PRPS1. This enzyme generates phospho‐ribosyl‐pyrophosphate (PRPP), which is utilized in the synthesis of purines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), among other metabolic pathways. Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age. Supplementation of the purine and NAD pathways outside of PRPP‐dependent reactions is a logical approach and has been reported in a handful of patients, two with S‐adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR). We present the clinical course of a fourth Arts syndrome patient who was started on therapy and review previously reported patients. All patients had stability or improvement of symptoms, suggesting that SAMe and NR can be a treatment option in Arts syndrome, though further studies are warranted.Phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in  Arts syndrome patients appear to have clinical improvement with S‐adenosylmethionine and nicotinamide riboside; however, larger studies are needed.1PRPS1 (OMIM *311850) is located at Xq22.3 and encodes for phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1). Phospho‐ribosyl‐pyrophosphate (PRPP) is utilized in the synthesis of purines, pyrimidines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), as well as amino acids histidine and tryptophan.PRPS1 deficiency, also known as Arts syndrome (OMIM #301835), is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections. Infections often precipitate worsening of symptoms, and many individuals pass away in early childhood.PRPS1 is not well characterized. X‐linked hearing loss accounts for <1%–2% of nonsyndromic hearing loss overall and PRPS1 variants were not identified in large cohorts of patients with nonsyndromic hearing loss.PRPS1 variants range from asymptomatic to varying degrees of isolated hearing loss to a more severe CMTX5 or Arts syndrome phenotype, with significant phenotypic variability.PRPS1 variants associated with PRPS1 superactivity (OMIM #300661). It has been hypothesized that the effect of PRPS1 variants on the local structure, ATP binding site, allosteric sites, and interface areas can be associated with certain phenotypes; however, this is not well delineated.Given the importance of PRPP in the synthesis of purines and NAD(P), supplementation of these pathways is a logical approach for these patients. S‐adenosylmethionine (SAMe) serves as source of purine precursors that is PRPP‐independent Figure . Similar2PRPS1 c.383A>T  (NM_002764.4). This specific variant met ACMG criteria PM2, PP3, PP2, PP1, and PP5 with no population frequency in gnomAD, deleterious in silico predictions at a highly conserved amino acid, missense variant in a gene with low rate of benign missense variation , co‐segregation in affected family members, and likely pathologic classification in Clinvar and in Mercati et al.The patient is the first son of nonconsanguineous white parents. He was born at 36 weeks to a 30‐year‐old G4P3 mother whose pregnancy was complicated by intrauterine growth restriction. His birth weight was 1.89 kg (WHO 0.1st percentile), birth length was 46 cm (WHO 1.4th percentile), and birth head circumference was 31 cm (WHO 0.3rd percentile). He did not pass his newborn hearing screening and was noted to have congenital nystagmus and hypotonia. He was diagnosed with severe congenital bilateral sensorineural hearing loss by auditory brainstem response at 2 months of age and subsequently received hearing aids. An electroretinogram showed retinal dystrophy. Subsequent genetic testing revealed a likely pathogenic variant in After discussion with family, he was started on 200 mg daily (20 mg/kg/day) of SAMe at 19 months, which was increased to 400 mg daily (approximately 40 mg/kg/day) at 20 months. At 20 months, he was also started on 300 mg daily (approximately 30 mg/kg/day) of NR. Medication doses were based on prior dosing and the nearest available capsule size. Parents reported subjective improvement in strength and endurance with therapy. Over the next few months, he made significant developmental gains, including walking with a walker at 21 months. He had done well with occasional upper respiratory tract infections without regression in skills, worsening hypotonia, or increased respiratory needs.At 24 months of age, he had significant regression after cardiac arrest secondary to respiratory failure from rhinovirus/enterovirus. Full immunologic evaluation—including lymphocyte subpopulations, T and B cell subset distributions, and immunoglobulins—was normal. He had appropriate vaccine titers for vaccines received, as he was under‐vaccinated. Head CT did not show significant changes; however, there was artifact present from cochlear implants. Brain MRI was unable to be obtained due to incompatibility with cochlear implants. At discharge 3 weeks later, he had lost head control, was not able to sit unsupported, roll over, or feed by mouth, prompting G‐tube placement. He was discharged with cough assist and vest to assist with secretion clearance, but did not require other respiratory support. Over the next couple of months, he regained many milestones and acquired additional milestones. At 26 months, he was sitting independently, pulling to stand, crawling, speaking (one to two words), and has resumed eating by mouth. He has had another upper respiratory tract infection without any clinical decline. Uric acid and purine metabolites remained similar while on SAMe and NR. Methionine remained in the normal range.PRPS1 c.383A>T variant. Other female family members, including a maternal aunt with hearing loss, are undergoing cascade genetic testing.The patient's mother, who had childhood onset hearing loss, was found to be a carrier for the 3n = 2) or SAMe and NR (n = 1). Their clinical data is summarized with our case in Table To date, three other Arts syndrome patients have been previously treated with SAMe  and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. This article does not contain any studies with animal subjects performed by any of the authors.


Background. Defects of mitochondrial DNA (mtDNA) involved in the function of the mitochondrial electron transport chain can result in primary mitochondrial diseases (PMDs). Various features can influence the phenotypes of different PMDs, with relevant consequences on clinical presentation, including the presence of hearing impairment. This paper aims to describe the hearing loss related to different PMDs, and when possible, their phenotype. Methods. A systematic review was performed according to PRISMA guidelines, searching Medline until December 2022. A total of 485 papers were identified, and based on specified criteria, 7 were included in this study. Results. A total of 759 patients affected by PMDs and hearing loss were included. The age of patients ranged from 2 days to 78 years old, and the male-to-female ratio was 1.3:1. The percentage of subjects affected by hearing loss was 40.8%, (310/759), and in most cases, hearing impairment was described as sensorineural, bilateral, symmetrical, and progressive, with different presentations depending on age and syndrome severity. Conclusions. PMDs are challenging conditions with different clinical phenotypes. Hearing loss, especially when bilateral and progressive, may represent a red flag; its association with other systemic disorders  should alert clinicians, and confirmation via genetic testing is mandatory nowadays.  Hearing loss is the most prevalent sensorial deficit, with a major impact on health perception. Depending on the age of onset, hearing loss, if not rehabilitated, has been linked to different disabilities, such as impaired language development in children and impaired interpersonal relationships, academic performances, social lives, and career opportunities, and even to cognitive decline in older adults ,2. It has been reported that more than 50% of pediatric cases of sensorineural hearing loss (SNHL) have a genetic etiology with a different mode of inheritance: autosomal dominant, autosomal recessive, X-linked, or mitochondrial. Even if most of the hereditary hearing loss is related to disorders of nuclear genes, in the recent literature, a role of mitochondrial genes has been claimed, since also these mutations have been described to be causative of SNHL . Mitochondria are sophisticated organelles of human cells, involved in key metabolic processes; they control several metabolic activities, such as oxidative phosphorylation of the electron transport chain ,5, repreWithin the inner ear, mitochondria are strictly related to the preservation of inner ear crucial functions, such as the generation of cochlear endolymphatic potential, as well as the transduction processes driven by hair cells and spiral ganglion neurons. It is evident that any impairment of the delicate energetic equilibrium of inner ear cells may result in the onset of SNHL .Nowadays, the term primary mitochondrial disorders (PMDs) describe, in the literature, a heterogeneous group of conditions related to defects of mitochondrial DNA (mtDNA) and/or of nuclear DNA (nDNA) encoding for structural mitochondrial subunits, causing disorders of the mitochondrial respiratory chain ,8. CompaThis review aims to describe the sensorineural hearing loss related to different PMDs, and when possible, their phenotypic presentation.A systematic review of the literature was performed using the Medline bibliographic database to identify relevant peer-reviewed published papers, in order to select the most comprehensive studies focused on hearing loss and mitochondrial disorders. The search was performed without any limitation and by two researchers (V.F. and G.F.) from inception to 30 December 2022. The search strategies were developed utilizing Medical Subject Headings (MeSH) terms.Papers including patients affected by PMDs were identified. Keywords used for the search were  AND “Hearing Loss” [MeSH]. A total of 485 papers were identified in the search.Studies on humans;Studies on PMDs;Studies with genetic analysis;Original studies on Cohort of patients >20;Studies including hearing loss details.The inclusion criteria were:Studies containing duplicated data from other published work;A cohort of patients <20;Studies published in languages other than English;Studies not focused on PMDs;Studies not including hearing loss details;Studies not including genetic analysis;Studies on specific family groups;Studies on animals.The exclusion criteria were:Of the papers initially selected, seven met the inclusion criteria. This review was conducted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines . The floThe research was based on previously published studies; thus, no ethical approval or patient consent was required.Two reviewers worked independently to obtain data. Evidence was extracted from the included studies and entered into an Excel database to collect the following information: first author, year of publication, country, age, sample size, gender, type of DNA defect , percentage of patients who developed SNHL, study design, and the phenotypic manifestation of the genetic alteration.The literature search identified seven papers, accounting for a total of 759 patients affected by PMDs who were investigated for hearing loss. All studies except two were retrospective. The year of publication ranged from 2006 to late 2022. The age of patients ranged from 2 days to 78 years old, and the male-to-female ratio was 1:1.3. The demographics and characteristics of the selected studies are summarized in In each study, the percentage of subjects affected by hearing loss among a cohort of patients with PMDs was evaluated, and in most cases, the PMDs were sensorineural, bilaterally symmetrical, and progressive , with diThe overall prevalence of SNHL among patients affected by PMDs was 40.8%, (310/759) with high variability among the papers. PMDs can be categorized according to the site of genetic impairments because of defects of mitochondrial DNA (mtDNA) mutations and deletions, or nuclear DNA (nDNA) mutations. It was possible to extract data about the genetic features of SNHL in all except one study, accounting for 272 of 310 patients. The mutation distribution is described in Among mtDNA alterations, the most frequently described was m.3243A>G, reported in all of the selected papers and accounting for 68.8% of cases. It was also responsible for a variety of phenotypes, with hearing impairment ranging from mild to profound at the time of the diagnosis, with an estimated mean progression of 5 dB per year by Sakata et al. . The maiUsually, in the context of mitochondrial multisystemic disease, SNHL presents as part of a complex clinical picture. Rarely does SNHL manifest as the onset or as the sole sign. Syndromes associated with m.3243A>G were the most frequent, as expected. The most common phenotypes associated with SNHL are illustrated in Where available, the information regarding the degree of hearing loss was analyzed. Only three papers described this aspect of SNHL, which was accordingly stated as mild in 40%, moderate in 34.7%, and severe to profound in 25.3% ,20,22.In some cases, high frequencies seemed to be mainly involved in the early stages of the diseases, displaying a descending slope curve on pure tone audiometry ,22.Most of the studies described an SNHL with postlingual onset. However, three papers reported early diagnosis before the age of 6 years old. Specifically, Elander et al. described a cohort of children affected by prelingual deafness and mtDNA impairment, postulating a possible relationship between mtDNA defects and severe hearing involvement. Finally, different degrees of hearing loss require different treatment options. In this regard, cochlear implant (CI) was reported by three authors, with a reported total number of 12 patients who underwent surgery, accounting for an overall percentage of 3.8%.https://pubmed.ncbi.nlm.nih.gov/?term=%22Mitochondrial+Diseases%22%5BMesh%5D&sort=date&size=50, last accessed on 30 December 2022). Understanding mitochondrial pathophysiology is a significant challenge for modern medicine, with increasing scientific interest in recent decades. Since the year 2000, an increasing number of papers have been published on this topic.  a low activity of DNA repair within the mitochondria and (ii) a higher rate of mtDNA mutations due to the continuous exposition to oxygen radicals. In particular, the presence of heteroplasmy  has been linked to different mitochondrial diseases (either inherited or acquired) ,31. The most common mitochondrial disorders linked to hearing loss are mitochondrial encephalopathy, lactate acidosis, and stroke-like episode (MELAS) syndrome; maternally inherited diabetes and deafness (MIDD) ; myoclonIn 1990, Goto et al. first discovered the m.3243A>G defect in a disorder called MELAS syndrome . PopulatBesides MELAS, other syndromes, such as maternally inherited diabetes and deafness (MIDD) , myoclonMost of the subjects affected by PMDs and SNHL have been rehabilitated by using hearing aids: the latter represents the main audiological rehabilitative tool for these patients . InteresIn our opinion, the analysis of both nDNA and mtDNA should be included in genetic counseling for SNHL, especially in cases of bilateral progressive postlingual deafness. In particular, when hearing loss is present with other diseases such as diabetes mellitus, especially if diagnosed at a young age in patients with low or normal BMI, maternal family history, and association with other systemic abnormalities, further genetic investigation (including mtDNA testing) should be always performed . To understand the inheritance pattern, for genetic counseling, a three-generation family history is necessary, with meticulous attention paid to maternal ancestry . FurtherTo the best of our knowledge, there are no recognized therapies for PMDs that can modify the course of the disease, thus far . UnfortuThe administration of mitochondrial co-factors often referred to as mitochondrial cocktails, such as creatine monohydrate, coenzyme Q-10, arginine, L-carnitine, creatine, and lipoic acid, has been proposed in the literature to (i) slow the progression of PMDs, (ii) increase ATP production, (iii) diminish the use of anaerobic sources, and (iv) decrease the production of reactive oxygen species ,58. UnfoNewly reported treatments for PMDs include (i) gene therapy, which is extremely complicated since the expression of mutant mtDNA differs through tissues ; and , into subjects affected by PMDs has been proposed, and few clinical trials are currently running with encouraging preliminary results . It is lThe main drawbacks of this review are: (i) the significant heterogeneity of the included studies, and, consequently, (ii) the complexities of the data analysis. Specifically, it was not always possible to classify the degree of SNHL. In the case of severe PMDs, the audiological investigations, and thus the features of hearing loss, were not always well described; however, in our opinion, especially for patients with encephalopathy, additional assessments  may help to rule out concomitant central processing disorders.PMDs are rare conditions, not well known, not well researched thus far, and have different clinical phenotypes. Hearing loss, especially when bilateral and progressive, may represent a red flag; its association with other systemic disorders  should alert the clinician, and confirmation via genetic testing is mandatory. Additional research about the mitochondrial mechanisms involved in inner ear cellular death is necessary in order (i) to understand the true prevalence and expression of SNHL in PMDs (including studies with long-term follow-up) and (ii) to identify potential therapeutic targets.Furthermore, establishing the long-term surveillance of patients with progressive SNHL can improve the diagnostic rate of PMDs and the comprehension of the phenotypes of these disorders.


Morphological changes of retina in patients with Wilson's disease (WD) can be found by optical coherence tomography (OCT), and such changes had significant differences between neurological forms (NWD) and hepatic forms (HWD) of WD. The aim of this study was to evaluate the relationship between morphological parameters of retina and brain magnetic resonance imaging (MRI) lesions, course of disease, type of disease, and sexuality in WD.A total of 46 WD patients and 40 health controls (HC) were recruited in this study. A total of 42 WD patients were divided into different groups according to clinical manifestations, course of disease, sexuality, and brain MRI lesions. We employed the Global Assessment Scale to assess neurological severity of WD patients. All WD patients and HC underwent retinal OCT to assess the thickness of inner limiting membrane (ILM) layer to retinal pigment epithelium layer and inner retina layer .p < .01), temporal parafovea zone , inferior parafovea zone , and nasal parafovea zone  in inner retina layer. Course of disease influenced the retina thickness. Male patients had thinner inner retina layer compared to female patients.Compared to HWD, NWD had thinner superior parafovea zone (108.07 ± 6.89 vs. 114.40 ± 5.54 μm, Our results demonstrated that WD had thinner inner retina layer compared to HC, and NWD had thinner inner retina layer compared to HWD. We speculated the thickness of inner retina layer may be a potential useful biomarker for NWD. Our results demonstrated that WD had thinner parafovea zones and partial perifovea zones in inner retina layer compared to HC, NWD had thinner parafovea zones in inner retina layer compared to HWD. This study confirmed the thickness of inner retina layer may be a potential useful biomarker for NWD , OCT may be a useful tool for measuring the degree of neurodegeneration in WD patients and may play role in monitoring disease progression. WD is an inherited autosomal recessive disorder that leads to copper accumulation in liver, brain, cornea, and other organs   and 6 × 6 mm2 (HD Angio Retina [6.0]) both centered on the fovea  and group of hepatic (HWD). We employed the Global Assessment Scale to assess the neurological severity of WD patients  layer to retinal pigment epithelium layer, inner retina thickness: ILM to inner plexiform layer (ILM–IPL).All patients underwent 3.0T brain MRI with a GE Discovery MR750, GE Medical Systems. All patients performed the following sequences: T1‐ and T2‐weighted scans, fluid‐attenuated inversion recovery and susceptibility‐weighted imaging. The presence of lesions on MRI in the following structures was collected: basal ganglia, cerebellum, brainstem, and other localizations in white matter.2.1T‐test and non‐normally distributed data were assessed with Mann–Whitney U‐test. For comparison among groups, a one‐way analysis of variance with Bonferroni and Tukey HSD post hoc correction was performed for normally distributed data, to adjust for multiple comparisons. Pearson (r) and Spearman (ρor rho orrs) correlation coefficients were used to assess linear and nonlinear correlations, respectively, between any OCT parameters and neurological severity. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS version 23), and p‐values below .05 were considered statistically significant.To avoid internal correlations, data were analyzed by using mean values of measurements taken from both eyes. Quantitative variables were described using mean and standard deviation (M ± SD). Group differences of demographic categorical variables were tested using the Chi‐square test. Normality of data was visually inspected and tested with Shapiro–Wilk. Group comparisons of normally distributed variables were done with 3A total of 42 WD patients (mean age 30.54 ± 9.83 years) were divided into 2 groups: NWD  and HWD . HC comprised 16 females and 24 males, with mean age of 30.42 ± 7.37 years.In order to assess the relationship between OCT parameters and course of disease, all recruited patients were stratified into three groups: course of disease shorter than 5 years (<5‐year group), 5−10 years (5–10‐year group), and longer than 10 years (>10‐year group). There is no significant difference in the onset of age, age of diagnosis, course of disease, latency from diagnosis to treatment, and treatment duration between NWD and HWD.3.1Compared to HC, WD had thinner superior parafovea zone, temporal parafovea zone, inferior parafovea zone, nasal parafovea zone, temporal perifovea zone, and nasal perifovea zone in inner retina layer Table .3.2Compared to HC, NWD had thinner parafovea zones, superior perifovea zone, and nasal perifovea zone in inner retina layer Table . Meanwhi3.3Previous studies showed that WD severity is associated with gender and the course of disease  Table . PBI gro4Our results indicated that WD had thinner parafovea zones and partial perifovea zones in inner retina layer compared to HC; NWD had thinner parafovea zones in inner retina layer compared to HWD. There was no significant difference in OCT parameters between HWD and HC. Our study found morphological change of retina occurs at NWD, and thinning of inner retina layer in HWD may be associated with neurological system injury. Therefore, the thickness of inner retina layer may be a potential biomarker for monitoring disease progression.OCT is a noninvasive high‐resolution optical imaging technology; details of the principles of spectral‐domain OCT had described in previous study (Nassif et al., Study showed that RNFL was thinner in WD compared to HC (Svetel et al., Langwinska et al.  proved mSvetel et al.  found thA study of a large cohort of WD patients confirmed there was a gender effect in index patients: Hepatic presentation was more common in females, and neurologic presentation was more common in males (Ferenci et al., The retina consists of axons and glia without myelin and may be a good structure for visualizing the degree of neurodegeneration (MacLaren et al., 5Our results demonstrated that WD had thinner parafovea zones and partial perifovea zones in inner retina layer compared to HC, and NWD had thinner parafovea zones in inner retina layer compared to HWD. This study confirmed the thickness of inner retina layer may be a potential useful biomarker for NWD, and OCT may be a useful tool for measuring the degree of neurodegeneration in WD patients and may play role in monitoring disease progression.6Our study had several limitations. First, we only compared OCT parameters in ABI group and PBI group, but WD also existed in other brain MRI lesions. We will apply brain semiquantitative scale performed by Dusek (Dusek, Litwin, et al., Data collection; analysis and manuscript writing: Wei‐Qin Ning. Data collection and manuscript writing: Chun‐Xiao Lyu. Study design; manuscript revision and interpretation of data: Zhi‐Hua Zhou and Ming‐Fan Hong. Data collection; analysis and interpretation of data: Sheng‐Peng Diao, Ye‐Qing Huang, Ai‐Qun Liu, Qing‐Yun Yu, and Zhong‐Xing Peng. All authors read and approved the final manuscript.The authors declare that they have no conflict of interest.https://publons.com/publon/10.1002/brb3.3014.The peer review history for this article is available at


We present a case report of a middle ear osteoma presenting as gradual unilateral conductive hearing loss in a healthy 32-year-old lady. The decision for treatment was influenced by the relatively small burden of the disease, and the size and location of the osteoma, which made the decision for surgical excision prohibitively difficult.Taking patient wishes and circumstances into account, the decision was made for a bone conduction hearing implant in conjunction with close follow-up. Middle ear osteoma is a benign tumor that rarely is seen in daily practice. Although its location within the middle ear tends to dictate clinical presentation, it most commonly presents as a slow, progressive form of conductive hearing loss. It is typically treated with surgical excision and ossicular chain reconstruction.Our case represents a particularly extreme example that involved the assimilation of all ossicles with severe hearing loss. Ultimately, the patient was treated with a conservative treatment strategy and consequently has had an excellent outcome.This case demonstrates an unusual case of middle ear osteoma and highlights how the decision for treatment should be tailored to each individual based on their unique circumstances.The patient is a 28-year-old lady who was referred to the Otology clinic at a major tertiary center with gradual hearing loss in her right ear. She described no history of otalgia, otorrhea, vertigo, facial muscle paralysis, or tinnitus. She had no prior history of ear surgery, nor a documented hearing test prior to presentation. Her past medical history was otherwise notable for recurrent acute otitis media as a child, polycystic ovarian syndrome, obesity, hypothyroidism, depression, and asthma. She regularly took thyroxine, escitalopram, a fluticasone/formoterol combination inhaler, and a salbutamol inhaler as required. She had a family history of ear disease, with her sister requiring grommets as a child. She was not currently working, had never smoked, and was a non-drinker. There was no history of head trauma, noise exposure, or familial hearing loss.On examination, there was a clearly defined white opacification of the right tympanic membrane (TM) Figure . It was Audiology demonstrated severe to moderate conductive hearing loss in the right ear. Pure tone hearing thresholds were 70 decibels (dB) at 500 hertz (Hz), 50 dB at 1000 Hz, and 50 dB at 2000 Hz. There was a Carhart notch on testing of bone conduction hearing thresholds, with 20 dB at 500 Hz, 15 dB at 1000 Hz, and 35 dB at 2000 Hz. Hearing thresholds were unremarkable in the left ear. The right ear had a type B tympanogram, and the left ear had a type A tympanogram. Acoustic reflex testing was not performed.A computerized tomography (CT) scan of the temporal bones was requested to evaluate the cause of her presentation Figures - 3.Imaging demonstrated a hyperdense, homogenous mass of 5.7 x 5.4 x 5.2 mm, which was of similar density to surrounding cortical bone at 1500 Hounsfield Units, suggestive of a middle ear osteoma. The mass arose from the posterior wall of the mesotympanum with the posterior half of the pars tensa overlying its lateral margin as supported by clinical examination. It had assimilated the handle of the malleus, the long process of the incus, and the head and neck of the stapes. This was considered to be the likely explanation for her conductive hearing loss. There was a normal appearance of the facial canal, and inner ear structures were morphologically normal.The patient was referred to the audiology implant clinic for a workup of the possible hearing implant. Aided testing was conducted with a bone-anchored hearing aid on a soft band. In a free field with her left ear masked, she performed well on consonant nucleus consonant testing with a score of 93%.Subsequent discussion at an implant multidisciplinary team meeting, taking into consideration of expressed patient concerns, led to the decision for a bone conduction implant. It was felt that surgery to remove the osteoma would have posed an unnecessary risk to both the facial nerve and inner ear.The patient received a Bonebridge implant  without issue and has had an excellent result. She is very happy with the outcome and is currently under clinical surveillance.Temporal bone osteomas are benign tumors typically found in the external auditory canal. Their occurrence within the middle ear is rare, though not unprecedented, with 39 cases documented since 1964 ,8. This Middle ear osteoma has been shown to most commonly arise from the promontory . While tMost reported cases have been treated with surgical excision of the osteoma, with respect to their location and structures involved . Given tTo our knowledge, no patient has received a bone conduction implant as part of their management, though this option has been previously discussed . Bone coMiddle ear osteoma is a rare cause of conductive hearing loss. We present a particularly extreme example involving the assimilation of all ossicles of the middle ear. To our knowledge, this has not been reported in the literature previously. The patient was treated conservatively following a multidisciplinary discussion between audiologists, surgeons, and the patient. To our knowledge, this is the first time a bone conduction hearing aid with close follow-up has been used to treat or compensate for a middle ear osteoma.


In addition, time plays an important role in the diagnosis. We identified the number of children who came for a diagnostic visit and analyzed the time of the first audiological visit, depending on the result of the hearing screening test performed in the first days of a child’s life and the presence or absence of risk factors of hearing impairment. (2) Methods: We analyzed 6,580,524 children, of which 8.9% required further diagnostics. The mean time of follow-up diagnostic visit in the analyzed group was 130 days and differed due to the presence or absence of risk factors for hearing loss before and after the neonatal period. (3) Results: Although the risk of hearing loss in children with risk factors is 2.31 to 6.38 times higher than in children without risk factors depending on the result of the screening test, more than 40% of parents do not report to scheduled audiological visits. (4) Conclusions: Doctors, nurses, and midwives who screen hearing at the neonatological level play an important role in educating parents about the possibility of hearing loss in a child and the need for an audiological examination. There are many models of newborn hearing screening programs  in the wThanks to the Polish Universal Neonatal Hearing Screening Program (PUNHSP), every newborn child in Poland has a chance of early detection of hearing impairment. The first examination is performed on the second or third day after delivery. In the event of risk factors (RFs) for hearing loss, abnormal results of the otoemission test (OAE), or no test, the child is referred for further diagnostics, which, according to the program assumptions, should start before the age of 3 months . BetweenIn the analysis, 6,580,524 children born from January 2003 to October 2020 were considered. The data were divided according to the results of the screening test and the presence of risk factors of hearing loss in the neonatal , ototoxicity, TORCH infections, low birth weight, Apgar < 4 in 1st min, Apgar < 6 in 5th min, hyperbilirubinemia, bacterial meningitis, intensive care > 7 days, and respirator support ) and post-neonatal period . The percentage of children reporting for further diagnostics and the percentage of children diagnosed with hearing loss in particular groups were analyzed in detail. Hearing screening results with the otoacoustic emission method were divided as follows: doubtful result in both ears 0.3%, doubtful result in one ear and correct in the other ear 0.4%, doubtful result in one ear and control  in the other ear 0.1%, correct in both ears 94.7%, correct in one ear and control in the other ear 1.7%, control in both ears 1.0%, and no test in both ears 1.9%. The screening results were divided into three parts, correct if the OAE criteria were met (pass), control if the OAE criteria were not met (refer), and doubtful if the result indicated neither correct nor control. In the further part of the analysis, the results of doubtful and control OAE were treated as requiring further diagnostics as control . Next, tN = 427,919) = 3402.098; p = 0.0001 , parents of children whose screening test showed the correct results of the OAE test in one ear and doubtful results in the other ear reported the least frequently; as many as 94.1% of them did not report for control tests, and the percentage of children diagnosed with hearing loss in this group was 9.8% . Among cThere were 264,351 children in the group with at least one risk factor for neonatal hearing loss and without RFs for the post-neonatal period. In the case of children with doubtful results in both ears, 54.5% of parents did not report for further diagnostics, and hearing loss was diagnosed in 12.9% of children. This means that RFs increase the risk of hearing loss in this group of children by more than five-fold (OR = 5.3). Among the children with doubtful results in one ear and correct results in the other, 46.3% of their parents did not report for further diagnostics, and 23.8% were diagnosed with hearing loss. The chance of developing hearing loss in this group increased three-fold (OR = 2.87) in the event of a risk factor. Among children who had a doubtful result in one ear and control in the other, 47.9% of parents did not report for further diagnosis, and 32.2% of children were diagnosed with hearing loss, which means that there is a chance of hearing loss in this group of children; in the case of the presence of a risk factor, it increases by six times (OR = 6.38). In the case of children with normal screening results, 42.6% of parents did not report for further diagnosis, and hearing loss was detected in 1.3% of children (OR = 0.02). In the case of children with correct results for the screening test in one ear and control in the other, 40.5% of children did not report for further diagnostics, and hearing loss was detected in 11.5% of diagnosed children, which means that the chance of hearing loss with concomitant RFs increases almost three-fold in this group of children (OR = 2.66). Among children with abnormal results in both ears, 45.4% of parents did not report for further diagnosis, and 32.9% of children were diagnosed with hearing loss. This means that the chance of hearing loss in the event of CR in this group of children increases almost threefold (OR = 2.65). Among children who were not screened at the first level, 45.8% did not report for further diagnostics, and 6.6% of children were diagnosed with hearing loss. This means that the chance of having hearing loss doubled when there were RFs for hearing loss (OR = 2.31) .In the group of children with no RFs for neonatal hearing loss and no RFs for post-neonatal hearing loss, 6310 children were registered. In this group of children, the lack of reporting at the diagnostic level ranged from 15.8% in children without screening to 38.7% in children with correct results of the OAE test in one ear and doubtful results in the other. Hearing loss was diagnosed in 32.3% of children with doubtful results in both ears, 27.7% of children with doubtful results in one ear and correct results in the other ear, 28.9% of children with doubtful results in one ear and control results in the other ear, 6.4% of children with correct results in both ears, 20.1% of children with correct results in one ear and control results in the other ear, 45.7% of children with correct results in both ears, and 15.7% of children without hearing screening.In the group of children with RFs for neonatal hearing loss and RFs for post-neonatal hearing loss, 6117 children were registered. In this group of children, the lack of reporting at the diagnostic level ranged from 3.6% in children with doubtful results in one ear and control in the other ear to 19.0% in children with doubtful results in both ears. Hearing loss was diagnosed in 34.4% of children with doubtful results in both ears, 48.8% of children with doubtful results in one ear and correct results in the other, 33.3% of children with doubtful results in one ear and control in the other ear, 4.5% of children with correct results in both ears, 20.7% of children with correct results in one ear and control in the other ear, 49.6% of children with correct results in both ears, and 20.2% of children without screening.Conducting a follow-up visit within an appropriate time for infants with suspected hearing loss detected during the first stage of screening is very important for the proper development of the child. Many countries around the world struggle with the problem of encouraging parents to report their children for detailed audiological diagnostics in a timely manner. The literature rarely describes the time of reporting depending on the result of the hearing screening test in the first days of a child’s life and the presence of RFs for hearing damage. Various countries in Europe report the average time to definitive diagnosis for children with hearing screening as ranging from 2 weeks in Malta to 12 months in Ukraine, while this ranged from 1 month in Cyprus to 55 months in Moldova for children without hearing screening ,7,8. Of In the PUNHSP, data on reporting at the diagnostic level concern only information received from centers participating in the program and registering visits to the CDB. The last detailed research conducted in Poland in 2014 shows that not 47.6% but 83.6% of children present for hearing screening [In the literature review, it can be seen that deficiencies in parental education were associated with a high rate of lost to follow-up. In such cases, appropriate data management strategies were used to avoid such situations . A US stAnother aspect of this analysis is the ability to undergo hearing screening but still have significant hearing loss. There is very little literature on the likelihood of a false positive OAE. In PUNHSP, hearing loss was recorded in 1.8% of children who had correct screening test results and no noted RFs for hearing loss. In this case, parents usually present themselves to the diagnostic level due to poor language development or behavioral problems. A hearing screening procedure may fail for several reasons: a false positive screening result, retrocochlear pathology with intact hair cell function, or progressive/delayed hearing loss .The strength of this study is the large number of children in the analyzed group and the uniformity of the program. All centers work the same way and perform the same tests during diagnosis. A limitation of the study is that we do not know how many parents were screened at private facilities.Doctors, nurses, and midwives who perform hearing screening at the neonatological level play an important role in educating parents about the possibility of hearing loss in a child and the need for an audiological examination. Therefore, funds for the supervision of reporting at the diagnostic level of PUNHSP are limited. Increasing the funds in the PUNHSP for the improvement of the quality of the system controlling the cases of lost to follow-up to control visits would allow for a decisive tightening of the PUNHSP system.


Hearing disability in preschool children can delay or impact oral communication and social skills. Provision of hearing screening tests by standard audiometry in low- to middle-income countries is problematic due to a lack of pediatric audiologists, standard hearing equipment, and standard soundproof rooms. Therefore, an innovative hearing screening tool that is easily accessible and inexpensive such as a mobile app should be considered. Headphones have been a crucial part of hearing screenings. Audiometric headphones, which serve as the reference standard, have been used in most studies. However, since audiometric headphones are not accessible in rural areas, we hypothesized that generic headphones can also be used in hearing screenings.This study aimed to determine the sensitivity, specificity, κ coefficiency, and time consumption of the PASS-Pro (Preschool Audiometry Screening System–Pro) app when using TDH39 headphones, Beyerdynamic DT 770 PRO headphones, and generic earmuff headphones compared to standard conditioned play audiometry.We recruited preschool children aged 4 to 5 years to participate in this study. The children received 3 PASS-Pro screening tests using different types of headphones in a quiet room and 1 standard conditioned play audiometry in a soundproof room. All tests were administered in random order. The agreement coefficient, sensitivity, specificity, and mean test duration were determined.P=.02, P=.002, and P=.004), respectively. The sensitivity for all headphones was 50% and the specificity was more than 88%. For moderate hearing loss screening, the κ coefficients were 0.206, 0.272, and 0.235 , respectively. The sensitivity for all headphones was 100% and the specificity was more than 92%. There were no statistical differences in sensitivity and specificity between the reference headphone (TDH39), Beyerdynamic DT 770 PRO headphone, and generic earmuff headphones . The PASS-Pro app used significantly less time to carry out hearing tests than conditioned play audiometry (P<.001).A total of 44 children participated in this study. For mild hearing loss screening, the κ coefficients between standard conditioned play audiometry and the PASS-Pro app using TDH39 headphones, Beyerdynamic DT 770 PRO headphones, and generic earmuff headphones were 0.195, 0.290, and 0.261 (The PASS-Pro app, used with generic headphones, is effective for conducting hearing screening tests in preschool children with high sensitivity and specificity.Thai Clinical Trials Registry TCTR20201229002; www.thaiclinicaltrials.org/show/TCTR20201229002 Hearing loss or hearing difficulties is a common cause of disability among people around the world. In 2012, the World Health Organization reported that 360 million people experienced hearing loss, indicating a prevalence of 5.3% in the global population  [In low- to middle-income countries, hearing difficulties affect people’s quality of life more than those living in high-income countries due to limited resources, such as medical staff, audiologists, hearing screening tools, and accessibility to medical treatment . HearingCurrently, standard hearing screening for children remains a major concern due to the lack of professional pediatric audiologists and soundproof rooms. The standard hearing test that is widely accepted for use among newborns to children aged 3 years is otoacoustic emission or automated auditory brainstem response and the test for children aged 3 to 6 years is the pure tone audiometry sweep test or conditioned play audiometry . These tIn our previous study , we testWe designed the app for limited-source areas, rural areas, and areas without medical services. However, we found that audiometric TDH39 headphones were inaccessible in the rural area under study. In this study, we further evaluated the diagnostic value of the PASS-Pro app using 3 types of headphones as well as generic headphones. We selected the comparison headphones according to their availability in the Thai market and their low to moderate price range.The objective of this study was to compare the sensitivity, specificity, κ coefficiency, and time consumption between standard conditioned play audiometry and the PASS-Pro (Preschool Audiometry Screening System–Pro) app using TDH39 headphones, Beyerdynamic DT 770 PRO headphones, and generic earmuff headphones.Children in northeastern Thailand were recruited between November 2020 and February 2021. The inclusion criteria were as follows: children aged 4 to 5 years, who were able to communicate using the Thai language, and who were able to cooperate with the audiologists and medical staff. The exclusion criteria included pathology on the pinna and external auditory canal (which could interfere with headphone insertion), blurred or distorted vision, and blindness. The withdrawal criteria included being uncooperative during the study or incomplete hearing screening tests.The specifications of the headphones used in this study are described in All participants received otoscopic examination and hearing tests a total of 4 times: 3 PASS-Pro screening tests using different types of headphones  in a quiet room and 1 standard conditioned play audiometry in a soundproof room. All tests were randomly allocated to the participants .An otolaryngologist examined each child’s external ears prior to the intervention. All audiologists in this study were blinded to the results of the hearing tests and the time spent doing each test to avoid bias.The PASS-Pro app was accessed through the Samsung Galaxy Tab A 10.5 Android tablet. Starting with the right ear at 40 dB, the app randomly provided 1 set of pictures (6 pictures per set), then sounded a 2-syllable word that corresponded to one of the pictures. The participant had 10 seconds to choose the correct picture after hearing the word. The app recorded whether the answer was correct or not before the next random set of pictures were displayed. The participant had to select the correct picture again for each level of hearing as 3 new sets of pictures were presented. Obtaining 2 out of 3 correct responses meant the participant had passed the hearing level. Subsequently, the app reduced the volume from 40 dB to 30 dB, then to 20 dB. The process was repeated with the left ear .The app stopped if the participant chose the correct picture fewer than 2 out of 3 sets of pictures in the same hearing level or did not choose the picture within 10 seconds. This was reported as hearing test failure for that level. The test results showed the hearing threshold and the time taken for each ear.The children’s hearing threshold was evaluated using air-conduction pure tone audiometry at 0.5, 1, 2, 3, and 4 kHz. Participants with hearing loss, confirmed by the audiometry, will be sent to the otolaryngologist for standard evaluation and treatment.Hearing screening with the PASS-Pro app was conducted in a standard quiet room at a hospital. The pure tone audiometry was conducted in a soundproof room.According to the American Academy of Audiology’s childhood hearing screening guidelines , a heariTo calibrate the system to prepare for the trial, we first equalized the word files to have an equal root mean square. We then calibrated each word individually at 20, 30, and 40 decibel hearing level (dB HL) using the reference headphones (TDH39).Through a 6cc coupler, a sound level meter was used to measure the peak power  outputs from the standard audiometer and the tablet for each word at 20-, 30-, and 40-dB HL settings. The calibration coefficient calculated at each measuring point was essentially an additional gain required that would make the tablet output the word with the same dBA peak when measured using the sound level meter. The Beyerdynamic DT 770 PRO and the generic headphones with earmuffs were calibrated using the same procedure as the TDH39 headphones.The study was approved by the Khon Kaen University Ethical Committee for Human Research (HE631548) and was registered in the Thai Clinical Trials Registry (TCTR20201229002). Written informed consent was obtained from all participants and participants were given the option to opt out. All data were deidentified. Compensation was provided for transportation and participation in the study.The sample size was calculated from κ estimation with an expected κ value of 0.5±0.3. A power of 95% and a significance level of .05 were used. The ideal sample size was calculated to be 44, with a 20% dropout rate.t test was used to compare average test duration of the app with conventional audiometry. For all tests, a P value of <.05 was considered to be statistically significant.Statistical analysis was conducted using STATA (StataCorp LLC). The agreement coefficiency, sensitivity, and specificity of the PASS-Pro app were determined. The McNemer test was used to compare the dichotomous data of the headphones with the reference headphones. A paired A total of 44 children participated in this study, comprising 19 (43%) female and 25 (57%) male participants. No participants dropped out of the study. Using standard conditioned play audiometry, we found that 31 (70%) children had normal hearing in both ears, 9 (21%) had mild or moderate unilateral hearing loss, and 4 (9%) had mild or moderate bilateral hearing loss. An otoscopic examination was performed on all children. Of the 44 children, 4 (45%) had a normal external ear canal and tympanic membrane and 5 (55%) had impacted cerumen.P=.02, P=.002, and P=.004), respectively. For moderate hearing loss, the κ values between TDH39 headphones, Beyerdynamic DT 770 PRO headphones, and generic earmuff headphones versus standard conditioned play audiometry were 0.206, 0.272, and 0.235 , respectively. The κ statistic indicated fair agreement between the headphones and audiometry .The average test duration was 579.8 seconds (range 421-1152 seconds) for conditioned play audiometry, 91.27 seconds (range 58-150 seconds) for the PASS-Pro app with TDH39 headphones, 80.39 seconds (range 46-113 seconds) for the PASS-Pro app with Beyerdynamic DT 770 PRO headphones, and 84.39 seconds (range 50-130 seconds) for the PASS-Pro app with generic headphones. The PASS-Pro app used significantly less time than conditioned play audiometry (Ps<.05) for all headphones. The sensitivity to detect mild hearing loss was 50% for all headphones while the specificity was more than 80%. Moreover, the sensitivity to detect moderate hearing loss was 100% for all headphones while the specificity was more than 90%. It can be inferred that generic headphones can be used for hearing screening.In this study, we found that the agreement between audiometry (the gold standard) and all headphones ranged from 69.52% to 94.32%. The κ statistic found a statistically significant correlation coefficient  from our previous study versus 50% (95% CI 6.76%-93.2%) in this study may have occurred by chance. Our previous study of 122 children aimed to evaluate the sensitivity of the PASS app for hearing screening. However, the current study’s main objective was not to evaluate the sensitivity and sensitivity but to evaluate the agreement between the headphones and standard audiometry.Our results agreed with those of other hearing screening apps that used various types of headphones. For example, Audiometer used earphones or earbuds , SHOEBOXAlthough the agreement between audiometry (the gold standard) and all headphones was high, the κ correlation coefficient between these tools indicated fair agreement. This can be explained by Cohen’s Kappa Paradox, which is usually found in sensitivity studies. The effects of the paradox arise when participants tend to be classified into one of the possible outcomes. This is either due to the nature of the outcome itself and its high prevalence or because at least one of the evaluators tends to assign more frequently to a specific outcome  .Due to the limited number of participants with hearing loss in this study, increasing the sample size in future studies should provide more accurate results. The PASS-Pro app provides only spondee words; the next software update should allow the app to produce pure tone sound for better agreement with standard audiometry.The standard reference audiometric speaker is typically supplied in the form of headphones. The design of the headphones allows it to be soundproof, suitable for high-frequency audiometry and high passive ambient noise attenuation. However, the headphones are large, heavy, and expensive whereas other types of devices such as earbuds and earphones are more portable and lightweight. Using earbuds or earphones for hearing screening may decrease the sensitivity of the system. However, to our knowledge, no study has been conducted to quantify this sensitivity difference yet.For future research, researchers should study commercially available portable earphones instead of generic headphones with earmuffs as the former can be directly plugged into the ear canal, are low cost, and are widely available. In this study, we limited the hearing screening test to quiet hospital rooms; therefore, the next study will be tested in a quiet community setting such as a home or school to obtain a larger sample size and emulate a real-world environment.In conclusion, the combination of the PASS-Pro app and generic headphones is a reliable method for conducting hearing screening tests in preschool children, offering both high sensitivity and specificity.


Double emulsions are complex emulsion systems with a wide range of applications across different fields, such as pharmaceutics, food and beverage, materials sciences, personal care, and dietary supplements. Conventionally, surfactants are required for the stabilization of double emulsions. However, due to the emerging need for more robust emulsion systems and the growing trends for biocompatible and biodegradable materials, Pickering double emulsions have attracted increasing interest. In comparison to double emulsions stabilized solely by surfactants, Pickering double emulsions possess enhanced stability due to the irreversible adsorption of colloidal particles at the oil/water interface, while adopting desired environmental-friendly properties. Such advantages have made Pickering double emulsions rigid templates for the preparation of various hierarchical structures and as potential encapsulation systems for the delivery of bioactive compounds. This article aims to provide an evaluation of the recent advances in Pickering double emulsions, with a special focus on the colloidal particles employed and the corresponding stabilization strategies. Emphasis is then devoted to the applications of Pickering double emulsions, from encapsulation and co-encapsulation of a wide range of active compounds to templates for the fabrication of hierarchical structures. The tailorable properties and the proposed applications of such hierarchical structures are also discussed. It is hoped that this perspective paper will serve as a useful reference on Pickering double emulsions and will provide insights toward future studies in the fabrication and applications of Pickering double emulsions. The ter1/O interface stabilized by the in situ modified PEI/silica particles and the O/W2 interface stabilized by the unmodified PEI/silica particles, stable W/O/W PDEs have been achieved. Zhang et al. .,35.32,35late PDE . Regulatlate PDE . On the late PDE ,53,66; f3O4 colloidal particles . Mo. Mo27]. tructure  were pre O phase . The PVA O phase . Similar O phase , possessMicrocapsules whose shells consist of densely packed colloidal particles are called colloidosomes . SimilarConventionally, simple W/O Pickering emulsions were commonly adapted to template the colloidal shell structures. However, this approach required subsequent transferring of the colloidosome into a continuous aqueous phase either by centrifugation or repeated washing, which would often induce extra damage to the colloidosome . Compare2) nanoparticles were dispersed in the oil phase and were reported to adsorb onto the W1/O and O/W2 interfaces upon the formation of W/O/W PDE, forming colloidal shell structures. The colloidosomes were subsequently fabricated upon removal of the oil phase  Research towards naturally derived particles that can stabilize simple W(2) To tune the surface wettability of hydrophilic naturally derived particles via surface modification methods. Moreover, the current application of PDE in oral delivery focuses primarily on the fabrication of the W/O/W delivery system, while exploration for O/W/O delivery is lacking. This is in alignment with the board range of products that are based on aqueous continuous systems. However, despite being limited, there are popular food products with continuous oil phases, such as butter, migraine, and spreads. More investigations in the preparation of O/W/O PDE for oral delivery could shed light on new formulations of the existing lipid-based food products. (3) PDEs are regarded as suitable delivery media for many nutraceuticals and phytochemicals, though PDEs are still rarely adapted as delivery systems for active ingredients due to their poor and uncontrollable stability when exposed to complex human digestive environments. Recent studies are starting to explore the precise tuning of the digestion and release of the encapsulants by engineering the numerous tunable properties of the PDEs. However, more controlled release solutions, such as pH-triggered release, salt-induced release, and temperature-controlled release, could be explored for the PDE as a crucial delivery system to better suit the human digestive system. (4) As described in previous sections, hierarchical structures such as microspheres and microcapsules, templated after PDEs, possess desirable characteristics and potentials for applications in terms of controlled release. However, their application in food products is rather limited as non-biocompatible polymers are often required for the polymerization step, which is a critical step to the formation of microstructure. PDE formulated with generally regarded as safe (GRAS) material could potentially give rise to microstructure with biocompatibility. Moreover, the microstructures’ reliance on synthetic polymers could be negated by researching the topic of biopolymerization, which is the polymerization of biopolymers, such as cellulose and wax. If a microcapsule could be templated after GRAS PDE, via bio-polymerization, then its food application could be granted. Meanwhile, in many studies, the morphology and configuration of the templating PDE, resulting from adjusting the parameters during preparation of the PDE, have been determined to play critical roles in the microstructure and properties of the fabricated hierarchical structures. However, rather few studies have examined the correlation between variations in the microstructure of the hierarchical structures resulting from tuning the configuration of the templating PDE, and the corresponding changes in the performance of such hierarchical structures in their proposed field of application. Efforts should be made to clarify such correlations and to provide insights for increasing the competency of PDE as a template for the fabrication of hierarchical structures with optimized and tailored performances. For instance, several studies have demonstrated the dual-function role of colloidal particles in PDE, for the cases of using iron oxides as interface adsorbed particles to achieve stabilization of the PDE while providing magnetic property to the fabricated hierarchical structure. As such, the development of nanoparticles responsive to environmental stimuli, such as pH, ionic strength, temperature, mechanical stress, and others, could be another emerging topic seeking to strengthen the versatility of PDE as a template material for hierarchical structures with special purposes. It would then be worthwhile for future studies to venture into exploring colloidal particles that possess dual-function roles and/or environmental responsive properties to provide improved efficacy or increased versatility of the fabricated hierarchical structures based on the templating PDE.PDE represents a promising alternative to single emulsion and conventional double emulsion stabilized solely by surfactants, with many unique advantages. Compared to a single emulsion, the multi-phases and the consequent multi-compartment properties of PDE allow for more complex tunability and applications, for example, manipulation of the properties of three phases versus two, as well as the potential for co-encapsulation and delivery. While compared to conventional double emulsions, PDE offered enhanced stability and environmental friendliness, meeting satisfaction toward practical purposes. Meanwhile, the rigidity and particle-adsorbed interfaces opened room for PDE to serve as a synthesis template for other hierarchical structures. Consequently, different kinds of colloidal particles and stabilization strategies have been studied extensively. For instance, a broad application prospect has been proposed for PDE; the applications of PDE were outlined in the illustrative


NCT02556736, NCT03326336 at clinicaltrials.gov). While its application to the hearing field is more recent, progress has been made over the past decade to adapt this new tool for hearing restoration.,Molecular Therapy, Methods and Clinical Development, Zerche et al. report the development of a new optogene that brings exciting prospects for the development of optical cochlear implants (oCIs) and their use in the clinic.Optogenetics, first introduced in 2006 ,Currently, patients with moderate to profound sensorineural hearing loss who get little benefit from hearing aids may be candidates for a cochlear implant (CI). The CI is a neural prosthesis that translates sound signals collected through an external microphone into electrical impulses delivered to the auditory nerve via an electrode array embedded in the cochlea. This technology has revolutionized the field of hearing restoration. Many patients benefit from CIs and display improved speech perception in favorable acoustic environments. Furthermore, early implantation in children leads to greatly improved language acquisition skills. This technology, however, is not perfect. Clinical outcomes are highly variable, and CI patients struggle in noisy environments. Furthermore, while CI patients can perceive rhythm, they have more difficulties discriminating complex tones associated with music and melodies.,,,While CI technology has greatly improved since its inception, CIs are inherently limited by the spread of the electrical field from each electrode that contacts and activates a group of spiral ganglion neurons (SGNs). To circumvent this limitation oCIs are being developed that take advantage of laser stimulation to offer improved spatial and temporal resolution. Implementation of the strategy for hearing restoration involves the use of adeno-associated viral (AAV) vectors, injected into the ear, to express a photosensitive protein, typically a derivative of bacterial channelrhodopsin (ChR), in the SGNs. Expression of the photosensitive protein renders SGNs sensitive to optogenetic stimulation, which, thanks to novel, faster probes, enables faithful and improved frequency coding.,Preclinical and clinical studies using ChR for optogenetic stimulation have taken advantage of compounds fused to fluorescent proteins (FPs). The work from Zerche et al. aims to develop and validate a new compound, devoid of a fluorescent tag, to limit possible adverse effects that may result from the introduction of a non-human sequence. Unfortunately, removal of FPs renders ChRs less excitable.Performance of the novel f-Chrimson-TSKir2.1 was assessed by injection of AAV2/9 vectors through the round window in postnatal P6-P7 mice and retroauricular insertion of a thin optical fiber into the scala tympani. Exposure to increasing light pulse intensity led to measurable optically evoked auditory brainstem responses (ABRs) at least up to 300 Hz with similar results for the new compound and f-Chrimson-EYFP.,,,While spatial resolution can be improved with oCI, temporal fidelity, which is essential for auditory function, remains a challenge. Although photosensitive channels with fast kinetics can allow better temporal coding for high-frequency stimuli, they are associated with decreased light sensitivity. In terms of temporal fidelity, the kinetics of channel closure is similar for f-Chrimson-TSKir2.1-P2A-Katsuhka and f-Chrimson-EYFP (4.9 ms). While still quite fast, f-Chrimson is slower than other optogenes.NCT05572073, NCT05821959 at clinicaltrials.gov). As such, a roadmap is now in place for the development of oCIs for hearing restoration in patients with sensorineural hearing loss.In summary, the newly designed f-Chrimson-TSKir2.1 provides a new and improved optogenetic agent for oCIs that is smaller and potentially less immunogenic. This study provides an important step forward for the development and application of oCIs toward a novel clinical approach for the treatment of hearing loss. Outcomes from current clinical trials aimed at restoring vision using optogenetics may impact the application of this technology to the field of hearing restoration. Importantly, safety and tolerability measures will be crucial in validating the use of AAV vectors to transduce remaining SGNs in patients. AAV-based therapies have been approved for several conditions in recent years, including for RPE65-linked vision loss.


No Native American/Alaska Native, Native Hawaiian/Pacific Islander, or ethnically Hispanic/Latinx subjects were represented. There were significant differences in MEN1 mutations among Black and White patients in immunohistochemical (13:40) and GENIE data , with 9 additional genes differentially mutated in the GENIE dataset. Genomic sequencing data for GEP-NENs is almost racially homogenous. Differences in pNEN genomics may exist between racial groups, highlighting a need for diversity in future genomic analyses of GEP-NENs to understand the putative influence of interracial genomic variation on GEP-NEN prevention, diagnosis, and therapy.Not all populations are poised to benefit from advancing genomics in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), as genomics have focused on White patients. This study aimed to evaluate racial populations represented in genomic studies of GEP-NENs and to provide evidence of differential genomic findings between racial groups in GEP-NENs. Manuscripts analyzing DNA, RNA, or DNA methylation in GEP-NENs were queried using PUBMED and EMBASE. NIH race/ethnicity term frequency was then determined by Natural Language Processing, followed by manual evaluation of tumor types and subjects by racial group. IHC of institutional tissue micro-arrays and analysis of AACR GENIE data analyzed was performed to determine mutational differences between Black and White pancreatic NEN (pNEN) patients. 313 manuscripts conducted the requisite genomic analyses, 16 of which included subject race data. Race data were included in 13/184 DNA, 4/107 RNA, and 1/54 DNA Methylation analyses. These studies included 89% White subjects (There is little diversity in genomic studies of GEP-NENs, which may exhibit clinically impactful variation in their tumor biology among racial groups. Improved diversity in such studies is imperative for understanding this variation and its potential impacts on disease prevention, diagnosis, therapeutic targeting, and clinical outcomes. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are a heterogeneous group of tumors arising from the enteroendocrine secretory cells of the gastrointestinal tract and endocrine pancreas. Pancreatic (pNEN) and small intestinal (siNEN) NENs are the most common types of GEP-NENs, accounting for 3%–5% and 35%–42% of pancreatic and small intestinal malignancies, respectively . Some GERegarding clinical outcomes, recent work has uncovered alarming disparities between White and minority GEP-NEN patients- particularly Black patients . Black pThere is robust precedent demonstrating differentially mutated, expressed, and regulated genes in various cancers among racial groups, representing potentially targetable differences in tumor biology . DNA methttps://www.ncbi.nlm.nih.gov/pubmed/) and EMBASE (https://www.embase.com/) databases  in GEP-NENs; conducting array-based or massively parallel next-generation sequencing analysis. Articles analyzing single gene expression, PCR arrays of < 5 genes (not including housekeeping genes), or point mutations at singular base loci  were excluded. Articles that included only preestablished cell line-based analysis were excluded. Articles such as editorials, letters, commentaries, reviews, clinical practice guidelines, and abstracts from conferences without associated published manuscripts were excluded. Meta-analyses or studies that exclusively studied previously published data, where one would not expect data on subject race to be uniquely presented, were excluded. Cases in which studies included multiple types of neuroendocrine neoplasms  were included only if the GEP-NEN component of the study met the inclusion criteria with other NEN types excluded. Furthermore, only the GEP-NEN cases in these studies were included in the analysis of racial/ethnic representation. Studies of mixed neuroendocrine and non-neuroendocrine neoplasms were excluded. Manuscripts focused on pediatric diagnoses were also excluded, as the incidence of all pediatric GEP-NENs is extremely low  and these cases may be less likely to conform to the wider distribution of representation across all GEP-NENs  using the python packages NLTK (v. 3.6.2) and PDFMiner.six (release 20201018) was used to determine the frequency of the words “Race,” “Ethnicity,” “African American,” “Black,” “Hispanic,” “Latino,” “Latina,” “Latinx,” “Asian,” “Native American,” “American Indian,” “Alaska Native,” “Native Hawaiian,” “Pacific Islander,” “Caucasian,” and “White,” in published original research manuscripts performing sequencing on GEP-NENs gathered by a systematic review of the literature as described above. Specifically, PDF files were read using the extract_text function from PDFMiner.six. Multi-word tokens were then generated using the above race/ethnicity terms using the MWETokenizer function from NLTK. Tokenization and keyword searching was then performed using MWETokenizer.tokenize and text.concordance functions. Natural language processing included supplemental materials where present. Subject numbers by racial group were then determined via manual review following NLP. All manuscripts that were negative for the race/ethnicity terms in our NLP search were likewise manually reviewed to verify that subject race/ethnicity data were not reported.DAXX, ATRX, and MEN1 genes, which is altered by most mutations, was determined by IHC performed on pNEN tissue microarrays  were used to generate a protein–protein interaction (PPI)-enrichment network using STRING version 11.5 (10 (observed enrichment/expected enrichment), with expected enrichment derived from randomly generated whole-genome background networks of similar size.Differentially mutated epigenetic regulatory genes from AACR GENIE -adjusted P values are reported alongside P values in the mutational analysis as q-values. The mutation comparisons made are reported in P values corrected using the FDR . Further inquiries may be directed to the corresponding author.The data generated in this study are available within the article and its Supplementary Data files. Other data used are available within the AACR Project GENIE Database (n = 1438), not performing a requisite (epi)genetic analysis (n = 691), or for analyzing only preestablished cell lines (n = 212). In total, 313 manuscripts met all inclusion criterion. PNENs were included in most studies (n = 220), followed by siNENs (n = 98) and colorectal NENs (n = 44) , followed by siNENs  and colorectal NENs  . The totn = 794; . These mn = 697), followed by pNENs (n = 695) and colorectal NENs , 5.8% Asian subjects , 4.0% “Other” subjects , and 1.2% Black subjects . No study reported race/ethnicity specific data for Hispanic/Latinx, Native American/Alaska Native, or Native Hawaiian/Pacific Islander subjects (n = 43) and 10% “Other” subjects (n = 5). It should be noted that the discrepancy between total GEP-NENs analyzed in these studies by tumor subtype  genetic analyses. Thirteen of 184 studies analyzing DNA included data on the race of their subjects, while 4 of 107 analyzing RNA, and 1 of 54 studies analyzing Methylation included such data . The ana n = 46; . These ssubjects . The sin = 0.27) . While tMEN1, DAXX, and ATRX are the most frequently mutated in pNENs, we investigated their mutational status across racial groups via IHC analyses. Negative staining on IHC indicates a protein-altering mutation, and has been shown to be highly concordant with mutation in these genes (P = 0.711), 2/40 (5%) White and 1/13 (7%) Black patients were negative for Atrx expression (P > 0.999), and 11/40 (28%) White and 0/13 Black patients were negative for Menin expression (P = 0.047). Previous studies have found loss of Daxx, Atrx, and Menin expression by IHC in pNENs to occur in 59%, 25%–85%, and 18%–72% of cases, respectively genomics, we began to question the applicability of previous findings to these groups. As pNENs were the most analyzed tumor in GEP-NEN (epi)genomics, and the genes se genes . Preexisse genes . Nine ofectively . The retectively .n = 24 and n = 399; ref. CHEK2 and MUTYH (DNA repair), NF2 and TP53BP1 [tumor suppression (TS)], KMT2D and EP300 [histone methyl- and acetyl- transferases  respectively], the CRKL and MAPK1 oncogenes, and SMARCB1 (part of the n/npBAF SWI-SNF chromatin-remodeling complexes). Most notably, we found profound differences in the rate of MEN1 mutations , with White patients having a much higher rate of MEN1 mutation compared with Black patients . Importantly, 4/10 genes found to be differentially mutated have direct roles in epigenetic regulation , supporting previously described differences in epigenetic aberrations between racial groups in cancer , with a total of 132 PPI's discovered within the network and a mean of 8.25 interactions per node (EP300 had the highest number of interacting partners (n = 14), followed by KAT2B (n = 13) and KDM6A/YY1 (n = 11 each). KMT2D, SMARCB1, and MEN1 each had 9, 8, and 6 interacting partners, respectively. Gene ontology (GO) enrichment analysis was then performed for biological processes, molecular functions, and cellular components, discovering 196 significantly enriched GO terms in our PPI network , forming the MLL3/4 histone methyltransferase complex that regulates H3K4me3 deposition in promoter regions throughout the genome, as well as interacts with the p53 pathway through many of its target loci genomics among racial groups to identify genomic aberrations that may be enriched in or unique to these populations.We demonstrate herein that few studies on the (epi)genetics of GEP-NENs include data on the race of their subjects. We find that pNENs and siNENs make up the greatest proportion of manuscripts’ topics and tumor specimens analyzed in the literature, as would be expected given their incidence compared with other GEP-NENs. We also find that GEP-NEN (epi)genomics overrepresents White subjects relative to the proportion of the U.S. population that they comprise . Indeed,YY1 chromatin remodeling gene are heavily enriched in Asian patient populations  has been shown to predict response to alkylating agents such as temozolomide, wherein understanding differences in this hypermethylation in Black patients might have immediate clinical implications (The inclusion of diverse patient populations in (epi)genetic studies of cancer is crucial to understanding and rectifying cancer health disparities, as well as further understanding the biology of various cancers. Therapeutic susceptibility is one important translational aspect of inter-racial (epi)genetic variation that highlights the need for diverse patient representation in sequencing analyses. For example, a phase III trial of the tyrosine kinase inhibitor (TKI) gefitinib for non–small cell lung cancer (NSCLC) found no benefit for any population other than those of Asian descent. EGFR mutations were then discovered to be far more prevalent in Asian patients with NSCLC compared with those of European descent 47% vs. 15%) . This le% vs. 15%ications . These pDAXX/ATRX and MEN1, the expression levels of somatostatin receptors 2 and 5, elements of the tumor immune microenvironment, and enzymes involved in hormone metabolism  as opposed to the inclusion of genetic ancestry when characterizing racially enriched genomic features. SRR is relatively easy to obtain while also being correlated with genetic ancestry; and its use has persisted in large-scale genomic analyses as a result. Furthermore, SRR acts as a surrogate metric for a highly complex array of behavioral, cultural, environmental, and social variables that are themselves influential in disease . Howeverectively . Geneticectively . In addiectively . Howevern = 899) that was constrained by the availability of completed insurance claim data. As this is the only study analyzing the impacts of treatment center volume on GEP-NEN outcomes to the authors’ knowledge, how the catchment populations of high-volume GEP-NEN research hospitals might be affecting the racial representation in GEP-NEN genomics remains unclear.Numerous obstacles have likely led to the current state of diversity in GEP-NEN genomics. Approximately 60% of patients with pNENs have metastasis upon presentation, precluding a curative resection that would generate tissue for biobanking. Alongside this, Black and other non-white patients are less likely to undergo surgery for GEP-NENs, even when they meet societal guidelines for surgical resection and are good surgical candidates . UnderstAACR's Minorities in Cancer Research Council and the National Cancer Institute's Partnerships to Advance Cancer Health Equity program, which aim to provide training, career development, and research funding for early-stage investigators and trainees from under-represented groups. Improving the diversity of the cancer research workforce may also improve the involvement of diverse groups in clinical trials and genomics studies, as researchers are motivated to address cancer health disparities in their communities and better understand the systemic, logistical, and cultural barriers they face  and n = 2,284). Because race representation was reported for whole cohorts rather than for cohort subsets that were included in (epi)genetic analyses, the results in n = 24 and n = 268, respectively) and our IHC data . While this disparity in representation illustrates the points made within and the statistical approach aimed to mitigate differences in sample size, these factors must be considered in the interpretation of our results. Accordingly, it is noted that unadjusted p-values are used herein to determine the number of significantly differentially mutated genes. The small number of subjects in the Black AACR GENIE cohort and the number of genes analyzed genetic analysis, highlighted by the discrepancy between the total numbers reported in n = 323;  renderedn = 323; . HoweverOur understanding of (epi)genetic variation among racial groups has important implications for our understanding of GEP-NENs, and may highlight genomic differences among racial groups influencing oncogenesis and tumor progression similarly to those described in other cancers. In conclusion, careful inclusion of diverse populations in (epi)genetic studies is integral for further understanding GEP-NEN biology, generalizing findings to diverse patient populations, and improving therapy for all.Figure S1Assays used to analyze biomolecules in the 16 studies of GEP-NENs that reported patient race.Click here for additional data file.Figure S2Comparison of racial group representation in GEP-NEN genomics, cancer genomics, and in the US population per 2020 census data.Click here for additional data file.Figure S3Composition of Black and White patient cohorts from the AACR GENIE dataset by sequencing assay ID’s, depicted by raw subject numbers (Left) and by % composition (Right). Only sequencing assays that included both Black and White patients were considered.Click here for additional data file.Supplementary Data S1-S3AACR Genie Comparisons (SD.1), STRING Interactions (SD.2), GO Enrichment of STRING data (SD.3)Click here for additional data file.Appendix 1Structured Queries to PUBMED and EMBASE for Systematic Literature Review of GEP-NEN Genomics Studies.Click here for additional data file.