the pre- and post-operative management of IBD. Another consideration is the role of MIS. Multiple cohort studies have shown benefit in IBD emergencies, and our data agrees that there is a benefit to length of stay . In our Another significant finding is the data showed no difference in outcome according to the operating surgeon in more urgent IBD emergencies, that is surgery required within 18 h. Table Current guidelines for elective surgery in inflammatory bowel disease recommend a colorectal surgeon with an interest in IBD and use of MIS whenever possible . There aTo capture clinical urgency, we have used the target time for the patient arrive in theatre which is reflected in the booking urgency. The recommendation by NCEPOD is that the consultant in charge of the care of that patient should decide the booking urgency, and it should reflect their clinical condition, we accept that this may be subject to bias . Actual NELA case ascertainment is estimated at 80%, so this dataset is incomplete. Nonlinear predictors were added as factor variables using NELA defined cut offs for low, normal and high. This was chosen over transformed polynomials as it has easier clinical interpretation but can result in loss of information. This is a retrospective observational study, reporting associations. A randomised control trial would be required to report causation. We were also unable to add other, potentially important confounders such as frailty and lactate because of missing data. As mentioned in methods, NELA has only recorded histology data from 2013 to 2016; however, this still represents one of the largest cohort studies for IBD in the UK and a valuable resource.Emergency laparotomy for IBD where there is less clinical urgency is associated with decreased mortality and length of stay when performed by a colorectal surgeon in comparison to a non-colorectal general surgeon. Where there is greater clinical urgency, there is little benefit of MIS or a colorectal surgeon above a non-colorectal general surgeon. This may have significant implications for how emergency IBD cases are classified and how emergency general surgery departments are structured. Further work in the area of urgency and timing of emergency surgery may help further distinguish these two groups of patients from one another.


Resting metabolic rate (RMR) represents the energy required to maintain vital body functions. In dietary practice, RMR is determined by predictive equations on the basis of using body weight or fat-free mass. Our study aimed to assess whether predictive equations used to estimate RMR are reliable tools for estimating the energy requirements of sport climbers. The study included 114 sport climbers whose RMR was measured with a Fitmate WM. Anthropometric measurements were performed with X-CONTACT 356. The resting metabolic rate was measured by indirect calorimetry and was compared with the RMR estimated by 14 predictive equations on the basis of using body weight/fat-free mass. All equations underestimated RMR in male and female climbers, except for De Lorenzo’s equation in the group of women. The De Lorenzo equation demonstrated the highest correlation with RMR in both groups. The results of the Bland–Altman tests revealed an increasing measurement error with increasing metabolism for most of the predictive equations in male and female climbers. All equations had low measurement reliability according to the intraclass correlation coefficient. Compared with the indirect calorimetry measurement results, none of the studied predictive equations demonstrated high reliability. There is a need to develop a highly reliable predictive equation to estimate RMR in sport climbers. Resting metabolic rate (RMR) is defined as the energy required to maintain vital bodily functions, such as energy substrate metabolism, respiration, body temperature and heart rate while the body is at rest . It is eIt has been suggested that RMR can be increased by resistance  and inteRecently, sport climbing has become increasingly popular. Since 2020, it has been included in the Olympic program and is carried out in three categories: bouldering, lead climbing and speed climbing. Climbers are characterized by a specific body type. A low percentage of body fat and low body mass are considered determinants of their climbing success . Along wRecently, more and more studies have evaluated energy availability across the representants of sport climbers because the representants of this discipline are suggested to be in danger of eating disorders resulting from the desire to lower their body weight ,15. RestCorrect RMR estimates are the basis for developing a personalized nutritional strategy, which contributes to athletic success. Identifying a predictive equation to precisely estimate RMR in sport climbers would help coaches and sports nutritionists work with climbers.Our study aimed to compare the accuracy of RMR calculated with 14 predictive equations, where RMR was measured by IC, and to identify the predictive equation with the highest correlation with the IC measurement results.The study included 114 regular sport climbers  from Wrocław, Poland. The criterion for inclusion in the study was at least 1 year of regular sport climbing. The exclusion criterion was recreational climbing with less than once-a-week climbing practice. Information on the study was spread through social media and directly through trainers at 5 climbing gyms. All climbers who were willing to take part for the duration of the study  and who fulfilled the criteria were accepted. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of Wrocław Medical University (number KB-45/2019).In order to determine the energy needs of the study participants, their resting metabolic rates were measured using indirect calorimetry. Resting metabolic rate was measured by IC with Fitmate WM  device. The study participants had been asked to come to the study after fasting, after an overnight rest and after avoiding intense physical activity an evening before measurements, which were taken in a darkened and soundproof room. The entire test took 12 min. In the first 2 min, we matched the participants’ respective breathing patterns to the measurement requirements. The actual RMR measurement took 10 min. Anthropometric measurements, such as body weight, body fat and fat-free mass, were performed with X-CONTACT 356  analyzer and a TANITA HR-001  stadiometer. Contraction force was measured with MAP 80K1 hand-grip dynamometer  to assess grip strength to body mass ratio (SMR). Systolic and diastolic pressure and pulse were measured using a sphygmomanometer in order to exclude performing an indirect calorimetry in a state of anxiety. High blood pressure and pulse values could falsely increase the results.In order to obtain the characteristic of the group and the level of advancement in climbing, participants filled out the questionnaire with the climbing grade section questions. Participants’ respective climbing grades were subjectively determined by assessing 3 routes established over the preceding 6 months. Self-reported climbing ability was considered as a valid representation of actual climbing ability . ParticiThe obtained results were compared to RMR results, estimated with 14 predictive equations. Resting metabolic rate was estimated with predictive equations on the basis of body weight, according to Harris–Benedict , Mifflint-test for related pairs. For the differences distributed nonnormally, we used the Wilcoxon signed-rank test. An intraclass correlation coefficient (ICC) was calculated for each equation to assess the correlation of each measurement, where RMR was measured with IC. The ICC values (mode “single fixed raters”) and their statistical significance were calculated with the use of function “ICC” (of the package “psych”). The Bland–Altman graphs were used to separately visualize the relationships between the two compared metabolic rates  for each gender.Statistical analyses were performed with STATISTICA v. 13.3  and by using the R-package “psych” . An analIn the group of women, the De Lorenzo and ten Haaf FFM equations demonstrated the highest correlation with the actual RMR, and in the group of men, the highest correlation was found for the De Lorenzo equation, followed by the ten Haaf FFM and ten Haaf BW equations. In both groups, Bernstein’s equation demonstrated the lowest correlation.In the group of women, we obtained the smallest mean difference with the ten Haaf FFM equation, and in the group of men, with the ten Haaf BW equation. The largest differences between the means in both groups were observed with the Bernstein’s equation. In the group of women, only the De Lorenzo equation overestimated RMR. The remaining equations underestimated RMR in the female and male groups. The intraclass correlation coefficient for all equations was very low, indicating very poor correlation between RMR measured with predictive equations and by IC.The majority of predictive equations in the Bland–Altman tests that are presented in Our study aimed to evaluate the accuracy of several predictive equations used to estimate RMR in a group of sport climbers compared to the RMR results measured by IC with a Fitmate WM. In our study, the mean values of anthropometric measurements were similar to those involving sport climbers in other studies analyzing the body composition of sport climbing representants ,15. CompMany commonly used equations to predict RMR are based on body weight (BW) alone, without considering muscle mass or fat-free mass (FFM) . People p < 0.001; R = 0.64; p < 0.01).Frankfield et al.  found thp < 0.001). In the group of men, the ten Haaf equations, based on FFM and BW, demonstrated an identical correlation (68%) . These findings are convergent with the latest systematic review of the accuracy of the RMR predictive equations in the group of athletes conducted by Marthino et al. [In the study by Jagim et al. , the Cuno et al. , where to et al. .In our study, RMR obtained with the Schofield and Owen equations demonstrated low accuracy for both men and women. The Harris–Benedict equation overlapped with the IC results by 44% in the group of men and by 56% in the group of women. The mean differences were 252.62 and 67.75 kcal, respectively, but in the group of women, the mean difference was not statistically significant. Similarly, in our study, the Cunningham equation demonstrated a high correlation with RMR in the group of women and a lower correlation in the group of men.Frings-Meuthen et al. , who stuMackay et al. , who assThe correct estimation of RMR is also crucial in preventing the onset of reduced energy availability, which can lead to relative energy deficiency in sport (RED-S) in male and female athletes ,30. GiveFuture research should aim to develop sport-specific RMR prediction equations to account for large differences in body composition and training levels commonly observed in different athletes . With thProperly assessing athletes’ energy requirements is an important element of their collaboration with sports nutritionists. A precise tool to enable that will allow the adjustment of energy supply according to the demand, resulting from the training undertaken, and will prevent unexpected changes in body weight due to RMR underestimation. On the other hand, there are various aspects that should be considered when developing predictive equations for sport representatives. Depending on the type of climbing preferred, such as bouldering, rope climbing and speed climbing, sport climbers may differ in their anthropometric measurements . In addiThe study has some limitations that should be mentioned. The analyzed group is characterized by various levels of advancement. As specific body anthropometric measurements, such as small body mass, low body fat and high fat-free mass, are characteristic of advanced and elite climbers, such values may not be represented by intermediates and beginners. A wide range of these components could influence the results. Additionally, a high fat-free mass value influences the resting metabolic rate, and the obtained results of Bland–Altman plots show that the higher the RMR values, the bigger the error, according to the results of the formula.To obtain the most accurate results from the indirect calorimetry test, it should be carried out for at least 30–40 min. In our study, this period was 10 min, with additional 2 min to match the participants’ respective breathing patterns to the measurement requirements. To obtain the most accurate results that could be used for developing a reliable RMR prediction for this discipline, as mentioned in the discussion, the results of different types of climbing representatives and various training macrocycles should be considered.None of the analyzed predictive equations is a reliable tool for estimating resting metabolic rate in both female and male representants of sport climbing. Developing a highly reliable predictive equation, one that is accurate for sport climbers in terms of their specific body compositions, seems to be an essential element in sports dietetics and a key factor to help athletes build their nutritional habits, which are an important component in their performance success.


Hearing loss has been identified as a potentially modifiable risk for dementia. This discussion paper reviews studies examining the impact of hearing loss interventions on cognitive decline and incident cognitive impairment, identified the challenges for research on the cognitive impacts of hearing interventions, and the likely benefits of hearing interventions for healthy aging and mental well-being.The online version of this article (10.1007/s00391-023-02178-z) contains supplementary material, which is available to authorized users. Due to aging populations and increasing numbers of people living with dementia, identifying treatments and strategies to prevent or delay the onset of dementia is a global priority. One report concluded that delaying the onset of dementia by only 2 years would reduce the prevalence of dementia by 20% . HealthyThis frequently quoted 8% statistic deserves some explanation. First, this statistic does not describe the strength of the risk of dementia at an individual level as sometimes stated , but theSecond, the calculation of the attributable fraction of dementia cases for each factor in the Lancet report was based on the levels of exposure for those factors in the United Kingdom (UK) and similar high-income countries. Levels of exposure to each risk factor and the relevant risk factors are different across countries, and so the attributable fraction of dementia cases is also different. For example, the level of tobacco smoking in China is around 2.5 times higher than in the UK. Smoking is therefore probably a much more important contributor to dementia risk in China than in the UK. Different risk factors may be important in low-income and middle-income countries, such as maternal and early life malnutrition. Levels of hearing loss may also be different across countries , it is pFinally, the conclusion that 8% of dementia cases are associated with hearing loss was based on a meta-analysis of 3 studies –9 that lBut an alternative explanation for hearing loss being associated with cognitive decline and risk of dementia is that cognitive declines impact hearing . ListeniLastly, hearing loss and dementia may be associated due to a common cause. Hearing loss could be a marker of neurological frailty due to disease processes that impact on both hearing and cognition . All theLastly, hearing tests may be confounded with cognitive factors. Cognitive factors may impact performance of hearing tests  and cognThere is evidence for all the above potential relationships between hearing and cognitive outcomes. Recent studies , 22 thatA key question then, is whether treating the hearing impairment  reduces the risk of dementia. Several prospective hearing aid and cochlear implant trials measured cognitive outcomes. Some reported improvement, some no change and some reported worse cognitive outcomes following hearing intervention . Most stFour studies reported lower incident cognitive impairment among hearing aid users compared to non-users  among hearing aid users versus non-users . It is Outcomes vary but on average cochlear implants restore functional hearing to a person with profound hearing loss . In contCosetti et al.  reportedn = 1000) from the Survey of Health Ageing and Retirement in Europe (SHARE). Völter et al. reported improvements in a delayed recall task among cochlear implant recipients, with a slight decline in performance on a delayed recall task among SHARE participants. Cochlear implant recipients improved on a working memory task, while there was no change in a working memory task among SHARE participants. Cognitive changes among cochlear implant recipients were not directly statistically compared with changes in the SHARE cohort. Unfortunately, different tests were used in the SHARE cohort to the cochlear implant recipients. Although cognitive tests may purport to assess the same cognitive domain, they may have different sensitivity to cognitive changes over time. Additionally, 21 cochlear implant recipients had dropped out since baseline (30% attrition rate), which may positively bias outcomes. Völter et al. reported that there was no correlation between improvement in speech perception and improvements in cognitive performance, and most improvements occurred within the first year after cochlear implantation. Völter et al. suggested that cochlear implantation and the subsequent rehabilitation program might have an indirect effect that positively impacted cognition .Völter et al.  attempteLiterature on the benefits of cochlear implantation on cognitive decline and incident cognitive impairment is ambiguous. The hearing aid literature is approximately equally divided between studies that reported a benefit and those that did not. The possibility of preventing or delaying dementia by treating hearing impairment is appealing, but there are challenges in understanding the benefits of hearing interventions.Several studies examined hearing intervention in relation to all cause incident dementia –32. DemeOther studies reported performance on a variety of cognitive outcome measures indexing a range of cognitive domains including attention, processing speed, executive functioning, short-term memory, working memory and long-term memory. The choice of cognitive outcome measures in each study appears to be predominantly based on what data were available. Some researchers hypothesize different effects of hearing loss on specific cognitive domains –54. RonnSpecific hypotheses about the relationship between hearing loss and cognitive outcomes and the mechanisms of effect of hearing interventions on cognition could be tested in longitudinal observational studies, for example using structural equation methodology . UnfortuThe manuscripts described in the supplemental tables typically call for prospective randomized controlled trials to provide a rigorous analysis of the impact of hearing interventions on cognitive outcomes. Such trials are under way –63, but We focused on device-based hearing interventions (cochlear implants and hearing aids), as they are the commonest interventions for hearing loss. There are also interventions that address the communication difficulties and psychosocial impacts of hearing loss with counselling and problem solving . AlthouThe jury is out on the benefits of hearing interventions in reducing the risk of dementia. The current WHO guidelines for risk reduction of cognitive decline and dementia say that there is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia . The praIn our opinion, the key benefit of hearing interventions in preventing dementia is probably via the interaction with hearing and cognition on functioning in daily life. Dementia is diagnosed based on cognitive impairment severe enough to impact on independent functioning in daily life  the lef. HearingClinicians who work with older people should discuss hearing interventions in the context of healthy living, and how communication is vital in facilitating an active independent and vibrant lifestyle. Orienting the discussion around hearing interventions as healthy lifestyle choices  may help put an appropriately positive spin on hearing care and encourage engagement and uptake of hearing interventions. An appealing proposition for people with hearing difficulties is that the benefits of hearing interventions extend beyond improved communication.Summary tables of hearing aid and cochlear implant intervention studies for adults with normal cognition with cognitive outcomes assessed over greater than 3 years


GJB2 gene are the most common genetic cause of congenital non-syndromic deafness. Pathological changes such as decreased potential in the cochlea, active cochlear amplification disorders, cochlear developmental disorders and macrophage activation have been observed in various GJB2 transgenic mouse models. In the past, researchers generally believed that the pathological mechanisms underlying GJB2-related hearing loss comprised a K+ circulation defect and abnormal ATP-Ca2+ signals. However, recent studies have shown that K+ circulation is rarely associated with the pathological process of GJB2-related hearing loss, while cochlear developmental disorders and oxidative stress play an important, even critical, role in the occurrence of GJB2-related hearing loss. Nevertheless, these research has not been systematically summarized. In this review, we summarize the pathological mechanisms of GJB2-related hearing loss, including aspects of K+ circulation, developmental disorders of the organ of Corti, nutrition delivery, oxidative stress and ATP-Ca2+ signals. Clarifying the pathological mechanism of GJB2-related hearing loss can help develop new prevention and treatment strategies.Hearing loss is the most common congenital sensory impairment. Mutations or deficiencies of the  GJB2 gene and Cx30 encoded by the GJB6 gene, the most abundant gap junction proteins in the inner ear, are expressed in the support cells of the organ of Corti (OC), the basal and intermediate cells of the stria vascularis, and fibroblasts in the spiral ligament. GJCs junctions formed by Cx26 plays an important role in the development, formation and maintenance of auditory function, and material exchange in inner ear cells. Up to now, more than 100 mutations associated with human hearing loss have been identified in the region of GJB2 gene. GJB2 mutation has been observed to be involved in the pathogenesis of hereditary deafness, delayed deafness and presbycusis. Although many valuable pathological phenomena have been elucidated using Gjb2 gene knockdown (KD) and Gjb2 mutant transgenic mice, the main pathological mechanism of hearing loss caused by GJB2 mutation is still unclear. This paper summarizes recent progress in research on GJB2-related hearing loss, attempting to identify the pathological mechanism of hearing loss caused by Cx26 mutation.Changes in the genes encoding gap junction proteins  are the most common genetic causes of hearing loss . Thus fa+ and a low concentration of K+, and endolymph is similar to intracellular fluid, with a low concentration of Na+ and a high concentration of K+; this leads to a difference in potential between different parts of the cochlea in the resting state , scala media (SM), and scala tympani (ST). The SV and ST contain perilymph fluid and traffic with each other through the cochlear aperture at the top of the cochlea , while tng state . As endoreocilia . Driven ndolymph . Cx26 muenomenon . Moreoveing loss .Gjb2 R75W transgenic mouse model  and Nuel’s space (NS) never opened and the postnatal development of OC was blocked . Morpholse model . Thus, iing loss . Dysplas variant . AdditioGJB2 mutation causes malformation of OC has not been fully clarified. Current research suggests that the opening of TC is related to the development of inner and outer pillar cells. Inoshita et al. observed that pillar cell bodies were differentiated from the surrounding cells during the expansion of TC at postnatal day (P)8 in both non-transgenic mice and Gjb2 R75W mice , OC and stria vascularis were significantly reduced in 6-month-old Gjb2+/– mice compared with Gjb2 loxP/loxP mice. These findings indicate that the function of the cochlear antioxidant defense system in Cx26-deficient mice is impaired. Dihydroethidium  was used to compare ROS content in the cochlea of Gjb2–/– mice at P5 and age-matched Gjb2 loxP/loxP mice. The results showed that the DHE signal in the cochlea of Cx26-deficient mice was significantly higher. Similarly, in the cochlea of Gjb2+/– mice aged 2, 6, and 12 months, the staining signals of DHE and 4-hydroxy-2-nonenal  were also observed to be significantly higher than those in age-matched Gjb2 loxP/loxP mice, while the 2-month-old Gjb2+/– mice showed no significant hearing loss compared with Gjb2 loxP/loxP mice. Moreover, the antioxidant stress signaling pathway Nrf2/ARE and its response product, the HO-1 enzyme, are also activated in the cochlea of Gjb2+/– mice. These findings indicate that oxidative metabolism and ROS play an important role in hearing loss caused by Cx26 KD. A significantly higher ROS level was also observed in the cochlea of Cx30 null mice (Reactive oxygen species (ROS) play an important role in cell biology . ROS aretabolism . The amoull mice . A genomull mice .+, K+, and Ca2+, while P2Y receptors are G protein-coupled metabotropic receptors that activate phospholipase C (PLC), resulting in the activation of the second messengers diacylglycerol and inositol trisphosphate (IP3). The P2Y1, P2Y2, P2Y4, P2Y6, and P2Y12 receptors have been reported to be expressed in the sensory and non-sensory cells of OC and the spiral ganglion neurons of developing rat cochlea , pannexin channels, anime channels, vessels and transports -mediated gene therapy has proved to be helpful in restoring the hearing of Gjb2 mutant mice. Using an AAV vector, the Gjb2 gene was successfully expressed in the cochlear Sertoli cells of newborn mice through the round window membrane, leading to significant improvements in the auditory responses and development of the cochlear structure (Cochlear implantation is an effective treatment strategy for patients with hearing loss caused by tructure . With thYJ and YW wrote the manuscript. WC designed the manuscript. QZ, YX, XG, and SZ provided the reference materials. All authors read and approved the final manuscript.