To achieve optimal performance and low injury occurrence in horse racing, it is important to understand hoof–surface interactions. This study measured hoof accelerations in retired Thoroughbred racehorses as they galloped over turf and artificial surfaces in four shoeing conditions , using hoof-mounted accelerometers. During hoof landing, accelerations were increased for hindlimbs and leading limbs and on turf compared to the artificial surface. Barefoot hooves experienced the lowest impact accelerations and contrasted most with steel. During the propulsive stage of the stride, accelerations at “foot-off” were increased for low stride times, particularly in the hindlimbs, and on the artificial track. Increased impact accelerations on turf and in shod conditions could be detrimental to health and have implications for musculoskeletal injuries, whereas increased foot-off accelerations on the artificial surface may reflect this surface returning energy to the hoof and aiding propulsion, which could confer a performance benefit. Further work is needed to relate these findings to injury risk and racing outcomes specifically, particularly in racehorses galloping at top speeds.p < 0.05). Day and horse–rider pair were included as random factors, and stride time was included as a covariate. Collective mean accelerations across x, y and z axes were 22–98 g at impact and 17–89 g at foot-off. The mean stride time was 0.48 ± 0.07 s (mean ±2 SD). Impact accelerations were larger on turf in all directions for forelimbs and hindlimbs (p ≤ 0.015), with the exception of the forelimb z-minimum, and in absolute terms, maximum values were typically double the minimum values. The surface type affected all foot-off accelerations (p ≤ 0.022), with the exception of the hindlimb x-maximum; for example, there was an average increase of 17% in z-maximum across limbs on the artificial track. The shoeing condition influenced all impact and foot-off accelerations in the forelimb and hindlimb datasets (p ≤ 0.024), with the exception of the hindlimb impact y-maximum. Barefoot hooves generally experienced the lowest accelerations. The stride time affected all impact and foot-off accelerations (p < 0.001). Identifying factors influencing hoof vibrations upon landing and hoof motion during propulsion bears implication for injury risk and racing outcomes.The athletic performance and safety of racehorses is influenced by hoof–surface interactions. This intervention study assessed the effect of eight horseshoe–surface combinations on hoof acceleration patterns at impact and foot-off in 13 galloping Thoroughbred racehorses retired from racing. Aluminium, barefoot, GluShu  and steel shoeing conditions were trialled on turf and artificial (Martin Collins Activ-Track) surfaces. Shod conditions were applied across all four hooves. Tri-axial accelerometers  were attached to the dorsal hoof wall . Linear mixed models assessed whether surface, shoeing condition or stride time influenced maximum (most positive) or minimum (most negative) accelerations in x, y and z directions, using ≥40,691 strides (significance at  Whole horse kinematics and injury mechanics are influenced by hoof–surface interactions. Establishing factors that control the timing and patterns of equine hoof motion throughout a stride cycle is necessary for optimising equine biomechanical function and performance, lessening the risk of injuries and enhancing economic gains. Thoroughbred racehorses galloping at high speeds during training and racing are particularly vulnerable to injuries ,2,3,4,5.Horses move asymmetrically over the course of a gallop stride cycle, so the sequence of footfalls influences the accelerations and loads experienced ,7. HooveMicro-fractures in subchondral bone, cartilage breakdown and joint degeneration have been documented in response to hoof landing during locomotion ,27,28,29Epidemiological evidence suggests that, in addition to surface conditions, certain types of horseshoes are associated with a higher risk of racehorse injury, and hence are a further key component of the hoof–surface interaction. For example, rim shoes that are similar to natural hoof shape may decrease injury risk , but somThe aim of this study was to investigate the hoof accelerations of galloping Thoroughbreds trialling four different shoeing conditions at gallop on turf and artificial surfaces. We hypothesised that the magnitude of impact accelerations would increase on turf compared to the artificial surface, due to greater surface hardness. We also predicted that the harder the shoe composition, the higher the impact vibrations would be, and we expected shod conditions to be associated with higher impact accelerations compared to barefoot. We hypothesised that hoof accelerations would be higher at foot-off on the artificial track because breakover has previously been shown to be faster on this surface . We alsoEthical approval for this study was received from the RVC Clinical Research Ethical Review Board (URN 2018 1841-2). Informed consent was given by the jockeys, farriers and owners of the horses participating in this study. Thirteen retired Thoroughbred horses in regular work and utilised for jockey education at the British Racing School (BRS) in Newmarket, UK, provided a convenience sample. All horses were considered sound by the jockey, farriers and BRS management prior to data collection. They ranged in age from 6 to 20 years old, had heights between 15.3 and 16.3 hh (1.6–1.7 m) and their masses, quantified using a weigh tape, ranged from 421 to 555 kg. Additional body dimensions, hoof morphometrics and shoe masses for the horses are reported in Reference . Four joHorses underwent trials on an artificial  and turf surface at the BRS in four shoeing conditions: aluminium raceplates , barefoot, GluShu  and steel shoes . The artificial track was a mixture of well-sorted quartz sand and CLOPFF fibre, and it was wax-coated. The turf track was well-drained owing to the predominantly chalk lithology beneath. The surfaces and shoeing conditions tested were selected on the basis that they would develop understanding of the currently widely used training and racing options in the UK. In addition, we sought to investigate easily accessible yet novel shoeing options, which could be adopted by racehorse farriers, trainers and owners in the future. Horses’ hooves were trimmed prior to data collection and/or the application of shoes by the farriery team . All farriers followed the same trimming procedure set out by the lead farrier (JC). The order of trials for the eight possible shoe–surface combinations was randomized. The horses underwent a warm-up period in walk, trot, canter and gallop prior to data collection. Each data trial consisted of a minimum of two runs, to generate data for the horses galloping on both leads. However, some horses participated in additional runs if they struggled to achieve the desired lead, behaved unusually in a trial (such as bucking) or if equipment fell-off and needed to be reaffixed. Full weather data on and preceding data-collection days are available in Reference . In summTri-axial accelerometers , recording at a sample rate of 5000 Hz and with a measurement range of ±500 g, were mounted to the dorsal hoof wall of each hoof in custom-made aluminium brackets . The braApproximate timings of individual gallop runs were noted during data collection. These were used to identify relevant blocks of accelerometry data, and a custom-written MATLAB script was used to extract these data. A second custom-written MATLAB script associated with a GUI was then used to identify features of interest at hoof impact and foot-off. In summary, strides were selected manually from blocks of accelerometry data and then visually enlarged. The approximate positions of impact and foot-off , as this best represents the nature of the main peak (sharp or broad) immediately following impact or foot-off. In addition, although the data representing areas under minimum and maximum peaks were similar, it was decided that the areas under maximum peaks depicted clearer trends and were likely to be more informative because they are associated with the accelerations transferred into the hoof in the distal to proximal direction. We also considered area data after the main peaks to be of more relevance than those that preceded the main peaks. As such, we summarise results for area data at impact and foot-off in the 5 ms time window after the maximum in p ≤ 0.003). The exceptions were y-maximum, which was unaffected by a shoe*surface interaction (p = 0.125); and z-minimum, which was unaffected by the surface type (p = 0.106). Minimum and maximum accelerations for the leading forelimb were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time (p ≤ 0.027). The exceptions were x-maximum, which was unaffected by a surface*stride time interaction (p = 0.122); and z-minimum, which was unaffected by either surface (p = 0.083) or a surface*stride time interaction (p = 0.704). Minimum and maximum accelerations for the non-leading forelimb were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time (p ≤ 0.035). The exceptions were x-maximum, which was unaffected by a shoe*stride time interaction (p = 0.052) or a surface*stride time interaction (p = 0.831); x-minimum, which was unaffected by the surface*stride time (p = 0.799); y-minimum, which was unaffected by the shoe (p = 0.114) and shoe*surface (p = 0.094); and z-minimum, which was unaffected by the surface (p = 0.530). Further details and comparisons amongst the shoe and surface conditions at impact are provided in Section 3.6All significance values that were output from the linear mixed models are available in p ≤ 0.024). The exceptions were x-maximum, which was unaffected by shoe*stride time (p = 0.082); and y-minimum, which was unaffected by surface*stride time (p = 0.102). The minimum and maximum accelerations for the leading forelimb were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time (p ≤ 0.037). The exceptions were x-maximum, which was unaffected by the surface (p = 0.602) or a surface*stride time interaction (p = 0.424); y-minimum, which was unaffected by the surface (p = 0.170); and z-maximum, which was unaffected by either shoe (p = 0.072) or a shoe*stride time interaction (p = 0.243). Minimum and maximum accelerations for the non-leading forelimb were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time (p ≤ 0.017). This was true for all axis directions. Further details and comparisons amongst the shoe and surface conditions at foot-off are provided in The minimum and maximum foot-off accelerations for forelimbs were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time (p ≤ 0.048). The exceptions were x-maximum, which was unaffected by a shoe*stride time interaction (p = 0.053); y-maximum, which was unaffected by the shoe (p = 0.053) or a shoe*stride interaction (p = 0.184). Minimum and maximum accelerations for the leading hindlimb were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time (p ≤ 0.029). The exceptions were y-maximum, which was unaffected by a surface*stride time interaction (p = 0.755); y-minimum, which was unaffected by the surface (p = 0.916); z-maximum, which was unaffected by a surface*stride time interaction (p = 0.962); and z-minimum, which was unaffected by either shoe (p = 0.145) or a shoe*stride time interaction (p = 0.067). Minimum and maximum accelerations for the non-leading hindlimb were significantly affected by the shoe; surface; stride time, and interactions between shoe and surface, shoe and stride time and surface and stride time (p ≤ 0.028). The exception was x-minimum, which was unaffected by a shoe (p = 0.267) or a shoe*stride time interaction (p = 0.431). Further details and comparisons amongst the shoe and surface conditions at impact are provided in Minimum and maximum impact accelerations for hindlimbs were significantly affected by the shoe, surface, stride time, and interactions between shoe and surface, shoe and stride time and surface and stride time (p < 0.001). The exception was x-maximum, which was unaffected by the surface (p = 0.144) or a surface*stride time interaction (p = 0.288). Minimum and maximum accelerations for the leading hindlimb were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time, and surface and stride time (p ≤ 0.044). The exception was x-maximum, which was unaffected by a shoe*stride time interaction (p = 0.090). Minimum and maximum accelerations for the non-leading hindlimb were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time . Further details and comparisons amongst the shoe and surface conditions at foot-off are provided in Minimum and maximum foot-off accelerations for hindlimbs were significantly affected by the shoe; surface; stride time; and interactions between shoe and surface, shoe and stride time and surface and stride time  for shoeing condition effects on impact are presented in p ≤ 0.026), with the exception of y-minimum in the non-leading forelimb (p = 0.114). In the hindlimbs, the shoeing condition significantly influenced all impact accelerations (p ≤ 0.010), with the exception of y-maximum for the combined dataset (p = 0.053); z-minimum in the leading hindlimb (p = 0.145) and x-minimum in the non-leading hindlimb (p = 0.267). The EMM impact accelerations were largest in terms of absolute magnitude for y-maximum in the leading hindlimb (mean of EMMs across shoeing conditions was 128.1 g), with the individual largest EMM acceleration of 142.7 ± 21.9 g (mean ±2 SE in this section) being recorded for the y-maximum in the steel shoeing condition. For the y-maximum parameter, steel was most different to the barefoot condition particularly in the leading hindlimb (EMM difference = Δ33.1 ± 4.1 g)  . Mean imn = 6) in the non-leading forelimb to 64.1 ± 30.8 g in the leading hindlimb. In contrast, the steel condition generated the highest absolute means for EMM accelerations for all limbs: these ranged from 53.1 ± 23.9 g in the non-leading forelimb to 74.2 ± 35.5 g in the leading hindlimb.The largest impact acceleration offsets amongst shoeing conditions, in absolute terms, were most commonly observed between the steel and barefoot conditions : 11/18 cp ≤ 0.024), with the exception of z-maximum in the leading forelimb (p = 0.072). In the hindlimbs, the shoeing condition significantly influenced all foot-off accelerations (p ≤ 0.044). The estimated marginal means (EMMs) for shoeing condition effects on foot-off are presented in The shoeing condition significantly influenced all foot-off accelerations in the forelimbs (n = 6) in the non-leading forelimb and the leading hindlimb, respectively, to 37.3 ± 23.7 g in the leading forelimb and 39.1 ± 21.6 g in the leading hindlimb. In contrast, the steel condition generated the highest absolute means for EMM accelerations for all limbs: these ranged from 40.2 ± 25.2 g in the non-leading forelimb to 43.8 ± 23.2 g in the non-leading hindlimb. However, it is important to note that the results showed a dependency on stride time , with the exception of z-minimum . In the hindlimbs, surface significantly affected all impact accelerations (p ≤ 0.015), with the exception of y-minimum (p = 0.916) in the leading hindlimb. All EMMs for surface effects on impact are presented in The surface type significantly influenced all impact accelerations in the forelimbs (n = 6) in the non-leading forelimb to 49.5 ± 23.8 g in the leading hindlimb. In contrast, absolute means for EMM accelerations on turf ranged from 59.8 ± 28.6 g in the non-leading forelimb to 87.7 ± 41.5 g in the leading hindlimb.Considering all six acceleration axes together in the individual limb datasets, the absolute means of EMM accelerations on the artificial surface ranged from 36.4 ± 15.7 g (p ≤ 0.022), with the exception of x-maximum (p = 0.602) and y-minimum (p = 0.170) in the leading forelimb. In the hindlimbs, surface type significantly affected all foot-off accelerations (p ≤ 0.047), with the exception of x-maximum (p = 0.144) in combined hindlimb data. The EMMs for surface effects on foot-off are presented in The surface type significantly influenced all foot-off accelerations in the forelimbs . The y-maximum data for the leading forelimb indicated that the greatest EMM difference of Δ72.8 ± 3.8 g (mean ± 2 SE in this section) was observed between the aluminium–turf and barefoot–artificial conditions. However, this was closely followed by the comparison between the steel–turf and barefoot–artificial conditions, which had an EMM difference of Δ71.4 ± 3.9 g. The only pairwise comparisons that were not significantly different were aluminium–artificial versus GluShu–artificial, aluminium–turf versus steel–turf and barefoot–turf versus GluShu–Turf (p = 0.166). Please note that the combined forelimb data were not significantly affected by a shoe–surface interaction  and GluShu–turf versus barefoot–artificial (EMM difference = Δ58.4 ± 3.4 g). Only the aluminium–artificial and GluShu–artificial combinations were not significantly different . All other comparisons for the combined hindlimb data were significant (p ≤ 0.006).The y-maximum data for the hindlimbs indicated that larger acceleration differences were at play amongst the shoe–surface combinations, relative to the forelimb data. For the combined hindlimb data, the EMM differences between the aluminium–turf versus barefoot–artificial and the GluShu–turf versus barefoot–artificial, each of Δ89.0 g, were the largest, followed by steel–turf versus barefoot–artificial, which had an EMM difference of Δ87.1 ± 3.8 g. There were four pairwise comparisons that were not significantly different: aluminium–artificial versus GluShu–artificial; aluminium–turf versus GluShu–turf; aluminium–turf versus steel–turf; and GluShu–turf versus steel–turf , and the GluShu–artificial and steel–artificial were also not significantly different (p = 0.104); all other comparisons highlighted significant differences (p ≤ 0.007).For the leading hindlimb, peak EMM acceleration differences reached Δ110.0 ± 5.7 g for the steel–turf versus barefoot–artificial condition, closely followed by GluShu–turf versus barefoot–artificial (EMM difference = Δ99.6 ± 6.0 g) and steel–turf versus aluminium–artificial (EMM difference = Δ99.4 ± 6.1 g). In contrast, the aluminium–turf versus GluShu–turf comparison indicated no significant difference (p = 1.0). All other comparisons were significant (p ≤ 0.029). The non-leading hindlimb data indicated that GluShu–turf versus barefoot–artificial was most different (EMM difference of Δ75.8 ± 5.2 g), followed by aluminium–turf versus barefoot–artificial (Δ72.8 ± 4.8 g) and steel–turf versus barefoot–artificial (Δ68.3 ± 4.8 g). The data therefore show that differences amongst shoe–surface conditions were greater in the leading limbs, for both hindlimbs and forelimbs. For the non-leading hindlimb, there were four non-significantly different conditions: aluminium–artificial versus GluShu–artificial; aluminium–turf versus GluShu–turf; aluminium–turf versus steel–turf; and GluShu–artificial versus steel–artificial ; all other pairwise comparisons were significant, with p-values <0.001.Accelerations at foot-off had smaller absolute magnitudes for EMM differences amongst shoe–surface combinations. For the combined forelimbs, the largest EMM difference of Δ11.1 ± 1.5 g was observed between the GluShu–artificial versus aluminium–turf, closely followed by the GluShu–artificial versus GluShu–turf (EMM difference = Δ10.7 ± 1.3 g) and the steel–artificial versus aluminium–turf (EMM difference = Δ10.2 ± 1.4 g). Only the aluminium–artificial versus barefoot–artificial, aluminium–turf versus GluShu–turf, barefoot–turf versus steel–turf and GluShu–artificial versus steel–artificial conditions were not significantly different (each with p = 1.00), aluminium–turf versus barefoot–turf (p = 1.00), barefoot–turf versus steel–turf (p = 0.375) and GluShu–turf versus steel–turf (p = 1.00); all other comparisons had p-values ≤0.049.For the leading forelimb, there were eight EMM differences with magnitudes exceeding Δ10 g. The largest differences were between GluShu–artificial and aluminium–turf (Δ17.3 ± 2.0 g), followed by GluShu–artificial versus barefoot–turf (Δ15.4 ± 2.2 g) and steel–artificial versus aluminium–turf (Δ14.4 ± 2.0 g). The following pairwise comparisons were not statistically different: aluminium–artificial versus barefoot–artificial (p ≥ 0.084).For the non-leading forelimb, the GluShu–artificial versus GluShu–turf and steel–artificial versus GluShu–turf comparisons, each had differences of Δ13.9 g. They were followed in magnitude by the barefoot–artificial versus GluShu–turf EMM difference (Δ12.4 ± 2.0 g). For this limb, there were seven pairwise shoe–surface comparisons that were not significantly different (p = 1.00). Amongst the combined hindlimb data, differences amongst conditions were comparable to the forelimb data. The largest EMM difference was for the barefoot–turf versus GluShu–turf (Δ12.5 ± 1.5 g), followed by the steel–artificial versus GluShu–turf (Δ11.6 ± 1.5 g). All other EMM differences were less than Δ10 g, and eight of these were non-significant  and steel–artificial versus steel–turf (Δ13.8 ± 2.0 g). Here, there were more comparisons that were not significantly different; the Impact accelerations for all axes showed weak negative correlations with stride time. There were moderate correlations between stride time and foot-off accelerations, in particular for the y-maximum and z-maximum parameters. Identifying factors that influence the accelerations experienced by a horse’s hoof during landing and take-off bears implication for the injury risk and performance of racehorses and jockeys on the racetrack. Although epidemiological evidence indicates that multiple factors are associated with injury risk, including horse characteristics , training and racing history, pre-existing injuries and race characteristics , the ground-surface conditions and hoof-shoeing conditions are factors that may be managed relatively easily and offer practical solutions to improve racing outcomes. This study emphasised the important influence that ground-surface type and shoeing condition have on tri-axial accelerations experienced at the dorsal hoof wall. The data presented indicated that the hoof accelerations experienced at impact were 1.4–1.9 times and 1.2–2.4 times greater on turf compared to the artificial track for the forelimbs and hindlimbs, respectively. This trend toward higher accelerations on turf than synthetic surfaces is consistent with previous studies comparing hoof impact variations on turf versus synthetic surfaces at the trot and canter . The accThe smallest relative difference between surfaces was observed for the z-minimum in all limbs, although this parameter was the most difficult to target consistently during data processing. For the forelimbs, the y-maximum and z-maximum showed the largest relative differences between surfaces . In the hindlimbs, the greatest relative difference between surfaces was apparent for the y-minimum (2.2–2.4 times greater on turf); however, as noted in the Results section, the largest absolute difference between surfaces was 78.1 g for the y-maximum parameter in the leading hindlimb. The differing sensitivity of the six acceleration axes to surface type between forelimbs and hindlimbs may indicate that the hoof orientation on and immediately after landing is consistently different between the forelimbs and hindlimbs. For example, it would make sense for the accelerations represented by z-maximum  to be most closely associated with horizontal braking. Forelimbs are responsible for decelerating the horse in each stride cycle ,81,82, aPrevious studies have indicated that the right hindlimb on a counter-clockwise track (this would be the non-leading hindlimb) has an overall higher incidence of fracture than the left hindlimb, but it shows no difference in injury risk due to surface type . In addiWhen all acceleration axes were considered together, the data indicated that impact acceleration peaks were 7–12% higher in aluminium shoes, 2–8% higher in GluShus and 10–18% higher in steel shoes when compared to the barefoot condition . This compares to a previously reported difference of 15% between shod and unshod horses during simulated impact loading at trot in an in-vitro model . HoweverFurther work is needed to establish the relative risk of damage to the hoof and more proximal limb structures in association with the observed variability in accelerations amongst barefoot and shod conditions at gallop. It will be important to establish whether there are certain thresholds for impact accelerations that may be conducive to the development of injuries or pathologies, such as osteoarthritis. Performance implications are also key. Previous work has suggested that a reduction in the decelerative peak may signify an increased stride efficiency, by permitting a smoother transition from retardation to propulsion . This maAt foot-off, the large acceleration spikes are caused by the hoof accelerating to the forward speed of the horse. Accelerations were more similar between turf and artificial surfaces when compared to the impact data  but were−1, this may explain why accelerations associated with the barefoot condition tended to be reduced on average. In addition, given it was the mixed lead data that represented more of the faster barefoot runs . The pairwise comparisons with the largest offsets included barefoot in 18/36 cases; however, in two of these instances (for the x-minimum), the barefoot condition actually had the larger accelerations of the two shoeing conditions. In some ways, these observations are surprising because a barefoot hoof would be expected to deform more on impact and subsequently return more energy to the hoof, which might be expected to lead to more rapid accelerations. Indeed, at the higher gallop speeds, barefoot hooves do appear to experience proportionally higher foot-off accelerations relative to the shod conditions . This isoot runs , it is cAt the upper range of gallop speeds assessed here, the foot-off accelerations were increased across all acceleration axes proportionally more in the hindlimbs compared to the forelimbs, with the exception of the x-minimum in the non-leading hindlimb. This trend also mirrors the observations in the breakover duration data . It likeTri-axial hoof accelerations at impact and foot-off in galloping Thoroughbreds were influenced by the horses’ shoeing condition and surface type. Accelerations were elevated at impact on the turf surface compared to the artificial track by 1.2–2.4 times across limbs, depending on the acceleration axis considered; acceleration magnitudes were largest and offsets between surfaces greatest along the hoof wall and in the dorso-palmar direction. Accelerations were, on average, 2–18% higher at impact in the shod conditions compared to barefoot, when considering all acceleration axis directions together, but they rose up to 30% more in steel. Preventing excessive shock loading and related musculoskeletal injuries in racehorses is of critical relevance to the racing industry. This work suggests that the combination of an artificial surface and barefoot hooves may be beneficial for minimising the exposure of the hoof and distal limb to large accelerations during hoof landing. At foot-off, it was most commonly observed that accelerations were amplified on the artificial surface compared to the turf; average accelerations per individual limb were 2–12% greater for the former. We inferred that the artificial surface deformed, at least to some extent, more elastically under load and subsequently recovered and returned a higher proportion of energy to the hoof. This will have aided propulsion, leading to more rapid hoof breakover, and it could confer a performance benefit. Overall, barefoot hooves typically experienced the lowest accelerations at foot-off; however, at top gallop speeds, accelerations for barefoot hooves appeared to increase at a relatively higher rate than for shod conditions. Further work is needed to relate these findings to injury risk and racing outcomes specifically, particularly in racehorses galloping at top speeds.


The study aimed to develop a consensus classification system for the reporting of sound localization testing results, especially in the field of cochlear implantation. Against the background of an overview of the wide variations present in localization testing procedures and reporting metrics, a novel classification system was proposed to report localization errors according to the widely accepted International Classification of Functioning, Disability and Health (ICF) framework. The obtained HEARRING_LOC_ICF scale includes the ICF graded scale: 0 (no impairment), 1 (mild impairment), 2 (moderate impairment), 3 (severe impairment), and 4 (complete impairment). Improvement of comparability of localization results across institutes, localization testing setups, and listeners was demonstrated by applying the classification system retrospectively to data obtained from cohorts of normal-hearing and cochlear implant listeners at our institutes. The application of our classification system will help to facilitate multi-center studies, as well as allowing better meta-analyses of data, resulting in improved evidence-based practice in the field. Sound localization is an important skill for perceiving and navigating the world around us. Fundamentally, localization allows one to determine the direction and distance of a sound source. This facilitates auditory scene analysis and selective attention ,2, as weDistinct physiological mechanisms underlie sound localization in the horizontal  and vertical domains. Humans live in a largely planar world and are considerably more adept at localizing sounds in the horizontal domain than in the vertical domain . ConsequThe accuracy of localization depends on several factors. First is the azimuthal position of the sound source: sounds presented at the interaural midline are more accurately localized than those presented laterally, and frontally presented stimuli are somewhat more accurately localized than those presented from behind . The chaSound-localization ability is often compromised by hearing loss. Asymmetric or bilateral hearing loss disrupts the delivery of binaural cues to higher neural structures for integration and processing. Peripheral hearing loss for an extended duration can also induce plastic changes in central hearing pathways, further compounding the issue . One of The ability of an individual to localize a sound source can be assessed using subjective or objective measures. Subjective measures employ tools such as questionnaires and other self-reported metrics. One such commonly used tool is the Speech, Spatial and Qualities of Hearing Scale (SSQ) . In thes(a)The geometry of the testing environment, such as the physical dimensions of the space, the use of anechoic rooms versus testing booths, etc.(b)The type, number, and location of sound sources, the distance of the loudspeakers to the listener, the inter-speaker angle, etc.(c)The type, number, presentation level, and duration of sound stimuli, which can be pure tones, wide- or narrow-band noise, speech-shaped noise, babble, individual human voices or conversations, or environmental sounds.(d)1-2-3, A-B-C, etc.) or according to the analog clock scheme, or by pointing with hands or other instruments, or the use of a point-and-click computer interface or drawings on paper.The manner of listener response, such as verbal identification of the source speaker according to a pre-arranged naming scheme , standard deviation (SD), mean absolute deviation (MAD), mean absolute error (MAE), and root-mean-squared error (RMSE). These metrics are not necessarily compatible, and measure subtly different properties of localization ability. ME measures systematic error, which is the degree to which the perceived sound location differs to the actual sound location. It is roughly equivalent to accuracy and can be influenced by asymmetries in the listener’s hearing physiology or hearing technologies, leading to a non-centered auditory image. SD and MAD are measures of precision, which is the dispersion of perceived sound locations relative to the actual sound location. These metrics are influenced by factors such as the overall function of the listener’s hearing, as well as listener uncertainty and fluctuations in attention. MAE and RMSE are compound metrics which incorporate both systematic error and dispersion. In both metrics, listener performance is compared to a theoretical model . It has been argued that MAE is superior to RMSE as a model-performance measure . Since RLocalization of sound source (b2302). The final consensus classification system, here referred to as the HEARRING_LOC_ICF scale, will improve the comparability of localization test results across institutes, localization testing setups, and listeners. In this paper, we propose a novel classification system for reporting localization accuracy from experimental testing procedures. This will be used as the basis for the development of a universal scale to allow comparison of results from different institutions. The World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) provides a framework for qualifying functioning and disability as well as the effectiveness of therapeutic interventions. Therefore, the use of the ICF framework provides a standard language to report on localization accuracy from different experimental testing procedures. A graded scale is used: 0 (no impairment), 1 (mild impairment), 2 (moderate impairment), 3 (severe impairment), and 4 (complete impairment). Core sets are provided for the classification of hearing loss , includiThe HEARRING group is a network of world leading centers and experts dealing with all aspects of hearing disorders. We believe that advancements in the field of hearing devices are achieved through international research and the pooling of collective experience. At our annual meeting in November 2017 in Perth, Australia, we concluded that currently there exists no consensus on which outcome measures and methods are the most appropriate to use during CI evaluation and follow-up. Most CI outcome measures also require specific background knowledge in their interpretation, which complicates multidisciplinary collaboration and communication in the multidisciplinary rehabilitation process. At the same meeting, the International Classification of Functioning, Disability and Health (ICF) model was discussed as a valuable tool to overcome these challenges. To study the possibilities of the ICF framework within the field of CI, an ICF core team was put together. In the subsequent meetings of the ICF core group in Innsbruck (in 2018 and 2019), Vienna (in 2018), and Antwerp (in 2020 and 2022), ICF core sets were discussed for severe to profound sensorineural hearing loss and cochlear implantation, since they were non-existent at that time. The primary aim of the ICF core group was to define an ICF core set for CI users, based on the ICF core set for hearing loss, including all relevant ICF categories to describe the impact of cochlear implantation on different aspects of health. In a first phase, an overview of which domains of functioning that should be measured was collected. Subsequently, valid assessment tools for each ICF category were discussed, and we aimed to align all methods across the different centers cooperating in this study. The quantifications for the selected questionnaires, pure tone audiometry, and speech audiometry were developed based on the ICF qualifier categorization suggested by the WHO and on the clinical experience of the involved experts in this study. As different localization setups are used in the clinics for objective localization testing, the ICF qualifier quantification was calculated separately per particular localization setup based on norm level and chance level and will be discussed in this paper. In a third ongoing phase, we aim to apply the newly developed ICF-based assessment protocol, including the HEARRING_LOC_ICF scale in clinical practice by using it to assess adult CI users before and 6 months after implantation in all participating centers. The results of this prospective longitudinal multicenter study in 63 adult CI candidates will be presented in an upcoming paper.No impairment: Performance ranging from 0°  to two standard deviations above the mean localization error of the normal-hearing group (NH + 2SD); Mild impairment: Performance ranging from NH + 2SD to NH + 2SD + ((CL − NH + 2SD)/3); Moderate impairment: Performance ranging from NH + 2SD + ((CL − NH + 2SD)/3) to NH + 2SD + (2 × (CL − NH + 2SD)/3); Severe impairment: Performance ranging from to NH + 2SD + (2 × (CL − NH + 2SD)/3) to chance level (CL); and Complete impairment: Performance at or worse than chance level  of normal hearing population of each specific setup (NH) and chance level (CL) of the setup. The chance level of the localization error is calculated as the mean of the magnitudes of the differences between the azimuth of a judged speaker and the azimuth of a presenting speaker across all possible combinations of presenting and judged speakers. Consequently, chance levels and norm values will vary based on the localization testing setup, so these values will need to be calculated for each experimental setup separately. Formally, the five categories can be described as: In order to demonstrate the improvement of comparability of localization results across individuals, populations, and institutes, we applied the HEARRING_LOC_ICF scale retrospectively to data obtained from cohorts of normal-hearing and cochlear implant listeners at our institutes. Norm data for each setup were retrieved from normal-hearing listeners with hearing thresholds for both ears (0.250–8 kHz) within the normal range based on age and sex, as defined by the BS 6951:1988, EN 27029:1991, and ISO 7029-1984 standards. The protocol was approved by the ethics committee of the Antwerp University Hospital (15/10/96) on 15 June 2015, by the South Metropolitan Health Service Human Research Ethics Committee (RGS0000000537) on 26 September 2017, by the Ethics Committee at the Medical University of Würzburg (199/20) on 23 April 2021, and by the Institutional Review Board at the Institute of Physiology and Pathology of Hearing (IFPS:KB/02/2017r). (a)Comparability across institutesTo investigate comparability of localization results across institutes, SSD CI populations were chosen to illustrate the use of the HEARRING_LOC_ICF scale. The HEARRING_LOC_ICF scale was calculated for the localization testing setup of the Antwerp University Hospital (UZA) in Belgium, for the World Hearing Center (WHC) in Poland, for the University Clinic of Würzburg (UKW) in Germany, and for the University of Western Australia (UWA) in Australia. An overview of the different setups and the application of the scale per institute can be found in (b)Comparability across localization testing setupThe procedural elements of localization testing can vary. An example of a source of procedural variation is the stimulus, which can vary in type, number, presentation level, and duration. While all other parameters remained unchanged, three different stimuli were compared in the SSD group of Mertens et al. : broadba(c)Comparability across listenersTo investigate comparability of localization results across listeners using the HEARRING_LOC_ICF scale, the scale was applied on data from the SSD group and a group with Asymmetric Hearing Loss (AHL) from Mertens et al. . The SSD(a)Comparability across institutescomplete impairment of sound localization in the unaided condition, measured with the HEARRING_LOC_ICF scale. In the aided condition, we observed a shift towards moderate impairment. The majority (42%) of all SSD CI patients experienced a moderate impairment with sound localization in the aided condition. Using the HEARRING_LOC_ICF scale, we pooled data from SSD CI recipients from different institutes . Overall(b)Comparability across localization testing setupcomplete impairment with sound localization. In the condition with the HP noise, the degree of observed impairment was more variable. This is in line with previous evidence that suggests that CI recipients rely mostly on ILDs and that their ITD sensitivity is generally supposed to be poorer . In the condition with a wider-band source, a shift was observed, with the majority (70%) reporting only moderate impairment with sound localization (As listed in lization .(c)Comparability across listenerscomplete impairment), the majority of the SSD group (50%) had only mild impairment with sound localization.Using the HEARRING_LOC_ICF scale, we were able to demonstrate the difference in localization accuracy in the CI-aided condition between the SSD group and the patients with asymmetric hearing loss from the study from Mertens et al. ; see Figcomplete impairment of sound localization in the unaided condition and moderate impairment in the aided condition. In the majority of the SSD CI group from UWA, on the other hand, only mild impairment was observed in the aided condition. This could be explained by the intensive training program the SSD CI recipients are offered, resulting in better sound localization accuracy [Sound localization is an important aspect of hearing, and its preservation or restoration is a major goal of hearing implant technologies. Sound localization measurement is commonly performed both in the assessment of the rehabilitation of hearing implant users, as well as in psychophysical research to improve hearing implant performance. Across institutions, there exist major variations in localization assessment. These include variations in the testing procedure as well as in the statistical and reporting metrics used. A standardized testing procedure has been reported elsewhere ; howeveraccuracy . Earlieraccuracy . AnotherThe HEARRING group hopes clinicians put this recommendation into practice. The application of our standard will help to facilitate multi-center studies, as well and allow better meta-analyses of data, resulting in improved evidence-based practice in the field.


The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors’ will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development. A part of a diverse group of non-protein signaling compounds called second messengers, the cAMP and cGMP signaling systems are ultimately involved in relaying the signal produced proteins . These eClinicalTrials.gov database, there are at least 1825 recorded clinical studies involving PDE inhibitors as of 2022. However, only a relatively small number of PDE inhibitors have entered market, while several initially promising therapeutic agents proved unsuccessful ; the former is activated in response to the receptor-ligand interaction, catalyzing the conversion of AMP/GMP into 3′-5′- cAMP/cGMP, while the latter catalyzes the cyclic nucleotides’ deactivation . The potccessful .During our investigation of trends within clinical trials , we haveThe cyclic nucleotide PDEs is a diverse superfamily of 11 families, encoded by 21 genes and responsible for catalyzing the 3′-cyclic phosphate bond hydrolysis in the cyclic nucleotide molecules, resulting in inactive compounds . StructuBiological functions of the individual families are diverse, including involvement in such processes, as myocytes contractility, male and female sex cells development and functioning, inflammatory cells activation, steroidogenesis or neuronal signaling . Such a The global efforts to exploit the PDE enzymes therapeutically have so far produced a large number of molecules with varying selectivity and therapeutic applications, as well as a growing number of agents under development . In the Chemically, the PDE inhibitors predominantly belong to a broad range of nitrogen-containing classes . At leasThe earliest identified class of PDE inhibitors is the class of xanthine derivatives, which provided important tools for the further development of this therapeutic class; acting as competitive inhibitors, these compounds are characterized by structural features that resemble the purine moiety of cyclic nucleotides: the heterocyclic ring which is comprised of a six-membered pyrimidine ring, conjoined with a five-membered ring containing nitrogen atoms . The earIn our dataset, we have included 87 unique PDE inhibitors. The In sections below, we will discuss various aspects of the PDE inhibitors’ clinical uses and research. For the approved agents, we will briefly discuss the rationale behind employing PDE inhibitors in the relevant disorders and discuss the efficacy and safety profiles of the included drugs. For the investigational agents, we will provide a summary on some of the currently available clinical and/or pre-clinical data, and will comment on the future of this important class of therapeutic agents, highlighting its currently evident strengths and weaknesses.As of 2022, we identified 35 agents that have been approved and authorized for marketing by either FDA or any other drug regulatory authority. The approval statuses and relevant trade names were determined through the DrugBank, Drugs@FDA and EMA Medicines databases records, Google search engine, or cited as per . The maj®, 2011) and EMA  in COPD; PDE 4-selective ibudilast, marketed in Japan and several other Asian markets for the use in asthma as Ketas® and Pinatos®, and non-selective enprofylline, marketed in asthma as Nilyph®.Obstructive respiratory diseases (OPD), such as asthma or the chronic obstructive pulmonary disease (COPD), have been one of the earliest marketed indications, associated with the PDE inhibitors. Asthma and COPD are common heterogeneous, typically inflammation-mediated diseases of the airways, characterized by the airflow limitation . Non-selThe rationale behind targeting PDEs to manage the airway diseases is based on the involvement of several families in the inflammatory and structural cells within the respiratory system. Among the individual PDE families, PDE 3, PDE 4, PDE 5, PDE 7, PDE 8, and PDE 9 have been described to hold the highest degree of relevance . InhibitIn the clinical setting, the evidence is scarce and limited to PDE 4 inhibitors in COPD, showing a benefit in improving lung function and reducing the likelihood of exacerbations, but without a significant impact on the quality-of-life, based on the results of a systematic review of clinical trials involving cilomilast, roflumilast, and tetomilast . A 1-yeaClinicalTrials.gov records mention two Recruiting Phase 3 studies of tanimilast in COPD , while ensifentrine is in two Ongoing Phase 3 trials in COPD and a Phase 2 study in asthma that has shown a dose-dependent bronchodilation similar to salbutamol, but without impacting potassium levels and having a less significant impact on heart rate and pulse rate  are a heterogeneous group of disorders affecting heart and blood vessels; the  includes®, 1961), amrinone  and milrinone , and non-selective pentoxifylline . Dipyridamole is approved as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement; in combination with aspirin , it is indicated for the stroke risk reduction. Amrinone and milrinone are both marketed in CHF, while pentoxifylline is approved in intermittent claudication. Other identified FDA approvals within this category include PDE 3-selective anagrelide , PDE 5-selective sildenafil  and its derivatives avanafil , tadalafil  and vardenafil , and PDE 3-selective cilostazol . Anagrelide is approved for treating thrombocythemia, secondary to myeloproliferative malignancies, as well as to reduce risks of thrombosis-related events. Sildenafil, along with avanafil, tadalafil, and vardenafil, are all marketed in ED; sildenafil and tadalafil are also marketed in pulmonary arterial hypertension as Revatio® (2005) and Adcirca® (2009), respectively. Cilostazol is approved in intermittent claudication. Additionally, a number of PDE inhibitors, such as cGMP-PDE-specific cicletanine, PDE 3-selective enoximone and olprinone, non-selective papaverine, ibudilast, and PDE 5-specific mirodenafil, udenafil, and lodenafil, have received marketing authorization in other regions. Cicletanine is authorized in France for the treatment of hypertension . Enoximone is marketed across Europe for the treatment of CHF, initially authorized in France ; olprinone is authorized for the same indication in Japan . Papaverine is another PDE inhibitor, used in ED, as well as vascular spasm-associated cerebral and peripheral ischemia; it is marketed worldwide under various trade names (® and Pinatos®). Mirodenafil  and udenafil  are both approved in the Asian markets for the treatment of ED. Lodenafil (Helleva®) is marketed for ED in Brazil. PDE 1-specific vinpocetine (Cavinton®) is marketed as a dietary supplement in managing cerebral vascular disorders and cognitive impairment. At least one cardiovascular PDE inhibitor is also used in veterinary practice; PDE 3-specific pimobendan is marketed under various trade names, including Acardi® (1997) for treatment of CHF in dogs.The earliest FDA-approvedde names . Ibudila2+ transient amplitudes and Ca2+ contents in the sarcoplasmic reticulum      . Vardena 20,325) , are heaatients)  has showatients)  has shown = 3,972 patients) (n = 150 patients)  , the useatients) . In throatients) . A recenatients)  have shoatients) .Here, PDE inhibitors have been shown to be valuable tools to improve the functional status in patients with vascular and CVDs. It is suggested that developing isoform-specific inhibitors and/or activators could improve the clinical value of PDE modulators in CVDs, while modulating isoform-specific protein-protein interactions within specific signalosome could provide a strategy to improve the molecules’ specificity . In HF, ®, 1996), apremilast , and crisaborole . Amlexanox was originally approved for the treatment of recurrent aphthous ulcerations in the oral mucosa; however, current FDA records list the drug as discontinued, presumably due to termination of licensing agreement between the drug’s developer, ULURU Inc., and Discus Dental Inc., the company that held exclusive rights for sales and marketing in the United States. Apremilast is approved for the treatment of active psoriatic arthritis and moderate-to-severe plague psoriasis, and crisaborole is approved in mild-to-moderate atopic dermatitis. Ibudilast, in addition to its previously mentioned uses in asthma and post-stroke dizziness, is marketed for allergic conjunctivitis as Ketas® and Eyevinal®. Recently, difumilast was marketed in Japan as Moizerto® (2021).Several PDE inhibitors have been marketed in inflammatory disorders affecting the skin and joints . The FDARecurrent aphthous ulcerations is a common chronic disease in the oral mucosa, characterized by solitary or multiple, recurrent, small ulcers with erythematous halos and yellow or gray pseudomembranes . Psoriasn = 505 patients)    , resulteatients) . Additioatients) , has shoatients) . Difamilatients) , has shoHere, PDE inhibitors are considered interesting additions to the established treatment strategies. Amlexanox is a first-line treatment option in apthous stomatitis . Apremil®), tofisopam (Grandaxin®) and caffeine (Cafcit®). Drotaverine is marketed in functional bowel disorders due to the smooth muscle spasm, while tofisopam is marketed in anxiety. Additionally, caffeine is approved by the FDA in 1999 for use in the apnea of prematurity.Three PDE inhibitors have been marketed in central and peripheral nervous system disorders : drotave2+ channel blocking  and labor augmentation. In IBS, drotaverine was shown to improve abdominal symptoms, including pain frequency and severity, and stool frequency, based on the results of a double-blind placebo-controlled study . In laboTo summarize, the nervous system disorders currently represent a niche use for PDE inhibitors. Drotaverine and tofisopam lack clinical evidence to discuss its wider applicability. Caffeine is being considered as the mainstay of apnea of prematurity pharmacotherapy; however, it is not considered to act primarily as a PDE inhibitor.In our dataset, we identified 52 PDE inhibitors which are either under ongoing investigation in clinical or pre-clinical studies, or which have been previously investigated but are either discontinued or have an unknown development status as of 2022. Among the agents in development , 7, indi2 receptor antagonism  and schizophrenia, are particularly prevalent. In schizophrenia, PDE 10A inhibition is reported as a plausible approach due to the expression pattern of PDE 10A in striatal medium spiny neurons and functional similarity of its inhibition to the dopamine Dtagonism . These atagonism . As of 2tagonism  and prodtagonism , but faiIn AD, PDE4 inhibitors represent the bulk of investigational approaches . The ratin vitro study on myeloma cells  and metabolic diseases. In blood disorders, tovinontrine is evaluated for sickle cell anemia in a Phase 2a Ongoing study to evaluate the long-term safety, tolerability and pharmacodynamics (NCT04053803). A gene therapy using an adeno-associated virus vector AAV2/5-hPDE6 is in a Phase 1/2 Ongoing trial (NCT03328130) in patients with retinitis pigmentosa. CC-11050 is currently evaluated in a Phase 2 Recruiting study in patients with leprosy and erythema nodosum leprosum (NCT03807362). The drug has also been studied in cutaneous lupus erythematosus, tuberculosis (TB) and HIV infection; published evidence in TB suggests that PDE inhibition can enhance the lung function recovery  in the mdx mice, it reduces the mRNA level of profibrotic genes in the gastrocnemius and diaphragm of the animal, and significantly reduced the percentage affected by fibrosis (In addition to the PDE inhibitors in clinical development, mentioned above, we have identified several experimental drugs. Among the novel indications here is Duchenne muscular dystrophy, potentially manageable using a PDE 4 and PDE 5 inhibitor combination therapy. According to an fibrosis .1 antagonist, providing a potential strategy to improve safety profile of PDE 10A inhibitors through reducing dopamine D2 and concomitantly potentiating dopamine D1 receptor-mediated neurotransmission (Many of experimental agents are PDE 10 inhibitors. JNJ-42314415, MR 1916, SEP-39, and ASP9436 are novel PDE 10 inhibitors with an antipsychotic activity; characterization of JNJ- 42314415, in particular, have showed that the effects of PDE 10A inhibition against dopaminergic stimulants and on catalepsy were potentiated by a Dsmission . In addismission .Several agents target novel PDE targets. BRL-50481, a PDE 7 inhibitor, have showed neuroprotector  and antivia PDE inhibition. Resveratrol was found to impart neuroprotection in brain ischemia by inhibiting PDEs and regulating the cAMP/AMPK/SIRT1 pathway, which reduces ATP energy consumption (One more agent to discuss is resveratrol, a naturally occurring polyphenol marketed as a dietary supplement due to its antioxidant properties . Severalsumption . Additiosumption  and amelsumption .Several studies involving resveratrol were done on human subjects as well, such as AD, Gulf War syndrome, T2DM, postmenopausal osteoporosis and COVID-19. In AD, it was found to alter the Aβ40 levels and the brain volume loss increase , decreasHere, we provide a comprehensive study of the clinical trials and FDA approved drugs in relationship to their therapeutic targets. As of 2022, the majority of commercially available PDE inhibitors are marketed in cardiovascular disorders and inflammatory diseases, offering valuable therapeutic options. Particularly, PDE 5 inhibitor are the first-line option in ED, while PDE 4 inhibitors are actively explored in inflammatory conditions of the skin and COPD, showing variable, but promising results. The ongoing clinical research moves towards diversification with CNS disorders being particularly prevalent, however, specifically schizophrenia and AD. Other interesting directions are mycobacterial infectious diseases, such as tuberculosis and leprosy, and potential applicability in COVID-19. The clinical evidence on efficacy is currently limited and often conflicting, however. Many of the investigational PDE inhibitors, particularly drugs investigated in asthma or COPD as an indication are either discontinued, suspended or are in an otherwise unknown status. A common reason seems to be lack of efficacy and/or unsatisfactory ADR profile; however, there are gaps in published evidence on most agents, making it difficult to assess the issue.via rational drug design based on evidence of the effect of structural features on safety. Additionally, increasing the isoform specificity and/or designing allosteric modulators is mentioned in the literature as a plausible strategy to improve the ADR profile and efficacy (Among the marketed agents, current issues include compliance-limiting ADRs and often insufficient clinical efficacy. A potential solution to the lack of efficacy could be directing drug development efforts to evaluate combinatory regimens, as suggested for PDE 5 inhibitors in ED; combining PDE 5 inhibitors with other therapeutic approaches, such as antioxidants, showed improved outcomes without increasing ADRs . A similefficacy .PDE enzymes are a long-established pharmacological target and the extensive research involving these proteins contributes to a continuous interest towards further expansion of the PDE inhibitors’ clinical use. The future development continues to diversify, particularly thanks to the experimental agents and/or agents in the preclinical development . We expeThe global market of PDE inhibitors is currently driven predominantly by the PDE 5 inhibitors and the unmet clinical needs and the increase in ED prevalence is also considered to contribute . It is eHere, we provide a comprehensive overview of PDE inhibitors with focus on novel agents and indications. The current clinical uses of PDE inhibitors include COPD, vascular and cardiovascular disorders and skin inflammatory disorders. There is a trend for diversification of clinical uses for PDE inhibitors with numerous novel agents being in clinical and preclinical development. While a significant portion of drugs under development have not been successful, the scientific community recognizes some of the present gaps in knowledge that had been slowing the development. The continuous efforts to develop and evaluate both the approved and novel agents will undoubtedly expand our understanding of the PDE pharmacology and will likely contribute to the further growth.


Neurogenin 1 (Ngn1) belongs to the basic helix–loop–helix (bHLH) transcription factor family and plays important roles in specifying neuronal differentiation. The present study aimed to determine whether forced Ngn1 expression contributes to bone homeostasis. Ngn1 inhibited the p300/CREB-binding protein-associated factor (PCAF)-induced acetylation of nuclear factor of activated T cells 1 (NFATc1) and runt-related transcription factor 2 (Runx2) through binding to PCAF, which led to the inhibition of osteoclast and osteoblast differentiation, respectively. In addition, Ngn1 overexpression inhibited the TNF-α- and IL-17A-mediated enhancement of osteoclast differentiation and IL-17A-induced osteoblast differentiation. These findings indicate that Ngn1 can serve as a novel therapeutic agent for treating ankylosing spondylitis with abnormally increased bone formation and resorption. Acp5), the osteoclast-associated receptor (Oscar), and cathepsin K (Ctsk) [Alpl), osterix (Sp7), bone sialoprotein , and osteocalcin (Bglap) by binding to the osteoblast-specific acting element (OSE) present in the promoter region [Bone homeostasis is maintained by the balance of tightly coupled processes between bone resorption by osteoclasts and bone formation by osteoblasts. However, an imbalance in these processes leads to skeletal disorders, such as osteoporosis, osteopetrosis, and rheumatoid arthritis ,2,3. OstK (Ctsk) ,5,6,7. OK (Ctsk) . All theK (Ctsk) ,9. Runx2r region ,11,12.Ngn1-null mouse models have revealed that the gene plays a critical role in the differentiation of glutamatergic spiral ganglion neurons during development. It contributes to the normal differentiation of glutamatergic spiral ganglion neurons by activating the downstream cascade of NeuroD1, Brm3a, GATA3, and neurotrophic factor receptors. Furthermore, in vitro studies using an Ngn1 overexpression model have revealed that Ngn1 stimulates the neuronal differentiation of neural progenitors but inhibits glial differentiation [Neurogenin 1 (Ngn1) belongs to the family of basic helix–loop–helix (bHLH) transcription factors. ntiation ,14,15,16The neural and skeletal systems are physically and functionally associated ,19,20,21The present study aimed to determine whether Ngn1 affects osteoclast and osteoblast differentiation. We found that the overexpression of Ngn1 in osteoclast or osteoblast precursor cells negatively regulated osteoclast or osteoblast differentiation by inhibiting the transcriptional activity of NFATc1 or Runx2, the master regulators of differentiation into osteoclasts or osteoblasts, respectively. The regulation of these two transcription factors by Ngn1 was associated with a direct interaction between Ngn1 and p300/CREB-binding protein-associated factor (PCAF).Ngn1 expression is very low during osteoclastogenesis and osteoblastogenesis, we overexpressed Ngn1 in osteoclast and osteoblast precursor cells using a retrovirus to investigate its role in bone cells. To determine the role of Ng1 in osteoclast differentiation, Ngn1 was overexpressed in BMMs. Ngn1 overexpression significantly suppressed the formation of TRAP-positive osteoclasts  partially but significantly rescued the Ngn1-induced suppression of osteoclast formation a. FurtheOsteoclast differentiation, although mainly induced by RANKL, can also be induced by other inflammatory cytokines ,30. TherSeveral studies have shown that histone acetyltransferases, including PCAF, p300, monocytic leukemia zinc finger protein (MOZ), and MOZ-related factor (MORF), stimulate osteoclastogenesis and osteoblastogenesis through the acetylation of both histone and non-histone proteins . PCAF isBoth NFATc1 and Runx2 are master transcription factors of osteoclast and osteoblast differentiation, respectively ,34. TheyNgn1 regulates Ngn1-dependent transcription by binding to E-box elements as a bHLH transcription factor, and also acts as a transcription repressor independently of its ability to bind to DNA. For example, Ngn1 sequesters the transcriptional coactivator complex comprising the CREB binding protein (CBP)/p300 and Smad1 from STAT by directly interacting with CBP, thus inhibiting glial cell differentiation . We founAnkylosing spondylitis (AS) is a common inflammatory autoimmune disease that is involved in disorders of the immune and skeletal systems . It is cIn the present study, the overexpression of Ngn1 negatively regulated osteoblast differentiation. Ngn1 inhibited the osteoclast differentiation induced by RANKL, as well as by TNF-α and IL-17A. Furthermore, Ngn1 suppressed the osteogenic differentiation and function induced by BMP2 and IL-17A. Together, these results suggest that the administration of Ngn1 can ameliorate excessive bone formation and resorption in inflammatory sites of AS. While multiple in vitro studies suggest that Ngn1 overexpression promotes proliferation during the development of spiral ganglion neurons and neuronal differentiation in pluripotent stem cells, little is known about the function of Ngn1 overexpression in vivo, except for reports that retina-like tissue is induced by ectopic Ngn1 expression from the Bestrophin1 promoter ,56. TherBonemarrow-derived macrophages (BMMs), isolated from the femurs and tibias of wild-type ICR mice by flushing with α-MEM , were cultured in α-MEM containing 10% FBS , 100 U/mL penicillin, 100 mg/mL streptomycin , and 30 ng/mL M-CSF, for 3 days. Nonadherent cells were removed, and adherent BMMs were differentiated into osteoclasts via incubation with α-MEM containing 10% FBS , 100 U/mL penicillin, 100 mg/mL streptomycin , M-CSF (30 ng/mL), and RANKL (10–150 ng/mL). Mature osteoclasts were fixed and stained for TRAP. Thereafter, TRAP-positive multinuclear cells with >3 nuclei were considered as osteoclasts.Primary osteoblast precursors were isolated from the calvarias of neonatal ICR mice via enzymatic digestion with 0.1% collagenase  and 0.2% dispase II . Primary osteoblast precursors were differentiated into osteoblasts by culturing in α-MEM containing 10% FBS , 100 U/mL penicillin, 100 mg/mL streptomycin , BMP2 (100 ng/mL), ascorbic acid (50 µg/mL), and β-glycerophosphate (100 mM). The cultured cells were lysed in 50 mM Tris-HCl (pH 7.4) containing 1% Triton X-100, 150 mM NaCl, and 1 mM EDTA and incubated with p-nitrophenyl phosphate substrate . ALP activity was then assessed by measuring the absorbance at 405 nm using a spectrophotometer. Cultured cells were fixed with 4% paraformaldehyde, stained with 40 mM alizarin red (pH 4.2), and washed with phosphate-buffered saline (PBS) to remove nonspecific staining. Then, the cells were visualized using the CanoScan 9000F Mark II scanner . The quantitation of alizarin red was performed by extracting alizarin red from the stained cells with 10% acetic acid for 30 min. Subsequently, the absorbance of the samples was measured at 405 nm via spectrophotometry.Plat-E cells were transfected using FuGENE 6 , as described by the manufacturer, to produce retroviral packages. Retroviral supernatants were collected 48 h post-transfection and then incubated with the cells of interest for 6 h with 10 μg/mL polybrene .Gapdh. The relative quantified value for the expression of each target gene compared with its calibrator is expressed as 2−(Ct−Cc), where Ct and Cc are the mean threshold cycle differences of the target and calibrator genes, respectively, after normalization to Gapdh expression. The relative expression for each sample is shown in a semi-log plot. The forward and reverse primer sequences (5′ → 3′) were as follows: Gapdh, TGACCACAGTCCATGCCATCACTG and CAGGAGACAACCTGGTCCTCAGTG; Nfatc1, CTCGAAAGACAGCACTGGAGCAT and CGGCTGCCTTCCGTCTCATAG; Acp5, CTGGAGTGCACGATGCCAGCGACA and TCCGTGCTCGGCGATGGACCAGA; Oscar, TGCTGGTAACGGATCAGCTCCCCAGA and CCAGGAGCCAGAACCTTCGAAACT; Ctsk, AGGAGGCATTGACTCTGAGATG and GTTGTTCTTATCCGAGCCAAGAG; Runx2, CCCAGCCACCTTTACCTACA and CAGCGTCAACACCATCATTC; Alpl, CAAGGATATCGACGTGATCATG and GTCAGTCAGGTTGTTCCGATTC; Ibsp, GGAAGGGAGACTTCAAACGAAG and CATCCACTTCTGCTTCTTCGT TC; and Bglap, ATGAGGACCCTCTCTCTGCTGCTCAC and AGAGCAAACTGCAGAAGCTGAGAG.We amplified the sequences of interest using specific primers in triplicate via qRT-PCR using SYBR Green  and Rotor-Gene Q (Qiagen). The transcript-level expression of target genes was normalized to that of Acp5, Oscar, Alpl, Bglap, or OSE reporter plasmids using FuGENE 6 for 48 h , as described by the manufacturer. The cells were lysed in Passive Lysis Buffer , and luciferase activity was measured in duplicate using the dual-luciferase reporter assay system .We transfected 293T cells with We transfected 293T cells with the peptide sequence DYKDDDDK (Flag)-PCAF, Flag-Neurogenin 1, human influenza agglutinin-NFATc1 (HA-NFATc1), or anti-master regulator of cell cycle entry and proliferative metabolism-Runx2 (Myc-Runx2), as indicated. The cells were washed with PBS and lysed with 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM EDTA, 0.5% Nonidet P-40, 1 mM PMSF, and a protease inhibitor cocktail. Proteins in the lysates were immunoprecipitated using PCAF  or Ac-lysine  antibodies overnight at 4 °C. Protein–antibody complexes were extracted using Pierce™ Protein G Agarose ; then, the proteins were separated via SDS-PAGE and transferred onto PVDF membranes . Nonspecific binding on the membranes was blocked by treating them with 5% skim milk in 10 mM Tri-HCl (pH 7.6), 150 mM NaCl, and 0.1% Tween 20 (TBS-T). The membranes were then immunoblotted with anti-Flag antibodies , anti-NFATc1 antibodies , or anti-–Myc antibodies . Signals were detected using ECL solution  and analyzed using the Azure 300 luminescent image analyzer .t-test for two independent samples or analysis of variance (ANOVA) with post hoc Tukey HSD test for multiple group comparisons. Results with p < 0.05 were considered statistically significant.All values are expressed as mean ± standard deviation (SD). Statistical significance was determined using a two-tailed Student’s


BackgroundExposure to recreational noise is an emerging public health problem leading to hearing loss. Young people often spend their leisure and relaxation time listening to unsafe levels of music on their personal audio systems. This study aimed to study hearing impairment among young adults due to exposure to various audio gadgets.MethodologyThis cross-sectional study was conducted among 241 patients and healthcare workers aged 20-40 years. The data collection instrument was a questionnaire including the history and patterns of usage of headphones. A mobile application-based hearing test, a validated Smartphone hearing screening technology, by the World Health Organization (hearWHO) was used to check hearing.ResultsOf the 241 adult participants (aged 20 to 40 years), 188 (78%) were males and 53 (22%) were females. The mean hearWHO score was 46.02 ± 9.854, ranging from 21 to 85. The mean hearWHO score for headphone usage with a music system of 50.45 ± 12.32 (p = 0.023) and television of 44.13 ± 8.595 (p = 0.015) was statistically significant. The mean hearWHO score for daily headphone users was 45.93 ± 9.67, for users using daily for more than two hours was 46.59 ± 10.34, for those using headphones for leisure was 47.51 ± 7.74, and for usage music/gaming was 48.71 ± 12.57. Subclinical hearing loss was seen in 201 (83.4%) headphone users. A higher proportion of subclinical hearing loss (74.1%) was noted among participants who used headphones for multiple reasons such as leisure, education, service, music, and gaming.ConclusionsIn this study, a high proportion of headphone users were found to have subclinical hearing loss. This study generated imperative facts for people and emphasize that they look after their hearing. This study introduces the applicability of new technology in an Indian setting where hearing healthcare is facing challenges. Exposure to recreational noise is an emerging public health problem leading to hearing loss. Young people often spend their leisure and relaxation time listening to unsafe levels of music on their personal audio systems or are exposed to high levels of music or noise at concerts, bars, sports arenas, and clubs . The higAccording to the National Health and Nutrition Examination Survey conducted in the United States in 2005, the prevalence of hearing loss among 12-19-year olds is 5.3%. It is estimated to be proportional to an increased number of people listening to music through headphones. A 2008 European Commission report documented an increase in the use of personal audio devices by the population .Some of the other harmful effects of listening through these hearing gadgets include ear infection, earache, numbness, adverse effect on the brain, congested air passage, external threats, hyperacusis, and multiple sclerosis. Over usage of headphones also increases psychological distress leading to becoming less attentive, unsocial, ignorant, less active, and thereby affecting individuals’ potential. Excessive usage of hearing gadgets may also lead to external threats such as accidents and even loss of life ,6.Considering the seriousness of the newly arising challenge of new technologies and the cumulative effects, it is essential to study both qualitatively and quantitatively the impact of these gadgets on health if used excessively. This study aimed to investigate hearing impairment among young adults due to exposure to various audio gadgets.This cross-sectional study was conducted in the Departments of Community and Family Medicine and ENT, All India Institute of Medical Sciences (AIIMS), Mangalagiri, Andhra Pradesh, from October 2020 to March 2021. Male and female patients and healthcare workers aged 20-40 years were enrolled in the study. The possibility of sensorineural deafness increases above the age of 40. In this study, we included employees or patients of AIIMS, Mangalagiri using headphones. The study participants needed to understand spoken numbers between 1 and 10. Patients who were very sick; had a history of ear surgery, history of diabetes, deafness, ear discharge, or any ear disease; were on ototoxic drugs; and were living/working in a noisy environment were excluded from the study. The sample size was calculated based on the prevalence of subclinical hearing loss of 15.6% in a study of the epidemiology and risk factors for leisure noise-induced hearing among Flemish young adults . The samThe data collection instrument was a questionnaire including information on patient demographics, namely, age, sex, marital status, residence, and others. The questionnaire included questions regarding subjective hearing status and medical history concerning ear block tinnitus, sound sensitivity, etc. In addition, questions on the history of usage of headphones, the duration of use, the maximum volume, whether participants slept with audio gadgets on play, and a history of other health problems were also included . We utilPatients attending routine outpatient units (OPDs) and eligible employees were randomly sampled and enrolled in the study. Investigators introduced themselves to study participants before the start of the interview. Study participants were given an information sheet and were explained the study objectives, procedure, and the rights of the participants. If the study participant agreed to participate in the study after going through the information sheet, written consent was taken from him/her. A video in English/Telugu was played to describe the study procedure. The study participants were interviewed according to the questionnaire in a separate barrier area in the OPD of the Department of Community and Family Medicine. All measures to prevent any risk of contracting coronavirus disease 2019 were strictly adhered to, including handwashing, mask usage, and social distancing, among others. Subsequently, the mobile application-based hearing test was conducted following the standard procedure. If participants had access to the mobile application, they were motivated to use their phones. For others, disposable headphones were used, and tablets were covered with polythene films. Any biomedical waste generated was disposed of as per the guidelines. The survey was continued until the final sample size was achieved. Any study participants provisionally diagnosed with hearing loss were referred to ENT for further evaluation.Operationally, study participants with hearing loss were defined as participants’ self-reported hearing loss, or as reported by the mobile-based hearing screening test with a score less than 50 . The depData analysis was conducted on the findings of 241 adults (20 to 40 years). In total, 188 (78%) males and 53 (22%) females participated in the study , phones, music systems, Mp3 players, and others was 21.2%, 40.2%, 84.2%, 9.1%, 5.4%, and 3.7%, respectively. The mean hearWHO score for headphone users with a music system was 50.45 ± 12.32 (p = 0.023) and for headphone users with TV was 44.13 ± 8.595 (p = 0.015); this finding was statistically significant  headphone users. Nearly 66.2% of participants in the age group of 21-35 years and 79.1% of males had subclinical hearing loss (Table .4% headp2 = 0.150) in the overall hearWHO score when none of the other factors was controlled for. The socioeconomic factors and patterns of usage of headphone variables  by community health professionals and discovered that adult referral rates were greatly impaired by age (p = 0.05) [Gender was not statistically correlated with hearing status in both univariate and multivariate analyses. In the univariate analysis, however, age was shown to be strongly associated with subclinical hearing loss. However, we could not predict clinical age-related hearing improvements in such a young age group based on the well-known relationship between age and hearing deterioration . Accordi = 0.05) . FurtherExcessive noise exposure has been identified as a risk factor for hearing loss in several studies ,23. The Hearing screening on a smartphone enables primary and secondary healthcare doctors to provide hearing care to underserved populations. Quality control and remote tracking for surveillance and follow-up are possible owing to active noise monitoring and data collection functionality. Studies have shown show that the computerized self-administered hearing test is a legitimate, accurate, and cost-effective method of determining unmasked air-conduction hearing thresholds -7. BecauThere are some limitations of this study. First, measuring sound exposure, that is, self-reported time, frequency, and sound levels of usage may be inaccurate, and no real loudness measures were taken to quantify the A-weighted equivalent levels. Second, both tonal audiometry and otoacoustic emissions were not used to identify participants with clinical hearing damage in this study. Furthermore, because the educational qualifications of the participants varied, their understanding may differ regarding the subjective evaluation of noise, and people may be biased to report their hearing status.Hearing is precious, and hearing damage due to excessive noise is irreversible. For affected people, quality of life deteriorates and healthcare costs can increase. Noise-induced hearing loss is preventable. In this study, a high proportion of headphone users were found to have subclinical hearing loss using the hearWHO application at the hospital level. This study generated imperative facts for people and emphasize the need to look after their hearing. This advocates for institution and program managers to develop standards to limit exposure to recreational noise. Furthermore, hearing-related services are often overlooked at the primary healthcare level. This study introduces the applicability of the new technology in an Indian setting where hearing healthcare is facing challenges. In developing countries with low access to hearing healthcare at the facility level, the hearWHO screen guides primary healthcare-level doctors to identify patients requiring a referral to an ENT specialist.


Intact tympanic membrane acts as a partition between the external ear and middle ear. Tympanic membrane perforation is one of the commonest causes of conductive hearing loss. Perforation size is the most important determination of hearing loss. The aim of this study was to find out the prevalence of tympanic membrane perforation among patients presenting to the otorhinolaryngology department of a tertiary care hospital.A descriptive cross-sectional study was carried out in the Department of Otorhinolaryngology and Head Neck Surgery of a tertiary care hospital from March 2021 to August 2021. Ethical approval was taken from Institutional Review Committee (Reference number: 57112021). Convenience sampling was done and data was collected from 414 patients presenting to the department. Collected data were entered, analyzed in Statistical Package for the Social Sciences version 21.0 and documented for study. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data.Among 414 patients, tympanic membrane perforation was seen in 100 (24.15%) . Among 100 patients with a total of 153 perforated eardrums, mild hearing loss was seen in the majority of the cases. Posterior perforation had a mean hearing loss of 40.41±5.96 dB, central had 39.09±3.13 dB, and anterior had 35.15±5.88 dB.Our study showed the prevalence of tympanic membrane perforation to be high when compared to other similar studies. Hearing loss was observed in all cases; the majority with mild hearing loss. The degree of hearing loss was more in larger and posterior perforation. It converts and amplifies air vibration. So, tympanic membrane perforation (TMP) can lead to conductive hearing loss.2Tympanic membrane perforation is one of the most common causes of hearing loss. In Nepal, chronic otitis media is the most common cause leading to TMP causing hearing loss followed by trauma and acute otitis media.Thus, the aim of this study was to find out the prevalence of tympanic membrane perforation among patients presenting to the otorhinolaryngology department of a tertiary care hospital.A descriptive cross-sectional study was carried out in the Department of Otorhinolaryngology and Head Neck Surgery, Nobel Medical College Teaching Hospital, Biratnagar, Nepal over a period of six months from 2021 March to 2021 August after taking ethical clearance from the Institutional Review Committee (Reference number: 57112021). All the patients within the age group of 11-70 years were included in this study after taking informed consent. Patients with active chronic otitis media squamous type, active chronic otitis media mucosal, acute suppurative otitis media, traumatic perforation, mixed hearing loss, otosclerosis, granulomatous disease were excluded.The sample size was calculated by using the formula,2 × p × q) / e2n = (Z2 × 0.54 × 0.46) / 0.052  = ,p = prevalence of tympanic membrane perforation as 54.85% based on study a previousq = 1 - pe = margin of error, 5%Hence, the required minimum sample size was 381. However, a sample size of 414 patients was taken for this study and a convenience sampling method was used.A detailed history was taken and the patient was examined thoroughly. Among 414 patients, diagnosis of chronic otitis media inactive mucosal type was made clinically. Pure tone audiometry, tympanometry, and endoscopy  were done for all the cases. The average air conduction threshold at 500, 1000, and 2000 Hz was calculated for the degree of hearing loss and was graded according to the WHO classification of hearing impairment.The tympanic membrane was divided into four quadrants by using two imaginary lines, one passing through the handle of the malleus and another line passing through the umbo by making an angle of 90 degrees with the first line. Perforations were classified into three groups based on the involvement of quadrants. Small perforation involved only one quadrant, medium perforation involved two quadrants, and large perforation involved three or four quadrants. Perforation occupying area anterior to handle of malleus of pars-tensa were labeled as anterior perforation and perforation posterior to that as posterior perforation. Perforation occupying area on either side of the handle of malleus on pars-tensa was leveled as central perforation.Collected data were entered, analyzed in Statistical Package for the Social Sciences version 21.0 and documented for study. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data.Among 414 patients, tympanic membrane perforation was seen in 100 (24.15%) . These 100 individuals aged 1170 years (mean age 33.60±14.21 years) with 153 perforated eardrums were then studied. Among these patients, 36 (36%) were males and 64 (64%) were females. Fifty-three (53%) patients had bilateral TMP and 47 (47%) patients had unilateral TMP. The age group 25-34 years had an average hearing loss of 45 dB, which was maximum among the other age group but also accounts for 30% of the total study population .In all cases of tympanic membrane perforation, hearing loss was documented. In right ear perforation 67 (67%), mild hearing loss was observed in most cases followed by moderate and severe hearing loss. No profound hearing loss was documented. Same findings were seen with left ear perforation . It was observed that hearing loss in posterior perforation was more than central and anterior perforation .It was observed that hearing loss is more in large perforation than in medium and small size perforation .2Tympanic membrane perforation (TMP) is one of the commonest causes of hearing loss. The main cause is a secondary infection due to upper respiratory tract infection and poor hygiene in developing countries. TMP can occur from injuries occurring due to ear picking habits, probing, syringing, etc. Tympanic membrane perforation causes conductive hearing loss in most cases but tympanic membrane perforation due to head injuries, blast injuries, etc. may cause inner ear injury leading to sensory neural hearing loss.4 and 7.8%.5 All the cases of TMP in this study presented with hearing loss which is similar to the another study.6 In this study, greater hearing loss was seen with the increase in the size of perforation which was comparable to other studies.7 In a series of studies done to assess middle ear function with tympanic membrane perforations, perforation size was the most important determination of hearing loss.10 In this study, posterior perforation had a greater degree of hearing loss compared to central and anterior perforation which held true to other study as well.11 Same result was seen in a 100 cases study done in 1993.12 But some studies stated that there is no significant variation in hearing loss according to location.13This study showed the prevalence of TMP to be 24.15% which is very high compared to the other studies which have shown 2.1%Small sample size and sampling bias could be the key limitation of this study. Further, this is based on data collected in a single hospital which limits the universality of the findings. Also, the sampling was done during the COVID pandemic which limited the data collection.The prevalence of TMP was high compared to other similar studies; however, the prevalence of hearing loss in TMP cases and degree of hearing loss according to the site and size was similar to other studies done in similar settings.