Revisiting astrocyte to neuron conversion with lineage tracing in vivo.

In vivo cell fate conversions have emerged as potential regeneration-based therapeutics for injury and disease. Recent studies reported that ectopic expression or knockdown of certain factors can convert resident astrocytes into functional neurons with high efficiency, region specificity, and precise connectivity. However, using stringent lineage tracing in the mouse brain, we show that the presumed astrocyte-converted neurons are actually endogenous neurons. AAV-mediated co-expression of NEUROD1 and a reporter specifically and efficiently induces reporter-labeled neurons. However, these neurons cannot be traced retrospectively to quiescent or reactive astrocytes using lineage-mapping strategies. Instead, through a retrograde labeling approach, our results reveal that endogenous neurons are the source for these viral-reporter-labeled neurons. Similarly, despite efficient knockdown of PTBP1 in vivo, genetically traced resident astrocytes were not converted into neurons. Together, our results highlight the requirement of lineage-tracing strategies, which should be broadly applied to studies of cell fate conversions in vivo.

A single factor elicits multilineage reprogramming of astrocytes in the adult mouse striatum.

SignificanceOutside the neurogenic niches, the adult brain lacks multipotent progenitor cells. In this study, we performed a series of in vivo screens and reveal that a single factor can induce resident brain astrocytes to become induced neural progenitor cells (iNPCs), which then generate neurons, astrocytes, and oligodendrocytes. Such a conclusion is supported by single-cell RNA sequencing and multiple lineage-tracing experiments. Our discovery of iNPCs is fundamentally important for regenerative medicine since neural injuries or degeneration often lead to loss/dysfunction of all three neural lineages. Our findings also provide insights into cell plasticity in the adult mammalian brain, which has largely lost the regenerative capacity.

Diagnostic value of contrast-enhanced CT in clear cell renal cell carcinoma: a systematic review and meta-analysis.

OBJECTIVE: Contrast-enhanced computed tomography (CECT) improves lesion contrast with surrounding tissues through the injection of contrast agents. This enhancement allows for more precise lesion characterization, aiding in the early diagnosis of clear cell renal cell carcinoma (ccRCC). This meta-analysis aims to assess the diagnostic efficacy of CECT in ccRCC and to provide an ideal imaging examination method for the preoperative diagnosis of ccRCC. METHODS: We conducted a comprehensive search across six major online databases: PubMed, Web of Science, Cochrane Library, WANFANG DATA, China National Knowledge Infrastructure, and Chinese BioMedical Literature Database (CBM). The objective was to collate and analyze studies that evaluate the diagnostic utility of CECT in the identification of ccRCC. Meta-disc 1.4 and Stata 16.0 were used to conduct a meta-analysis and evaluate the diagnostic accuracy of CECT for ccRCC. RESULTS: The meta-analysis included 17 relevant studies investigating the diagnostic value of CECT for ccRCC. The combined sensitivity and specificity of CECT were 0.88 (95% confidence interval: 0.83-0.91) and 0.82 (95%CI: 0.75-0.87), respectively. Positive diagnostic likelihood ratio = 4.87 (95%CI: 3.47-6.84), negative diagnostic likelihood ratio = 0.15 (95%CI: 0.11-0.21), and diagnostic odds ratio = 32.67 (95%CI: 18.21-58.61). In addition, the area under the ROC curve was 0.92 (95%CI: 0.89-0.94), indicating that CECT has a decent discriminative ability in diagnosing ccRCC. CONCLUSIONS: CECT is recognized as a highly effective imaging tool for diagnosing ccRCC. It provides valuable guidance in the preoperative assessment and planning of surgical strategies for patients with ccRCC.

AMPK and PPARdelta agonists are exercise mimetics.

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

NEK6 is an injury-responsive kinase cooperating with STAT3 in regulation of reactive astrogliosis.

In response to brain injury, resident astrocytes become reactive and play dynamic roles in neural repair and regeneration. The signaling pathways underlying such reactive astrogliosis remain largely unclear. We here show that NEK6, a NIMA-related serine/threonine protein kinase, is rapidly induced following pathological stimulations and plays critical roles in reactive astrogliosis. Enhanced NEK6 expression promotes reactive astrogliosis and exacerbates brain lesions; and conversely, NEK6 downregulation dampens injury-induced astrocyte reactivity and reduces lesion size. Mechanistically, NEK6 associates with and phosphorylates STAT3. Kinase activity of NEK6 is required for induction of GFAP and PCNA, markers of reactive astrogliosis. Interestingly, NEK6 is also localized in the nucleus and binds to STAT3-responsive genomic elements in astrocytes. These results indicate that NEK6 constitutes a molecular target for the regulation of reactive astrogliosis.

Suprapubic-assisted laparoendoscopic single-site surgery versus standard laparoscopic nephrectomy: A propensity score-based analysis.

OBJECTIVES: To compare suprapubic-assisted laparoendoscopic single-site surgery nephrectomy with standard laparoscopic nephrectomy. METHODS: A retrospective case-control study comparing three surgeons' experience with 122 suprapubic-assisted laparoendoscopic single-site surgery nephrectomy and 107 standard laparoscopic nephrectomy was carried out. Operative time, estimated blood loss, intraoperative complications, intraoperative conversion, postoperative bowel recovery, postoperative analgesics, postoperative visual analog pain scale score, postoperative length of stay, days before going back to work, postoperative complications and Patient Scar Assessment Questionnaire were compared after propensity score matching. RESULTS: A total of 97 matched pairs were obtained after propensity score matching. There were no statistically significant differences between the suprapubic-assisted laparoendoscopic single-site surgery nephrectomy and standard laparoscopic nephrectomy groups with respect to operative time, estimated blood loss, intraoperative complications, intraoperative conversion, postoperative bowel recovery, length of stay and postoperative complications. Suprapubic-assisted laparoendoscopic single-site surgery nephrectomy group had decreased postoperative analgesics (20.9 vs 23.5, P = 0.04), visual analog pain scale score at 24 h (4.28 vs 5.28, P = 0.000), visual analog pain scale score at discharge (1.01 vs 1.47, P = 0.000), days before going back to work (28.4 vs 31.9, P = 0.000) and Patient Scar Assessment Questionnaire score (34.0 vs 42.0, P = 0.000), compared with the standard laparoscopic nephrectomy group. CONCLUSIONS: Suprapubic-assisted laparoendoscopic single-site surgery nephrectomy and standard laparoscopic nephrectomy are equivalent in terms of the safety and efficacy. However, suprapubic-assisted laparoendoscopic single-site surgery nephrectomy confers less postoperative pain, fewer days before going back to work and better cosmetic result when compared with standard laparoscopic nephrectomy.

Astrocyte-Specific Deletion of Sox2 Promotes Functional Recovery After Traumatic Brain Injury.

Injury to the adult brain induces activation of local astrocytes, which serves as a compensatory response that modulates tissue damage and recovery. However, the mechanism governing astrocyte activation during brain injury remains largely unknown. Here we provide in vivo evidence that SOX2, a transcription factor critical for stem cells and brain development, is also required for injury-induced activation of adult cortical astrocytes. Genome-wide chromatin immunoprecipitation-seq analysis of mouse cortical tissues reveals that SOX2 binds to regulatory regions of genes associated with signaling pathways that control glial cell activation, such as Nr2e1, Mmd2, Wnt7a, and Akt2. Astrocyte-specific deletion of Sox2 in adult mice greatly diminishes glial response to controlled cortical impact injury and, most unexpectedly, dampens injury-induced cortical loss and benefits behavioral recovery of mice after injury. Together, these results uncover an essential role of SOX2 in somatic cells under pathological conditions and indicate that SOX2-dependent astrocyte activation could be targeted for functional recovery after traumatic brain injury.

Protective effects of mesenchymal stromal cells on adriamycin-induced minimal change nephrotic syndrome in rats and possible mechanisms.

BACKGROUND AIMS: Minimal change nephrotic syndrome is the most frequent cause of nephrotic syndrome in childhood. Current treatment regimes, which include glucocorticoid hormones and immunosuppressive therapy, are effective and have fast response. However, because of the side effects, long treatment course, poor patient compliance and relapse, novel approaches for the disease are highly desired. METHODS: The adriamycin-induced nephrotic rat model was established. Rats were allocated to a model group, a prednisone group or mesenchymal stromal cell (MSC) group. Clinical parameters in each treatment group were determined at 2 weeks, 4 weeks and 8 weeks. The messenger RNA (mRNA) levels of synaptopodin, p21 and monocyte chemoattractant protein-1 were determined through the use of quantitative real-time-polymerase chain reaction. Protein levels were determined by means of Western blot or enzyme-linked immunosorbent assay. Podocytes were isolated and apoptotic rate after adriamycin with or without MSC treatment was analyzed by means of flow cytometry. RESULTS: MSC intervention improved renal function as assessed by urinary protein, blood creatinine and triglyceride levels. MSC intervention reduced adriamycin-induced renal tissue damage visualized by immunohistochemistry and light and electron microscopic analysis and reduced adriamycin-induced podocyte apoptosis. After MSC intervention, mRNA and protein levels of synaptopodin and p21 in renal cortex were significantly increased. MSCs also restored synaptopodin mRNA and protein expression in isolated podocytes. In addition, monocyte chemoattractant protein-1 mRNA in renal cortex and protein level in serum of the MSC treatment group were significantly decreased compared with that in the adriamycin-induced nephropathy model group. CONCLUSIONS: Our data indicate that MSCs could protect rats from adriamycin-induced minimal change nephrotic syndrome, and the protective effects of MSCs are mediated through multiple actions.

A role for adult TLX-positive neural stem cells in learning and behaviour.

Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.

Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.

Case report: A rare case of synchronous mucinous neoplasms of the renal pelvis and the appendix.

Background: Mucinous neoplasms are tumors arising in the epithelial tissue, characterized by excessive mucin secretion. They mainly emerge in the digestive system and rarely in the urinary system. They also seldom develop in the renal pelvis and the appendix asynchronously or simultaneously. The concurrence of this disease in these two regions has not yet been reported. In this case report, we discuss the diagnosis and treatment of synchronous mucinous neoplasms of the right renal pelvis and the appendix. The mucinous neoplasm of the renal pelvis was preoperatively misdiagnosed as pyonephrosis caused by renal stones, and the patient underwent laparoscopic nephrectomy. Herein, we summarize our experience with this rare case in combination with related literature. Case presentation: In this case, A 64-year-old female was admitted to our hospital with persistent pain in the right lower back for over a year. Computer tomography urography (CTU) showed that the patient was confirmed as right kidney stone with large hydronephrosis or pyonephrosis, and appendiceal mucinous neoplasm (AMN). Subsequently, the patient was transferred to the gastrointestinal surgery department. Simultaneously, electronic colonoscopy with biopsy suggested AMN. Open appendectomy plus abdominal exploration was performed after obtaining informed consent. Postoperative pathology indicated low-grade AMN (LAMN) and the incisal margin of the appendix was negative. The patient was re-admitted to the urology department, and underwent laparoscopic right nephrectomy because she was misdiagnosed with calculi and pyonephrosis of the right kidney according to the indistinctive clinical symptoms, standard examination of the gelatinous material, and imaging findings. Postoperative pathology suggested a high-grade mucinous neoplasm of the renal pelvis and mucin residing partly in the interstitium of the cyst walls. Good follow-up results were obtained for 14 months. Conclusion: Synchronous mucinous neoplasms of the renal pelvis and the appendix are indeed uncommon and have not yet been reported. Primary renal mucinous adenocarcinoma is very rare, metastasis from other organs should be first considered, especially in patients with long-term chronic inflammation, hydronephrosis, pyonephrosis, and renal stones, otherwise, misdiagnosis and treatment delay may occur. Hence, for patients with rare diseases, strict adherence to treatment principles and close follow-up are necessary to achieve favorable outcomes.

Case Report: A MiT family translocation renal cell carcinoma in the renal pelvis, calyces and upper ureter misdiagnosed as upper tract urothelial carcinoma.

Background: Upper tract urothelial carcinoma (UTUC) is the most common urothelial malignancy in the renal pelvis or ureter. Renal pelvic carcinoma accounts for 90% of all tumours in the renal pelvis, so the mass in the renal pelvis is usually considered a UTUC. Renal cell carcinoma (RCC) in the renal pelvis, calyces and upper ureter is extremely rare, especially MiT family translocation RCC, which makes this case even more uncommon. Case presentation: We report the case of a 54-year-old man had intermittent painless gross haematuria with occasional blood clots and urodynia for 2 years. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) scan showed an enlarged left kidney, and a soft tissue mass was seen in the renal pelvis, calyces and upper ureter. The patient's urine-based cytology was positive three times. Due to the severity of the upper ureteral lumen stenosis, we did not perform pathological biopsy during ureteroscopy. In the current case, clinical symptoms, imaging examinations, urine-based cytology, and ureteroscopy were combined to obtain a preoperative diagnosis of UTUC. Therefore, robot-assisted laparoscopic left radical nephroureterectomy and retroperitoneal lymphadenectomy were performed. Unexpectedly, the patient was pathologically diagnosed with MiT family translocation RCC after surgery. The surgery was uneventful. There was no intestinal tube injury or other complications perioperatively. The postoperative follow-up was satisfactory. Conclusion: MiT family translocation RCC in the renal pelvis, calyces and upper ureter is extremely rare, and can be easily confused with UTUC, resulting in the expansion of surgical scope. Preoperative ureteroscopy and biopsy or tumour punch biopsy should be used to obtain accurate pathology as far as possible, and the selection of correct surgical method is conducive to a good prognosis for patients.

Case report: Robot-assisted laparoscopic partial nephrectomy for renal cell carcinoma in a patient with situs inversus totalis and abdominal cocoon.

Background: Situs inversus totalis (SIT) is a congenital condition wherein organs in abdominal or thoracic cavity are mirrored from their normal positions. Abdominal cocoon, is a rare disease of unknown aetiology that is characterised by total or partial small intestine encapsulation by a compact fibrocollagenous membrane. Aside from having two extremely rare conditions (SIT and Abdominal cocoon), our patient developed renal cell carcinoma (RCC), which makes this case even more uncommon. Case Presentation: We report the case of a 64-year-old man who was admitted to our hospital with an extremely rare case of localized RCC in the left kidney complicated with SIT and abdominal cocoon. Computer tomography urography (CTU) and angiography (CTA) showed that the patient was confirmed as having SIT, for the space-occupying lesion in the left kidney, clear cell RCC (ccRCC) was considered, the lesion in the right kidney was probably cystic. We diagnosed our patient as having a cT1aN0M0 left RCC, and the RENAL score was 7x. With partial nephrectomy (PN) being the preferred treatment approach, robot-assisted laparoscopic partial nephrectomy (RALPN) was performed after obtaining informed consent. After insertion of the laparoscope, adhesions were observed between the entire colon and the anterior abdominal wall. Then, abdominal cocoon was diagnosed. The surgery was uneventful, and the tumour was resected successfully while preserving the tumour capsule. No intestinal injury or any other complication occurred in the intraoperative or postoperative, and the patient recovered well after the operation. Conclusion: PN is an extremely challenging procedure in patients with SIT and abdominal cocoon. The da Vinci Xi surgical system and thorough preoperative assessment allowed the surgeon to overcome stereotyping, visual inversion, and successfully perform PN in a patient with SIT and abdominal cocoon without increasing the risk of complications and preserving as much renal function as possible. Considering the satisfactory outcomes, this report may hopefully provide a practical reference for the treatment of RCC in patients with other special conditions.

Chemical screens in aging-relevant human motor neurons identify MAP4Ks as therapeutic targets for amyotrophic lateral sclerosis.

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.

Activation of postnatal neural stem cells requires nuclear receptor TLX.

Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The molecular mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphology for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq analysis of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulates p21 expression in a p53-dependent manner, and acute removal of p53 can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.

Case report: Misdiagnosis of accessory spleen in the left adrenal region as an adrenal tumour after splenectomy.

Background: Adrenal tumours are common in urology and endocrinology, and the diagnosis of adrenal tumours were mainly depends on imaging diagnosis. Howerver, misdiagnosis can still occur for some adrenal space-occupying lesions without specific manifestations or abnormal biochemical indexes. Methods: We report the case of a 55-year-old patient with a soft-tissue mass in the left adrenal region, and have no specific manifestations or abnormalities in biochemical indexes. The patient had undergone open splenectomy 20 years ago for splenic rupture caused by traffic-accident trauma, and had a 10-year special history of hypertension. Because of the uncertain nature of the mass, surgical treatment was recommended. Results: The surgeon managed to remove the left adrenal region mass. During the surgery, the adrenal source was excluded. In the histological examination, the splenic corpuscle and splenic medullary structure were seen under the microscope, and an accessory spleen was diagnosed. Conclusions: The accessory spleen was located in the adrenal region rarely, and can easily be misdiagnosed as an adrenal tumour. When the cases show abnormal adrenal space-occupying lesions in imaging examinations, non-adrenal diseases should be considered. we need to combine different imaging techniques for analysis, and think more about it, avoid misdiagnosis leading to unnecessary surgery.

Giant superficial angiomyxoma of the male perineum: A case report.

Superficial angiomyxoma (SA) is a rare benign tumor that occurs either in the superficial dermis or subcutaneously. It often occurs in the trunk, neck, or limbs, and grows slowly. The diameter of the tumor is usually less than 5 cm. A giant SA of the perineum in men is very rare. We detailed the diagnosis and treatment of male patients with perineal SA and performed a literature review. We report a case of a 42-year-old male patient. He was admitted to hospital with a perineal mass found more than 1 year previously. A pelvic contrast-enhanced computed tomography scan in our hospital suggests that a round slightly hypointense foci of about 6.0 cm × 8.6 cm × 4.5 cm in size with still clear borders was seen below the penile corpus cavernosum in the perineum. We performed a perineal mass excision under continuous epidural anesthesia. A postoperative pathology report diagnosed perineal SA. There was no recurrence at follow-up for 27 months up to May 2022. Perineal SA is rare and should be combined with patient history and imaging to ensure complete excision of the mass margins. Adherence to long-term postoperative follow-up is the key to curing this case.

Tumor-Promoting ATAD2 and Its Preclinical Challenges.

ATAD2 has received extensive attention in recent years as one prospective oncogene with tumor-promoting features in many malignancies. ATAD2 is a highly conserved bromodomain family protein that exerts its biological functions by mainly AAA ATPase and bromodomain. ATAD2 acts as an epigenetic decoder and transcription factor or co-activator, which is engaged in cellular activities, such as transcriptional regulation, DNA replication, and protein modification. ATAD2 has been reported to be highly expressed in a variety of human malignancies, including gastrointestinal malignancies, reproductive malignancies, urological malignancies, lung cancer, and other types of malignancies. ATAD2 is involved in the activation of multiple oncogenic signaling pathways and is closely associated with tumorigenesis, progression, chemoresistance, and poor prognosis, but the oncogenic mechanisms vary in different cancer types. Moreover, the direct targeting of ATAD2's bromodomain may be a very challenging task. In this review, we summarized the role of ATAD2 in various types of malignancies and pointed out the pharmacological direction.

PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis.

Lipid homeostasis and inflammation are key determinants in atherogenesis, exemplified by the requirement of lipid-laden, foam cell macrophages for atherosclerotic lesion formation. Although the nuclear receptor PPARdelta has been implicated in both systemic lipid metabolism and macrophage inflammation, its role as a therapeutic target in vascular disease is unclear. We show here that orally active PPARdelta agonists significantly reduce atherosclerosis in apoE(-/-) mice. Metabolic and gene expression studies reveal that PPARdelta attenuates lesion progression through its HDL-raising effect and anti-inflammatory activity within the vessel wall, where it suppresses chemoattractant signaling by down-regulation of chemokines. Activation of PPARdelta also induces the expression of regulator of G protein signaling (RGS) genes, which are implicated in blocking the signal transduction of chemokine receptors. Consistent with this, PPARdelta ligands repress monocyte transmigration and macrophage inflammatory responses elicited by atherogenic cytokines. These results reveal that PPARdelta antagonizes multiple proinflammatory pathways and suggest PPARdelta-selective drugs as candidate therapeutics for atherosclerosis.

Systematic review and meta-analysis of extended high-frequency audiometry in tinnitus patients.

BACKGROUND: This study aimed to systematically evaluate the detection effect of extended high-frequency audiometry (EHFA) in tinnitus patients and provide a theoretical basis for the clinical diagnosis of tinnitus. METHODS: We conducted a computer-based search for randomized controlled trial (RCT) literature on extended audiometry in tinnitus patients using the PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Elsevier Science Direct databases. The search dates ranged from the database establishment date to February 2020. Risk of bias in the included literature was evaluated using the RCT bias risk assessment standard provided in the Handbook for Systematic Reviews for Interventions (version 5.0.2, 2008, Chapter 9). Finally, Review Manager 5.3 software was used to conduct a meta-analysis of the included literature. RESULTS: The retrieved literature was systematically screened. A total of 10 RCTs were included in the meta-analysis, which involved a total of 1,389 tinnitus patients. The results of the meta-analysis showed that at the frequencies of 14 kHz and 16 kHz, there was visible difference in detection rate of hearing threshold (DR-HT) between the 2 groups [odds ratio (OR) =0.21, 95 confidential interval (CI): 0.14-0.32, Z=7.29, P<0.00001] and (OR =0.14, 95% CI: 0.07-0.27, Z=5.96, P<0.00001) respectively. When the frequency was 18 kHz, there was a significant statistical difference in DR-HT between the 2 groups (OR =0.13, 95% CI: 0.07-0.24, Z=6.50, P<0.00001), and at 20 kHz, the statistically significant difference in DR-HT between the 2 groups was high (OR =0.17, 95% CI: 0.12-0.23, Z=10.38, P<0.00001). DISCUSSION: EHFA had a critical effect on tinnitus patients. The meta-analysis provided evidence for early hearing loss in tinnitus patients. EHFA played a crucial role in the clinical diagnosis of tinnitus patients.