Human 8-cell embryos enable efficient induction of disease-preventive mutations without off-target effect by cytosine base editor

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.

Evaluation of subjective scale in allergen nasal provocation test / 临床耳鼻咽喉头颈外科杂志

Objective:To compare the clinical value of visual analogue scale （VAS）, Lebel scale and total nasal symptom scores （TNSS） in evaluating nasal allergen provocation test （NAPT）. Methods:A total of 151 patients suspected of allergic rhinitis admitted to the Department of Otolaryngology-Head and Neck Surgery of our hospital from April 2020 to September 2020 were included, of which 76 were positive for house dust mites and 75 were negative for allergens. Nasal airway resistance（NAR） was measured by active anterior nasal manometry. Nasal symptoms were evaluated by VAS, Lebel and TNSS. House dust mite allergen was used for NAPT by spray method. An increase≥40% in NAR was used as the gold standard for objective evaluation of NAPT. ROC curves of VAS, Lebel and TNSS were drawn to compare the evaluation effectiveness of different subjective evaluation methods, and the optimal critical point of each ROC curve was obtained. Results:With NAR increased by ≥40% as the gold standard, the area under ROC curve of VAS was 0.884, and the sensitivity and specificity were 97.75% and 80.65%, respectively. The area under ROC curve of Lebel was 0.773, and the sensitivity and specificity were 68.54% and 75.81%, respectively. The area under ROC curve of TNSS was 0.792, and the sensitivity and specificity were 68.54% and 79.03%, respectively. There was no significant difference between Lebel and TNSS（P>0.05）. The VAS differed significantly from Lebel and TNSS（P<0.05）. The Kappa values of VAS, Lebel, TNSS and NAR were 0.803, 0.432 and 0.459, respectively. Conclusion:The VAS, Lebel, TNSS subjective scale and NAR are consistent in evaluating the efficacy of NAPT, with the VAS assessment showing highest consistency with NAR. As objective assessment instruments are not widely used in China, subjective assessment method could be adopted to evaluate the efficacy of NAPT in clinical practice, and VAS scale is recommended as a priority.

Susceptibility factors of occurrence of allergic rhinitis / 中国基层医药

Objective:To analyze the genetic and environmental factors that may contribute to the development of allergic rhinitis (AR) in patients, and provide a scientific basis for formulating intervention measures.Methods:This is a case-control study. A cross-sectional survey was conducted on AR patients who received treatment at The First Affiliated Hospital of Nanchang University from June 2017 to March 2019 using a self-designed questionnaire on AR susceptibility factors. Logistic regression analysis of AR susceptibility factors was performed.Results:There were 242 patients in the AR group and 258 patients in the non-AR group (control group). The average age of all patients was (13.16 ± 5.63) years. 56.8% of included patients were male. Multivariate logistic regression analysis showed that AR onset was associated with neonatal jaundice ( OR = 6.043), respiratory infections within 6 months after birth ( OR = 8.123), diarrhea ( OR = 3.868), eczema ( OR = 4.540), living in urban areas ( OR = 2.477), home decoration after birth ( OR = 3.042), moldy ceilings or walls ( OR = 38.255), home gardening ( OR = 3.752), and exposure to smoking environments ( OR = 2.574). Conclusion:The etiology of AR is complex, and its onset is influenced by various factors such as genetic factors, environmental factors, and related disease factors. It is necessary to strengthen the promotion and education of AR prevention knowledge, pay attention to environmental hygiene, and take personal protection measures.

Bedside diagnosis of isolated transient vertigo in middle-aged and elderly patients / 中风与神经疾病杂志

@#Objective To study the common etiological components and bedside diagnostic skills of isolated transient vertigo (ITV).Methods We performed a single-center observational study that had consecutively recruited 424 middle-aged and elderly patients presenting with vertigo episodes lasted less than three minutes in the Neurology Department of Shanghai Tongji Hospital from January 2018 to January 2020.The clinical characteristics were collected and analyzed according to the established format and vertigo causes were analyzed.Binary Logistic regression analysis was used to determine some clinical parameters to benign paroxysmal positional vertigo (BPPV) and vascular ITV (vITV).Results In all 424 patients,BPPV accounted for 65.09% (n=276),vITV for 20.51% (n=87).Fifty-two cases (18.84%) of BPPV were diagnosed as posterior circulation ischemia (PCI) and 12 cases (14.63%) of vITV were suspected as BPPV.Logistic Regression analysis showed that onset time of vertigo<30 s,vertigo provoked by lying down or turning over in the supine position and typical nystagmus by positional maneuver were the independent predicted factors of BPPV (P<0.001).The higher risk of vITV was found in association with intolerance of head movement,trunk balance disturbance,spontaneous nystagmus and intolerance by positional maneuver (P<0.001).There was no independent correlation between vascular risk factors and vITV (P>0.05).Conclusion BPPV and vITV are the most common etiologies of ITV in the middle-aged and elderly patients.The etiology of ITV can be quickly and effectively distinguished by some specific clinical features and target bedside examinations.

Endovascular recanalization of the symptomatic non-acute occlusion of large intracranial artery of circulation: preliminary study / 中华放射学杂志

Objective To investigate the feasibility,safety and efficacy of endovascular recanalization of the symptomatic occlusion of large intracranial artery in anterior circulation.Methods From October 2015 to December 2017,13 patients with symptomatic non-acute occlusion of large intracranial artery in anterior circulation were enrolled into this study and underwent endovascular recanalization.The initial procedural results,including the rate of successful recanalization and perioprocedural complications,and angiographic and clinical follow-up results were collected.The functional outcome was evaluated at discharge and 90 days.Results Recanalization was successful in 11 out of 13 patients.Perioperative complications occurred in 8 cases,including distal embolization in 7 cases (3 with symptom and 4 without),in which intracerebral hemorrhage associated with embolectomy was found in 1 case;and distal embolization concomitant with artery dissection in 1 case.At discharge,the symptoms of 10 out of 11 patients with successful recanalization were improved and 1 was unchanged;one of 2 patients with recanalization failure was aggravated and 1 was unchanged.After the procedure,1 patient with successful recanalization,but complicated with intracerebral hemorrhage associated with embolectomy was lost at follow-up,thus angiographic follow-up was available in the remaining 10 patients.Of the 10 patients,1 patient developed in-stent restenosis at 12 months and 9 patients had no hemodynamic stenosis/reocclusion.The clinical follow-up was available in 12 patients.No recurrence of TIA or stroke was found in 9 cases with successful recanalization except for 1 case who developed in-stent stenosis and suffered from TIA.At the follow-up of 90 days,l0 patients with successful recanalization showed good function (mRS∶0-2),2 patients with recanalization failure were deteriorated.Conclusions In strictly selected patients with symptomatic non-acute occlusion of large intracranial artery in anterior circulation,endovascular recanalization was feasible and safe,which may improve patients' symptoms in a short term and reduce the recurrence rate of stroke,but its definite efficacy needs to be confirmed by studies with larger sample and longer follow-up.

The relationship between smoking status and epidermiology of asthma in people aged over 14 years in China / 中华内科杂志

Objective To study the relationship between bronchial asthma and smoking status in Chinese people.Methods Asthma epidemiological survey and stratified-cluster-random method survey were performed in residents over 14 years in 8 provinces (cities) of China from February 2010 to August 2012.Asthma was diagnosed based upon case history,clinical signs and lung function test.Smoking status was investigated by questionnaire.Results Sampling population was 180 099 and 164 215 were valid.A total of 2 034 subjects were diagnosed as asthma including 79 692 men and 84 523 women.The overall prevalence rate of asthma was 1.24％ (2 034/164 215).Smokers were 23.8％ (39 137/164 215) in the whole population.Smokers were 34.5％ (702/2 034) in asthmatic patients,compared with 23.7％ (38 435/ 162 181) in no-asthmatic population.The incidence of asthma was 1.79％ and 1.06％ in smokers and nonsmokers respectively (P ＜0.001),suggesting that OR of smoking was 1.70 (95％ CI 1.55-1.86,P ＜ 0.001).According to asthma control test (ACT) score,the level of asthma control in non smoking group was higher than that in smoking group(43.2％ vs 35.3％).The times of hospitalization due to acute exacerbations (0.51 vs 0.41 events/person/year),total hospitalization rate (27.35 ％ vs 20.12％),annual emergency room visits (0.80 vs 0.60 events/person/year) and emergency room visit rate (31.77％ vs 24.47％) were all much higher in smoking asthmatic patients than those in non smoking asthmatic patients,indicating that the level of asthma control in smoking patients was significantly worse than in non smoking patients.Conclusions The smoking rate in Chinese people over 14 years is still high.The prevalence rate of asthma in smokers is significantly higher than that of non-smokers.The level of asthma control in smokers is significantly worse than that in non smokers.

Analysis of aeroallergen spectrum in patients with allergic rhinitis in Nanchang area / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To determine the distribution of allergens in patients with allergic rhinitis in Nanchang area and provide the clinical reference for management strategies with regional character.</p><p><b>METHODS</b>Patients with symptoms of allergic rhinitis were given skin prick test (SPT) from March 2012 to May 2013. Among the patients, the distribution of all allergens was analyzed. The positive rate was compared with gender, age, occupation, season, course of disease and so on.SPSS 17.0 software was used to analyze the data.</p><p><b>RESULTS</b>Among 5 654 patients, the total positive rate of SPT was 56.07%, with dermatophagoides pteronyssinus (46.94%), dermatophagoides farina (35.99%), blomia tropicalis (31.34%) as the major allergens. With age increasing, the positive rate of allergen decreased. There was statistically significant difference (χ² = 261.372, P < 0.01) . There was significant difference of the positive rate in different occupations (χ² = 170.859, P < 0.01), the highest rate was found in student (66.12%) and the lowest was found in farmer (41.56%). There was significant difference of variation with months (χ² = 227.333, P < 0.01), the most in October, 68.88%. There was significant difference of the positive rate of dust mites in different seasons (χ² = 204.343, P < 0.01), the highest in autumn, the lowest in winter. There was no correlation between the positive rate and course of disease (P > 0.05).</p><p><b>CONCLUSIONS</b>Dust mites were identified as the most common allergens among patients with allergic rhinitis in Nanchang area.Occupation is one of the influencing factors for the positive rate.</p>

Clinical observation of the adverse effects of standardized dust mite allergen preparation in the treatment of allergic rhinitis / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To observe the adverse effects of specific immunotherapy (SIT) with standardized dust mite allergen preparation in the treatment of allergic rhinitis.@*METHOD@#Three hundred and eighty-six patients with allergic rhinitis who received subcutaneous SIT with a standardized dust mite allergen preparation were enrolled in this study. The patients were treated for at least 15 weeks,adverse effects after each injection from dosing phase to maintenance phase were recorded and incidence of adverse effects were analyzed.@*RESULT@#Of all the patients,adverse reactions occurred in 42 patients (10. 9%),10 local reactions (2. 6%) and 36 systemic side effects (9. 3%) which included 34 mild ,1 moderate and 1 severe side effects (no fatal) were reported respectively. None had anaphylactic shock. Among three treatment options, incidence of routine program was the highest (21.1%),followed by adult cluster program (11. 9%), adverse effects of children cluster program was the least (1. 5%). The adverse effects often happened in the middle and late phase of does addition period and early phase of maintenance period.@*CONCLUSION@#SIT with standardized dust mite allergen preparation in the treatment of allergic rhinitis is a safe and effective treatment by complying with the guidelines and taking specific interventions.