Avoidance-motivational intensity modulated the effect of negative emotion on working memory.

Although many studies have explored the association between negative emotion and working memory, the findings remain controversial. The present study investigated the role of avoidance-motivational intensity in modulating the effect of negative emotion on different processes (maintenance versus manipulation) of verbal and spatial working memory. Two experiments employed the modified delayed match-to-sample paradigms to separate the two processes of verbal and spatial working memory under different emotional states, respectively. In Experiment 1, participants were asked to perform the delayed match-to-sample task with or without reordering the characters (manipulation process of verbal working memory). In Experiment 2, mental rotation was used as the manipulation process of spatial working memory. The results showed that negative emotion only affected the manipulation process, but not the maintenance process. Relative to neutral and low avoidance-motivated negative conditions, the manipulation processes of both types of working memory were impaired under the high avoidance-motivated negative condition. No significant difference was observed between low avoidance-motivated negative condition and neutral condition. Our results are discussed in relation to efficiency processing theory and motivational dimensional model of affect. We conclude that negative emotional states with high avoidance-motivational intensity impair the manipulation process of verbal and spatial working memory.

The Sleep Quality of the Frontline Healthcare Workers and the Improving Effect of Tai Chi.

Background: A number of studies have documented that coronavirus disease 2019 (COVID-19) brought more negative impact on the physical and psychological functioning of frontline healthcare workers. Especially, sleep quality was focused. This study aimed to investigate the sleep quality of frontline healthcare workers, risk factors for sleep quality, and the effect of Tai Chi training. Methods: A total of 98 frontline healthcare workers were recruited, coming from the infection department, fever clinic, laboratory, and medical imaging department in a COVID-19-designated hospital in Shanghai. Of them, 50 participated in a 2-week intervention and were randomized to receive a Tai Chi training or relaxation training. Participants were assessed at baseline, 7 and 14 days after participation. Demographic information, sleep quality, and anxiety were measured by using the demographic questionnaire, Pittsburgh Sleep Quality Index (PSQI) and Beck Anxiety Inventory (BAI). Results: 13.3% participants were above the cut-off score (>10) for the PSQI. Regression analysis showed gender, age, working years, and job category had effect on sleep quality. Compared to the control group, participants in the Tai Chi training group had lower scores on both PSQI (p < 0.05) and BAI (p < 0.01) after the 2-week intervention. Conclusion: It was demonstrated that poor sleep quality existed in the frontline healthcare workers, which was related to gender, age, working years, and job category. Tai Chi training can dramatically improve their sleep quality and reduce anxiety symptoms.

Number Needed to Treat Network Meta-Analysis to Compare Biologic Drugs for Moderate-to-Severe Psoriasis.

INTRODUCTION: Number needed to treat (NNT) estimates are a practical metric to help identify the most effective therapies. Our objective is to compare 11 biologic drugs for moderate-to-severe psoriasis in terms of NNT. METHODS: The NNT data were obtained from a Bayesian network meta-analysis of 42 double-blind, randomized, phase 3 clinical trials for 11 biologics (adalimumab, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab, and ustekinumab). We determined NNT to achieve Psoriasis Area and Severity Index (PASI) 75/90/100 responses at weeks 4, 8, 12, 16, and 48/52 and Dermatology Life Quality Index (DLQI) response 0, 1 at week 12. RESULTS: Highest efficacy (lowest NNT) was with brodalumab and ixekizumab for PASI 90 at weeks 4, 8, and 12; ixekizumab for PASI 90/100 at week 16; and brodalumab for PASI 100 at week 12. After 48/52 weeks, risankizumab had the highest efficacy for PASI 90/100 overlapping with guselkumab, brodalumab, and ixekizumab for PASI 90 and with brodalumab and ixekizumab for PASI 100. Ixekizumab had the highest efficacy for DLQI (0,1) at week 12. CONCLUSIONS: Brodalumab and ixekizumab had the lowest NNTs for achieving PASI responses at early time points and were not significantly different than risankizumab and guselkumab after 48/52 weeks.

PTSD Symptoms and Sleep Quality of COVID-19 Patients During Hospitalization: An Observational Study from Two Centers.

BACKGROUND: The outbreak of COVID-19 has developed into a pandemic. Data are required that specifically address the psychological consequences in COVID-19 confirmed patients. This study mainly aimed to examine posttraumatic stress disorder (PTSD) symptoms and sleep quality among COVID-19 confirmed patients during hospitalization. METHODS: An observational study was conducted in two designated hospitals in Wuhan, China. Data were collected from 190 patients hospitalized with laboratory-confirmed COVID-19 infection between February 10, 2020 and March 13, 2020. RESULTS: The mean age of the 190 confirmed patients was 55.7 years (SD = 13.7), of which 96 (50.5%) were female and 88 (46.3%) had family members or acquaintances infected with COVID-19. Lymphocytopenia was presented in 62 (32.6%) patients and 25 (13.2%) patients showed oxygen desaturation. The prevalence of high PTSD symptoms was 22.6% among the 190 patients. The median time from symptom onset to first medical visit and hospitalization was 2 days (IQR, 1-5) and 16 days (IQR, 10-27), respectively. Patients' PTSD symptoms were positively related to the time from symptom onset to first medical visit (r = 0.156, p < 0.05) and hospitalization (r = 0.181, p < 0.01). There were significant correlations between sleep quality and PTSD symptoms (r = 0.312-0.547, p < 0.01). CONCLUSION: The prevalence of high PTSD symptoms was 22.6% among hospitalized COVID-19 patients. Early diagnosis and treatment of COVID-19 symptoms are beneficial to infected patients both physically and psychologically. With the recovery of physical symptoms, psychological intervention is desired to promote the trauma recovery in COVID-19 patients.

The impact of the COVID-19 pandemic on the mental health of young people: A comparison between China and the United Kingdom.

PURPOSE: As COVID-19 spreads globally and affects people's health, there are concerns that the pandemic and control policies may have psychological effects on young people (age from 17 to 35 years). This psychological impact might vary in different countries, and thus we compared the prevalence of self-reported psychological distress, loneliness and posttraumatic stress symptoms (PTSS) among young people in the United Kingdom (UK) and China at the beginning of the COVID-19 pandemic. METHODS: Data of this study came from two sources. One source was the first wave of COVID-19 study in Understanding Society, a special wave of the UK household longitudinal study, which provided the high-quality, national-wide representative panel data. The sample comprised 1054 young people. The other source was an online survey on the mental health of 1003 young people from Shanghai, a highly developed area in China. The questionnaire included questions on the prevalence of common mental disorders (cut-off score ≥ 4), loneliness and potential PTSS (cut-off ≥ 33). Univariable analyses were conducted to test the differences in the self-reported prevalence of psychological distress and loneliness between the two groups. Multivariable logistic regression analyses were run to explore the predictors of psychological distress and loneliness among all the young people from England and Shanghai. RESULTS: Among the samples with self-reported psychological distress, the UK sample accounted for 34.4% (n=1054) and the Chinese sample accounted for 14.1% (n=1003). The difference between the two groups was statistically significant (p < 0.001). Additionally, 57.1% of people in the UK and 46.7% in China reported that they sometimes or often felt lonely, of which the difference is statistically significant (p < 0.001). Regression analysis of the entire samples showed that nationality, gender, psychotherapy and loneliness were significant predictors of 12-item General Health Questionnaire scores, while the variables of age and living alone were not. Significant predictors of self-reported loneliness were the nationality, gender, age, living alone and psychotherapy. In China, 123 (12.3%) young people, 49 men (11.3%) and 74 women (13.0%), met the criteria of PTSS symptoms (cut-off scores ≥ 33). These scores were only collected in China. CONCLUSION: This evidence suggests that mental health and loneliness reported by young people were lower in China than that in the UK during the studied period. More research is needed to understand these differences. If the differential negative psychological impacts are confirmed, country-specific measures of prevention and intervention should be adopted to improve the mental health of young people under the ongoing impact of the pandemic.

Neural presbycusis at ultra-high frequency in aged common marmosets and rhesus monkeys.

The aging of the population and environmental noise have contributed to high rates of presbycusis, also known as age-related hearing loss (ARHL). Because mice have a relatively short life span, murine models have not been suitable for determining the mechanism of presbycusis development and methods of diagnosis. Although the common marmoset, a non-human primate (NHP), is an ideal animal model for studying age-related diseases, its auditory spectrum has not been systematically studied. Auditory brainstem responses (ABRs) from 38 marmosets of different ages demonstrated that auditory function correlated with age. Hearing loss in geriatric common marmosets started at ultra-high frequency (>16 kHz), then extended to lower frequencies. Despite age-related deterioration of ABR threshold and amplitude in marmosets, outer hair cell (OHC) function remained stable at all ages. Spiral ganglion neurons (SGNs), which are the first auditory neurons in the auditory system, were found to degenerate distinctly in aged common marmosets, indicating that neural degeneration caused presbycusis in these animals. Similarly, age-associated ABR deterioration without loss of OHC function was observed in another NHP, rhesus monkeys. Audiometry results from these two species of NHP suggested that NHPs were ideal for studying ARHL and that neural presbycusis at high frequency may be prevalent in primates.

Prevalence and risk factors for acute posttraumatic stress disorder during the COVID-19 outbreak.

BACKGROUND: To examine the prevalence of and risk factors for acute posttraumatic stress disorder (PTSD) shortly after the massive outbreak of COVID-19 in China. METHODS: An online anonymous survey was conducted between 30 January and 3 February, 2020. The survey included two self-administered questionnaires: one collected personal information (gender, age, education background), current location, recent epidemic area contact history, the classification of population, and subjective sleep quality; the other was the PTSD Checklist for DSM-5 (PCL-5). RESULTS: A total of 2091 Chinese participated in the current study. The prevalence of PTSD among the Chinese public one month after the COVID-19 outbreak was 4.6%. Multiple linear regression analysis revealed that gender (p < 0.001), epidemic area contact history (p = 0.047), classification of population (p < 0.001), and subjective sleep quality (p < 0.001) could be regarded as predictors for PTSD. LIMITATIONS: First, the majority of participants in this study were the general public, with confirmed or suspected patients being a small part. Second, the measurement of PTSD in this study might be vulnerable to selection bias because of an online self-report study, such as participants' recruitment. Third, the prevalence of PTSD in this study was estimated by an online questionnaire rather than a clinical interview. CONCLUSIONS: The results suggested that some Chinese showed acute PTSD during the COVID-19 outbreak. Therefore, comprehensive psychological intervention needs further implementation. Furthermore, females, people who had recent epidemic area contact history, those at high risk of infection or with poor sleep quality deserve special attention.

The prevalence of PTSS under the influence of public health emergencies in last two decades: A systematic review and meta-analysis.

BACKGROUND: Since the beginning of 21st century, several major public health emergencies (PHEs) have threatened the health of people globally. Posttraumatic stress symptoms (PTSS) was one of the most concerned mental health problems. The objective of this study is to systematically estimate the prevalence of PTSS under the influence of PHEs. METHOD: We searched both English and Chinese databases. This meta-analysis used a random-effects model to estimate the prevalence of PTSS. Subgroup analyses were conducted to analyze the source of heterogeneity. Meta-regression model was used to calculate the proportion of the variance explained by subgroup moderators. RESULTS: Forty eligible studies (n = 15,538) were identified. The results revealed a pooled prevalence of PTSS of 17.0% (95%CI: 13.5%-21.2%), higher than that of previous epidemiological survey, with high between-studies heterogeneity (Q = 1199, I2 = 96.75%, p < .001). There was variance of prevalence in different countries (4.0%-36.5%) and epidemics (12.1%-36.5%). The prevalence of PTSS showed the feature of fluctuation in the change of time (Q = 6.173, p = .290). Patients had higher prevalence (26.2%) compared to healthcare workers (HCWs) (18.5%) and community samples (12.4%) and frontline HCWs had marginally significantly higher estimated rate than general HCWs (22.2%, 95%CI:16.0%-30.1% vs. 10.4%, 95%CI: 6.4%-16.6%). The variance of prevalence screened by interview and self-reported was significant (Q = 3.393, p = .05) and studies with higher quality possessed lower prevalence (high:12.4%; moderate: 17.3%; low: 18.0%). The total variance explained by subgroup moderators was estimated 64% by meta regression model. LIMITATIONS: Limitations include high level of heterogeneity between studies and within subgroups as well as the lack of studies with high quality and using probability sampling. CONCLUSIONS: This study suggested that the PTSS was common under the influence of PHEs. It was crucial to further explore the psychological mechanism and effective strategies for prevention and intervention in future research with more high-quality studies.

Mitochondrial Dysfunction and Therapeutic Targets in Auditory Neuropathy.

Sensorineural hearing loss (SNHL) becomes an inevitable worldwide public health issue, and deafness treatment is urgently imperative; yet their current curative therapy is limited. Auditory neuropathies (AN) were proved to play a substantial role in SNHL recently, and spiral ganglion neuron (SGN) dysfunction is a dominant pathogenesis of AN. Auditory pathway is a high energy consumption system, and SGNs required sufficient mitochondria. Mitochondria are known treatment target of SNHL, but mitochondrion mechanism and pathology in SGNs are not valued. Mitochondrial dysfunction and pharmacological therapy were studied in neurodegeneration, providing new insights in mitochondrion-targeted treatment of AN. In this review, we summarized mitochondrial biological functions related to SGNs and discussed interaction between mitochondrial dysfunction and AN, as well as existing mitochondrion treatment for SNHL. Pharmaceutical exploration to protect mitochondrion dysfunction is a feasible and effective therapeutics for AN.

Characterization of promoters for adeno-associated virus mediated efficient Cas9 activation in adult Cas9 knock-in murine cochleae.

CRISPR/Cas9 gene editing enables the treatment of hearing loss in congenitally deaf neonatal mice via both viral and non-viral delivery. While adeno-associated virus (AAV)-mediated gene delivery systems have been shown to be effective tools for gene replacement in the inner ear, application of the AAV-mediated CRISPR/Cas9 gene-editing approach for this purpose is yet to be documented. Based on our previous findings, we focused on the effects of several AAVs delivered via canalostomy injection in adult mice. Among the AAVs examined, AAV8 showed the greatest efficiency and specificity in transducing inner hair cells (IHC). The ability of Cre-expressing AAV8 to activate Cas9 in floxed-Cas9 knock-in (Cas9 KI) mice was further evaluated. We compared the effects of six different promoters (CMV, CAG, hSyn, CaMKIIa, GFAP, and ALB) of AAV8 delivered to the inner ear of adult Cas9 KI mice. Our findings showed that three AAV groups (CMV, CAG and hSyn promoters) infected the inner ear efficiently with different tropisms. Notably, AAVs with CMV, CAG, and hSyn promoters infected diverse cell types in mature murine cochleae, including IHCs. In particular, AAV8-hSyn showed high affinity to IHCs and spiral ganglion neurons (SGN). Neither the AAV8 virus itself (except AAV8-CAG) nor the surgical procedures used caused damage to HCs or impaired normal hearing. Our findings indicated that injection of AAV-Cre into mature inner ear efficiently induces Cas9 activation to achieve safe and efficient gene editing and different constituent promoters confer diverse infection patterns in cochlea, expanding the repertoire of gene-editing tools for regulating gene expression in target cells of the inner ear as part of the collective effort to rescue genetic hearing loss and develop effective gene therapy techniques.

China experience from COVID-19: Mental health in mandatory quarantine zones urgently requires intervention.

The study investigated the quarantine of COVID-19 and its impact on mental health. The results showed that there was a significant difference in PTSD Checklist for DSM-5 scores between the quarantine group and the non-quarantine group. As a result, the mental health of residents in mandatory quarantine zones urgently requires intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Posttraumatic stress symptoms of health care workers during the corona virus disease 2019.

Corona virus disease 2019 (COVID-19) outbreak has attracted worldwide attention. The COVID-19 outbreak is unique in its rapid transmission and results in heavy stress for the front-line health care workers (HCWs). The current study aimed to exam posttraumatic stress symptoms (PTSSs) of HCWs fighting for the COVID-19 and to evaluate their sleep quality after 1-month stressful suffering. Three hundred seventy-seven HCWs working in different provinces of China participated in the survey between February 1 and 5. The demographic information was collected first. Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) and the Pittsburgh Sleep Quality Index (PSQI) were selected to measure PTSSs and sleep quality. Results showed that 1 month after the outbreak, the prevalence of PTSSs was 3.8% in HCWs. Female HCWs were more vulnerable to PTSSs with hazard ratio of 2.136 (95% CI = 1.388-3.286). HCWs with higher exposure level also significantly rated more hyperarousal symptoms (hazard ratio = 4.026, 95% CI = 1.233-13.140). There was a significant difference of sleep quality between participants with and without PTSSs (z value = 6.014, p < .001) and among different groups with various contact frequencies (chi-square = 7.307, p = .026). Path analysis showed that there was a significant indirect effect from exposure level to PTSSs through sleep quality (coefficient = 1.750, 95% CI of Boostroop test = 0.543-2.998). In summary, targeted interventions on sleep contribute to the mental recovery during the outbreak of COVID-19. Understanding the mental health response after a public health emergency might help HCWs and communities prepare for a population's response to disaster.

Prevalence and predictors of PTSS during COVID-19 outbreak in China hardest-hit areas: Gender differences matter.

The outbreak of COVID-19 in China in December 2019 has been identified as a pandemic and a health emergency of global concern. Our objective was to investigate the prevalence and predictors of posttraumatic stress symptoms (PTSS) in China hardest-hit areas during COVID-19 outbreak, especially exploring the gender difference existing in PTSS. One month after the December 2019 COVID-19 outbreak in Wuhan China, we surveyed PTSS and sleep qualities among 285 residents in Wuhan and surrounding cities using the PTSD Checklist for DSM-5 (PCL-5) and 4 items from the Pittsburgh Sleep Quality Index (PSQI). Hierarchical regression analysis and non-parametric test were used to analyze the data. Results indicated that the prevalence of PTSS in China hardest-hit areas a month after the COVID-19 outbreak was 7%. Women reported significant higher PTSS in the domains of re-experiencing, negative alterations in cognition or mood, and hyper-arousal. Participants with better sleep quality or less frequency of early awakenings reported lower PTSS. Professional and effective mental health services should be designed in order to aid the psychological wellbeing of the population in affected areas, especially those living in hardest-hit areas, females and people with poor sleep quality.

Prolonged grief disorder in Chinese Shidu parents who have lost their only child.

Background: China has the largest population of '"loss-of-only-child' parents, that are also known as Shidu parents in Chinese society; however, little is known about their unresolved grief. Objective: This is the first study to examine the grief symptoms, prevalence, comorbidity and potential predictors of prolonged grief disorder (PGD) in such parents, taking into consideration that the new PGD diagnostic criteria ICD-11 will soon be implemented in China. Methods: 149 Shidu parents completed assessments of PGD (PG-13), PTSD (PCL-C), depression (CES-D) and general psychiatric morbidity (GHQ-12) via in-person interviews. Results: Of the 149 Shidu parents, 22.2% met the PGD criteria, with a mean of 7.59 years post-loss, and 62.4% experienced daily longing or yearning. Regression analysis indicated that fewer years since loss, subjective perception of poor economic situation, female gender and more hospital visits were prominent risk factors for the development of PGD. Older age of the parents at the time of child loss was also associated with PGD. Parents with PGD had higher comorbidity of PTSD or depression compared with those without PGD. Conclusions: There is a high prevalence of PGD and a high rate of comorbidity between PGD and PTSD or depression in Shidu parents in China, which highlights the need of timely developing effective assessments and interventions to prevent PGD in this population, particularly in female, recently bereaved, low-income and aged parents who lost their only child.

Antecedentes: China tiene la población más grande de padres que han perdido a su hijo único, conocidos como los padres shidu en la sociedad china; sin embargo, se conoce poco respecto a su duelo no resuelto.Objetivo: Este es el primer estudio en evaluar los síntomas de duelo, y la prevalencia, comorbilidades y predictores potenciales del trastorno de duelo prolongado (TDP) en este tipo de padres, tomando en consideración que los nuevos criterios diagnósticos para el TDP de la CIE-11 se implementarán pronto en China.Métodos: 149 padres Shidu completaron evaluaciones para TDP (PG-13), TEPT (PCL-C), depresión (CES-D) y morbilidad psiquiátrica general (GHQ-12) mediante entrevistas en persona.Resultados: De los 149 padres shidu, 22,2% cumplieron los criterios para TDP, con un promedio de 7,59 años pospérdida, y 62,4% experimentaron nostalgia y anhelo. Los análisis de regresión indicaron que menos años luego de la pérdida, una percepción subjetiva de una pobre situación económica, el sexo femenino, y un mayor número de consultas en hospitales eran factores de riesgo prominentes para el desarrollo de TDP. Una mayor edad de los padres al momento de la pérdida del niño también se asoció con TDP. Los padres con TDP tenían mayor comorbilidad de TEPT o depresión comparados con aquellos que no tenían TDP.Conclusiones: Existe una alta prevalencia del TDP y una alta tasa de comorbilidad entre el TDP, el TEPT o la depresión en padres Shidu en China, lo cual resalta la necesidad de desarrollar a tiempo evaluaciones e intervenciones efectivas para prevenir el TDP en esta población, en particular en mujeres, en deudos recientes, en aquellos con bajos ingresos, y en padres de edad avanzada que perdieron a su hijo único.

Developments of prolonged exposure in treatment effect of post-traumatic stress disorder and controlling dropout rate: A meta-analytic review.

Prolonged exposure (PE) has been proved as an efficacious psychological treatment for post-traumatic stress disorder (PTSD). There are mainly two changed formats of PE: the modified PE (mPE) and the PE combined with drug (PE/d). Symptom reduction following these two PE training formats has been reported in the patients with PTSD. However, very little is focusing on the direct comparison of mPE + PE/d and PE. Therefore, this paper aims to compare the mPE + PE/d with PE on the PTSD treatment effect and the dropout rate directly through the meta-analysis. Eighteen studies with total sample size of 1,397 met the final inclusion criteria. The results showed that mPE + PE/d had significantly lower posttreatment PTSD severity than control group (relaxation, wait list, etc.). There was no significant difference between mPE + PE/d and PE on the posttreatment, the follow-up PTSD score, and the posttreatment dropout rate. Compared with PE, lower PTSD symptoms and marginally lower dropout rate following the treatment were observed in the PE/d group. PE/d yielded a significantly larger effect size than mPE when compared with PE on the posttreatment PTSD symptom severity. The significance of the above results would not be changed even if studies causing high heterogeneity were removed. Although PE/d enhanced treatment effect and lowered dropout rate when compared with PE, it was still insufficient to draw the conclusion that formats of adjustments would specifically improve the implementation of PE. Further studies are warranted to develop an easily accomplished and efficacy-guaranteeing PE programme for PTSD patients.

Risk factors for PTSD of Shidu parents who lost the only child in a rapid aging process: a cross-sectional study.

BACKGROUND: The elderly population is rising globally, especially in China where a large population base causes the largest number of older adults in the world. Notably, Shidu people who are over the age of 60 and have lost their only child have drawn great public attentions as they become more elderly, medically unstable and worse mentally unhealthy. Posttraumatic stress disorder (PTSD) is one of the most common consequences resulted from the loss of the only child. However, few previous studies have examined PTSD in Shidu older aldults, and the risk factors are a relatively understudied area. Our study aims to estimate the prevalence and potential risk factors of PTSD and improve the possibility of early identifying the high-risk Shidu parents with PTSD, and successively provide timely and effective interventions. METHOD: Based on the register of population statistic information provided by the health family planning commission, 149 participants were enrolled randomly. Data was collected by interviews and questionnaires. Socio-demographic and bereavement-related information and physical health outcomes were obtained. PTSD Checklist-Civilian Version was used to screen for bereavement-related PTSD. RESULT: The morbidity of PTSD reached 30.9%, while in the group of age over 60 the morbidity reached 31.6%. Stratified by potential demographic risk factors, SDPs have significant between-group differences of PTSD. Specially, being women, higher income, losing the single child at older age, more serious medical conditions and being Shidu for a shorter period indicated higher severity of PTSD in SDPs. The single child dying at a older age and from accidence were also significant indicators. Regression analysis showed the gender of SDPs, hospital visits, and the cause of child death significantly predicted the severity of PTSD. CONCLUSION: With the accelerate process of aging, especially in China, Shidu older adults become a group deserved more attentions. PTSD is clearly a possible reaction to the loss of the only child. The gender and hospital visits of the Shidu older adults and the causes of their child's death significantly related to the prevalence of PTSD, which could help to improve the possibility of early intervening.

Adeno-associated virus vector enables safe and efficient Cas9 activation in neonatal and adult Cas9 knockin murine cochleae.

Adeno-associated virus (AAV)-mediated gene delivery systems have been shown to be effective tools for gene manipulation in the inner ear. For example, hair cells (HCs) and multiple other cell types can be transduced by the local injection of AAVs into the inner ear. However, application of the AAV-mediated CRISPR/Cas9 gene-editing approach to the inner ear in adult mice has not yet been studied. Based on our previous work, we investigated several AAV serotypes in neonatal and adult mice in parallel, and found that AAV8 had the top efficiency to transduce inner HCs. We then tested the ability of Cre-expressing AAV8 to activate Cas9 in floxed-Cas9 knockin mice, and observed significant Cas9 activation in the inner ear of both neonatal and adult animals. Neither the AAV8 virus itself nor the surgical procedures used to deliver it-cochleostomy for neonatal mice and canalostomy for adult mice-caused any damage to HCs or impaired normal hearing. Our studies indicate that the local injection of AAV8-Cre can induce Cas9 activation to perform safe and efficient gene editing in the inner ear, expanding the repertoire of gene-editing tools for regulating gene expression in the inner ear as a part of efforts to rescue genetic hearing loss, initiate regeneration of HCs, or develop gene therapy techniques.