Functional correction of CFTR mutations in human airway epithelial cells using adenine base editors

Mutations in the CFTR gene that lead to premature stop codons or splicing defects cause cystic fibrosis (CF) and are not amenable to treatment by small-molecule modulators. Here, we investigate the use of adenine base editor (ABE) ribonucleoproteins (RNPs) that convert A•T to G•C base pairs as a therapeutic strategy for three CF-causing mutations. Using ABE RNPs, we corrected in human airway epithelial cells premature stop codon mutations (R553X and W1282X) and a splice-site mutation (3849 + 10 kb C > T). Following ABE delivery, DNA sequencing revealed correction of these pathogenic mutations at efficiencies that reached 38–82% with minimal bystander edits or indels. This range of editing was sufficient to attain functional correction of CFTR-dependent anion channel activity in primary epithelial cells from CF patients and in a CF patient-derived cell line. These results demonstrate the utility of base editor RNPs to repair CFTR mutations that are not currently treatable with approved therapeutics.

Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency

Adenosine deaminase 2 deficiency (DADA2) is a rare inherited disorder that is caused by autosomal recessive mutations in the ADA2 gene. Clinical manifestations include early-onset lacunar strokes, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic defects. Anti–tumor necrosis factor therapy reduces strokes and systemic inflammation. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Autologous HSPC gene therapy may be an alternative curative option for patients with DADA2. We designed a lentiviral vector encoding ADA2 (LV-ADA2) to genetically correct HSPCs. Lentiviral transduction allowed efficient delivery of the functional ADA2 enzyme into HSPCs from healthy donors. Supranormal ADA2 expression in human and mouse HSPCs did not affect their multipotency and engraftment potential in vivo. The LV-ADA2 induced stable ADA2 expression and corrected the enzymatic defect in HSPCs derived from DADA2 patients. Patients’ HSPCs re-expressing ADA2 retained their potential to differentiate into erythroid and myeloid cells. Delivery of ADA2 enzymatic activity in patients’ macrophages led to a complete rescue of the exaggerated inflammatory cytokine production. Our data indicate that HSPCs ectopically expressing ADA2 retain their multipotent differentiation ability, leading to functional correction of macrophage defects. Altogether, these findings support the implementation of HSPC gene therapy for DADA2.

Effect of Tai Chi Combined With Kinesio Taping on Posture Control of Football Players With FAI: Protocol For a Randomized Controlled Trial

Background: Functional ankle instability (FAI) of college football players is an important risk factor affecting their training and competition. Physical therapy and appropriate sports intervention can improve the stability of FAI patients. Previous studies have shown that Tai Chi (TC) and Kinesio Taping (KT) can improve the posture control ability of FAI patients. However, whether Tai Chi combined with kinesio taping effect patch can be used as an effective exercise for the rehabilitation of college football players with FAI is not yet proven.Methods/design: 53 FAI college football players were randomly assigned to 3 groups: TC+KT (n=20); TC+KTp (Placebo Kinesio taping, KTp, placebo) (n=17); KT (N=16). The TC+KT group received TC and KT functional correction technical intervention, the TC+KTp group received TC and placebo KT technical intervention, and the KT group received KT functional correction technical intervention. Each of the three groups received 30 minutes each time, 3 times a week, for a total of 6 weeks of intervention training. Star Excursion Balance Test (SEBT) and UniPedal Stance Test (UST) at baseline (before), 4 weeks after intervention (middle) and 6 weeks after intervention (after) , Toe Touch Test (TTT) for evaluation.Discussion: For the first time in this trail, the impact will be evaluated. If the results are the same as expected, they will provide evidence that Tai Chi combined with kinesio taping sticking intervention can promote the posture control of college football players with FAI.。Trial registration: Chinese Clinical Trial Registry, ChiCTR1900027253.Registered on 6 November 2019.

Optimization of anesthetic tactics in the surgical treatment of multiple primary non-small cell lung cancer

The article describes a clinical case of surgical treatment of a patient with multiple primary malignant lesions of the lungs (cancer of the left lung, central peribronchial nodular tumor with involvement of the upper lobe and distal parts of the main bronchus; cancer of the right lung, central tumor with involvement of the upper lobar bronchus). Radical treatment became possible due to using the potential of artifi cial gas exchange of both lungs with two devices with fundamentally different ventilation mechanics. The choice of an optimal tactics for the functional correction of the supposed hypoxemia by volumetric and high-frequency pulmonary ventilation allowed avoiding an imbalance in the ventilation/perfusion ratio and preventing the development of life-threatening complications, as well as ensured an adequate gas exchange for the patient during surgical treatment.

Functional movement screen evaluation system for the prevention of military training injuries: a prospective study in China

Background: Military training injury is a difficult problem in the field of military training. This study aimed to evaluate the effectiveness and feasibility of functional movement screen (FMS) evaluation system and individualized intervention measures in preventing military training injuries.Methods: A total of 420 recruits from a unit of the People's Liberation Army of China (PLA) were included as the research object. According to random grouping method, they were divided into observation group (Group A) and control group (Group B) , with 210 patients in each group. Before recruit training, individual FMS were performed, and functional correction training was performed in the observation group according to the test scores, while no intervention measures were applied in the control group. After three months of training, the tests were repeated. Age, body mass index (BMI) and incidence of military training injuries were recorded during the training period.Results: There was no statistical difference between the two groups in age, BMI, FMS score before the training (P > 0.05). After receiving functional correction training, the FMS score of the Group A was higher than that of the Group B, and the difference was statistically significant (P < 0.05). The incidence of military training injury in Group A and Group B was 20.95% and 44.02%, respectively (P < 0.05), and the difference was statistically significant.Conclusion: The evaluation system of FMS and individualized intervention measures are feasible and effective in predicting and reducing the occurrence of military training injuries.

Effects of functional correction training on injury risk of athletes: a systematic review and meta-analysis

Background We explored functional correction training using the Functional Movement Screen (FMS™) tool. We also analyzed the effects of training on the injuries of athletes in a systematic review and meta-analysis of non-randomized clinical trials. Methodology We collected twenty-four articles from PubMed, CENTRAL, Scopus, ProQuest, Web of Science, EBSCOhost, SPORTDiscus, Embase, WanFang, and CNKI that were published between January 1997 to September 2020. Articles were selected based on the following inclusion criteria: randomized and non-randomized controlled trials, studies with functional correction training screened by FMS™ as the independent variable, and studies with injury risk to the athlete as the dependent variable. Data conditions included the sample size, mean, standard deviation, total FMS™ scores, number of injuries, and asymmetry movement patterns after interventions in the experimental and control groups. Exclusion criteria included: conference abstracts, cross-sectional studies, articles with retrospective study design. Results Twelve non-randomized trials were included in the meta-analysis. The injury risk ratio of athletes after functional correction training was 0.39 RR (95 CI [1.50–1.93]; Z = 15.53; P < 0.0001; I2 = 2.6%), indicating an improvement of athletes functional patterns. Conclusion Grade B evidence indicates that functional correction training based on FMS™ may improve the functional patterns of athletes and Grade D evidence indicates that it may reduce the risk of sports injury. However, the true effect is likely to be different from the estimate of the effect. Therefore, further studies are needed to explore the influence of functional correction training on the injury risks of athletes. Protocol registration: CRD42019145287.

Outcome of treatment with modified Ponseti technique in atypical congenital talipes equinovarus

Background: The atypical congenital talipes equinovarus (CTEV) patients tend to have a different clinical foot presentation with small great toe, deep transverse crease of sole, tender swollen dorsum of foot and rigid equinus.Methods: This study was conducted in GMC Jammu to evaluate efficacy of modified Ponseti technique in atypical CTEV patients. It was a prospective study and the patient data was collected during OPD visits of patients from August, 2018 to June, 2020. Twenty-one patients were diagnosed as atypical CTEV and were managed with modification of conventional Ponseti technique and percutaneous release of achilles tendon was done in all patients. Three patients were lost to follow-up. Hence, the final number of study participants was 18 (n=18).Results: With modified Ponseti technique, functional correction was achieved in all the patients in our study. The average number of casts required was 8 (range; 5-10). At final follow-up visit, all feet are functionally corrected. Only one case of relapse was seen.Conclusions: Early diagnosis and treatment with modified Ponseti technique is an effective and easy method of treatment in atypical CTEV.