Hmox2-/-), which plays a key role in oxygen sensing in the carotid body, exhibit spontaneous apneas during sleep and elevated levels of catecholamines. Here, using RNA-sequencing we investigated the transcriptomic changes in aortic ECs and heart tissue to understand the changes that occur in Hmox2-/- mice. In addition, we evaluated cardiac structure, function, and electrical properties by using echocardiogram and electrocardiogram in these mice. We found that Hmox2-/- mice exhibited aortic EC activation. Transcriptomic analysis in aortic ECs showed differentially expressed genes enriched in blood coagulation, cell adhesion, cellular respiration and cardiac muscle development and contraction. Similarly, transcriptomic analysis in heart tissue showed a differentially expressed gene set enriched in mitochondrial translation, oxidative phosphorylation and cardiac muscle development. Analysis of transcriptomic data from aortic ECs and heart tissue showed loss of Hmox2 gene might have common cellular network footprints on aortic endothelial cells and heart tissue. Echocardiographic evaluation showed that Hmox2-/- mice develop progressive dilated cardiomyopathy and conduction abnormalities compared to Hmox2+/+ mice. In conclusion, we found that Hmox2-/- mice, which spontaneously develop apneas exhibit EC activation and transcriptomic and functional changes consistent with heart failure.Obstructive sleep apnea (OSA) is a common breathing disorder that affects a significant portion of the adult population. In addition to causing excessive daytime sleepiness and neurocognitive effects, OSA is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not completely understood. Using exposure to intermittent hypoxia (IH) to mimic OSA, we have recently reported that mice exposed to IH exhibit endothelial cell (EC) activation, which is an early process preceding the development of cardiovascular disease. Although widely used, IH models have several limitations such as the severity of hypoxia, which does not occur in most patients with OSA. Recent studies reported that mice with deletion of hemeoxygenase 2 ( Obstructive sleep apnea (OSA) is a common disorder with a prevalence of 24% in men and 9% in women (based on apnea-hypopnea index ≥5) . PopulatPathophysiologically, OSA is characterized by recurrent obstruction of upper airway leading to cessation of air flow resulting in intermittent hypoxia (IH), arousals, and activation of sympathetic nervous system , 16, 17.Using the IH exposure model in mice, we have recently studied the effect of IH on endothelial cell (EC) function . EC actiHmox2-/-) may also be used as a model of OSA [Hmox2-/- mice showed a blunted hypoxic ventilatory response [Hmox2-/- mice develop spontaneous apneas during sleep [Hmox2-/- mice can be used as a model to mimic sleep apnea. However, how the cardiovascular system may be affected in the Hmox2-/- model of sleep apnea has not been studied. Here, we studied whether Hmox2-/- mice exhibit EC activation similar to the IH model of OSA. We also investigated the transcriptomic changes in aortic ECs and heart tissue as well as the functional changes in heart function in Hmox2-/- mice.In addition to IH, recent studies suggest that mice with deletion of hemeoxygenase 2  and their wildtype littermate controls (Hmox2+/+). All animal experiments were performed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines [All experiments and procedures involving animals were approved by the Institutional Animal Care and Use Committee at the University of Chicago (Protocol number 72573). We used mice with deletion of Hmox2 —target gene interactions gene regulatory network enrichment analysis was done with R DoRothEA package using mouse regulons . DoRothETransthoracic echocardiography  was used to evaluate left ventricular (LV) systolic function and structure while mice were under light anesthesia (0.5–1% isoflurane). Two-dimensionally guided M-mode images of the LV were acquired in the parasternal long and short axes to measure LV cavity dimensions, anterior and posterior wall thicknesses, and fractional shortening. LV ejection fraction was calculated based on these measurements. Electrocardiogram (ECG)  was performed to determine heart rate, rhythm and conduction intervals in mice. Electrodes were placed subcutaneously in the limbs for lead II position for continuous ECG monitoring up to 5 minutes in each session. RR interval, PR interval, QRS duration, and QT interval were recorded and analyzed from limb leads in lead II. AF, atrioventricular block (AVB), premature beats, pauses, supraventricular, and ventricular arrhythmias were documented on ECG recordings.The data were analyzed in Prism 9 . All data are shown as mean ± standard deviation. Significance was determined by unpaired, two-tailed Student’s t-test (for comparisons between two samples) or by one-way ANOVA using Bonferroni’s correction for multiple comparisons. Statistical significance was defined as *p<0.05, **p<0.005, ***p<0.001, ****p<0.0001.Hmox2-/- mice exhibit spontaneous apneas during sleep [Hmox2-/- as a model of sleep apnea; however, the cardiovascular changes in Hmox2-/- are not completely understood.Increasing evidence suggest that Hmox2 plays an important role in oxygen sensing , 44. Furng sleep , 30. TheHmox2 deficiency is associated with EC activation, we isolated aortic ECs from both Hmox2+/+ and Hmox2-/- mice to measure expression of genes associated with EC activation. As previously reported [Hmox2+/+ mice, Hmox2-/- mice had spontaneous apneas and increased systemic levels of catecholamines  activation . To detereported , 30, comolamines . We also-/- mice . We founed to IH  Fig 1A)Hmox2 deft to ECs . Nicotinclerosis , 47. Connd nampt . CollectHmox2-/- model, we performed RNA-sequencing in ECs isolated from Hmox2-/- and Hmox2+/+ mice. The t-sne plot showed good separation between samples from Hmox2-/- and Hmox2+/+ mice based on differentially expressed genes (DEGs)  enrichment analysis showed that blood coagulation, hemostasis, positive regulation of cytokine production, activation of immune response and positive regulation of cell adhesion were activated in ECs from Hmox2-/- mice  of DEGs in ECs from Hmox2-/- mice including cellular respiration, oxidative phosphorylation, blood circulation, cardiac muscle cell development and muscle contraction, and ribonucleotide metabolic processes. Additionally, enrichment analysis of DEGs across GO, KEGG and MGI_phenotype multiple datasets by Enrichr-KG tool also significantly identified cardiomyopathy and oxidative phosphorylation KEGG pathways and abnormal glucose homeostasis MGI-Mouse phenotype along with the above stated GO terms  . Compare-/- mice . Fig 2C -/- mice . In contGO terms . These rHmox2-/- mice. Consistent with our data, a recent study in which the investigators performed single cell RNA-sequencing on mouse aorta reported the presence of a cluster of aortic ECs which express high levels of troponin and other myocyte markers [Hmox2-/- and Hmox2+/+ mice. We confirmed the loss of Hmox2 gene in heart tissue isolated from Hmox2-/- mice   . Compare-/- mice . Fig 3C -/- mice . Similar-/- mice . GSEA of-KG tool , These rHmox2-/- mice in comparison with their wild-type control littermates were very similar in terms of their GO_BP enrichments  activities were analyzed with DoRothEA TF-target interactions (regulons) tool and TF activities were inferred in parallel with pathway footprints  activities of otprints . Consist tissues . Hif1a tbination .Hmox2-/- mice showed decreased expression of genes involved in cardiac muscle development, we evaluated cardiac structure and function of these mice by using echocardiographic images. Left ventricle (LV) chamber size, wall thickness and systolic function were measured. Young (6–8 weeks old) or aged (6 months old) Hmox2-/- mice developed significant LV dilation as shown by increased LV end diastolic diameter and LV end systolic diameter compared to Hmox2+/+ heart  (Hmox2-/- mice versus hearts in Hmox2+/+ mice (86.43±2.03% in young and 61.06±2.95) . In parallel, we found that LV posterior wall thickness and interventricular septum thickness in young and aged Hmox2-/- hearts were decreased. LV ejection fraction was significantly worsened through aging process of Hmox2-/- mice. Also, LV dilation (systolic and diastolic) and wall thickness were deteriorated with aging of Hmox2-/- mice. Thus, these morphological changes in Hmox2-/- hearts were consistent with dilated cardiomyopathy and heart failure with reduced ejection fraction. We also studied cardiac electrical properties in all mice by analyzing ECG characteristics. Young Hmox2-/- mice showed similar heart rate compared to Hmox2+/+ mice; however, ECG recordings showed higher heart rate in aged Hmox2-/- mice. This increase in heart rate was likely due to reduced LV ejection fraction and cardiomyopathy. There was atrioventricular conduction delay in young and aged Hmox2-/- mice as reflected by prolonged PR interval; however, QRS duration was comparable in Hmox2-/- and Hmox2+/+. Hearts from young and aged Hmox2-/- mice showed a repolarization abnormality with shorter QT interval compared to hearts from control mice. These results are consistent with the development of dilated cardiomyopathy in Hmox2-/- mice and are also in agreement with the transcriptomic data showing DEGs enriched in cardiac muscle development.Since heart tissue from  groups) . This waOSA is a highly prevalent condition affecting up to 20% of the adult population in the US . Recent Hmox2-/- mice as a spontaneous model of sleep apnea [Hmox2-/- mice not only develop spontaneous apneas but also exhibit elevated levels of catecholamines [Exposure to IH is often used as a model to study the mechanisms of OSA. Although it is widely used, the IH model also has limitations . IH doesep apnea . They alolamines , 30.Hmox2-/- mice to better understand the impact of OSA and increased catecholamines on EC function. We found that aortic ECs from Hmox2-/- mice exhibit hallmarks of activation. RNA-sequencing demonstrated that compared to aortic ECs from Hmox2+/+ mice, ECs from Hmox2-/- mice had a significant number of DEGs enriched in blood coagulation, hemostasis, positive regulation of cytokine production, activation of immune response and cell adhesion, which were also consistent with EC activation and dysfunction and vascular inflammation. In addition, oxidative phosphorylation and cellular respiration were processes that were downregulated in ECs from Hmox2-/- mice. These results are consistent with the published data showing EC activation with other models of OSA including IH [Hmox2-/- mice exhibit increased expression of pro-inflammatory cytokines and nuclear factor κB activation, which are consistent with EC activation [In this study, we investigated the transcriptional changes that occur in aortic ECs in uding IH , 53, 54.tivation .Hmox2-/- mice. These surprising findings were consistent with a recently published data using single cell RNA-sequencing in mouse aortic ECs [Hmox2-/- and Hmox2+/+ mice. Compared to control, heart tissue from Hmox2-/- mice had DEGs enriched in mitochondrial gene expression and translation, and aerobic respiration. Similar to what we found in ECs, cardiac muscle development was one of the processes downregulated in heart tissue from Hmox2-/- mice. Furthermore, MGI-Mouse Phenotype terms of decreased skeletal muscle fiber diameter, abnormal muscle physiology and decreased cardiac muscle contractility were associated with the loss of Hmox2. The gene expression changes that we observed in heart tissue from Hmox2-/- mice are in agreement with the changes that occur in cardiomyocytes exposed to IH in vitro [Analysis of transcriptomic data also showed enrichment of DEGs in cardiac muscle development and contraction, which were downregulated in ECs from rtic ECs . Lukowskrtic ECs . It is pin vitro –59. Expoin vitro –59.Hmox2-/- mice, we then evaluated whether Hmox2-/- mice had any functional limitations. Echocardiographic evaluation showed structural and functional changes consistent with dilated cardiomyopathy, which progressed with aging. Collectively, we found that Hmox2-/- mice, which spontaneously develop apneas and increased systemic level of catecholamines have EC activation, and cardiac dysfunction.Given that genes that were involved in cardiomyocyte development and contractility were downregulated in Hmox2. Consistent with the downregulation of the hypoxia pathway, analysis of transcription factors showed reduced activity of HIF1α in samples from Hmox2-/- mice.Integrative analysis of the transcriptomes from aortic ECs and heart tissue showed that they share common network footprints. Using functional genomics tools, we found that PI3K, Estrogen, Trail, VEGF and EGFR, cellular survival pathway footprints were activated, while hypoxia, p53, WINT cellular stress response pathway footprints were downregulated with the deletion of Hmox2-/- mice to OSA. Since Hmox2 is deleted in ECs and heart tissue, the effect of loss of Hmox2 on ECs and heart tissue may not be solely due to increased apneas but may also be caused by the loss of Hmox2 gene in these cells/tissues. Further studies are warranted to determine whether the effects of IH are similar to those observed in Hmox2-/- mice. Second, we also used bulk RNA-sequencing in heart tissue instead of single cell RNA-sequencing. Since the majority of the cells in heart tissue are cardiomyocytes, the bulk RNA-sequencing likely provided information of cardiomyocytes but the signal from other cells in the heart tissue including coronary ECs, macrophages, and fibroblasts were likely lost. Third, while we showed progression of dilated cardiomyopathy in aged mice, our sequencing data were obtained from young mice. Finally, we did not study the mechanisms underlying the cardiac changes we observed in Hmox2-/- mice. HMOX2 has been implicated in the regulation of inflammation, redox sensing, oxidative stress and wound healing [Our study had several limitations. First, we did not have another model of OSA such as IH exposure in wild-type mice as a control group limiting the translation of our findings in  healing , 60–64.  healing , 60–63.  healing .Hmox2-/- mice, a spontaneous OSA model, showed expression of genes consistent with EC activation, downregulation of genes involved in cardiac muscle development and contractility, and developed progressive cardiomyopathy. While enrichment of DEGs in aerobic respiration suggested a change in mitochondrial function as a mechanism for the cardiac changes in Hmox2-/- mice, further studies will be needed to better understand the mechanisms leading to heart failure in these mice.In conclusion, our data in S1 Fig(A) apnea index using body plethysmography and (B) catecholamine levels in plasma in Hmox2+/+ and Hmox2-/- mice (n = 5 for Hmox2+/+ and n = 10 for Hmox2-/-). *p<0.05. NE: norepinephrine, Epi: epinephrine.We measured (TIF)Click here for additional data file.S2 FigHmox2 using qPCR in (A) aortic ECs and (B) heart tissue from Hmox2+/+ and Hmox2-/- mice.We measured mRNA expression of (TIF)Click here for additional data file.S3 FigHmox2-/- and Hmox2+/+ mice (n = 3/strain), across GO, KEGG and MGI-Mouse phenotype datasets by Enrichr-KG tool. Nodes are genes (green) and functional terms, edges connect genes to their enriched terms in the enrichment graph.Enrichment analysis of significantly (LogFC ≥1 and p≤0.05) DEGs from RNA-sequencing data from aortic ECs isolated from (TIF)Click here for additional data file.S4 FigHmox2-/- and Hmox2+/+ mice (n = 3/strain), across GO, KEGG and MGI-Mouse phenotype datasets by Enrichr-KG tool. Nodes are genes (green) and functional terms, edges connect genes to their enriched terms in the enrichment graph.Enrichment analysis of significantly (LogFC ≥1 and p≤0.05) DEGs from RNA-sequencing data from mouse heart tissue from (TIF)Click here for additional data file.S1 TextHmox2. We also show the results about the apnea index, plasma catecholamine levels and Hmox2 expression in aortic ECs and heart tissue from Hmox2-/- mice.We provide methods on the measurement of apnea index, plasma catecholamines and qPCR for (DOCX)Click here for additional data file.


Hearing impairment is an important disabling disease worldwide. However, there is still no effective method for damaged auditory hair cell regeneration. This Research Topic contains basic and clinical research and a review of manuscripts related to the pathogenesis and intervention of hearing diseases.Ernst et al. supposed there are two key concepts with residual hearing preservation. First, the surgeon must follow with soft surgery and administer corticosteroids to the patient after surgery either systemically or intratympanically. Second, the appropriate CI electrode array must be determined by the cochlear anatomy and pattern of hearing loss of each patient. Their group further investigated inducible NO synthase isoform (iNOS) expression in different cell types of the inner ear after CI surgery. Through the detection of physiological indicators in the cochlea, it was found that compared with patients in the sham surgery group, post-CI patients experienced decreased cochlear blood flow after surgery, and the cochlear microvascular permeability substantially increased. The iNOS expression levels decreased in many cell types in the organ of Corti after CI surgery. Therefore, the author suggests that the disturbance of the inner ear microenvironment after CI surgery may be related to changes in NO-related signaling pathways. Inhalative application of NO or pharmacological induction of iNOS may provide a therapeutic regimen for residual hearing preservation during CI surgery.To restore hearing function in those with severe hearing loss, cochlear implantation (CI) is a well-established surgical treatment. However, some patients may experience residual hearing loss after undergoing CI surgery. Ma et al. focused on the role of miR-29a during aging-related hearing loss. By evaluating the hearing level, they found that miR-29a mutant mice exhibited poor hearing levels compared with littermates at 2 months after birth, and those mice had hearing loss that gradually worsened until 5 months later. Subsequently, they discovered cochlear pathology changes in miR-29a−/− mice and showed that the stria vascularis was thinner and that spiral ganglion neurons were decreased in miR-29a−/− mice. Out hair cells (OHCs) and inner hair cells (IHCs) were significantly lost, and stereocilia fusion was observed in miR-29a KO mice. GO annotation and KEGG pathway enrichment analysis revealed that the miR-29 family is related to extracellular matrix gene expression. Col4a family gene and laminin family gene expression was increased after miR-29a deficiency and could induce basal membrane thickening. These results elucidate new mechanisms for the onset of age-related hearing loss and provide new ideas for presbycusis treatment.Li et al. reviews cisplatin ototoxic mechanisms and prevention strategies. In addition to the apoptotic pathway, the author also introduced the mechanisms of autophagy and mitophagy in cisplatin ototoxicity. More evidence has shown that apoptosis and the mitophagy pathway have the same regulator, and foreign drugs can induce the activation of the mitophagy pathway to antagonize cisplatin ototoxicity. The author also provides the most recent approaches to cisplatin ototoxicity prevention and treatment in this review, including some new drugs currently undergoing clinical trials. In terms of drug research and development, the main focus is on mechanisms such as antioxidant activity, inhibition of transporter proteins, and regulation of apoptosis and autophagy signaling pathways. The recent development of materials science has also provided new methods for the prevention and treatment of cisplatin ototoxicity. The agents can easily pass through the inner ear blood-labyrinthic barrier and provide new technologies for drug delivery.As a canonical antitumor drug, cisplatin has been widely used in the clinic for malignant tumor treatment. However, cisplatin has greatly limited use due to ototoxicity and neurotoxicity. Lai et al. has performed much work on NIHL and explored the important role of calcium channels in NIHL. Recent research results from Lai indicate that MDL-28170 could inhibit calpain activation, which is a family of calcium-dependent cysteine proteases. Intraperitoneal injection of MDL-28170 before noise exposure attenuated noise-induced hearing loss and cochlear pathologies. As a substrate for calpain-1, its activation during noise exposure could be inhibited by MDL-28170. Additionally, MDL-28170 therapy increased p85 and p-Akt (s473) in OHCs and reversed the decrease in PI3K/Akt signaling following noise exposure. These results show that treatment with MDL-28170 is a promising strategy for NIHL prevention.Noise-induced hearing loss (NIHL) is a major public issue causing hearing impairment. GJB2 gene plays an important role in cochlear development and maintaining HC normal function. Wang et al. reviewed GJB2-related inner ear disorders and hearing loss. They suggested that Gjb2 mutation caused K+ circulation impairment may not be the main pathological mechanism of deafness. They also introduced the Gjb2 gene mutation that caused cochlear structure development disorder and mainly focused on the tunnel of Corti and Nuel's space formation. Furthermore, the manuscript introduced the idea that Gjb2 mutation will cause cochlear sensory epithelium energy supply deficiency. Therefore, cochlear nutritional deficiency causes an increase in oxidative metabolites and affects antioxidant defense pathway activation. Wang et al. further proposed that Gjb2 mutation-induced Cx26 dysfunction can affect inner ear ATP release and Ca2+ signaling transmission, which can reduce active cochlear mechanics and hearing sensitivity.As the most common gene mutation that could cause congenital non-syndromic deafness, the Xiao and Li reviewed epigenetic regulation in HC survival and regeneration. They introduced epigenetic regulation in the cell cycle and inner ear HC development. Epigenetic regulation will affect HC formation signaling and spiral ganglion neuron development pathways. Furthermore, epigenetic modification plays a critical role in D-gal-induced mimicking of presbycusis, ototoxic drug-induced hearing loss and noise-induced hearing loss. Researchers have also used compounds to regulate epigenetic modification to alleviate acquired hearing loss. Epigenetic regulation is also crucial for inner ear HC regeneration, which offers an opportunity for hearing loss therapy. By regulating DNA epigenetics, inner ear progenitor cells will change their proliferation and transdifferentiated abilities and further induce progenitor cell lines into hair cell-like cells.Epigenetic regulation plays an important role in gene transcription and regulation. + SCs are regarded as endogenous progenitor cells for HC regeneration. Smith-Cortinez et al. tracking of LGR5 expression in mature adult mice between P30 and P200 showed that Lgr5 mRNA expression was not significantly different between Lgr5GFP mice and WT mice. Furthermore, they used furosemide plus kanamycin injection to induce hair cell damage and found that Lgr5 expression persisted 28 days after ototoxic damage in SCs. Through mRNA level validation, they found that the expression of Lgr5 increased after 7 days of acute ototoxic injury and returned to normal levels after 28 days. These results provide a therapeutic window for inner hair cell regenerative therapies in the future.As a marker of tissue-resident stem cells, LGR5 is expressed in mammalian cochlear supporting cells (SCs), and LGR5For this Research Topics include cochlear implantation, the pathogenesis of presbycusis, the prevention of noise-induced hearing loss and inner ear hair cell regeneration-related research. These research findings provide new ideas for the prevention and treatment of acquired hearing loss. Furthermore, they also provide evidence for the time window of sensory hair cell regeneration after injury.ZH: Supervision, Validation, Writing—original draft, Writing—review and editing. SZ: Writing—original draft. QZ: Writing—review and editing. YS: Writing—review and editing. XF: Writing—review and editing. WZ: Writing—review and editing.


No study has examined the combined association of dietary inflammatory index (DII) of the diet and resting metabolic rate (RMR) on cardiorespiratory fitness (CRF). Therefore, we investigated the combined association between DII and RMR on CRF.This cross-sectional study was conducted on 270 adult subjects. The DII was calculated using a validated semi-quantified food frequency questionnaire. RMR was measured using an indirect calorimetric method. Socioeconomic status, anthropometric measures, body composition and blood pressure were documented by a trained interviewer. CRF was assessed by using Bruce protocol. Binary logistic regression was performed to find the association of CRF with DII/RMR categories in various models.2Max (mL/kg/min), VO2max (L/min) and VO2max relative to lean body mass (LBM) was lower in participants that were classified as high DII/low RMR compared to those in low DII/high RMR. After controlling for age, sex, education status, smoking status, and physical activity those who were in the high DII/low RMR group, compared to the low DII/high RMR group were 28% less likely to have higher VO2max (ml/kg/min) . Moreover, had 25% lower odds of VO2max (L/min) which was significant . In addition, were 21% less likely to have higher VO2max (LBM) .The participants categorized into four groups including: (1) low DII/high RMR, (2) low DII/low RMR, (3) high DII/low RMR, (4) high DII/high RMR. The mean of VOOverall, consumption of a pro-inflammatory diet in combination with low RMR status is associated with lower odds of CRF compared to those who had anti-inflammatory diet in combination with high RMR status among Iranian healthy adults. This study suggests that researchers should focus on combined relationships rather than single pair-wise associations for having a better judgment. VOProtocol , which iβ-carotene, vitamin A, vitamin C, vitamin D, vitamin E, vitaminB6, vitaminB12, fiber, folic acid, niacin, riboflavin, thiamin, iron, zinc, selenium, magnesium, onion, caffeine) were computed on a daily basis [Z score values were converted to percentiles and centered by doubling them and subtracting one. DII scores for food parameters are derived by multiplying the centered percentile value of each food parameter by the overall food parameter score [Dietary inflammatory index scores were calculated by multiplying 29-item nutrients or foods based on the inflammatory weights they carry according to Shivappa et al. method . Firstlyly basis . To normer score . Lastly,2max(ml/kg/min) = 30.0, VO2max(L/min) = 2.04, and VO2max(LBM) = 47.94. ANCOVA test was performed to compare the mean of CRF among DII/RMR groups after adjusting for potential confounders such as age, sex, smoking status, energy intake, physical activity and BMI. Binary logistic regression was performed to find the association of CRF with DII/RMR categories in various models. First, we adjusted age and sex. Then, we additionally controlled for smoking and physical activity status. To obtain the overall trend of odds ratios across the combined effect of DII and RMR, we considered these classifications as an ordinal variable in the logistic regression models and the first tertiles regarded as the reference group. All statistical analysis was performed with the SPSS  for Windows 25.0 software package . The level of statistical significance was pre-set at p < 0.05.Statistical tests such as Kolmogorov–Smirnov and Shapiro–Wilk were used to determine the normality of distributions. There was a normal distribution for all variables. After that, subjects were categorized according to their DII and RMR median values. We computed four independent groups by combining DII and RMR dichotomized groups . To compare general characteristics across the four groups, we used one-way analysis of variance (ANOVA) and chi-square tests for quantitative and qualitative variables, respectively. To compare participants’ dietary intakes within four groups, analysis of covariance (ANCOVA) to adjust for energy intake. We used ANOVA to examine significant differences across the four above-mentioned groups. Post hoc Tukey test was used to compare pair-wise mean differences. CRF values were then transformed into binary variables according to the upper and lower median values. The median values were VOThe general characteristics of participants are shown in Table Table 2Max (mL/kg/min) was lower in participants that were classified as high DII/low RMR compared to those in low DII/high RMR , this significant association was remained significant after controlling for confounders . Post hoc Tukey test revealed no significant differences between other categories in comparison with low DII/high RMR group. Participants with a high DII score and low RMR had lower VO2Max (L/min) and VO2Max (LBM) compared with those with low DII score and high RMR. However, the mean of VO2max (L/min) and VO2max (LBM) after adjustment for confounders, had no significant differences in any classification (Table The mean of VOon Table .Table 3M2max (ml/kg/min) ; this association remained significant after adjusting for confounding variables . Moreover, we found that participants in high DII/low RMR group, had lower odds of VO2max (L/min) which was significant . When potential confounders were taken into account, such association remained significant . In the crude model, those who were in the high DII/low RMR group, compared to the low DII/high RMR group, were less likely to have higher VO2max (LBM) ; this association remained significant after adjusting for confounding variables . There was also no significant combined association of dietary inflammatory index and resting metabolic rate on cardiorespiratory fitness even after controlling for covariates.Multivariate adjusted odds ratios and 95% confidence intervals for CRF by the combined effect of DII and RMR are given in Table 2Max (mL/kg/min), VO2max (L/min) and VO2max (LBM) was lower in participants that were classified as high DII/low RMR compared to those in low DII/high RMR. After controlling for covariates, those who were in the high DII/low RMR group, compared to the low DII/high RMR group were 28% less likely to have higher VO2max (ml/kg/min). Moreover, we found that participants in high DII/low RMR group had 25% lower odds of VO2max (L/min) which was significant. In the final model, those who were in the high DII/low RMR group, compared to the low DII/high RMR group were 21% less likely to have higher VO2max (LBM).According to our cross-sectional study, the mean of VO2max and a significant increase in RMR in both sexes. Eventually, the results showed that following a moderate-intensity aerobic exercise program along with reduced caloric intake from foods lead to an increased RMR and weight loss and body fat in obese people [2 showed that VO2max is positively associated with RMR [2max and lower RMR, had better body composition profiles including lower visceral fat, trunk fat, and body fat mass [2Max, and (c) 7% decrease in RMR, without any change in blood lipids. It should be noted that increasing in body weight and specially body fat may cause the drop in CRF and RMR.In line with our results, a study by Potteiqer et al.  showed te people . A crosswith RMR . Moreovefat mass . Moreovefat mass . On the fat mass . Previoufat mass . Anotherfat mass . In addifat mass  showed t2Max (ml/kg/min). In contrast, previous results from a case–control study by Scott et al. showed the DII score was associated with systemic inflammation increase and less lung function. They also reported that an increase by one unit of DII score can elevate the risk of asthma by 70% [The highest quantity of oxygen that an individual may utilize when participating in intense or strenuous activity is known as VO2 max or maximal oxygen consumption. This measurement is generally considered the best indicator of cardiovascular fitness and aerobic endurance . Payandea by 70% .Contrarily, in Asia, Ren et al. found only a slight association between the DII and the prevalence of the metabolic syndrome components (with the exception of blood pressure) among adults in eight Chinese cities . SimilarTwo possible mechanisms mentioned in studies regarding the effect of physical activity on RMR are as follows: physical activity can affect RMR by accelerating muscle growth and affecting physiological processes. Cardiorespiratory fitness also appears to be a key predictor of RMR, although it operates independently of skeletal muscle mass . This diSeveral limitations are better to be considered in the explanation of our findings. The main limitation of our study is its cross-sectional design which does not accurately state the cause-and-effect relationship. Another limitation is the low sample size of our study. Also, we calculated DII based on 29 dietary items and data regarding 16 dietary items were not available in this study. However, some strengths of our study should be noted that the present study is the first study from Iran to examine the combined association of dietary inflammatory index and RMR on cardiorespiratory fitness. As well, we have used the standardized 168 items FFQ that has been collected for the Iranian eating habits assessment. Moreover, we adjusted several important confounders which could affect our main results. Therefore, the results of the present study can be a positive step in the direction of anti-inflammatory diet recommendations by physicians.In conclusion, consumption of a pro-inflammatory diet in combination with low RMR status is associated with 28% lesser odds of having better CRF compared with those with anti-inflammatory diet with high RMR among Iranian healthy men and women. In other words, we have observed the importance of physical activity and how the inflammatory index can influence it. However, more studies on this area are needed to confirm the veracity of our results. This study suggests that researchers should focus on dietary indexes rather than single antioxidant nutrients for having a better judgment.


Neonates undergo neonatal hearing screening to detect congenital hearing loss at an early stage. Once confirmed, it is necessary to perform an etiological workup to start appropriate treatment. The study objective was to assess the different etiologies, risk factors, and hearing results of infants with permanent hearing loss and to evaluate the efficacy and consequences of the different screening devices over the last 21 years.We conducted a single-center retrospective cohort analysis for all neonatal hearing screening program referrals and performed an etiological workup in case of confirmed hearing loss. We analyzed the evolution of the etiological protocols based on these results.The governmental neonatal hearing screening program referred 545 infants to our center. Hearing loss was confirmed in 362 (66.4%) infants and an audiological workup was performed in 458 (84%) cases. 133 (24.4%) infants were diagnosed with permanent hearing loss. Ninety infants  had sensorineural hearing loss, and the degree was predominantly moderate or profound. The most common etiology in bilateral sensorineural hearing loss was a genetic etiology (32.1%), and in unilateral sensorineural hearing loss, an anatomical abnormality (26.5%). Familial history of hearing loss was the most frequently encountered risk factor.There is a significant number of false positives after the neonatal hearing screening. Permanent hearing loss is found only in a limited number of infants. During the 21 years of this study, we noticed an increase in etiological diagnoses, especially genetic causes, due to more advanced techniques. Genetic causes and anatomical abnormalities are the most common etiology of bilateral and unilateral sensorineural hearing loss, respectively, but a portion remains unknown after extensive examinations. Therefore, most developed countries have National Neonatal Hearing Screening (NNHS) programs . Flander“Kind&Gezin”, recently renamed “Opgroeien” is an agency of the Flemish government that contributes to the well-being of children. The governmental agency deals with the development of children concerning health, prevention, morbidity, etc. . They imSince the introduction of national hearing screening programs, there has also been an evolution in the etiological workup protocols. For example, PCR analyses have been further developed to identify congenital Cytomegalovirus (cCMV) in dried blood spots, comprehensive genetic testing using massively parallel sequencing techniques showed its effectiveness for hearing loss in 2010 and national gene panels were introduced in 2015 –13. The The importance of screening is generally accepted and implemented in countries and health care systems that can afford it. On the downside, overscreening or too stringently screening can become a waste of resources and besides the financial loss, it can provoke unnecessary anxiety in parents of allegedly deaf infants . TherefoPrior to the start of the study, ethical approval was obtained by the ethical committee of University Hospital Brussels with number B.U.N. 143201836386. Here, we study the infants referred to our center after neonatal hearing screening over the last 21 years. We characterized the demographics, etiology, hearing results, risk factors and follow-up rates of the infants from a single tertiary center located in Brussels, perhaps one of the most multicultural cities of Europe. We will assess strengths and shortcomings of the current neonatal hearing screening program and propose recommendations.2.in utero infections (TORCHES), hyperbilirubinemia, bacterial meningitis, ototoxic medication and syndromic abnormality , OtoAcoustic Emissions (OAE's) and tympanometry are performed, to determine the type and severity of the congenital hearing loss. The severity of the hearing loss is subdivided into “mild” 31–45 dB nHL), “moderate” (46–70 dB nHL), “severe” (71–90 dB nHL) and “profound” (>91 dB nHL) hearing loss . The cli5 dB nHL,We initiated the workup, with the necessary additional examinations once we had substantiated the hearing loss. Genetic testing and the possibility of a congenital CMV infection were assessed when dealing with a case of sensorineural hearing loss. Diagnosis of a cCMV infection was made when CMV was detected in urine and/or saliva until three weeks after birth. In most cases, infants presented after this time frame, and the diagnosis of a cCMV infection was made after PCR analysis on dried blood spots (DBS). This is a neonatal screening test that detects rare, non-curative diseases via a few blood drops taken soon after birth, usually via the heel. Until 2015, the etiological workup for sensorineural hearing loss consisted of a “standard test” battery in our center consisting of a cervical vertebral column x-ray, ultrasonography of the kidneys, ECG, and an ophthalmological consultation. The introduction of gene panels has largely replaced or expanded this system in the last couple of years. In the case of bilateral sensorineural hearing loss, we perform genetic testing. In the beginning, only a few genes were screened such as GJB2 and GJB6. This resulted in a low diagnostic window because of the great genetic heterogeneity of hearing loss. Guided by the clinical presentation of sensorineural hearing loss either a gene panel for targeted, syndromic or non-syndromic hearing loss is performed by the laboratories of Center of Medical Genetics (CMG) Antwerp .Most of the infants involved with sensorineural hearing loss underwent radiological imaging, usually an MRI, to evaluate the anatomy of the inner ear and/or retrocochlear structures. In conductive hearing loss cases, such as an ear canal atresia, a CT scan was performed. Sometimes, an additional targeted blood sample or urine analysis was carried out. An Auditory Neuropathy Spectrum Disorder (ANSD) is diagnosed in the absence of ABR thresholds, present otoacoustic emissions and/or cochlear microphonic (CM). Currently, we follow the protocol presented by Liming et al., sometimes supplemented by additional studies based on the clinical presentation , 18. If 3.The Flemish NHS program referred 545 infants (327 boys and 218 girls) for diagnostic analysis for congenital hearing loss. The Algo Portable device referred 90 infants, the Algo 3I device 178 infants and the Maico 11MB device referred 277 infants. A full audiological and an etiological workup was performed on 458 (84%) infants. After etiological workup 325 infants had bilateral normal hearing. This also includes infants with transient hearing loss, for example otitis media with effusion, that disappeared either spontaneously or after placement of tympanic tubes. We diagnosed 133 (24.4%) infants with permanent hearing loss of which 105 received a complete etiological workup See . In 28 i3.1.A bilateral sensorineural hearing loss was found in 56 infants see . In 18  and nine (26.5%) infants respectively. It includes six with a vestibulocochlear nerve aplasia, one Mondini malformation, one inner ear defect and one enlarged vestibular aqueduct. In addition, a congenital cCMV infection was found in four (11.8%) infants and a genetic cause (trisomy 21) in one infant (3%). No infants with a metabolic pathology were found. Among the unilateral sensorineural hearing losses, “moderate” and “profound” hearing loss were the most common, with ten and fifteen infants respectively see .3.3.A bilateral conductive hearing loss was seen in five infants in the form of aural atresia (2), ossicle fixation (1) or part of a syndrome (achondroplasia and Hajdu-Cheney syndrome) diagnosed by CT. There were no infants found with a unilateral conductive hearing loss.3.4.An Auditory Neuropathy Spectrum Disorder was diagnosed in ten infants . There was presence of otoacoustic emissions and/or a cochlear microphonic but abnormal or absent auditory brainstem responses.3.5.At least one of the 11 risk factors was found in 241 (44.2%) of the 545 infants. Of the boys, 45.6% had risk factors in comparison to 42.2% of the girls. A familial history of hearing loss was present in 82 infants or had a 28.5% share in the distribution of risk factors see . Of the 3.6.Finally, we correlated the result of the neonatal hearing screening with the audiological result in our reference center see . On the 4.The implementation of neonatal hearing screening programs has ensured that infants with congenital hearing loss are detected early, and that rehabilitation can be initiated timely. This is important for language and speech development, social and emotional development, and academic performance later in life , 5. The The diagnostic yield after a complete etiological workup for bilateral congenital sensorineural hearing loss in our population over the last 21 years is 48.2%. A genetic cause is found in 32.1% in bilateral sensorineural hearing loss, which is comparable to the study of Van Beeck et al. . They foIn our population, the genetic causes are due to a non-syndromal cause in 83.3% and to a syndromal cause in only 16.7%. There are fewer syndromic causes found compared to other centers and the available literature . PossiblIf imaging is requested at our center, it is almost always an MRI unless a conductive hearing loss is suspected. However, some studies show that in unilateral sensorineural hearing loss, temporal bone abnormalities are found in 29–40% on CT. Only in 10–25% a MRI could show an abnormality . We therIn this study, 87 (16%) infants were lost to follow-up, which is similar to other studies but remains an area of concern . The traIn this study could be seen that not only infants with a risk factor have permanent hearing loss but also infants without any risk factors. Therefore, it is still necessary to screen all infants and not only infants with risk factors. In addition, the prevalence of congenital hearing loss is 1.33 per 1,000 in newborns but rises in adolescents to 3.5 per 1,000 , 23, 24.The strengths of this study are the large study population which allowed us to do a thorough etiological and audiological evaluation. Additionally, this study provided a critical review of different screening devices and their impact on the false-positive rate. However, there are some limitations. Firstly, not all available etiological tests were systematically and retrospectively performed in the entire study population. In the early years, additional examinations were progressively requested based on clinical suspicion. In addition, gene panels have only become available in recent years and many genetic diagnoses were probably missed in the early years due to the limited diagnostic methods available at the time. Also, not both imaging modalities (CT and MRI) were requested for all sensorineural hearing losses, which probably meant that some anatomical abnormalities were not found. Another limitation is that the NICU population is not included in this study, since the neonatal hearing screening program is not performed in this population. This could influence the etiological diagnoses and risk factors. Lastly, there is still a significant proportion of infants who are lost to follow-up or did just a partial workup. Unfortunately, we couldn't retrospectively identify the ethnicity of all the infants.5.This study described a significant increase in the number of refers since the change of screening devices with an increase in the number of false-positive referrals. Genetic causes are the most common etiology of bilateral sensorineural hearing loss and anatomical abnormalities of unilateral sensorineural hearing loss, but a large portion remains unknown after extensive examinations. Our data demonstrated an increase in etiological diagnoses over the years, because of the availability of more extensive genetic testing. In the future, attention should be paid to try to further reduce the number of false positives, unknown causes and lost to follow-up. This can be achieved by regularly evaluating the screening protocol, properly involving parents in the workup, and further investigating a possible expansion of the neonatal hearing screening program.


The spectrum of immune-mediated neuropathies is broad and the different subtypes are still being researched. With the numerous subtypes of immune-mediated neuropathies, establishing the appropriate diagnosis in normal clinical practice is challenging. The treatment of these disorders is also troublesome. The authors have undertaken a literature review of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Guillain–Barre syndrome (GBS) and multifocal motor neuropathy (MMN). The molecular, electrophysiological and ultrasound features of these autoimmune polyneuropathies are analyzed, highlighting the differences in diagnosis and ultimately treatment. The immune dysfunction can lead to damage to the peripheral nervous system. In practice, it is suspected that these disorders are caused by autoimmunity to proteins located in the node of Ranvier or myelin components of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. The electrophysiological presence of conduction blocks is another important factor characterizing separate subgroups of treatment-naive motor neuropathies, including multifocal CIDP , which differs from multifocal motor neuropathy with conduction block (MMN) in both responses to treatment modalities and electrophysiological features. Ultrasound is a reliable method for diagnosing immune-mediated neuropathies, particularly when alternative diagnostic examinations yield inconclusive results. In overall terms, the management of these disorders includes immunotherapy such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the development of more disease-specific immunotherapies should expand the therapeutic possibilities for these debilitating diseases. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common autoimmune neuropathy that can be monophasic, progressive, or relapsing. The etiology is unclear, with damage predominantly to the myelin sheath leading to demyelination and, with a prolonged process, axonal loss. A cellular and humoral response is involved in the autoimmune response ,2. The dThere is a typical form of CIDP characterized by gradually increasing symmetrical muscle paresis of the proximal and distal limbs over a period of at least eight weeks with hypo or areflexia with sensory disturbances, weakness, less commonly cranial nerve involvement, optic disc edema and autonomic dysfunction.distal CIDP , 7–15% presents with sensory loss in the distal limbs as well as gait instability,multifocal CIDP , 4–14% involvement of asymmetric sensory and motor fibers, more often in the upper limbs,focal CIDP 4–14% involvement of one limb or nerve plexus ,sensory CIDP 3.5–14%—only sensory fibers are involved, characterized by gait ataxia, impairment of vibration and position sense and changes in cutaneous sensation,motor CIDP 4–9%—only motor fibers both proximally and distally ,6,7,8,9.A greater challenge is the diagnosis of the CIDP variants:The EFNS/PNS criteria  are the most commonly used in routine clinical practice and research and include clinical, electroneurography and adjunctive guidelines, which increase diagnostic sensitivity . DonedduIn a clinical study carried out at the Department of Neurology Erasmus MC University Medical Center in Rotterdam, which enrolled approximately 122 patients from different centers in the country with a diagnosis of CIDP, it was shown that one-third of the patients were diagnosed with a different form of polyneuropathy and one-fifth of the patients had a completely different diagnosis ,14. StudThe diagnosis of the classic form of CIDP is generally unproblematic, the diagnostic challenge is the variants of CIDP. The distal form of CIDP requires differentiation from axonal neuropathies  genetic or anti-MAG IGM neuropathy, POEMS syndrome . Anti-MAG antibody neuropathy is the most common IG M paraproteinemic neuropathy characterized by predominant sensory symptoms, ataxic gait, tremor upper limb with motor involvement and disability occurring late in the course of the disease. The disease is usually slowly progressive but may severely affect functional activities. The IgM paraprotein is typical for monoclonal gammapathy but also for MGUS, a lymphoproliferative disorder such as Waldenstrom’s Macroglobulinemia lymphoma or chronic lymphocytic leukemia CLL. The choice of treatment generally depends on the severity of the neuropathy. No adequate immunotherapy has so far been shown to be effective in anti-MAG neuropathy. Rituximab a chimeric monoclonal antibody against CD 20 +B lymphocytes has been assessed in two randomized controlled trials and nowadays is the most used in anti-MAG antibody neuropathy treatment. Despite being effective in less than half of patients with anti-MAG antibody polyneuropathy it seems to be the treatment of choice thanks to its safety and good tolerable profile. Additional potential therapies might include rituximab with associated chemotherapeutic agents such as chlorambucil or bendamustine. The BTK inhibitor ibrutinib in patients with anti-MAG neuropathy needs further confirmation in larger populations especially because of its good profile  ,16,17. PImmune-mediated neuropathies are a broad category of diseases that differ in their time course, affected nerve fibers and disease associations. The authors undertook a literature review of the differential diagnosis of CIDP, with particular emphasis on multifocal motor neuropathy (MMN) and Guillain–Barre syndrome (GBS). The molecular, electrophysiological and ultrasonographic features of selected autoimmune polyneuropathies were analyzed, highlighting differences in diagnosis and ultimately treatment.The authors searched the literature concentrated on CIDP, GBS and MMN with special reference to differential diagnosis. PubMed via MEDLINE and Google Scholar searches from early 1990 to 28 February 2023 were used. Reviews and published studies with subsequent verification of their reference lists for relevance to the subject were included. Conference abstracts and papers written in languages other than English were excluded. Keywords used: chronic inflammatory demyelinating polyneuropathy, CIDP, variants, Guillain–Barre syndrome, GBS, acute polyneuropathy variants, multifocal motor neuropathy, MMN, immunology, inflammatory process, nodal and paranodal antibodies, serum, cerebrospinal fluid, electrophysiological study, ultrasound study, and the treatment of immunological polyneuropathies. In addition to using individual keywords, the authors used PubMed Advanced Search Builder to find the most significant records. Three analysts  worked separately to find the most relevant papers by sifting through the search engines.The researchers worked individually and compiled a list of appropriate full-text manuscripts, followed by a discussion and comparison of the two lists. The 113 publications were the most relevant to the study and included in this review.In the previously published studies, antigens against myelin proteins P0, P2, PMP-22, tubulin and gangliosides GM1, LM1, and sulfated glucuronosyl paragloboside (SGPG) were identified as targets of immune attack in CIDP . KlehmetCurrently, a new pathogenetic diagnostic category of autoimmune paranodopathies has been identified. It was the identification of antibodies directed against target structures of the paranodal region that allowed these neuropathies to be distinguished from other inflammatory neuropathies, including CIDP. The cell adhesion molecules contactin 1 (CNTN1) and contactin-related protein 1 (Caspr1) on the axonal side and neurofascin 155 (NF155) on the terminal myelin loops represent proteins important for the complex axoglial interactions configuring the nerve into three domains: nodes, paranodes and interstitials. The generation of antibodies against these axoglial regions conditions the disruption of the anatomy of the node of Ranvier modifying the neurophysiology of nerve conduction by affecting the saltatory conduction of myelin fibers without inflammation ,29.Prior infections are reported in up to 70% of patients with Guillain-Barre Syndrome (GBS) ,31. TherIn comparison to gangliosides, sulfatides such as 3-O-sulfogalactosylceramide represent a class of glycolipids with a sulfate group instead of neuraminic acid. In the peripheral nervous system, sulfatide is mainly located in the incomplete myelin of Schwann cells, but can also be found in the node and paranode. Whenever sulfatide is lacking or attacked by autoimmune reactions, the lateral loops and part of the nodes of Ranvier will be disorganized and, as a result, the myelin sheath may not function properly. Autoantibodies to sulfatide have been identified mainly in peripheral immune-mediated polyneuropathies (IMPN) with axonal damage ,42. GianAnti-GM1 antibodies in the IgM class can also be found in amyotrophic lateral sclerosis, GBS variants including acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). Therefore, the presence of anti-GM1 antibodies is not specific or required for the diagnosis of MMN ,45,46,47Serum IgM anti-ganglioside (anti-GM1) antibodies are prevalent in at least 40% of patients with multifocal motor neuropathy (MMN)  and, accAccording to many authors, protein levels in the (CSF) are not an accurate marker. Although protein levels in the CSF are in the supporting criteria for CIDP, in studies carried out in selected groups of patients diagnosed with CIDP, protein levels were normal in the CSF and elevated protein levels were observed in patients with diagnoses other than CIDP. 3, but when it increases to approximately 50 cells per mm3, an infectious background such as HIV, Lyme disease, sarcoidosis or lymphoma should be excluded [Most laboratories accept 0.45 g/L of protein in the PMR as normal, the implementation of values of 0.50 g/L for patients under 50 years of age and 0.60 g/L for those over 50 years of age has been proposed on the basis of clinical studies for patients with CIDP as an auxiliary criterion. Elevated protein levels in the CSF may result from a number of conditions, e.g., spinal stenosis, and diabetes mellitus. Cytosis in the CSF should not normally exceed 10 cells per mmexcluded .Acute and chronic inflammatory neuropathies are associated with an increase in neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and plasma, but NfL is only approved as a prognostic biomarker in Guillain–Barré syndrome. T-tau in plasma is a new biomarker that could be a potential tool in the diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies ,60. The protein concentration in the cerebrospinal fluid (CSF), however, does not distinguish the type of immune-mediated neuropathies. In MMN the cerebrospinal protein level is not so often elevated (9–18% cases) as in MADSAM or other atypical CIDP forms, although one of the supportive diagnostic criteria of MMN is the elevation of protein in the CSF (<1 g/L) ,62,63.To minimize errors in electroneurophysiological examination, 5–8 motor nerves should be examined–ideally eight, as in the case of delicate sensory fibers, plexus or root involvement, lesions may not be registered on routine electroneurography. In order to increase the accuracy of the electroneurography examination, it is worth examining the contralateral side. CISP (Chronic immune sensory polyradiculoneuropathy) is an involvement of the dorsal sensory roots with preserved normal neurographic parameters of sensory and motor responses, but there are no data on whether the lesions are demyelinating or whether it is the sensory form of CIDP, which is why it is not classified as a variant of CIDP . CISP isThe finding of demyelination on electroneurography fulfilling the electroneurophysiological criteria, but in the absence of clinical signs for CIDP, it is advisable to look for other causes of demyelinating polyneuropathy. The interpretation of nerve conducting study results is particularly difficult when the response amplitude is reduced below 1 mV in which case the presence of conduction blocks cannot be excluded. Incorrect technical as well as potential marker positioning can cause deviations in electroneurograph examinations ,6,12.The electroneurographic result requires clinical correlation. Even unequivocal demyelination is not diagnostic for CIDP when clinical signs are absent, in which case a search for other causes of demyelinating polyneuropathy is indicated.Electromyography and nerve conduction studies can be useful in distinguishing GBS from its mimics. Three to seven days after the onset of the first symptoms of GBS, early non-specific changes can be found on electrophysiological examination, i.e., absent or prolonged H-reflexes and/or F-wave latency, sural sparing pattern. In acute motor axonal neuropathy (AMAN), the examination usually shows a pattern of low, complex amplitudes of muscle action potentials or even inexcitable motor nerves, and a partial motor conduction block or complete conduction block can be observed in the nerve conduction study (NCS) of AMAN. This phenomenon is interpreted as “reversible conduction failure”. Complement is deposited in the nodes of Ranvier and paranodal regions on peripheral nerves. Subsequently, the nerves may develop Wallerian degeneration causing significant and long-lasting axonal damage, or may reverse, recognizing conduction failure. This phenomenon explains the relatively rapid recovery of some severely impaired AMAN patients. Acute motor and sensory axonal neuropathy (AMSAN) would show low-amplitude motor and sensory potentials. Miller–Fisher syndrome is more commonly reported with reduced or absent sensory nerve action potentials ,65,66. Pivotal neurophysiological criteria in the diagnosis of multifocal motor neuropathy (MMN) are the diagnosis of conduction block (CB) of motor fibers exclusively, with normal sensory conduction through the same segment in mixed nerves. The two most commonly involved nerves are the median nerve and ulnar nerve, in their forearm segments, not in the typical areas of compression. Additionally, the block is focal and occurs suddenly, and, at least in the earliest stages of the disease, motor conduction distal to the site of the block may remain normal ,49. The The figures summarize the characteristic nerve conduction study findings for CIDP A, GBS FB and MMNUltrasound is increasingly being used in the diagnostic evaluation of CIDP and other polyneuropathies of different etiology. Ultrasound can detect nerve enlargement and changes in the nerve structure, which are common in CIDP. In particular, the cross-sectional area (CSA) and cross-sectional area variability of the nerves can be measured to assess for nerve enlargement. Additionally, a change in echogenicity, fascicle size, nerve vascularity, and epineurium thickness can provide clues to diagnosis and neuropathy activity ,70.CSA reference values for peripheral nerves and brachial plexus have been reported in various studies in the literature ,72. It mThe cross-sectional area variability is a more complex parameter, and the differentiation of normal from pathological heterogeneity of CSA remains an important limitation of this modality of ultrasonographic examination. Several measures have been introduced in the literature to quantify the pathological heterogeneity of CSA. The first measure is the intranerve CSA variability, which is defined as the ratio of the maximal CSA to the minimal CSA for each nerve. The second measure is the internerve CSA variability, which is defined as the ratio of the nerve with the maximal intranerve CSA variability to the nerve with the minimal intranerve CSA variability for each patient. Additionally, a third measure, called the side-to-side difference ratio of the intranerve CSA variability, has been introduced, which is defined as the ratio of the side with the maximal intranerve CSA variability to the side with the minimal intranerve CSA variability for each nerve ,76,77. TNerve enlargement was found in 69–100% of CIDP patients ,81 leadiStudies showed that the CSA of the brachial plexus and the median nerve were the most adequate measurements to distinguish between CIDP and axonal neuropathy, with the diagnosis of CIDP most likely if there was an enlargement in at least two sites in proximal median nerve segments and/or the brachial plexus ,82,83. Eftimov et al.  found thThe relationship between ultrasonography findings and functional disability remains uncertain, according to several studies ,76. SomeStudies have shown that ultrasound can accurately diagnose CIDP, especially in patients when other diagnostic tests are inconclusive. It is still speculative, whether echo signal and enlargement patterns result from distinct pathologies associated with certain autoantibody specificities, and until now studies answering those questions are lacking . MMN studies have shown a greater side-to-side intranerve variability than in CIDP . In AIDPUltrasound is a valuable tool in the diagnostic and monitoring process of CIDP . The metThe main goal of CIDP treatment is to slow the progress of the illness, improve movement and reduce the disability. The first line of immunotherapy is the steroids or Immunoglobulins. Daily oral corticosteroid doses commonly used are prednisone 60 mg equivalent to methylprednisolone 48 mg slowly reduced over 6–8 months depending on clinical response and possible side effects. There is no evidence that a higher dose is more effective. An alternative to oral corticosteroid treatment is intravenous corticosteroids Solu-Medrol 500–1000 mg per day for 4 days per month for 6 months. Corticosteroids are not recommended as a first-line treatment for motor CIDP as they may intensify symptoms. In motor CIDP immunoglobulin should be considered as initial treatment. There are side effects of corticosteroid treatment such as osteoporosis, gastric ulceration, diabetes, cataracts, and arterial hypertension. Corticosteroids should be regularly checked for if the current dose is still required; potential side effects may predominate benefits for treatment in low disability disease. Immunoglobulin treatment is strongly recommended as a dose of 2 g/kg is divided over 2–5 days every 2–6 weeks. Unfortunately, not all patients respond to the first course, so clinical experts recommend a second course a few weeks after the first course. Most patients require immunoglobulins maintenance treatment with usual doses of 1 g/kg every 3 weeks (0.4–1 g kg every 2–6 weeks). If the treatment is effective and the patient is stable the dose can be reduced by 25% per infusion or the treatment interval lengthened. This can be conducted every 6–12 months for the first 2–3 years of treatment. There is no evidence of a difference in effectiveness between different immunoglobulin preparation for treating CIDP. Plasma exchange is a second way of treatment for CIDP. In five exchanges over two weeks, peripheral veins should be used. The research studies did not show differences between the induction treatment for plasma and immunoglobulin, but plasma exchange may be less well tolerated and more difficult to administer. Adding an immunosuppressant or immunomodulatory drug may be considered but there is no evidence to recommend any particular drug. Azatioprine, mycophenolate mofenil or cyclosporin may be added to immunoglobulin or corticosteroids as maintenance treatment. Cyclophosphamide, ciclosporin or rituximab may be considered in patients who are resistant to immunoglobulin, corticosteroids or plasma exchange ,89. For Pathophysiologically, the autoimmune attack is directed at myelin components in demyelinating GBS (AIDP) and at Ranvier’s node, paranodal and juxtaparanodal regions, in axonal forms of GBS, as well as in Miller Fisher Syndrome (MFS). Underlying the immune process in the axonal forms is molecular mimicry between microbial antigens and axonal components. These anti-ganglioside antibodies, directed mainly to GM1 and GD1a in the axonal form of GBS and to GQ1b in MFS, cause axonal damage in nodal regions and at nerve terminals, resulting in conduction block, which may be reversible, with subsequent well-being, or alternatively, there may be axonal degeneration and worse clinical condition. The underlying basis for this difference in treatment outcome is unknown ,93. In aThe combined treatment (PE followed by IVIg infusion) in one randomized trial showed a non-significant trend toward improvement in comparison to treatment with only PE . The firThe identification of patients with MMN is important as the majority of them can be successfully treated with IVIg. Subcutaneous immunoglobulin (SCIg) may be an option for IVIg, but the evidence is very inconclusive. Further trials are required to identify patients with MMN in whom IVIg withdrawal is possible and to affirm the effectiveness of SCIg as an alternative supportive therapy .Immunotherapies should expand therapeutic options for these devastating diseases. The FcRn blocker efgartigimod, a humanized IgG1-derived Fc fragment, which competitively inhibits the FcRn, is currently under investigation in CIDP . MoreoveAlthough adherence to the EFNS/PNS guidelines for CIDP would substantially diminish the proportion of misdiagnoses, there remains a small number of patients who fulfill these criteria for CIDP but may have an alternative diagnosis (‘true mimics of CIDP’), such as POEMS syndrome, CANOMAD , and neurolymphomatosis. Pain, systemic symptoms, suggestive electrophysiological findings and/or the presence of a monoclonal protein in the serum should raise the suspicion of a CIDP mimic. Initial response to steroids or IVIG, over-reliance on CSF and electrophysiological findings may be confounding. These patients may experience a delay in making a correct diagnosis and initiating appropriate treatment, leading to significant disability and morbidity. Several studies have concentrated on polyneuropathies that mimic CIDP; our target was to review the most relevant molecular, electrophysiological and ultrasound differences of immune-mediated neuropathies, including CIDP, GBS and MMN.According to the study, diagnostic errors often involved underestimation of proximal muscle weakness, lack of knowledge of CIDP variants or subjective perception of improvement after immunotherapy.


Hearing impairment is a prevalent disabling condition among children; all newborns should undergo a universal newborn hearing screening (UNHS). Unfortunately, many newborns who fail the screening test are lost to follow-up. Our study aims to evaluate parents’ perceptions of UNHS and to identify predictors for newborn hearing screening recall in Saudi Arabia. A cross-sectional study involving Saudi parents with 0-to-18-year-old children born in Saudi Arabia was conducted. Descriptive statistics and binary logistic regression were used to describe the participants’ characteristics and to identify UNHS recall predictors. A total of 1533 parents were surveyed. Overall, 29.9% of them recalled a hearing screening at birth, while 22.2% reported no hearing screening, and 47.8% were unable to remember. Only (6.9%) participants reported a failed hearing screening, of which 75.9% recalled a follow-up recommendation. Females, parents aged 30–34 years, consanguineous parents, and parents of newborns who were treated with antibiotics were more likely to recall hearing screening compared to others. This study highlights inadequate awareness of UNHS among parents. Our findings support the need to improve the reporting system of UNHS results and implement educational programs to increase parents’ recall of hearing test results and ensure early follow-ups for neonates with failed test results. Hearing impairment is a prevalent disabling condition . The WorAlthough risk factors for hearing loss may be encountered at various times throughout life, people are most vulnerable to its effects at key life stages, such as the prenatal, perinatal, childhood, and adolescent years, as well as adulthood and older age . The majAuditory development in humans begins around the 20th week of gestation and continues for three years . TherefoThe National Institute of Health has advised that all newborns should be screened early for hearing impairment, ideally before hospital discharge . CurrentIn 2016, The Saudi Arabian Ministry of Health launched the UNHS program . DespiteThe effects of untreated hearing loss on an individual’s quality of life include communication and speech, cognition, employment and education, social isolation, loneliness, and stigma as well as effects on the economy and society as measured by the years lived with disability (YDLs) and disability-adjusted life years (DALYs) .There are limited studies in the Middle East that have examined the predictors of parental recall of newborn hearing screenings. Exploring parental attitude and recalls of UNHS is very important because it affects the parents’ practices and referral to further testing and diagnosis, ultimately leading to the early identification of newborns with hearing impairments and an improvement in their quality of life if they receive the appropriate treatment and management. Our study aims to evaluate parents’ perceptions of UNHS and to identify predictors for newborn hearing screening recall in Saudi Arabia.A cross-sectional study using a previously validated questionnaire was conducted in Saudi Arabia between April and May of 2021 to evaluate parents’ perceptions of UNHS and to identify predictors for newborn hearing screening recall.Saudi parents with children aged 0 to 18 and born in Saudi Arabia were eligible to participate in the study.The survey was posted on social media platforms, including WhatsApp, Twitter, and Facebook. A convenience sampling technique was used to select participants who met the study’s inclusion criteria and completed the questionnaire. The questionnaire tool was distributed via social media platforms. The survey asked the parents to provide information about their child’s hearing and neonatal hearing screening. Parents who had multiple children were asked to report on their youngest child regardless of their health status.We used a self-administrated online questionnaire which was adapted from a previous study  22]. Th. Th22]. p-value), estimated using OpenEpi VER 3.0 [To estimate the sample size, we used the WHO recommendations. The required sample size should be equal to or greater than 385 participants to achieve a 95% confidence interval and a 5% significance level ( VER 3.0 .p ≤ 0.05) was applied to indicate the statistical significance of the results, and a significance level of 5% was assigned.SPSS version 27 was used to conduct statistical analysis on the collected data. Categorical variables were presented as frequency and percentage. Binary logistic regression analysis was conducted to identify predictors of hearing screening test recall. A 95% confidence interval .A total of 1533 participants were involved in this study. More than half of them (65.2%) were females. More than half of them (56.7%) were aged below 40 years. Around 64% of the study participants reported holding a bachelor’s degree. Almost two-thirds of the participants (66.3%) reported their monthly income being 5000 SAR or above. A total of 39.4% reported that one or both parents are suffering from chronic disease(s). Around one-third (29.4%) of the participants reported that they are relatives. Around 12.0% of the participants reported that they or a family member had a hearing impairment that started before the age of 40 years. When we asked the participants about the status of their child’s conditions at birth, the vast majority of them (84.1%) reported that their child(ren) was born in a hospital, 21.8% were treated for jaundice, 20.4% were in the neonatal intensive care unit (NICU), and 18.3% treated for an infection requiring antibiotics. Less than one-third of the study’s participants (29.9%) confirmed that their child(ren) had a hearing screening test at birth, of which 23.4% reported that their child(ren) passed the test in both ears. For those who have reported problems concerning hearing screening tests at birth (n = 29), 75.9% reported that they were recommended to have a follow-up. The most commonly reported recommendations were evaluation by ENT specialists and obtaining a hearing test within a few months with 31.8% and 22.7%, respectively. p ≤ 0.05). On the other hand, older parents (who are aged 46–55 years) and parents who suffer from any chronic diseases were less likely to recall hearing screen tests compared to others (p ≤ 0.05). Binary logistic regression analysis identified that females, those aged 30–34 years, consanguineous parents, and parents of a newborn treated for an infection requiring antibiotics were more likely to recall hearing screen tests than others (When the participants were asked whether their child(ren) had a hearing screening test at school, only 12.4% of children received a hearing screening at school, with 77.1% of parents confirming that their child passed the hearing test. The majority (85.7%) of those who failed the hearing test (n = 7) reported following up with their child(ren).In Saudi Arabia, all hospitals perform a hearing screening test on newborns. National standards for hearing screening tests for older children are being considered. We asked the participants whether they would support national legislation that would require routine hearing screening tests in older children. More than half of them (62.0%) reported that they would recommend this legislation for children aged 2–3 years (preschool). When the participants were asked who they would take him/her to see if they had concerns in the future regarding their child’s hearing, the vast majority of them (80.1%) reported audiologist, refer to For every 1000 newborns, 1 to 2 are born with a permanent hearing loss in either one or both ears ; when a A hearing screening test determines whether or not a person may have hearing loss. Hearing tests are simple and painless. Hearing tests are painless and safe. The ear probes are gentle, and there are no loud noises. In fact, infants often nod off during screening. It simply takes a few minutes most of the time . All newThe UNHS is now considered the standard of care in many countries worldwide, with a primary goal of rapidly identifying newborns with hearing impairment and facilitating early diagnosis and intervention . Prior rOur findings indicate almost one-third of participants (29.9%) recalled their child receiving a hearing screening, but nearly half of the participants (47.8%) were unaware of whether their child had a hearing screening at birth, and nearly a quarter of participants 22.2%) report that no screening was performed. These unfortunate findings might indicate poor parental awareness of the negative sequelae of unaddressed hearing impairment. A relatively lower but equally concerning percentage of parents who were uncertain of their child’s hearing screening at birth was observed in a national survey conducted in the United States (47.8% vs. 31.5%). These findings indicate that lack of parental awareness may be a significant impediment to the global benefits of UNHS programs [.2% reporOur results indicate that 6.9% of the parents who recalled a hearing screening were referred for a failed test in one or both ears. This is relatively higher than the benchmark (4%) recommended by The Joint Committee on Infant Hearing for the final referral rate to diagnostic evaluation . SeveralReferral rates are probably influenced by the child’s age, protocol design, and the number of screening steps . For insDespite the improved coverage rate of the UNHS across both developed and developing countries, loss of follow-up (LTF) remains a significant barrier to the benefits of the program ,33. The Our study sought the demographic predictors of parental recall of hearing screening. Female participants, parents aged 30–34, and consanguineous parents were more likely to recall hearing screening at birth . Pynnonen et al. found no significant association between the gender and age of parents and parental recall of hearing screening . Most 30A high consanguinity rate of 29.9% among our study participants is not surprising given the high overall rate of consanguineous marriages in Saudi Arabia . ConsangThis study showed that parents of children who were treated for infection with antibiotics during neonatal period were 41% more likely to recall UNHS. Pynnonen et al. reported a similar observation where parents with children who had risk factors, including treatment with antibiotics during neonatal period . BacteriNumerous strategies can be implemented to enhance the effectiveness of UNHS programs, reduce the psychological stress and anxiety associated with failed screening tests, and ensure appropriate follow-up if warranted ,28,36. FThe UNHS has assisted in the identification of children with congenital hearing impairment . The schIn our study, only 12.4% of parents reported that their children had undergone a school-based hearing screening. In Saudi Arabia, all hospitals conduct neonatal hearing screening as a part of routine newborn care. Nevertheless, screenings for older children are being considered, but they are not yet part of routine care. Hearing screenings are conducted in most Swedish public schools . A studyFrom the prenatal and perinatal stages through old age, prevention of hearing loss is crucial. Nearly 60% of hearing loss in children is caused by preventable factors that may be avoided with the deployment of public health initiatives. Immunization, excellent maternal and childcare habits, genetic counseling, and the recognition and treatment of common ear disorders are a few of them . EffectiVarious limitations apply to our research. We are constrained by parental recall bias, and the cross-sectional aspect of the study restricts us from drawing any broad conclusions. Additionally, a self-administered questionnaire via an internet platform may be biased.This study highlights inadequate awareness of UNHS among parents. Our findings support the need to improve the reporting system of UNHS results and implement educational programs to increase parents’ recall of hearing test results and ensure early follow-up for neonates who failed test results.