Objective To evaluate the effect of therapeutic hypercapnia on the balance between cer-ebral O2supply and demand in the patients undergoing arthroscopic shoulder surgery in the beach chair posi-tion(BCP). Methods Forty-eight patients of both sexes, aged 21-64 yr, weighing 45-80 kg, of Ameri-can Society of Anesthesiologists physical statusⅠorⅡ, scheduled for elective arthroscopic shoulder surgery in the beach chair position, were divided into 2 groups(n=24 each)using a random number table: control group(group C, end-tidal pressure of carbon dioxide 35-40 mmHg)and therapeutic hypercapnia group (group H, end-tidal pressure of carbon dioxide 45-50 mmHg). The regional cerebral oxygen saturation (rSO2)was recorded after induction and before BCP, immediately after BCP, at 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 min after BCP and at the end of surgery(T0-12). The occurrence of cerebral desaturation events, extubation time, duration of stay in postanesthesia care unit, development of nausea and vomiting and requirement for vasoactive drugs were recorded during surgery. Results Compared with the baseline at T0, the rSO2was significantly decreased at T1-12in group C and at T2-6in group H(P<005). The rSO2was significantly higher at T1-12, and the incidence of cerebral desaturation events was lower in group H than in group C(P<005). There was no significant difference between the two groups in the extubation time, dura-tion of stay in postanesthesia care unit, incidence of nausea and vomiting or requirement for vasoactive drugs (P>005). Conclusion Therapeutic hypercapnia can improve the balance between cerebral O2supply and demand in the patients undergoing arthroscopic shoulder surgery in the BCP.

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.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems