The 2BTP‐2F‐T not only combines the advantages of small NFA and polymeric acceptors (PYF‐T‐o) with similar units but also exhibits superior characteristics of high absorption coefficient and high electron moblity(µe)) with less dependence on molecular packing. Using PM6 as the donor, a remarkable efficiency of 18.19% is obtained with an open circuit (Voc) of 0.911 V, short current circuit (Jsc) of 25.50 mA cm−2, and fill factor (FF) of 78.3%, which is much better than that of the corresponding monomer (16.54%) and PYF‐T‐o (15.8%) based devices. The much‐improved efficiency results from two aspects: 1) an enhanced FF due to the largely improved µe and well‐controlled morphology ; 2) a higher value of (Jsc × Voc) due to its higher absorption coefficient and efficient charge generation at a similar low energy loss. Furthermore, the PM6/2BTP‐2F‐T device possesses the longest T80 lifetime to light‐soaking and comparable high thermal stability with PM6/PYF‐T‐o. The results indicate that the “N‐π‐N” type oligomeric acceptor has a great application prospect due to its superior high efficiency and improved stability in organic solar cells.A novel “N‐ A novel oligomeric acceptor 2BTP‐2F‐T, constructed by linking two non‐fullerene acceptors with thiophene, is reported. It exhibits superior characteristics over its monomer and polymer, including higher absorption coefficient and electron mobility in pristine materials, and welltuned morphology in PM6 blends, pushing an attain of efficiency of 18.19% with improved fill factor and short circuit current under similar energy loss. The invention of small molecular non‐fullerene acceptors (NFA), such as ITIC, Y6, and their analogs, has pushed the OSC efficiency to higher than 18%, and all‐polymer OSCs efficiency over 17% with high thermal stability. An oligomer‐type acceptor with higher molecular weight (MW) would be expected to combine the advantages of both, because 1) compared to its small NFA counterpart, it is anticipated to decrease the diffusion rate in the blend films by the vastly increased MW, improving the device stability; 2) compared to its polymeric counterparts, it could obtain definite molecular structure, absence of chains entanglements and increased diffusion coefficient, leading to an easier morphology control and improved device performances.Organic solar cells (OSCs) show excellent application prospects in flexible and portable devices because of their light‐weight property, flexibility, and low cost.6, 7 Currently, small molecules of typical NFA and small molecular donors sometimes are also called oligomeric molecules with MWs of ≈1500–2000. Obviously, the MW of oligomers with less than 2500 can hardly meet our requirements. Oligomeric conjugated molecules with three or more definite arms are also reported. However, their MW is still hardly larger than 2500, due to their small repeating units such as the perylene diimine, naphthalene diimide, diketopyrrolopyrrole, or their derivatives; additionally, their poorer absorption spectrum or non‐ideal charge transport resulted from their non‐planar molecular backbone or non‐ideal morphology limit their device performances. That is a similar situation for ladder‐core armed with electron‐deficient end groups. Motivated by the excellent device performance of the polymer acceptor with a moderate MW (≈20 000), and also the rigid molecular backbone of Y‐series NFA, linking the efficient Y‐series NFA in a proper sequence might be a possible strategy to construct our objective oligomer‐type acceptors.Then, the main point is how to construct an oligomeric acceptor to achieve the advantages mentioned above. The traditional oligomers feature identical structures with definite repeating units, and their MW should be located between 1000 of the “small molecules” and 10 000 of the polymers.17 Curπ‐N” type of oligomeric acceptor 2BTP‐2F‐T  with similar building units, the N‐π‐N oligomeric acceptor 2BTP‐2F‐T exhibits not only a combined advantage of them, but also superior molecular properties, including an in‐between absorption range but with a higher absorption coefficient, and enhanced electron mobility with moderate molecular packing. Using PM6 as the donor, 2BTP‐2F‐T obtained a remarkable power conversion efficiency (PCE) of 18.19% with an open‐circuit voltage (Voc) of 0.911 V, a short‐circuit current (Jsc) of 25.50 mA cm−2, and a fill factor (FF) of 78.3%, which is much higher than that of the corresponding monomer (16.5%) and PYF‐T‐o (15.9%) based devices. The excellent device performance for PM6/2BTP‐2F‐T is a combined result of improved FF and enhanced value of (Jsc × Voc) with a small energy loss (0.53 eV), due to the joint contributions of its excellent material property, and easily well‐tuned morphology with a small Urbach energy of 22.74 meV. Additionally, the encapsulated PM6/2BTP‐2F‐T device possesses the longest T80 lifetime  under illumination in the air condition, and its thermal stability is also comparable to that of PM6/ PYF‐T‐o. The result indicates that the “N‐π‐N” type oligomeric acceptor has promising application due to its ability to obtain maximized efficiency and improved stability in OSCs.In this article, we designed and successfully synthesized an “N‐T Figure 1a with a22.1 The oligomeric acceptor 2BTP‐2F‐T was prepared through Stille coupling with monomer and linker with a high yield of 70%. Consequently, compared to the symmetrical NFA or the monomer, the synthesis of 2BTP‐2F‐T only takes an extra step but with a high yield; in contrast to the polymer (PYF‐T‐o), the yield of 2BTP‐2F‐T was probably higher due to its easier purification, no MW distribution, and no batch‐to‐batch variations. Noteworthy, because the performance of commercial PJ1 is not as good as PYF‐T‐o, we use PYF‐T‐o as its corresponding control polymer.The monomer was synthesized through an asymmetrical Knoevenagel reaction from its precursor BTP‐CHO , tetrahydrofuran (THF), and chlorobenzene (CB), demonstrating its good solution processability.As seen in the top view of T Figure , the dih2BTP‐2F‐T, monomer, and PYF‐T‐o were investigated and compared both in the CF solutions and neat films, and the detailed data are summarized in Table 2BTP‐2F‐T, PYF‐T‐o exhibits the red‐shifted absorption while the monomer shows the blue‐shifted absorption spectrum, which should be due to easier pre‐aggregation for the polymer and the increased effective length for the dimer. The tendency of their absorption‐onset variation in the film was consistent with their solution; however, their differences become smaller, which is ascribed to the largest red‐shifts for the monomer and the least red‐shifts for the polymer  at the maximized absorption peak. The superior absorption for 2BTP‐2F‐T should be the combined effect of its higher absorption coefficient of dimer in solution due to its increased molecular conjugation  and reduction (ERE) potentials using the following equations: EHOMO = −e(EOX − EFc/Fc + + 4.8), ELUMO = −e(ERE − EFc/Fc + + 4.8). The calculated highest occupied molecular orbital (HOMO) energy levels were −5.68, −5.67, and −5.64 eV for monomer, 2BTP‐2F‐T, and PYF‐T‐o, respectively. And their corresponding lowest unoccupied molecular orbital (LUMO) energy levels were −3.81, −3.84, and −3.82 eV. In comparison to the monomer, 2BTP‐2F‐T shows a slightly higher HOMO but lower LUMO energy level, which is consistent with its slightly red‐shifted absorption and indicates a probable decreased Voc. Summarily, 2BTP‐2F‐T exhibits similar in‐between energy levels compared with monomer and PYF‐T‐o, which is a matched energy level with PM6  peak in out‐of‐plane (OOP) direction and (100) peak in‐plane (IP) direction. The calculated π–π stacking distance for (010) peak in the OOP direction is 3.64, 3.79, and 3.87 Å, for monomer, 2BTP‐2F‐T, and PYF‐T‐o, respectively; their corresponding coherence crystal length (CCL) is 24.9, 18.6, and 16.9 Å, respectively. The d‐spacings and CCLs of 2BTP‐2F‐T are located in the middle of monomer and PYF‐T‐o, indicating its in‐between molecular assemble ability, which well explains its intervening absorption red‐shifts from solution to film as we discussed above. This inferior molecular packing of 2BTP‐2F‐T than that of monomer is probably due to its slightly un‐planar molecular backbone resulted from the joint of the two monomers; its more ordered packing than that of polymer should be attributed to its much weaker or absence of molecular chain entanglement, which could be observed from the increased q value of the (100) peak  and contact angle measurements were carried out to characterize the molecular packing at thermal annealing (TA) condition (TA = 100 °C), and surface tension of three materials. As shown in their 2D images and 1D curves Figure 2a,b, thek Figure .2BTP‐2F‐T exhibits moderate molecular packing ability and π–π stacking distance, however, it obtains the highest averaged electron mobility (μe) of 1.55 × 10−3 cm2 V−1 s−1, which is slightly higher than that of the monomer (9.17 × 10−4 cm2 V−1 s−1) and much higher than that of PYF‐T‐o (2.20 × 10−4 cm2 V−1 s−1)  Figure . Compareobility μe of 1.55obility μe of 1.55χ, and ultimately act on the morphology. The surface tensions calculated from contact angle . The in‐between surface tension for 2BTP‐2F‐T leads to an intervening Flory–Huggins interaction parameter χ for PM6/2BTP‐2F‐T (χ = 0.14), compared to that of PM6/monomer (0.08) and PM6/PYF‐T‐o (0.19).The change of the molecular backbone would also impact the molecular surface tensions and lead to a different Flory–Huggins interaction parameter 2.22BTP‐2F‐T ethyl]phosphonic acid (2PACz)/active layer/poly (PNDIT‐F3N)/Ag was fabricated to investigate the device performance of T Figure 3a. The fo in this study compared to the reported literature should be attributed to the changed electron/hole interlayer. The best J–V curves and statistical distributions of PCEs of ≈20 pieces of devices are shown in Figure /2BTP‐2F‐T is its high Jsc and FF. The tendency for the Voc variation has mainly resulted from their differed energy bandgap rather than the energy loss, which we will discuss in the following section. As seen from the external quantum efficiency (EQE) curves of the best devices  dependent on the effective voltage   and charge collection efficiency (ηcoll) could be calculated from the following functions: ηdiss = Jph (under short‐circuit condition)/Jsat; ηcoll = Jph (under maximum power output condition)/Jsat. The ηdiss is calculated to be 97.43% and 99.45%, and 96.94% for the devices based on PM6/monomer, PM6/2BTP‐2F‐T, and PM6/PYF‐T‐o, respectively, and their corresponding ηcoll is 85.01%, 91.23%, and 83.15%, respectively. The highest value of ηdiss and ηcoll demonstrates that the 2BTP‐2F‐T‐based device wins the most efficient charge generation and the best charge collection compared to those of monomer‐ and polymer‐based devices.The efficient utilization of the absorbed photons and high FF in PM6/) Figure  was applα (fitted from the function of J ∝ (Plight)α; Plight represents the incident light intensity) and the ideal factor n (fitted from the function of Voc∝nkT/q ln(Plight); k is Boltzmann constant, T is the temperature in Kelvin, and q is the elementary charge) were applied to estimate the recombination mechanism for the three devices. For the device based on PM6/2BTP‐2F‐T, α is equal to 1 , demonstrates that the device based on PM6/2BTP‐2F‐T effectively inhibits the trap‐assisted recombination. The decreased n value is probably due to its smallest energetic disorder as deduced from its smallest Urbach energy (EU) value, which is described in the following parts. The photon‐physical result suggested that the N‐π‐N type oligomeric acceptor 2BTP‐2F‐T could effectively enhance the efficiency of charge generation and charge collection while suppressing trap‐assisted recombination simultaneously. Thus, higher Jsc and FF are obtained.The power index  of J ∝ Plightα2.32BTP‐2F‐T blends. As shown in 2D GIWAXS , and PM6/PYF‐T‐o (93 Å), respectively. This trend is totally opposite to the change in their miscibility, which is probably due to the different diffusion speeds of their corresponding acceptors escaping from their mixed regions originating from their differed MW. Consequently, although PM6/2BTP‐2F‐T shows smaller miscibility (χ = 0.14) than that of PM6/monomer (χ = 0.08), however, it forms a more interpenetrating film than that of PM6/monomer, which could be intuitively seen in height atomic force microscopy (AFM) images  images . The CCLs of (010) peak in the OOP direction for the three blends are at ≈20 Å, and hence, the smallest hole mobility for PM6/PYF‐T‐o should be due to its largest π–π stacking distance in the charge transport direction (3.77 Å) than that of PM6/2BTP‐2F‐T (3.73 Å) and PM6/monomer (3.65 Å).The above results indicate that PM6/s Figure , compareμe in their pristine film, the blends exhibited almost no reduced values and the same changing trend, and they are 1.55 × 10−3, 1.73 × 10−3, and 4.46 × 10−4cm2 V−1 s−1 for PM6/monomer, PM6/2BTP‐2F‐T, and PM6/PYF‐T‐o, respectively. The highest μe with a moderate π–π stacking further convinced the high morphology tolerance of 2BTP‐2F‐T and its advantage in morphology regulation. Obviously, the excellent electron/hole transport 2BTP‐2F‐T in the blend is the combined result of its intra‐molecular charge transport and its well‐ and easier‐tuned morphology featured with fibrous structure, moderate π–π stacking, and the optimal interpenetrating network. We reiterate that the high tolerance of μe to the morphology and easier‐tuned morphology for N‐π‐N oligomeric acceptor are its prominent superiority in OSCs, which potentially push it to obtain the maximized PCE in OSCs.Compared to the 2BTP‐2F‐T is also responsible for its longest charge lifetime of 22 µs, which is much longer than that of PM6/monomer (17 µs) and PM6/PYF‐T‐o (7 µs), as characterized by transient photovoltage , as compared to that of PM6/monomer (23.3 ns) and PM6/PYF‐T‐o (21.4 ns). The excellent charge properties for PM6/2BTP‐2F‐T facilitate its charge collection and ensure its much higher FF and improved absorbed photon utilization (Jsc).Besides the best charge transport ability, the optimized morphology for PM6/2.42.4.1E) measurements were carried out to elucidate the potential of the N‐π‐N type oligomeric acceptors. The total ΔE can be spitted into three parts: 1) ΔE1 represents radiative recombination loss above the bandgap, which is based on the Shockley–Queisser (SQ) theory limits. ΔE1 is directly decided by the energy bandgap. 2) ΔE2 represents radiative recombination loss below the bandgap; 3) ΔE3 represents non‐radiative recombination loss below the bandgap, which could be quantified by external quantum electroluminescence efficiency (EQEEL).Energy loss  is in between that of PM6/monomer (0.54 eV) and PM6/PYF‐T‐o (0.52 eV). The energy band‐gap (Eg) is calculated from the precise measurement of the EQE, with a value of 1.48, 1.45, and 1.42 eV for monomer, 2BTP‐2F‐T, and PYF‐T‐o blend , while the smallest ΔE3 (0.184 eV) and PM6/PYF‐T‐o exhibits exactly the reverse result with an ΔE2 of 0.049 eV and an ΔE3 of 0.208 eV. As for PM6/2BTP‐2F‐T, both the values of ΔE2 (0.068 eV) and ΔE3 (0.199 eV) are in between. This is probably because their small energy offset between Eg and energy of charge transfer (CT) states estimated from normalized fourier‐transform photocurrent spectroscopy external quantum efficiency (FTPS‐EQE) curves and electroluminescence (EL) spectra of devices  is obtained through an exponential fit to the FTPS‐EQE spectra to evaluate the degree of energetic disorder  and PM6/ PYF‐T‐o (EU = 24.79 meV), indicating the smallest width of the tail of the electronic density of disorder (DOS). It should be mentioned that all the EU for the three devices is comparable to the thermal energy kBT (25.8 meV) at room temperature. The small EU for the three devices guarantees their minimized loss of (ΔE2 + ΔE3) (<0.28 eV). The smallest EU of PM6/2BTP‐2F‐T enables less trap‐assisted recombination of the charge, and a much longer charge lifetime, benefiting the improvements of FF and Jsc.The low degree of energetic disorder at interfaces in the active layers enables free charge separation to outcompete trap‐assisted non‐radiative recombination of the CT state, gaining excellent device performance with small ΔE.31 Hen2BTP‐2F‐T exhibits more efficient charge generation, higher absorption coefficient, and an optimal morphology with a smaller energetic disorder, leading to ultimately a high Jsc. The much higher Jsc with similar ΔE for PM6/2BTP‐2F‐T leads to a maximized (Voc × sJc) in the three devices  of the three encapsulated devices to light soaking (100 mW cm−2) under air conditions and thermal stability at 80 °C under a nitrogen atmosphere were investigated. Conventional devices with ITO/poly:poly(styrenesulfonate) (PEDOT:PSS)/active layer/PNDIT‐F3N/Ag structure were used in the light‐soaking stability and thermal stability test. Figures 80, while curves in Figure The much higher MW of cceptors.15 The80 to light soaking under air condition based on PM6/2BTP‐2F‐T device exhibits 7 times longer (443 h) than that of PM6/monomer (62 h); beyond belief, it also demonstrates 2.4 times longer than that of PM6/PYF‐T‐o (185 h). Besides the morphology factors, the higher optical chemical stability of the 2BTP‐2F‐T was also observed in a recently reported result measured under a nitrogen atmosphere. The lifetime of T80 to heat treatment for the PM6/2BTP‐2F‐T is also much longer than that of PM6/monomer (54 h vs 20 h) and comparable to that of all‐polymer OSCs PM6/PYF‐T‐o (57 h). Noteworthy, further prolonging the heating time, the PM6/2BTP‐2F‐T shows a slightly decreased rate of device attenuation than that of PM6/PYF‐T‐o  More favorable morphology, including the smallest energetic disorder, moderate π–π stacking, and appropriate interpenetrating network; 2) Improved charge properties, including higher hole/electron mobility, longer charge lifetime, and faster charge extraction; 3) Efficient charge generation with similar energy loss; 4) Better light‐soaking stability and comparable thermal stability to its polymeric counterparts. The high efficiency of over 18% in OSCs, together with its improved stability, suggests a bright future for the N‐π‐N oligomeric acceptor type OSCs.In this article, we designed an N‐The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Aim - To study auditory symptoms and audiometric exams of teachers and classroom noise levels. Material and Method: Data from two groups, GI (40 teachers) and GII (40 voluntaries) were studied as follows: age, gender, working conditions, audiometric exams, and classroom noise levels. Results - In GI there were more females (86%), working in basic teaching (75%), in classes with 21-40 students (70%), with workloads between 26 and 40 hours per week (47%), and variable professional teaching time. Most teachers in GI reported excessive classroom noise (93.5%) and auditory symptoms (65%). In GI, 25% of teachers presented audiometric alterations (versus 10% of controls), with an acoustic notch predominating . Noise levels close to 87dBA were recorded in classes at all teaching levels. Conclusions - occupational hearing loss may occur in teachers. Further studies are needed to confirm this proposition.Teachers frequently report auditory symptoms and excessive noise in classrooms, but noise level measurements are not done routinely. Study model - a prospective clinical trial. Noise-induced occupational hearing loss has been a long-time concern of health professionals. Research on this condition has focused mostly factory and manufacturing workers.7An investigation of noise-induced hearing loss in teachers would require confirmation of excessive noise levels in work environments by measuring classroom noise during classes. Pereira et al.The audiometric configuration of noise-induced hearing loss shows symmetrical, mild to moderate sensorineural hearing loss mostly at 3,000 and 4,000 Hz.11Most authors believe that an individual may develop noise-induced hearing loss if exposed to constant or intermittent noise at 85dB during at least eight hours of work a day.These comments show the need for evaluating in greater depth the work environment of teachers to identify factors that affect hearing in these professionals.•identify auditory symptoms;•assess auditory acuity;•verify classroom noise levels;•correlate audiometric test results to noise exposure;•compare audiometric test results of teachers and of a volunteer control group.Participants in this study included public and private school teachers and aimed to:The study was approved by the Botucatu Medical School Research Ethics Committee for investigation in human beings (Document number 113/2003). All participants signed a free informed consent form. The series included a sample group (GI) that included 80 teachers from 10 public and private schools in the city of (Sao Paulo state). A control group (GII) was also included to facilitate the interpretation of auditory test results. This group was composed of 40 similarly aged non-teacher volunteers to which were applied the same exclusion criteria.The sample group (GI) included 69 women (86%) and 11 men (14%). The control group included 67.5% women and 32.5% men. The age range of teachers was 24 to 59 years (mean = 40.2 years), concentrating on the 36 to 50 year age group (55%). The duration of professional activities was uniform throughout the sample group .Figure 1The weekly workload was as follows: 20 teachers (25%) worked less than 25 hours, 38 teachers (47.5%) worked between 26 and 40 hours, and 22 (27.5%) worked more than 40 hours. There were 60 elementary school teachers (75%), 13 pre-school teachers (16%), and 7 junior school teachers (9%). There were 21 to 40 students per classroom for 56 teachers (70%); there were fewer than 20 students per classroom for 10 teachers (12.5%); there were over 40 students per classroom for 14 teachers .Exclusion criteria were: a history of otorrhea or otological surgery; congenital or family deafness; auditory pathway malformation; current or past work in another activity where there is/was exposure to excessive noise; use of ototoxic drugs; users of individual sound amplification devices; a history of cranial trauma; altered immitance tests; and work in special subjects . Inclusion criteria were: work as a teacher for over five years; a minimum weekly workload of 20 hours in curricular subjects.Protocol - teachers initially were interviewed to obtain protocol data on age, gender, auditory symptoms, and working conditions .Assessment of auditory acuity - teachers in the sample group and control group volunteers initially underwent otoscopy. An assessment of auditory acuity was done with appropriately calibrated devices. Tests included pure tone audiometry  and logoaudiometry (speech audiometry). Audiometric results were classified according to Russo & Santos (1993);12 normal results were air and bone auditory thresholds between 0 and 25dBNHL. Hearing loss according to audiometry was classified as: flat, sloping, rising, inverted U, and notches . When audiometric thresholds were 0 or 5 dB, and if there was a 25dB reduction of the audiometric threshold at 4,000 and/or 6,000Hz only, the authors classified the audiometric configuration a tending to notches. Speech therapists working as collaborators did the auditory assessments.Measurement of environmental noise - an appropriately calibrated decibelimeter (Larson & Davis® model 812) was used. This device was operated by a single trained technician, who measured classroom noise levels in different teaching levels in three situations: during teacher explanations, during student participation, and during classroom discussions. Minimum and maximum measurements were made, and the energy-equivalent noise level (Leq), which is the average of the sound energy during the measurement period using a dB(A) frequency filter.Statistics - data was analyzed using the chisquared method and the comparison of proportions test based on a normal distribution. The significance level was p values equal to or below 0.05.Report of classroom noise - 93.75% of teachers reported excessive classroom noise.Auditory symptoms - Results of audiometric tests - audiometric tests  and 3 anAll of the participants had a type A normal tympanometric curve.Classroom noise level - maximum and minimum classroom sound pressure level verification values and the Leq are shown on This study shows that there were more female teachers in the sample group. Many of them had classrooms with many students and worked over 40 hours a week. This workload probably reflects low wages and the need to supplement the family income, as some authors have pointed out.14The working environment of teachers should receive more attention, given the time they remain in classrooms. Crowded classrooms generate significant noise and place excessive demands on phonation. In this context noise verification has not been routine or even required. Most of the teachers in this study reported excessive classroom noise. 190 of 240 teachers assessed by Pérez Fernandez & Preciato LópezBased on our study we believe that teachers exposed to classroom noise may develop occupational hearing loss throughout their career, given the significant number of auditory symptoms, frequent reports of excessive classroom noise, a large number of altered audiometries compared to the control group (40 × 18), and high classroom sound pressure values in teachers belonging to the GI group. Many teachers had notches in their audiometric configuration, reinforcing the abovementioned assumption. This curve is typical of noise-induced hearing loss and was found in only 1 control group volunteer and in 18 sample group teachers. This diagnosis, however, is based on a reduction of audiometric thresholds when compared to pre-placement exams, which have not been standardized for teachers. Confirmation, therefore, is limited.Verification of classroom sound pressure levels is not done routinely, but our investigation revealed elevated values, ranging from 59.8 dB (A) to 89 dB (A). If the acceptable noise level for industry workers is 85dB, and that studies on acoustics applied to education suggest tolerable classroom sound pressures of 40 to 70dB(A),2,16 we conclude that teachers are exposed to excessive noise levels, notwithstanding Bovo & Galceran's17 findings of classroom noise levels up to only 55dB.The regulating rule number 15 of the Ordinance 3.214/78,18 which defines tolerance levels for exposure to noise, refers to continuous and intermittent noise, such as that in classrooms. JiangVarious authors in past decades have tried to demonstrate the harmful effects of exposure to excessive noise on auditory pathways. This includes studies of industry machine operators,The high frequency of auditory symptoms, constant reports of excessive classroom noise, the detection of a significant percentage of altered exams with a predominance of notches, and verification of high environmental noise levels, suggest that occupational hearing loss due to noise exposure is present in teachers. This diagnosis needs to be confirmed through pre-placement and periodic exams and further careful studies similar to this paper.


Hearing is one of the main forms of connection between human being and the environment; however, hearing loss is still diagnosed very late in Brazil, which directly interferes with the child's development.The aim of this study was to check the knowledge pediatricians and gynecologists have about the risk factors for the deafness, the way they acquired such knowledge and parent education about the subject.We enrolled 119 doctors from three public hospitals of the city of Recife. An interview was applied, before and after the educational campaign on the matter. The study was descriptive, cross-sectional, case series-type. Data analysis was descriptive and inferential.The results showed that only 3 of the 18 hearing loss risk factors listed had gotten answers above 50% in the initial stage of the study and 53.84% of the professionals educated the families. All the answers had increased in the second stage.The results emphasize the need to pay more attention to this matter; therefore, primary care is an inexpensive and efficient way to fight hearing loss. This bond requires whole auditory pathways, which make it possible for certain sounds to become familiar before birth, such as the mother's heart beats and voice.,Hearing loss is a public health issue, but it is still diagnosed late in Brazil, resulting in losses that directly affect the global development of children.,The incidence of acquired hearing loss in Brazil has increased markedly in recent years; the main reason is lack of prevention of the main infectious and contagious diseases. Consequently, pre- and perinatal hearing losses account for 65% of deafness cases.,,Neonatal hearing screening may be done universally for all live births or for children with risk factors for hearing loss. Estimates suggest that the prevalence of neonatal hearing loss is about 1 to 3 for each 1,000 neonates; this number increases to 1 to 6 for each 1,000 children admitted into neonatal intensive care units.13,About 50% of hearing losses may be suspected in the neonatal unit when hearing screening is done. Of all newborn, 7 to 12% have at least one risk factor for hearing loss; 2.5 to 5% of risk neonates have moderate to severe hearing lossHealth care professionals should know about the factors that cause hearing loss, especially those that affect children in the prenatal, perinatal and immediately postnatal phases, so that hearing loss may be detected early. Every effort is only valid if professionals involved in neonatal care are aware and ready to set in motion diagnostic and (re)habilitation processes.Gynecologists are the first health care professionals to contact women before conception; it is therefore paramount for these professionals to know about risk factors to offer primary prevention of hearing loss.,These four professionals are part of a multidisciplinary team, and it is essential for them to know about the risk factors so as to help prevent hearing loss and avoid the tragic effects resulting from lack of auditory stimulation.The purpose of this study was to investigate the knowledge pediatricians and gynecologists have about the risk factors for hearing loss, and to underline the importance of such knowledge within the medical community. Additional aims were to check whether families were being oriented about the risk factors for hearing loss and about hearing screening for neonates, to verify how such knowledge was acquired, and to disseminate the need for multidisciplinary work.This was a descriptive, cross-sectional study – a case series, with a sample of 119 medicine graduates, from both genders, with specialization or residency in gynecology and/or pediatrics. They were broken down into two groups; one was formed by 65 gynecologists and the other by 54 pediatricians. The participants were members of the clinical staff of the hospitals investigated and we included only those who participated in the two stages of the study which investigated three public reference maternal-pediatric hospitals in the city of Recife. This study was approved by the Ethics in Research Committee of the Catholic University of Pernambuco, under protocol # 092-2004/6-7. After the participants signed the informed consent form and the committee approved, we started to collect the data by means of a semi-directed interview, followed by the distribution of an information folder, which characterized the first stage of data collection.The interview was made up of five questions, including the interviewee's knowledge regarding risk factors for hearing impairment, how knowledge was acquired, education regarding hearing health and risk factors, how this education was done. The risk factors described by the American Committee on Auditory Hearing Loss (Joint Committee on Infant Hearing) in 2008 are: family history of sensorineural hereditary hearing loss, maternal consanguinity, syndromes, congenital infections  baby's craniofacial malformations, including the pinna, the external auditory canal, hyperbilirubinemia (with levels requiring exsanguinous transfusion), use of ototoxic medication such as: aminoglycosides, their association with diuretic agents and also chemotherapeutic agents, bacterial meningitis, Apgar scores between 0 and 4 on the 1st minute or 0 to 6 on the 5th minute, use of mechanical ventilation for more than five days, baby's ICU stay for more than forty-eight hours, recurrent or persistent otitis media for more than three months, suspicion of family members with speech and hearing delays and language delay, head trauma with loss of conscience or skull fracture.On the following week, at the end of the interviews, we ran an educational campaign , ending the first stage. The second stage, carried out with a minimum type of one month after the first stage, when the same interview was applied to the individuals participating on the first stage, in order to compare the studies.For data and outcome analyses we used the 2003 Microsoft Office Excel, by means of a descriptive statistical analysis.Similar interviews were made of each health care professional in two steps: before and after the educational campaign. These interviews consisted of five questions; answers to each question were tabulated to show the frequency of responses to each alternative at both moments. Some subjects gave more than one answer to some of the questions.The responses in this study were similar to those in other studies, as we will show next.Congenital infection may be transmitted pre- and perinatally from mother to child, and may be avoided by providing information during prenatal visits. Lack of knowledge about hearing loss risk factors among gynecologists is a significant concern. There is still a high rate of deafness due to infection in our country; congenital infection is a major contributing factor in this context. These conditions are avoidable by dealing with environmental health conditions and providing medical care and training for health care professionals.,The importance and efficacy of actions that promote hearing health has been demonstrated in a previous study;Contrary to the arguments of Russo and SantosAlthough showing a higher rate of positive answers about health care orientation on hearing health and risk factors for hearing loss compared to gynecologists, pediatricians are not an absolute majority.Neonatal hearing screening programs aim to diagnose hearing loss as early as possible in infancy, to undertake periodical monitoring for confirmation purposes, to identify progressive deafness and late manifestation of hearing loss, and to monitor the development of hearing.For these goals to be met, parents should be adequately informed about the importance of caring for the hearing of their children.A high rate of evasion of parents is considered as the main hurdle against the success of hearing screening programs. Some reasons for parents not returning as recommended, are as follows: lack of information about the causes, symptoms and impact of hearing loss on the global development of their children; a common idea among mothers that their children are not at risk for hearing loss; and anxiety among mother when their children are being tested.26The neonatal hearing screening program is part of the Early Detection of Child Hearing Loss project for users of the Unified Health System (SUS). Informing mothers about Neonatal Hearing Screening is part of the routine in visits; again, knowledge about this topic is paramount.,Recent surveys have shown that professionals in the public health care system allege lack of resources, equipment and specific knowledge to investigate and monitor the development of hearing in children. Nevertheless, promotion measures are not costly but were not carried out routinely by the participants in our sample as shown at the first moment of this study.Speech therapists and otorhinolaryngologists have an important role in orienting medical professionals and counseling parents, as these specialists understand in detail the complexity of hearing screening and treatment of diagnosed cases.,,The purpose of providing knowledge about indicators of risk for hearing loss is to identify newborn that may require further care; this is of special relevance in developing countries where hearing screening is not available for every child. The aim is to reduce individual losses and public health costs.Health care problems are considered a social issue, not only because of their importance for quality of life, but because of the political and economic nature of health care within appropriate social and economic structures.It should be borne in mind that hearing health measures should include the following actions: promotion of health, surveillance, monitoring, and interventions. It is extensive work requiring a multidisciplinary approach.33Initiatives to implement hearing screening programs remain a struggle for professionals dealing with hearing loss. Nevertheless, actions aiming at increasing collective awareness about this topic do not necessarily imply in new federal or state laws, and may be done rapidly and simply at a low cost. Interdisciplinarity and collective health measures should be fostered to reach such goals.Concurring with the present study, several authors have underlined the need for programs to disseminate information about neonatal hearing screening and the prevention of deafness; in this context, every professional whose work includes caring for the newborn may cooperate in the efforts to identify hearing loss at the ideal moment.35Our data revealed that generally the number of risk factors recalled by health care professionals was low, and that medical training has an important role in learning about this topic.Orientation about risk factors for hearing loss and auditory health is given infrequently.Promotional actions generate positive impact, which is evidenced by satisfactory increases in knowledge about this topic among the study sample. Thus, effective strategies need to be implemented so that risk factors for hearing loss may be identified, such as primary care for deafness programs, and the need for multidisciplinary work to extend information about this topic.


We reported a case of a 61-year-old male patient with anacusis, cerebellar syndrome, myoclonus, and frontal signs. The brain magnetic resonance imaging showed bilateral striated hyperintensity of the fluid-attenuated inversion recovery and restricted diffusion in the diffusion-weighted imaging and hypointense areas corresponding to the apparent diffusion coefficient in the cerebral cortex. The autopsy revealed positive immunohistochemistry for the PrPSc protein. Creutzfeldt–Jakob disease presenting with hearing loss is unusual. A 61-year-old man presented with progressive bilateral hearing loss, and gait disturbance for 2 months. On examination, he presented anacusis, cerebellar syndrome, myoclonus, and frontal signs. Brain magnetic resonance imaging (MRI) showed bilateral striatum fluid-attenuated inversion recovery hyperintensity and restricted diffusion on diffusion-weighted imaging and corresponding apparent diffusion coefficient hypointense areas in the cerebral cortex . The eleIn the literature, few cases of bilateral hearing loss have been reported as an initial symptom of Creutzfeldt-Jakob disease (CJD). In our review, these cases were evaluated with audiometry and/or auditory evoked potentials. In only one of the cases, the auditory evoked potentials showed a central pattern of hearing loss. Two cases, including ours, had vestibulocochlear pattern involvement, another case was normal, and in the remaining cases, it was not possible to carry out the test or if the result was inconclusive.Other causes of hearing loss associated with progressive encephalopathy should be taken under consideration, such as Whipple’s disease, Lyme disease, human immunodeficiency virus, Susac disease, sarcoidosis, central nervous system vasculitis, lymphoma, and paraneoplastic disease.Prion disease should be considered in cases of rapidly progressive dementia with myoclonus; however, in one-third of the cases, it may initially manifest with atypical symptoms such as aphasia, pure ataxia, and visual or hearing loss. In atypical cases, the recognition of typical patterns for CJD on the brain is MRI and is of great importance to guide for further investigation.  Despite of bilateral hearing loss being a rare form of initial presentation of CJD, it should be part of the differential diagnosis of progressive encephalopathies with auditory symptoms.


Albino and pigmented rat strains are widely used in models to study retinal degeneration and to test new therapies. Here, we have summarized the main topographical and functional characteristics of the rat retina focussing on photoreceptors and retinal ganglion cells (RGCs), the beginning and end of the retinal circuitry, respectively. These neurons are very sensitive to injury and disease, and thus knowing their normal number, topography, and function is essential to accurately investigate on neuronal survival and protection. Rattus norvergicus) and mice (Mus musculus) are the preferred species . Because they are nocturnal animals for specific research questions , diurnal rodents such as squirrels, Nile rats or common degus are also established models.Preclinical research in visual sciences is generally conducted in small mammals, mostly rodents and, to a lesser extent, rabbits or pigs. Rabbits are  used to study the anterior part of the eye, the cornea, while rodents are  used to investigate the retina, optic nerve, and retinorecipient areas. Within rodents, rats  and an RGC:cone ratio close to 1:1 characteristics that provide high resolution. Within the macula there is a depression, the fovea centralis, where most of retinal layers are missing but the cones, thus optimizing visual acuity. In rats there is no macula or fovea, instead they have a visual streak with higher RGC and L/M-cone densities  were developed in 1906, Sprague Dawley  in 1925, and C57/Bl6 mice (inbred pigmented) in 1921. These strains are now very well characterized genetically and physiologically  and cone photoreceptors (L and S) and the electroretinographic waves used to study their function in the healthy rat retina.Majority of RGCs are found in the ganglion cell layer (GCL), the innermost layer of the retina sharing location with displaced amacrine cells (50% of the cells in the GCL in rat) and glial cells  because they express the photopigment melanopsin. Thanks to this pigment they sense light irradiance and regulate the circadian rhythm and the pupillary reflex .RGCs univocal identification is necessary to assess the extent of degeneration after a given insult or disease and to know if an experimental therapy is effective  is 82,979 ± 1,787 and in pigmented  a little higher, 84,818 ± 4,119. The m+RGC population is similar in both strains , S-opsin (S-cones), and L/M-opsin (L/M-cones). For cones it is possible to quantify each of the outer segments in flatmounts and assess their total numbers  in healtA and D in In rats, S-cones, which sense blue light, are more abundant in albino  than in pigmented animals . However, the population of L/M cones, which perceive red-green light, is similar among them . S-cones are more abundant in the ventral retina and the extreme periphery, the retinal rims  while thRods are very abundant, with an estimated population of 50 million  has been used as a non-invasive technique to assess retinal functionality and to establish more solid diagnoses of retinal pathologies. Numerous studies have characterized the functional response of the rat retina with full-field ERG  the retina produces an electrical signal known as the rod response, consisting of a positive deflection of the electrophysiological tracing of about 250 μV amplitude. This response is generated by the rod bipolar cells, because of the decrease in glutamate release by rods and its action on mGluR6 receptors.In response to low-intensity full-field stimuli (intensities between −4 and −2 cd.s/m2), the rat b-wave reaches up to 800 microvolts in amplitude.By increasing light intensity, the mixed response the best known of all waves, is obtained. The mixed response is the major component of the ERG and is used both clinically and experimentally. It consists mainly of two components: (i) the first to appear is a negative component, the a-wave, generated by the absorption of light in the photoreceptor outer segments and the closure of cGMP-gated cationic channels  there is loss of rods or cones but no of RGCs. Functionally, the highest wave amplitudes are obtained from 2-month-old rats thereafter all amplitudes decrease gradually  and non-vision forming (melanopsin+) RGCs, and S- and L/M- cones in the same retina. Analyzing all these populations together is a very powerful approach hardly exploited and very useful to work with models that proceed with the death of all these populations, such as ischemia/reperfusion or retinal dystrophies or to assess the different vulnerability of each population to injury. For instance, m+ipRGCs are more resilient to injury or disease than Brn3a+RGCs , by the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional “Una manera de hacer Europa” project: PI19/00071 (MA-B), the RETICS subprograms of Spanish Networks OftaRed RD16/0008/0026 and RD16/0008/0016 (MV-S).


Superficial siderosis, a progressive, debilitating, neurological disease, often presents with bilateral impairment of auditory and vestibular function. We highlight that superficial siderosis is often due to a repairable spinal dural defect of the type that can also cause spontaneous intracranial hypotension.Retrospective chart review of five patients presenting with moderate to severe, progressive bilateral sensorineural hearing loss as well as vestibular loss. All patients had developed superficial siderosis from spinal dural defects: three after trauma, one after spinal surgery and one from a thoracic discogenic microspur.The diagnosis was made late in all five patients; despite surgical repair in four, hearing and vestibular loss failed to improve.In patients presenting with progressive bilateral sensorineural hearing loss, superficial siderosis should be considered as a possible cause. If these patients also have bilateral vestibular loss, cerebellar impairment and anosmia, then the diagnosis is likely and the inevitable disease progress might be halted by finding and repairing the spinal dural defect. Superficial siderosis (SS) is a rare neurological disease due to repeated acute, or chronic low-level subarachnoid hemorrhage . The claAs this study was a retrospective chart review of the authors own private anonymized patients it had implicit approval from an Institutional Review Board.Pt 1. Male born 1945.1980. Aged 27, has a traffic accident resulting in a traumatic foot drop. Aged 30, presents with headaches after hitting his head against a window frame. Subdural hematoma discovered 3 months later. Operated (burr holes); immediately after operation acute recurrence needing craniotomy.2000. Aged 55, consults an otolaryngologist about impaired hearing and balance. Audiogram shows symmetrical sensorineural hearing loss (SNHL) Fig. . No vest2008. Aged 63, consults a neurologist (author MSW) for deteriorating balance, anosmia and bilateral sensorineural hearing loss (SNHL). Using walking frame. Romberg test positive on foam; clinical head impulse test shows bilateral impairment of the vestibulo-ocular reflex (VOR), gaze-evoked nystagmus, impaired smooth pursuit, brisk tendon reflexes, and reduced sense of smell. Audiogram shows profound bilateral symmetrical high-frequency SNHL Fig.  with absPt 2. Male born 1957.1982. Aged 25, has a partial right brachial plexus avulsion after a traffic accident resulting in a pseudo-meningocele. Able to return to work after rehabilitation.1989. Aged 32, has the first of several subarachnoid hemorrhages, eventually attributed to small blood vessels in the pseudo-meningocele.1995. Aged 38, has devascularization surgery of the pseudo-meningocoele [1999. Aged 42 consults a neurologist. The findings are gait ataxia, inability to tandem walk, a positive head impulse test and positive Romberg test. There are no cerebellar or long-tract signs. Normal sense of smell. Audiogram reported to show a mild bilateral high frequency SNHL as well as a mild-to-moderate mixed low frequency hearing loss on the right. Caloric and rotational tests were reported to show moderately impaired symmetrical responses.2001. Aged 44, consults another neurologist (author GMH). The findings are gait ataxia, inability to walk tandem, positive clinical head impulse test from all 6 semicircular canals, and reduced sense of smell. Audiogram shows symmetrical SNHL  for worsening balance for 1 year, who finds a spastic ataxic gait, difficulty tandem walking, impaired smooth pursuit eye movements, primary position upbeat nystagmus, hyperreflexia, and extensor plantar reflexes. MRI brain shows widespread SS involving supratentorial and infratentorial structures as well as both vestibulocochlear nerves. MRI whole spine shows SS of entire spinal cord and evidence of prior anterior and posterior cervical decompression with internal fixation. There is residual compression C2 to C3 and a pseudo-meningocele at C3 to C5. Dynamic CT myelogram via cisternal puncture shows immediate opacification of the pseudo-meningocele surrounding the C3 to C4 vertebral body prosthesis and the right side of the neck, indicating a CSF leak. The spinal cord herniates into a dural defect on the left at the former upper C4 vertebral body level. Ossified posterior longitudinal ligament at C2 to C5 and C7 to T2 and residual spinal canal stenosis at C7 to T1. Operation (author JBW) via a posterior intradural approach for reduction of spinal cord hernia and intradural repair of large dural defect at C3.2016. Aged 59, needing a scooter to get about. Continuing CSF leak shown on progress MRI spine. Operated again (by author JBW) now via a combined anterior extradural and posterior intradural approach and resealed. Starts chelation with deferiprone.2018. Aged 61, developing frontal executive dysfunction [2021. Aged 64, now wheelchair bound and has a permanent urinary catheter. Pure tone-audiogram shows thresholds have deteriorated by 20–30 dB since 2011 but he now has no speech discrimination . At laminectomy (author JWB) the dural defect is found slightly rostral to the bony spur and is repaired via an intradural approach. The spinal cord is noted to be xanthochromic  with progressively deteriorating balance. He has no postural headache or other symptoms of intracranial hypotension. He has a background of boxing and rugby but not of major injuries. On examination he has profound hearing impairment and no sense of smell. He does have direction-changing, gaze-evoked, horizontal nystagmus, bidirectionally positive horizontal and vertical clinical head impulse test, impaired smooth pursuit and visually enhanced vestibulo-ocular reflex, gait ataxia, lower limb ataxia, brisk lower limb deep tendon reflexes, extensor plantar reflexes and a positive Romberg test, only on foam. The VOR from all 6 semicircular canals is severely impaired on video head impulse testing. Brain MR shows widespread SS, especially in the posterior fossa, but no changes of intracranial hypotension  about his deteriorating speech and balance. He now has signs of cerebellar impairment, including dysarthria, a wide-based gait, inability to tandem walk, and direction-changing gaze-evoked nystagmus, but no long tract signs. He has anosmia. He also has signs of peripheral vestibular impairment, namely, impaired horizontal and vertical vestibulo-ocular reflexes on clinical head impulse testing, and a positive Romberg test only on foam. Lateral semicircular canal function is bilaterally, asymmetrically (left more than right) impaired on caloric and rotational testing, but is normally suppressed by vision. MRI now shows cerebellar atrophy as well as SS, but no change in the vestibular schwannoma. Commences chelation therapy with deferiprone.2012. Age 64, has MR whole spine which suggests a thoracic epidural CSF collection. CT myelogram shows CSF leak at right T1 level. At laminectomy (author MAS) a right T2 defect is found and repaired.2014. Vestibular schwannoma treated with stereotactic radiosurgery.2017. Aged 69, notes further deterioration in hearing , and right (gain = 0.27) lateral semicircular canal function.Hemosiderin, a breakdown product of hemoglobin, is neurotoxic. This will not usually be obvious after a single subarachnoid hemorrhage but will manifest when there are repeated subarachnoid hemorrhages or chronic, low-level subarachnoid bleeding. Both situations can produce leptomeningeal subpial hemosiderin deposition.It is helpful to consider SS as 2 types . Type 1 Imbalance also occurs in most patients and vestibular function is usually similarly impaired but is not always tested. This is especially the case in neurology/neurosurgery departments, where the patient’s imbalance is wholly attributed to the obvious cerebellar impairment. When vestibular function is tested, the impairment can be severe and asymmetrical , 24, 25.This possibility becomes even more likely if the patient also has anosmia . Once thThese dural defects can also produce SIH, which if present, might show on the brain MRI as pachymeningeal enhancement, venous engorgement or “brain sag” . If indeOf our five patients, four showed a similar clinical pattern: spinal injury or spinal surgery, followed decades later  by slowlIn each case, impairment of hearing and balance was the earliest clinical indication of the problem, so that otologists, neurotologist and audiologists have a unique opportunity to recognize SS early enough that there might be a chance to halt its progression. The hearing loss in SS is bilateral, sometimes asymmetrical, and can show retrocochlear features, such as absent acoustic reflexes as well as disproportionate impairment of speech discrimination, sometimes with roll-over , 23. It A practical policy might be as follows: patients with progressive bilateral SNHL, especially young (< 40) patients with retrocochlear audiometric features, especially those who give a history of head or spine, injury or surgery, should be asked about their balance and their sense of smell. If from their answers there is possible impairment of one or both, then cerebellar function should be examined  and vestibular function tested with a video head impulse test and a foam Romberg test  and olfa


Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics. Aging is a complex process driven, at least in part, by hallmarks of aging, including cellular senescence, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular communication , 2. Of tINK4a/Rb and/or p53/p21CIP1 tumor suppressor pathways. p16INK4a, p21CIP1, and p53 are cyclin-dependent kinase inhibitors and a tumor suppressor that act in a coordinated manner and/or independently to arrest cell cycles in G1  and senescence-associated heterochromatin foci  and morphological features  that make them distinguishable from normal cells  13). Ly. Ly13). es in G1 –17. Exprnescence –20. For nescence , which inescence . Epigenenescence , 25. Furtin foci , 27. Thetin foci .Although SnCs are growth arrested in the cell cycle, they are still metabolically active . Many SnCellular senescence is thought to have evolved as an antitumor mechanism where the SASP induced by oncogene-induced senescence recruits immune cells to facilitate SnC removal , 34. SnCInk4ap16-high senescent cell reporter mice (LUCp16 and p16-CreERT2-tdTomato mice) revealed that Ink4ap16-expressing SnCs progressively increased with age and drove aging and cancer processes in mice , and others (SnCs upregulate distinct antiapoptotic pathways (SCAPs) for survival, which can serve as molecular targets for pharmacological interventions to promote senolysis. Several SCAPs and their key proteins have been identified as senolytic targets for drug development. The feasibility of targeting SnCs was first demonstrated using the senolytic combination of dasatinib plus quercetin (D+Q) . Subsequd others , 85. In d others , 85. To d others .Compounds that reduce the detrimental effects of the SASP or suppress senescence without inducing SnC death are termed senomorphics, also known as senostatics. Most senomorphics act by interfering with transcriptional regulators of the SASP, such as inhibitors of ATM, p38 MAPK, JAK/STAT, and the NF-κB and mTOR pathways , 85. OneAlthough cellular senescence is generally thought to be an irreversible cell fate, recent studies suggest that senescence in certain cell types is a dynamic process that can be reverted to allow SnCs to reenter the cell cycle , 92. ForA common characteristic of SnCs is increased lysosomal SA-β-gal activity, which hydrolyzes the β-glycosidic bond formed between a galactose and its organic moiety. This enzymatic activity can be exploited to design galactose-based prodrugs by covalently attaching galactose or acetyl galactose groups to a cytotoxic molecule. The fused galactoside prodrugs are processed preferentially in SnCs after cellular uptake, resulting in the release of active cytotoxic drugs and selective killing of SnCs. The feasibility of this strategy has been demonstrated by several galactose-based prodrugs, notably SSK1, prodrug A (JHB75B), and Nav-Gal –100. IntProteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI) . PROTACs3/Rapa NPs exhibited high uptake by SnCs via surface recognition and anti-senescence effects (2-microglobulin (B2M) epitope, another senescent surfaceome protein , have been tailor-made as nanocarriers to target SnCs for senescence detection and therapeutic interventions . The lar effects . Molecul effects –114 were protein . B2M nan protein . Other k protein , zinc ox protein , and quearticles . HoweverThe immune system plays an important role in clearing SnCs. Under physiological conditions, SnCs can stimulate both innate and adaptive immune responses by secreting SASP factors or elevating particular surface antigens in order to recruit immune cells, such as T cells, macrophages, NK cells, and neutrophils, for their clearance –122. HowAs discussed above, numerous strategies have been developed to target the pathological effects of SnCs, including induction of SnC death (senolysis), suppression of the detrimental effects of the SASP (senostasis), and possible rejuvenation of senescence status  . As suchSMARCB1, coagulation factor IX (F9), and KAT7 , a compound targeting one type of SCAPs, the BCL-2 family of proteins, is another extensively studied senolytic compound showing comparable outcomes to D+Q and fisetin in multiple mouse models  60, 61,, 166–170The senolytic FOXO4-DRI peptide, designed to target another important node on a SCAP, the FOXO4-p53 complex, ameliorated premature aging pathologies caused by doxorubicin-induced chemotoxicity . RecentlHowever, it is important to note that despite the enormous therapeutic potential of senotherapeutics shown in various preclinical tests, the efficacy and potential adverse effects should be formally assessed in human clinical trials.Preclinical studies demonstrated that the accumulation of SnCs with age drives age-related diseases and pharmacologically clearing SnCs can alleviate pathologies in preclinical models of age-associated disorders including cancer, cardiovascular disease, and neurological, liver, kidney, musculoskeletal, lung, eye, hematological, metabolic, and skin diseases, even at a late life stage . These eINK4a- and p21CIP1-expressing cells in adipose and skin biopsies. Further, examination of patient blood samples also found a reduction in SASP factors   only one year after the demonstration of their senolytic activity . This opMP-9/12) . CollectThe preclinical data suggested a key role of SnCs in AD. This has led to the initiation of pilot clinical trials (NCT04063124 and NCT04685590) examining the effects of intermittent D+Q treatment in adults aged 65 or above with the clinical diagnosis of early-stage AD to determine its feasibility in modulating the progression of AD and its safety profile .L inhibitor UBX-1325 is in a clinical trial to treat patients with diabetic macular edema or neovascular age-related macular degeneration with a single intravitreal injection. Preliminary results from this study suggested a reduction in central subfield thickness and improved visual acuity . Although the application of navitoclax in these trials was not intended to test the senolytic activity of navitoclax in humans, adding another arm measuring senescence markers could provide more insights into the clinical outcomes.The success of senolytic treatment in alleviating multiple age-associated diseases in preclinical models as well as human pilot clinical trials triggered many clinical studies to examine the effects of D+Q, fisetin, and Unity Biotechnology’s senolytic compounds on metabolic dysfunction, frailty, AD, kidney function, osteoarthritis, COVID-19, and more . Fisetinl acuity . AnotherGiven the key role of cellular senescence in driving aging and many age-related diseases, various strategies have been attempted and developed to achieve senolysis, senostasis, and even senoreversal. Indeed, the success of senotherapeutics in preclinical model systems and promising preliminary results of pilot trials have sparked numerous clinical trials to assess the effectiveness of senotherapeutic drugs in slowing disease progression, reducing disease severity, alleviating frailty, and improving resilience. However, many challenges remain.Despite the increasing efforts to characterize SnCs and their SASP in normal physiological and specific disease models, detecting and quantifying senescence and SnCs remains challenging. Currently, there are no universal markers specific for SnCs. Increased β-galactosidase activity at pH 6.0 is widely used as a senescence marker; however, it is not a definite feature of SnCs, as it can be detected in other cells or under certain conditions –179. NotAs there are no available universal senescence markers, a pan-senolytic or pan-senotherapeutic capable of targeting all types of SnCs is unlikely to be realistic. Combining several senotherapeutic drugs and/or strategies targeting SnCs could be a way to improve efficacy and reduce side effects. For example, the combination of dasatinib and quercetin has been shown to efficiently kill a broader spectrum of SnCs than either treatment alone , 180. InThe SnC surfaceome–based immunotherapies offer an alternative strategy to target SnCs by leveraging the natural immune response. However, it is challenging to identify antigens that are specifically expressed on SnCs, especially in humans. Therefore, extreme caution and extensive safety studies are required before application of these immunotherapy approaches in the clinic to treat senescence-related dysfunctions. In addition, immunotherapies are typically more expensive than small molecule–based therapies, which may limit their practical applications.Testing senolytic efficacy in preclinical studies using animal models of natural and accelerated aging as well as chronic diseases has laid the foundation for human clinical trials , 182. NoIn summary, with the advancement of novel technologies, it can be anticipated that more progress will be made in tackling the challenges of characterizing SnCs using more biologically relevant biomarkers. Improving in vivo models of diseases and aging will also unlock the full potential of senotherapeutics and allow for the translation of senotherapeutics into clinical use.


Massive efforts are being made to develop coronavirus disease 2019 (COVID-19) vaccines at an unprecedented rate. The vaccinations' adverse impact profile, on the other hand, has not been well established. Neurological complications are increasingly reported as a result of these vaccines. One such complication identified is immune-mediated inflammatory polyneuropathy, which affects peripheral nerves and neurons. We report a case of chronic inflammatory demyelinating polyneuropathy (CIDP) post-mRNA-1273 (Moderna) COVID-19 vaccine. Recognizing this complication and distinguishing it from Guillain-Barré syndrome enables timely initiation of treatment. Additionally, our report highlights a possible link between vaccination and subsequent development of CIDP, but conclusive evidence of a causal relationship requires more extensive studies. The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a global pandemic in March 2020. COVID-19 viral infection is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [Viruses and vaccines can induce autoimmune neuropathies via various mechanisms, including antigen mimicry, cytokine overexpression, and activation of self-reactive T-cell clones, resulting in aberrant major histocompatibility complex (MHC) class II expression . The linNumerous vaccines have been associated with various neurological problems, including seizures with the pertussis vaccine, meningoencephalitis with the Japanese encephalitis vaccine, and giant cell arteritis with the influenza vaccine. Transverse myelitis, encephalitis, GBS, and optic neuritis have been documented following vaccination with human papillomavirus, rubella, yellow fever, measles, tetanus, rabies, and hepatitis A or B . COVID-1Outside VAERS of the CDC, the reported data on COVID-19 vaccination-related chronic inflammatory demyelinating polyneuropathy (CIDP) are scarce. As of March 2022, there are 22 reported events in VAERS in the USA when searched under CIDP and Moderna vaccine. Out of 22 reported events, one event is documented by a healthcare provider confirming CIDP, and one event is documented by ER provider suggestive of CIDP without further diagnostic confirmation. Eight events were documented by patients or family members without citing confirmation of diagnosis through a healthcare provider or any mention of administration of relevant therapeutics, but event descriptions were consistent with neurological symptomatology in line with CIDP. Three events reported by patients or family members cited the confirmation of diagnosis through a healthcare provider. Two events reported by patients were suggestive of a relapse of CIDP rather than a new occurrence. Seven events reported by patients were not consistent with CIDP or any neurological symptomatology. Therefore, probably wrongly reported under CIDP. There is no reported published report on CIDP associated with the Moderna vaccine.We present a case of an elderly female who developed lower extremities weakness gradually over five months. Clinical, pathognomonic, lab, and electromyography (EMG) findings were consistent with CIDP. Outside a few reports in VAERS, this is the first case of CIDP documented following immunization with the Moderna COVID-19 (mRNA-1273) vaccine.The patient was a 66-year-old female with a past medical history significant for type 2 diabetes mellitus with neuropathy, hypertension, and hyperlipidemia, who presented to the hospital with a five-month history of progressive lower extremity weakness and difficulty walking, and frequent falls. Her A1C was normal, and she was treated with basal insulin, short-acting insulin, and metformin. Eight months prior to admission, the patient had received Moderna COVID-19 two vaccine series. She experienced mild fever and malaise after the second dose, followed by residual fatigue lasting several weeks. Three months after that, she woke up with no feeling in both her legs and right arm weakness. She was admitted to the hospital for a stroke workup. She was hospitalized for evaluation of a transient ischemic attack. Brain imaging was unremarkable. The stroke workup was negative. She was discharged on aspirin and atorvastatin with a neurology follow-up. She also had a urinary tract infection identified, which was treated with appropriate antibiotics.Her leg weakness kept on gradually worsening over the next two months when she also started having electric, shooting pain moving upwards from toes to hips and both legs. She also started noticing more bilateral arm weakness. Further, over the course of the next three months, she had a faster progression of her symptoms. She started using a wheelchair, as she could not get up from the couch. Her frequency of falls gradually increased to one to two daily falls on average. Symptoms were now associated with numbness and tingling in bilateral upper extremities, poor oral intake, and unintentional weight loss of 40 pounds over eight months. Bilateral leg weakness followed a waxing and waning pattern with an overall gradual decline in her strength. She tried as-needed ibuprofen for her extremity pain. She was evaluated by neurology service and was found to have hyporeflexia on the exam. She had unremarkable cervical, thoracic, and lumbar spine magnetic resonance imaging (MRI). No abnormal spinal cord signal, intrathecal enhancement, or thecal sac stenosis was seen. She had an unremarkable screening colonoscopy.She was subsequently hospitalized for further evaluation and underwent extensive workup. Physical examination revealed decreased motor strength in all extremities involving proximal and distal muscles, more in the legs than arms. Decreased sensations of light touch were noted in all extremities. She had absent deep tendon reflexes in both lower extremities. Muscle tone and bulk were normal. Her complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, C-reactive protein, creatine kinase, and thyroid-stimulating hormone were unremarkable. Serum protein electrophoresis showed a questionable protein band that was suspicious for being a monoclonal protein in the gamma globulin region. Serum immunofixation revealed IgG kappa monoclonal protein and a slightly abnormal IgG lambda monoclonal protein, which was not apparent in the less sensitive serum electrophoresis study. Urine protein electrophoresis showed predominantly glomerular proteinuria with an additional protein band that could potentially be a monoclonal protein. Urine immunofixation revealed IgG kappa monoclonal protein. Vitamin B1, folate, vitamin D, copper, and vitamin B12 levels were within the normal range. Lumbar puncture revealed clear CSF and albuminocytological dissociation as demonstrated in Table Nerve conduction studies demonstrated an absent sural sensory nerve response. The peroneal motor nerve response distal latencies were prolonged with significantly reduced amplitudes and significantly slowed proximal conduction velocities. The tibial motor nerve response distal latencies were significantly prolonged with reduced amplitudes. The F response was absent on the right and prolonged on the left. The nerve conduction results were consistent with prolonged distal latencies and decreased amplitudes in the bilateral peroneal and tibial motor nerve conductions, absent right sural sensory potential, and widespread active and chronic denervation in all muscles tested in both lower extremities. This pattern supported the diagnosis of CIDP with both axonal and demyelinating features. Concentric needle electromyography of the lower extremities demonstrated diffusely abnormal insertional activity with both fibrillations and positive sharp waves in all the tested muscles. The activated motor units of the lower extremities demonstrated increased motor unit complexities, increased amplitudes, and reduced recruitment patterns. In conclusion, electrodiagnostic findings were consistent with severe bilateral neuropathy with acute and chronic denervation changes consistent with CIDP. There were no findings to suggest myopathy or myositis Tables -5.She was treated with a 2 gm/kg dosing regimen of intravenous immunoglobulin (IVIG) therapy. She was discharged to a rehabilitation facility. At the three-month follow-up, significant improvement in her symptoms was noted. She was continued on IVIG treatment with a 0.6 gm/kg x two days every four weeks regimen.Due to the significant prevalence of neurological diseases in the population and the vast number of vaccinated people, some of these conditions will manifest within the post-vaccination timeframe. As a result, establishing a causal link between vaccination and neurological disease will be a tough endeavor.The current vaccines in use in the USA are Moderna (mRNA-1273), Pfizer-BioNTech BNT162b2), and Johnson & Johnson's Janssen Ad26.COV2.S). These vaccines are generally well-tolerated. Mild symptoms such as pain at the injection site, redness, fevers, headaches, or myalgias are common side effects. Numerous neurological adverse effects have been recorded following the administration of all current COVID-19 vaccines, most notably after Ad26.COV2.S and ChAdOx1 nCoV-19 (Oxford/AstraZeneca). While the occurrence of GBS is recognized in COVID-19 patients, several GBS cases have been associated with COVID-19 vaccines, particularly those containing adenoviral components. Neuropathies following vaccination are uncommon, and CIDP development during the post-vaccination interval is exceedingly rare, occurring in less than 2% of the individuals . Moreove2b2, and .COV2.S. GBS and CIDP are immune-mediated illnesses in which the precise mechanism behind the pathophysiology of the immune response is unknown. GBS pathogenic episodes can generate antibodies against peripheral nerves and myelin sheath epitopes, leading to an autoimmune process. CIDP is often an idiopathic condition in which an immune response is directed against myelin components due to an autoimmune process involving primarily immunological mechanisms mediated by T cells. Hence, cellular immune mechanisms are a vital feature of CIDP. Infiltration of macrophages into nerves and perivascular inflammation on nerve biopsies imply that cell-mediated mechanisms are involved in demyelination. CIDP patients may have elevated T helper cells in the CSF . SegmentThe distinction between GBS and CIDP is important. GBS is the most prevalent cause of acute flaccid paralysis, characterized by autonomic dysfunction, sensory abnormalities, and varying degrees of weakness. Although the specific pathophysiology is unknown, this disorder is believed to result from an autoimmune response. GBS is often preceded by a respiratory or gastrointestinal infection. CIDP is a chronic disorder and the most common autoimmune polyneuropathy in adults. As per established criteria, a time period of more than eight weeks to recognize the greatest weakness in CIDP is used to differentiate it from AIDP, which reaches a nadir in four weeks or less. CIDP is characterized by a subacute to chronic onset that typically takes more than eight weeks to manifest paresthesias, loss of sensations, proximal and distal weakness, areflexia, asymmetric conduction velocity slowing with conduction-block like characteristics on electrodiagnostic testing, and association with albuminocytologic dissociation (elevated CSF protein without pleocytosis) . Nerve pCIDP is diagnosed based on specific clinical history and symptoms. CSF analysis, electrophysiological studies, and nerve biopsies are all important diagnostics, beneficial in excluding other possible diagnoses than in identifying CIDP. The absence of electrophysiological or histological evidence consistent with CIDP does not preclude the diagnosis. Similar caution should be exercised when interpreting demyelinating characteristics in nerve conduction studies or nerve biopsies performed on patients without clinical evidence of CIDP. CIDP has a variable prognosis like multiple sclerosis due to its heterogeneity. On average, 20-65% of patients experience a relapsing and remitting course, and the remainder experience a progressive course . Most ofThe objective of this case report is to give essential information about the occurrence of new-onset CIDP, its clinical course, and diagnostic data that may be relevant in the management of comparable post-COVID-19 vaccination presentations. The progression of this patient's symptoms (both motor and sensory) was far more rapid than would be expected with diabetic polyneuropathy. Her symptoms were a bit too symmetric for diabetic amyotrophy. Around 90% of patients with CIDP have a high CSF protein level (more than 45 mg/dL) without CSF pleocytosis -32, whicIn our case, the relationship between the second dose of the mRNA-1273 (Moderna) vaccination and the onset of neuropathy is very evident, implying that the vaccine may have a triggering effect. This case report contributes to the limited body of evidence suggesting that immunization may contribute to the etiology of CIDP by providing one of the first detailed accounts of CIDP provoked by the Moderna vaccine. A close temporal link between vaccination, symptom onset, and a thorough diagnostic work-up to rule out other possible causes met the WHO criteria for identifying the causality of an adverse event following immunization on an individual basis. This led to the conclusion that this adverse event was most likely caused by the immunization.Our observations, combined with those of earlier case reports, indicate that COVID-19 vaccinations may be associated with inflammatory neuropathies. Awareness of this uncommon but possible adverse effect is critical for prompt diagnosis and treatment. The occurrence of CIDP described in this case coincided with the Moderna COVID-19 vaccine. More research is needed to determine whether our patient's clinical presentation was just a coincidence or if there is a cause-and-effect relationship. This is the first reported case of CIDP, which developed post-mRNA-1273 (Moderna) vaccination outside of very few reports in VAERS. At this point, the true link between this case and COVID-19 vaccination remains uncertain. Further work will be required in the future to ascertain a true association between COVID-19 vaccinations and CIDP rather than a mere coincidental finding. When comparing the incidence of CIDP following vaccination to the incidence of CIDP occurring spontaneously, large observational studies will be required to establish a causal relationship. As we learn more about the long-term consequences of COVID-19 vaccines, adding any such information to clinical databases and research is incredibly valuable.


Background: Hearing loss affects approximately two out of every 1,000 newborns. Genetic factors and congenital cytomegalovirus (CMV) infections account for around 90% of the etiology. The purpose of this study was to develop and test a whole genome sequencing (WGS) approach to detect deafness-related genetic variants and CMV infections simultaneously in newborns.Method: Deafness-related genes causing congenital or childhood hearing loss were curated and selected for newborn screening. Nine dried blood spots from newborns with known genetic variants (n = 6) or CMV infections (n = 3) were employed to develop and validate the WGS testing and analytic pipeline. We then pilot tested the WGS analysis on 51 de-identified clinical samples.Results: 92 gene-disease pairs were selected for screening hearing loss in newborns. In the validation test, WGS accurately detected all types of genetic variants, including single nucleotide variations, insertions/deletions, and copy number variations in the nuclear or mitochondrial genome. Sequence reads mapping to the CMV reference genome were discovered in CMV infected samples. In the pilot test, WGS identified nine out of 51 (18%) newborns carrying pathogenic variants associated with deafness.Conclusion: WGS can simultaneously detect genetic variants and CMV infections in dried blood spot specimens from newborns. Our study provides proof of principle that genome sequencing can be a promising alternative for newborn screening of hearing loss. Hearing loss has an estimated incidence of 0.1–0.3% in newborns, and its causes vary . GeneticUniversal hearing screening in newborns has been implemented since the 1990s and has proven remarkably successful for the early identification of neonates with hearing loss, leading to interventions that have improved language development and social interaction . HoweverEnvironmental factors are also important contributors. Congenital cytomegalovirus (CMV) infection is the most prevalent one, accounting for 21% of the prelingual hearing loss . With thWhole genome sequencing (WGS) is an attractive approach for NHS . WGS canIn this study, we developed and validated an analytic pipeline using WGS to identify genetic variants and human CMV infections. We then pilot tested this pipeline on 51 de-identified clinical samples. Our study provides proof of principle that genome sequencing can be a promising alternative for newborn screening of hearing loss.This study was performed with the approval of the Institutional Review Board of BGI (IRB-20016-T2).SLC26A4 (n = 1), compound heterozygous variants in GJB2 (n = 1), homozygous variants in MYO7A (n = 1), a 3.7 Mb CNV (n = 1), and mitochondrial variants in MT-RNR1 (n = 2). The selected samples covered all the variant types associated with hearing loss, including single nucleotide variations, insertions/deletions, and copy number variations, in heterozygous or homozygous statue. Homoplasmy and heteroplasmy of the mitochondrial variants were also covered. The three positive samples with CMV infections were specifically selected with a different level of viral loads. Following this validation analysis, we pilot tested the validated pipeline on samples from 51 newborns. All the dried blood spot samples were collected by heel prick form 3-day-old babies and routinely stored at room temperature.Deafness-related genes were curated and selected for WGS analysis in newborn screening. Nine dried blood spot samples were used to develop and validate the WGS analytic pipeline. These six positive samples with known deafness-related genetic variants were specifically selected, including compound heterozygous variants in MT-RNR1 and MT-TS1) were added because MT-RNR1 is definitively associated with maternally-inherited, aminoglycoside-induced hearing loss and MT-TS1 is definitively associated with mitochondrial nonsyndromic hearing loss . Briefly, two dried blood spots were punched into a 1.5 ml Eppendorf tube with 360 μl Buffer ATL and incubated at 85°C for 10 min. A total of 40 μl proteinase K was added with incubation at 56°C for 60 min, followed by addition of 400 μl Buffer AL with incubation at 70°C for 10 min. Then, 400 μl ethanol was added and the sample was mixed by pulse-vortexing. The mixture was then transferred to a QIAamp Mini spin column and centrifuged at 6,000 × g for 1 min. 500 μl Buffer AW1 was added, followed by centrifuging at 8,000 × g for 1 min, and then 500 μl Buffer AW2 was added and the samples were centrifuged at 20,000 × g for 3 min. The QIAamp Mini spin column was placed in a clean 1.5 ml microcentrifuge tube with 80 µl Buffer TE and incubated at room temperature for 1 min. Finally, the tube was centrifuged at 12,000 × g for 1 min to collect the DNA.The genomic DNA was fragmented using covaris S220 . DNA fragments between 100 bp and 300 bp were selected using AMPure XP beads (AGENCOURT). The selected DNA fragments were then repaired to obtain blunt ends and modified at the 3’ end to add dATP as a sticky end. A dTTP-tailed adapter sequence was ligated to both ends of the DNA fragments. The ligation product was heat-denatured together with splint oligos that were reverse-complementary to a specific strand of the product, and the single-strand molecule was ligated using DNA ligase. The remaining linear molecule was digested with exonuclease, obtaining a single-strand circular DNA library. The library was subjected to rolling circle amplification to generate DNA nanospheres. Whole-genome sequencing was then performed on an MGISEQ-2000 with 100-bp paired-end fragments .The WGS data were analyzed using our in-house WGS analysis pipeline following Genome Analysis Toolkit (GATK) best practices . BrieflyALMS1/alstrom syndrome, ATP6V1B1/DRTA2, BTD/biotinidase deficiency, COL4A5/alport syndrome, GJB3/erythrokeratodermia variabilis, DSPP/dentinogenesis imperfecta, GJB6/clouston syndrome, and TCOF1/treacher-collins syndrome. Two gene-disease pairs (COCH/DFNA9 and DNMT1/ADCADN) characterized by progressive sensorineural hearing loss were excluded because of the disease’s age of onset. The age of onset for DFNA9 is approximate 20 years old (MT-RNR1 and MT-TS1) were manually added. MT-RNR1 is definitively associated with maternally inherited, aminoglycoside-induced hearing loss, and MT-TS1 is definitively associated with mitochondrial nonsyndromic hearing loss. Both gene-disease pairs were previously approved by the ClinGen Hearing Loss Expert Panel but were not listed on the ClinGen website  were finally included in the WGS analytic pipeline for screening hearing loss in newborns. The 84 genes included some of the genes most strongly linked with deafness and recommended for newborn screening, namely and TMC1 .Of these, 48 gene-disease pairs were associated with nonsyndromic hearing loss and 44 with syndromic hearing loss . AutosomTo develop and validate a WGS pipeline for detecting genetic variants and CMV infections, WGS data from nine samples with known causes of deafness were analyzed. Overall, our sequencing produced a median of 99.54% mappable bases with coverage of at least 20X in the human nuclear genome and 98.92% mappable bases with coverage of at least 2000X in the mitochondrial genome . These mOTOA (85.82%) and STRC (64.42%)  . These tMT-RNR1 gene was detected  leading to Smith-Magenis syndrome was found in HL-V4. In HL-V5 and HL-V6, homoplasmy and heteroplasmy of the mitochondrial variant m.1555A>G in the detected .The other three samples  were known to have CMV infections. The viral load, confirmed by qPCR, differed between the samples. Sequencing reads mapping to CMV reference genome increased substantially with the increase in viral load, with 4,551, 28,924, and 20,876 reads in the samples, respectively .GJB2 gene was detected in five individuals and was the most prevalent in the population. CMV infection was not detected in any of these 51 samples. All pathogenic variants detected by WGS in the pilot study were validated by Sanger sequencing  were found to carry pathogenic variants in one of the 84 deafness-related genes . NM_0040quencing .To facilitate the integration of WGS into newborn screening, we curated and selected 84 deafness-related genes (92 gene-disease pairs) using criteria established by expert groups . We thenGenetic factors and congenital CMV infection are two major causes of congenital and childhood hearing loss . A comprWGS has several advantages for newborn hearing screening. First, limited genetic screens only include a small number of pre-selected variants. This presents an inherent ethnic bias, which is an important drawback in a population with racial and ethnic diversity . WGS, hoSTRC and OTOA) have homologous regions in the human genome, which explains their low coverage in our WGS data. The STRC gene encodes stereocilin, a large extracellular structural protein found in the stereocilia of outer hair cells in the inner ear (GJB2 gene (STRC is highly homologous to pseudogene pSTRC (99.6% of coding regions and 98.9% including introns)  . OTOA enir cells . It has eletions . ConsideUSH2A gene  in the H2A gene . AlthougH2A gene . To obtaAnother challenge of implementing WGS as a screening test in newborns is the burden of variant interpretation . To overOne important caveat that we wish to stress is that the viral load of CMV might be low in peripheral blood specimens. This led to low test sensitivity when dried blood spots from newborns’ heel were used . Samples3 pfu/ml in urine or low than 1 × 104 copies/mL in urine (It is also worth noting that the association between CMV infections and hearing loss relies on the virus loads. Boppana et al. revealed that the risk of hearing loss was low when the viral DNA is less than 5 × 10in urine . In addiin urine . That isIn summary, WGS can simultaneously detect genetic variants and CMV infections in dried blood spot specimens from newborns. Our study provides proof of principle that genome sequencing can be a promising alternative for newborn screening of hearing loss.


Osteomas are rare benign bone tumors of the bone lamellar portion, that usually originate from the paranasal sinuses where they are pedicled. In the temporal bone, they are usually found in the external auditory canal and are extremely rare in the middle ear. Temporal bone osteomas have a preference for the outermost portion of the external auditory canal, while exostoses affect its most internal portion. In the temporal bone, its presence has been described in the mastoid, in the squama and in the internal auditory canal, however with marked preference for the external auditory canal1. In the medical literature, there are 60 cases of temporal bone osteomas described, originating outside the external acoustic meatus2. According to Harley et al.3 only 12 of these osteomas were found in the middle ear; and they also reported that only five of these patients complained of hearing loss, while the others were diagnosed by chance. Unal et al.4 also spoke about the conduction hearing loss in cases of middle ear osteomas. Silver et al.5 are among the authors that stressed the lack of symptoms in middle ear osteomas and, on the other hand, Muraoka et al.6 showed how important CT scan is in otorhinolaryngology in general, most specially the 3D type. Hearing loss is conductive, unilateral and progressive. Temporal bone osteomas occur mostly in young patients, present as single-unilateral lesion, of unknown etiology. It is possible that they originate from the bone capsule connective tissue and they are histologically similar to those observed in the external acoustic canal. The goal of this paper is to report a case of middle ear osteoma associated with conductive hearing loss, for which the diagnosis hypothesis was of otosclerosis.D.C.S., 23 year old male student, born in Belo Horizonte, came to us complaining of progressive left side hearing loss associated with a mild tinnitus in the previous 3 months, with no family history of hearing loss. Otoscopic examination did not reveal ear drum or middle ear alteration in any of the sides. Tuning fork tests confirmed left side hearing loss; Weber’s test lateralized to the left side and negative Rinne’s test. Audiogram confirmed a moderate conductive hearing loss and impedanciometry showed an Ar curve. A temporal bone CT scan without contrast was ordered in axial and coronal views, which showed a calcic density image on the left epitympanum, contiguous with the incus short arm, measuring 0.6 x 0.8 mm, with well defined boundaries, going from the Chaussé spur, all the way to the lateral semicircular canal. The stapes was free and there now joint alterations between the malleous and the incus .Figure 1Middle ear osteomas affect mainly the young population, it may cause conductive-type progressive hearing loss and bear normal otoscopic exam. Although it is a rare type of disorder, one must be attentive towards such possibility; and it is important to consider the differential diagnosis with other middle ear disorders, especially fenestra otospongiosis, because of its higher prevalence. The temporal bone CT scan, besides providing additional information on the Fallopian Canal route, its relationship with the stapes, the status of the other ossicula, it provides for an assessment of pre and post fenestra otosclerosis, considering clinical manifestations such as those described here allows for less operative surprises and more accurate diagnosis.For most of the authors in the literature, the middle ear osteoma treatment is based on observation until the time when the hearing loss becomes relevant for the patient or, when there are other complications related. This was the treatment offered to and accepted by the patient. The patient was also advised that in his case, surgery would approach the incus and the stapes, different from the previous one that involved the stapes and the footplate when considering otosclerosis. Thus, together with the patient, we decided for a follow up of his hearing loss with audiometric and tomographic exams.Although rare, osteomas should be considered in the differential diagnosis of conductive hearing loss. Temporal bone CT scan, in cases of fenestra otospongiosis, provides additional information on the oval window, the stapes, the cochlea, the Fallopian canal and the other ossicula, which helps to check for other alterations which were not clinically suspected.