State transition and intercellular communication of synovial fibroblasts in response to chronic and acute shoulder injuries unveiled by single-cell transcriptomic analyses.

PURPOSE: We aimed to investigate the heterogeneity of synovial fibroblasts and their potential to undergo cell state transitions at the resolution of single cells. MATERIALS AND METHODS: We employed the single-cell RNA sequencing (scRNA-seq) approach to comprehensively map the cellular landscape of the shoulder synovium in individuals with chronic rotator cuff tears (RCTs) and acute proximal humerus fractures (PHFs). Utilizing unbiased clustering analysis, we successfully identified distinct subpopulations of fibroblasts within the synovial environment. We utilized Monocle 3 to delineate the trajectory of synovial fibroblast state transition. And we used CellPhone DB v2.1.0 to predict cell-cell communication patterns within the synovial microenvironment. RESULTS: We identified eight main cell clusters in the shoulder synovium. Unbiased clustering analysis identified four synovial fibroblast subpopulations, with diverse biological functions associated with protein secretion, ECM remodeling, inflammation regulation and cell division. Lining, mesenchymal, pro-inflammatory and proliferative fibroblasts subsets were identified. Combining the results from StemID and characteristic gene features, mesenchymal fibroblasts exhibited characteristics of fibroblast progenitor cells. The trajectory of synovial fibroblast state transition showed a transition from mesenchymal to pro-inflammatory and lining phenotypes. In addition, the cross talk between fibroblast subclusters increased in degenerative shoulder diseases compared to acute trauma. CONCLUSION: We successfully generated the scRNA-seq transcriptomic atlas of the shoulder synovium, which provides a comprehensive understanding of the heterogeneity of synovial fibroblasts, their potential to undergo state transitions, and their intercellular communication in the context of chronic degenerative and acute traumatic shoulder diseases.

A Transosseous Suture as an Alternative to Suture Anchor on Anterior-Avulsion Greater Tuberosity Fragment Fixation in Neer Three-Part Proximal Humeral Fracture: A Biomechanical Study.

OBJECTIVE: Greater tuberosity (GT) fragments were communicated, and additional techniques to increase the GT fragment stability after the locking plate fixation was necessary. This study aimed to analyze the reinforcement effects on the anterior-avulsion GT fragment in Neer three-part proximal humeral fractures (PHFs) using transosseous suture and suture anchor techniques. METHODS: Eighteen fresh-frozen human cadaveric shoulder specimens were used in the study. Standardized fracture of the GT and surgical neck was created in 18 human cadaveric proximal humerus. The GT fragments were reinforced with transosseous suture (TS), suture anchor (SA), and suture in addition to the PHILOS plate fixation. The fixed humerus was tested by applying static loading to the supraspinatus tendon. Load forces and fragment displacement were evaluated by a biomechanical testing machine, and the load to 3- and 5-mm displacements, load to failure, and mode of failure were recorded for all specimens. Nonparametric variables were examined by the Kruskal-Wallis test, and the Bonferroni post hoc test was used to analyze the mean loads to create 3- and 5-mm displacements as well as the failure load. RESULTS: The age, female proportion, and bone mineral density showed no statistically significant differences between the three groups. The mean loading force to create 3-mm and 5-mm displacement in the TS group (254.9 ± 77.4, 309.6 ± 152.7) were significantly higher than those in the suture group (136.1 ± 16.7, 193.4 ± 14.5) (P = 0.024, P = 0.005). For the SA group, the force to create 3- and 5-mm displacement (204.3 ± 60.9, 307.8 ± 73.5) were comparable to those in the TS group (P = 0.236, P = 0.983). Moreover, the loading force to failure in the TS group (508.6 ± 217.7) and SA group (406.6 ± 114.9) was significantly higher than that in the suture group (265.9 ± 52.1) (P = 0.021, P = 0.024). In the TS group, three failed due to tendon-bone junction rupture; bone tunnel broken occurred in two specimens; suture rupture could also be seen in one specimen. All specimens in the suture group failed because of suture rupture. In the SA group, three specimens failed due to suture rupture; two failed secondary to tendon-bone junction rupture; and one failed because of shaft fracture. CONCLUSIONS: Transosseous suture is a new type of reinforcement for GT fragment in Neer-three part PHFs. The transosseous suture was superior to the suture only in the reinforcement of the anterior-avulsion GT fragment of Neer three-part PHFs, and it had comparable biomechanical strength to the suture anchor.

Fracture Line Morphology of Greater Tuberosity Fragments of Neer Three- and Four-Part Proximal Humerus Fractures.

OBJECTIVE: In complicated Neer three- and four-part proximal humerus fracture (PHF), greater tuberosity (GT) fragments are often comminuted, and the currently widely used locking plate may not fix GT fragments effectively. A further understanding of morphological characteristics of the GT fragments may help explore new fixation devices. This study aimed to determine the fracture line morphology of the GT fragment of Neer three- or four-part PHF and analyze the location relationship between the locking plate and the GT fragment. METHODS: Seventy-one three-dimensional computed tomography scans of Neer three- and four-part PHF were retrospectively reviewed between January 2014 and June 2019. Fracture fragments were reconstructed and virtually reduced in the Mimics software, and fracture lines of GT fragments were depicted on a humerus template in the 3-matic software and then were superimposed altogether. The common sites of the GT fracture were identified, and the location relationship between the locking plate and GT fragments was analyzed in a computer-simulated scenario. RESULTS: The fracture line morphology of GT fragments was similar between Neer three- and four-part PHF. The overall morphology of GT fragments was in a fan shape, which could be summarized as anterior, superior, posterior, and middle lines. Of these, we identified 51 split and 29 avulsion type GT fragments based on the Mutch classification, and they could occur simultaneously in a PHF. The overall morphology of split type fragments was in a fan shape, and avulsion type fragments showed a quite distinguishable distribution pattern. A GT fragment could be classified as anterior-split, posterior-split, complete-split, anterior -avulsion, and posterior-avulsion type based on its morphology and location. The median percentage of fragment area covered by the plate was 32.3% in all of the fragments, and it was 69.4%, 23.0%, 37.2%, 21.8%, 0.0% in anterior-split, posterior-split, complete-split, anterior-avulsion, and posterior-avulsion type GT fragments. We defined the posterior-split, anterior-avulsion, and posterior-avulsion type GT fragments as the risky GT fragments, and they occurred in 43 (60.6%) Neer three- and four-part PHFs. CONCLUSION: The fracture line morphology of GT fragments of Neer three- and four-part PHF was in a fan shape. GT fragments could be classified based on their location and morphology. The extent of GT fragment coverage provided by the locking plate differed in various fragment types, and we identified the anterior-avulsion, posterior-avulsion, and posterior-split type fragments as the risky GT fragments with a high incidence rate in Neer three- and four-part PHFs.

Tuberosity reconstruction baseplate for shoulder hemiarthroplasty: Morphological design and biomaterial application.

Background: Shoulder hemiarthroplasty is prone to tuberosity malposition and migration, reducing the rate of tuberosity healing. We proposed to design a tuberosity reconstruction baseplate to assist in tuberosity integration and to evaluate the mechanical properties of baseplate made from the novel biomaterial carbon fiber reinforced polymer (CFRP) composites. Methods: The three-dimensional model of native proximal humerus was constructed by computed tomography (CT) data. The morphological design of baseplate was based on the tuberosity contour and rotator cuff footprint. Finite element models were created for different thicknesses of CFRP composites, poly (ether-ether-ketone) (PEEK) and titanium-nickel (TiNi) alloy. The permissible load and suture hole displacements were applied to evaluate the mechanical properties. Results: The structurally optimized model made of CFRP composites provided superior strength and deformability, compared to the PEEK material and TiNi alloy. Its permissible load was above 200 N and the suture hole displacement was between 0.9 and 1.4 mm. Conclusion: This study proposed a method for designing tuberosity reconstruction baseplate based on morphological data and extended the application of biomaterial CFRP composites in orthopedics field. The optimized model made of CFRP composites allowed a certain extent of elastic deformation and showed the possibility for dynamic compression of tuberosity bone blocks.

Designing and validating a comparison card method for quantification of glenoid bone defect.

To design and investigate a comparison card to evaluate the glenoid bone defect compared with Sugaya method. 33 patients with bony Bankart lesions were included. The comparison card and Sugaya method were performed on two occasions by three participants. The intra-group correlation coefficient (ICC) analysis and the inter-group correlation coefficient analysis of two measurements was performed. The concordance of the two methods was assessed using Bland-Altman analysis. Firstly, the percentage of defect measured by Sugaya method was 10.32 ± 8.38, and the comparison card method was 10.26 ± 8.41, 10.15 ± 8.23, and 10.62 ± 8.48, separately. There was no statistically significant difference (P > 0.05). The second measurement showed it was 10.37 ± 8.39 for Sugaya method, and 10.23 ± 8.37, 10.15 ± 8.35, 10.54 ± 8.49 for the comparison card, without a statistically significant difference (P > 0.05). For the comparison card, the intra- and inter-observer ICC values were all > 0.75. In the first measurement, Bland-Altman analysis demonstrated agreement between the two methods (bias, -0.03; SD, 0.48; - 0.97- 0.91; 95% CI, - 0.1999- 0.1413). Agreement was also found between them (bias, 0.07; SD, 0.61; - 1.13- 1.26; 95% CI, - 0.1509- 0.2812) in the second measurement. The comparison card method has similar accuracy with Sugaya method, which is of great reliability and convenience.

A Nomogram to Predict Delirium after Hip Replacement in Elderly Patients with Femoral Neck Fractures.

OBJECTIVE: Postoperative delirium (POD) is a common complication, and clinical practitioners have taken measures to improve the quality of life after hip replacement surgery. We aim to establish a nomogram to predict POD in elderly patients with femoral neck fractures (FNFs) after hip replacement. METHODS: A total of 384 elderly patients (267 females) with an average age of 75.8 years who underwent hip replacement from June 2010 to May 2020 were retrospectively reviewed. Patients were divided into delirium and non-delirium groups according to the confusion assessment method. The risk factors for POD were analyzed by multivariate logistic regression, and the nomogram was established based on the results. RESULTS: The incidence of POD was 33.33% (128/384). Univariate analysis showed that advanced age, diabetes, lacunar cerebral infarction, surgery type, intraoperative blood loss, electrolyte imbalance, and anemia were risk factors for POD (p < 0.05). Multivariate logistic regression revealed that the independent risk factors for POD were age (OR = 1.332, 95% CI [1.224, 1.449], p < 0.01), surgery type (OR = 0.351, 95% CI [0.137, 0.900], p = 0.029), electrolyte imbalance (OR = 4.407, 95% CI [1.947, 9.977], p< 0.01), anemia (OR = 10.819, 95% CI [4.573, 25.598], p < 0.01). The prediction equation was established; logistic (p) = -25.469 + 0.277*X1(age[value = years of age]) + 1.293*X2(surgery[value = 0 for "total hip replacement" or value = 1 for "hemiarthroplasty"]) + 1.510*X3(electrolyte imbalance[value = 0 for "no" or value = 1 for "yes"]) + 2.157*X4(anemia[value = 1 for "hemoglobin with < 120g/L in male and < 110g/L in female patients" ]) or 2.975*X5(anemia[value = 1 for "hemoglobin with <90g/L"]). The area under the curve was 0.957 (95% CI [0.938, 0.976], p < 0.01). CONCLUSION: The incidence of POD in elderly patients with FNF after hip replacement is high. The nomogram incorporating age, surgery type, electrolyte imbalance, and anemia could provide an individualized prediction for POD among FNF patients after hip replacement, which may help the physician determine appropriate perioperative management.

Finite Element Analysis of Proximal Femur Bionic Nail (PFBN) Compared with Proximal Femoral Nail Antirotation and InterTan in Treatment of Intertrochanteric Fractures.

OBJECTIVE: To compare the biomechanical properties of proximal femur bionic nail (PFBN), proximal femoral nail antirotation (PFNA) and InterTan in the treatment of elderly intertrochanteric fractures AO/OTA 31-A1.3 by finite element analysis. METHODS: We used Mimics, Unigraphics and other software to establish normal femur and AO/OTA 31-A1.3 fracture models, and reconstructed PFBN, PFNA and InterTan intramedullary nail models, and assembled them on the fracture model. The ANSYS software was used to compare the femoral von Mises stress distribution, deformation distribution, and internal fixation stress distribution of each group under a load of 2100 N. RESULTS: It could be seen that the femoral maximum stress, femoral maximum displacement, and maximum stress of internal fixation of the PFBN group were lower than those in the PFNA group and the InterTan group. The maximum femoral stress of the PFBN was 190.25 MPa, while the maximum stress of the femur of the PFNA and InterTan groups were 238.41 Mpa and 226.97 Mpa. The maximum femoral displacement of each group were located at the top of the femoral head, and the maximum displacement of the PFBN group was 14.373 mm, and the maximum displacement values of the PFNA and InterTan groups were 19.49 and 15.225 mm. For the stress distribution of intramedullary nail, the maximum stress of the three kinds of internal fixation was located on the main nail. The maximum stress of PFBN was 1191.8 MPa, compared with 2142.8 MPa for PFNA and 1702.3 MPa for InterTan. And the maximum stress on the PFBN pressure nail was 345.35 MPa, compared with 868.6 MPa for the PFNA spiral blade and 545.5 MPa for InterTan interlocking twin nails. CONCLUSION: Compared with PFNA and InterTan, PFBN has better mechanical properties. The biomechanical characteristics of PFBN are more advantageous than PFNA and InterTan internal fixation system in the treatment of femoral intertrochanteric fractures.

Relevance between Proximal Humeral Migration and Rotator Cuff Tears.

Background: Proximal humeral migration is common in patients with rotator cuff tears. In this study, we aimed to evaluate the relevance between proximal humeral migration and some rotator cuff tear-related factors. Methods: A total of 75 patients with unilateral rotator cuff tears were retrospectively included from August 2016 to January 2018 who underwent magnetic resonance imaging and X-ray examinations before enrollment. We introduced the upward migration index (UMI) to stratify the patients into three groups, Group A: 1 < UMI ≤ 1.3; Group B: 1.3 < UMI ≤ 1.4; and Group C: UMI > 1.4. Pearson correlation analysis and logistic regression analysis were used to evaluate the relationship between UMI and age, sex, body mass index, pain, fatty degeneration grade, tear size, and thickness of ruptured tendon. Then, the χ 2 test and receiver operator characteristic curve were applied to measure the diagnostic value of UMI. Results: The average UMI was 1.34 ± 0.07, ranging from 1.16 to 1.48. For the Pearson correlation analysis, there was a negative correlation between UMI and tear size (R = -0.68, p < 0.01), and also, there was a negative correlation between UMI and the visual analogue scale score (R = 0.342, p < 0.01). What is more, there was a negative correlation between UMI and the fatty degeneration grade (R = -0.373, p < 0.01). Ordinal multinomial logistic regression analysis indicated that tear size (ß = -1.825, p < 0.001) was the independent predictor of UMI, which was a risk factor for humeral upward migration. The cutoff points of UMI were 1.38 and 1.3 to determine tears and distinguish large tears from small ones. Conclusions: UMI is a good predictor for humeral upward migration, which is related to the tear size of posterosuperior cuff tears. When the UMI is <1.3, a large tear should be alerted. Combining physical examination and X-ray is helpful for evaluating rotator cuff tears.

Efficacy and safety of free medial plantar flap in repair of the high-voltage electrical burns in hands.

PURPOSE: The purpose of this work was to validate the efficacy and safety of free medial plantar flap in repair of hand wounds resulted from high-voltage electrical burn. METHODS: 22 patients with high-voltage electrical burn wounds were retrieved between July 2016 and July 2018 in the Affiliated Zhengzhou Central Hospital of Zhengzhou University. All the wounds were the entrance of high-voltage electrical current. After thorough debridement, the blood vessels, nerves, tendons, joints were exposed to defects with different degrees. The soft tissue defects were repaired with the free medial plantar flap repair in 12 patients and medium-thickness skin graft in 10 patients. Postoperative management was similar between the two groups. RESULTS: All the operations were completed within 6 h. In the free medial plantar flap group, the mean follow-up period was (11.3 ± 2.4) months, ranging from 9 to 15 months, and all flaps survived; there were no vessel crises. Flaps of 10 patients healed without any complications, and local necrosis occurred in two cases, with healing after debridement. The two-point discrimination (TPD) was 7.0-11.0 mm, and the mean DASH score was 45.6 ± 7.4. In the medium-thickness skin graft group, the mean follow-up period was (10.9 ± 1.8) months. All flaps survived, and local contracture occurred in 3 cases. The TPD was 8.0-11.0 mm, and the mean DASH score was 60.7 ± 9.3. CONCLUSIONS: The free medial plantar flap is an ideal option for repairing the hand soft defects resulted from the high-voltage electrical burn.

A clinical nomogram predicting unplanned intensive care unit admission after hip fracture surgery.

BACKGROUND: Despite the improvement of surgical procedures and perioperative management, a portion of patients were still at high risk for intensive care unit admission owing to severe morbidity after hip fracture surgeries. The purpose of this study was to analyze influencing factors and to construct a clinical nomogram to predict unscheduled intensive care unit admission among inpatients after hip fracture surgeries. METHODS: We enrolled a total of 1,234 hip fracture patients, with 40 unplanned intensive care unit admissions, from January 2011 to December 2018. Demographics, chronic coexisting conditions at admission, laboratory tests, and surgical variables were collected and compared between intensive care unit admission and nonadmission groups using univariate analysis. The optimal lasso model was refined to the whole data set, and multivariate logistic regression was used to assign relative weights. A nomogram incorporating these predictors was constructed to visualize these predictors and their corresponding points of the risk for unplanned intensive care unit admission. The model was validated temporally using an independent data set from January 2019 to December 2019 by receiver operating characteristic area under the curve analysis. RESULTS: In the development group, we identified age, chronic heart failure, coronary heart disease, chronic obstructive pulmonary disease, Parkinson disease, and serum albumin and creatinine concentration were associated with unscheduled intensive care unit admission using multivariate analysis. The final model had an area under the curve of 0.854 (95% confidence interval, 0.742-0.966). The median calculated odds ratio of intensive care unit admission based on the nomogram was significantly higher for patients in the intensive care unit admission group than in the non-intensive care unit admission group (65.93% vs 0.02%, P < .01). The validation group proved its high predictive power with an area under the curve of 0.96 (95% confidence interval, 0.91-0.99). CONCLUSION: In this study, we identified several independent factors that may increase the risk for unexpected intensive care unit admission after hip fracture surgery and developed a clinical nomogram based on these variables. Preoperative evaluation using this nomogram might facilitate advanced intensive care unit resource management for high-risk patients whose conditions might easily deteriorate if not closely monitored in general wards after surgeries.

WITHDRAWN: Fracture line morphology of greater tuberosity fragments of Neer 3 and 4 part proximal humerus fractures.

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Correction: Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study.

[This corrects the article DOI: 10.1038/s41413-020-0084-5.].

Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a 15-year follow-up from a prospective cohort study.

The most severe sequelae after rehabilitation from SARS are femoral head necrosis and pulmonary fibrosis. We performed a 15-year follow-up on the lung and bone conditions of SARS patients. We evaluated the recovery from lung damage and femoral head necrosis in an observational cohort study of SARS patients using pulmonary CT scans, hip joint MRI examinations, pulmonary function tests and hip joint function questionnaires. Eighty medical staff contracted SARS in 2003. Two patients died of SARS, and 78 were enrolled in this study from August 2003 to March 2018. Seventy-one patients completed the 15-year follow-up. The percentage of pulmonary lesions on CT scans diminished from 2003 (9.40 ± 7.83)% to 2004 (3.20 ± 4.78)% (P < 0.001) and remained stable thereafter until 2018 (4.60 ± 6.37)%. Between 2006 and 2018, the proportion of patients with interstitial changes who had improved pulmonary function was lower than that of patients without lesions, as demonstrated by the one-second ratio (FEV1/FVC%, t = 2.21, P = 0.04) and mid-flow of maximum expiration (FEF25%-75%, t = 2.76, P = 0.01). The volume of femoral head necrosis decreased significantly from 2003 (38.83 ± 21.01)% to 2005 (30.38 ± 20.23)% (P = 0.000 2), then declined slowly from 2005 to 2013 (28.99 ± 20.59)% and plateaued until 2018 (25.52 ± 15.51)%. Pulmonary interstitial damage and functional decline caused by SARS mostly recovered, with a greater extent of recovery within 2 years after rehabilitation. Femoral head necrosis induced by large doses of steroid pulse therapy in SARS patients was not progressive and was partially reversible.

Hip Replacement as Alternative to Intramedullary Nail in Elderly Patients with Unstable Intertrochanteric Fracture: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and safety of hip replacement and intramedullary nails for treating unstable intertrochanteric fractures in elderly patients. METHODS: Randomized clinical trials (RCTs) to compare hip replacement with intramedullary nail in the management of elderly patients with unstable intertrochanteric femur fracture were retrieved from Cochrane Library (up to January 2018), CNKI (China National Knowledge Infrastructure), Wanfang Data, PubMed, and Embase. The methodological quality of the included trials was assessed using the Cochrane risk of bias assessment tool, and relevant data was extracted. Statistical analysis was performed by Revman 5.3. Where possible, we performed the limited pooling of data. RESULTS: Fourteen trials including a total of 1067 participants aged 65 and above were included for qualitative synthesis and meta-analysis. The methodological quality of the included study was poor. The meta-analysis indicated that the hip replacement group benefited more than the intramedullary nail group in terms of the bearing load time (WMD -14.61, 95% CI -21.51 to -7.7, P < 0.0001), mechanical complications (OR 0.34, 95% CI 0.21 to 0.57, P < 0.0001), and post-operative complications (OR 0.46, 95% CI 0.22 to 0.93, P = 0.03). While the intramedullary nail was superior to arthroplasty regarding the intraoperative blood loss (WMD 58.36, 95% CI 30.77 to 85.94, P < 0.0001). However, there were no statistical significances in the length of surgery (WMD 5.27, 95% CI 4.23 to 14.77, P = 0.28), units of blood transfusion (WMD 0.34, 95% CI -0.16 to 0.85, P = 0.18), length of hospital stay (WMD -1.00, 95% CI -2.93 to 0.93, P = 0.31), Harris hip score (WMD 0.31, 95% CI -0.39 to 1.01, P = 0.38), and mortality (OR 1.24, 95% CI 0.12 to 13.10, P = 0.86). CONCLUSIONS: This systematic review and meta-analysis provided evidence for the efficacy and safety of hip replacement and intramedullary nail in treating unstable intertrochanteric fractures. However, the results should be interpreted cautiously because of methodological limitations and publication bias.

Risk Factors for Functional Outcomes of the Elderly with Intertrochanteric Fracture: A Retrospective Cohort Study.

OBJECTIVE: To identify baseline factors relevant to functional outcomes and health-related quality of life in the elderly with intertrochanteric fractures. METHODS: For the present study, 168 patients with intertrochanteric fracture who were assigned to different treatments between January 2016 and December 2017 were retrospectively selected. Hip function was assessed by Harris hip score (HHS), and health-related quality of life was evaluated by Barthel index (BI) of activities of daily living (ADL) and EuroQol 5-dimensions (EQ-5D) score, respectively. Data were analyzed by t-test, ANOVA, Pearson's correlation, χ2 -test, and multivariate linear regression. RESULTS: A total of 164 (97.6%) patients completed the follow-up, with an average follow-up time of 15.7 ± 6.9 months; 39 (23.8%) patients died during the follow-up period and 125 (76.2%) patients were eligible for the functional analysis. HHS at final follow-up of 125 patients was 71.8 ± 13.1, and the following were associated with hip functional recovery: age (-0.45, 95% confidence interval (CI) -0.73 to -0.18, P < 0.01), serum albumin (0.65, 95% CI 0.04 to 1.27, P < 0.05), and ADL at discharge (0.18, 95% CI 0.01 to 0.33, P < 0.05). The Barthel index at final follow up in this cohort was 80.2 ± 18.1, and multivariable linear regression analysis showed that age (-0.49, 95% CI -0.85 to -0.12; P < 0.05), ADL score at discharge (0.29, 95% CI 0.07 to 0.51; P < 0.05) and internal fixation (16.3, 95% CI 3.3 to 29.3; P < 0.05) were associated with ADL at final follow-up. EQ-5D at final follow-up was 0.74 ± 0.2, with which HHS (0.012, 95% CI 0.011 to 0.013; P < 0.01) was positively associated. CONCLUSION: We identify several baseline factors associated with hip functional outcome, health utility, and ADL in the elderly after an intertrochanteric fracture, of which we could modify mutable factors to achieve better outcomes. These findings could help to inform treatment and functional prognosis.

EVA1A/TMEM166 Regulates Embryonic Neurogenesis by Autophagy.

Self-renewal and differentiation of neural stem cells is essential for embryonic neurogenesis, which is associated with cell autophagy. However, the mechanism by which autophagy regulates neurogenesis remains undefined. Here, we show that Eva1a/Tmem166, an autophagy-related gene, regulates neural stem cell self-renewal and differentiation. Eva1a depletion impaired the generation of newborn neurons, both in vivo and in vitro. Conversely, overexpression of EVA1A enhanced newborn neuron generation and maturation. Moreover, Eva1a depletion activated the PIK3CA-AKT axis, leading to the activation of the mammalian target of rapamycin and the subsequent inhibition of autophagy. Furthermore, addition of methylpyruvate to the culture during neural stem cell differentiation rescued the defective embryonic neurogenesis induced by Eva1a depletion, suggesting that energy availability is a significant factor in embryonic neurogenesis. Collectively, these data demonstrated that EVA1A regulates embryonic neurogenesis by modulating autophagy. Our results have potential implications for understanding the pathogenesis of neurodevelopmental disorders caused by autophagy dysregulation.