Background: Awake prone positioning (PP), or proning, is used to avoid intubations in hypoxic patients with COVID-19, but because of the disease's novelty and constant evolution of treatment strategies, the efficacy of awake PP is unclear. We conducted a meta-analysis of the literature to assess the intubation rate among patients with COVID-19 requiring oxygen or noninvasive ventilatory support who underwent awake PP. Methods: We searched PubMed, Embase, and Scopus databases through August 15, 2020 to identify relevant randomized control trials, observational studies, and case series. We performed random-effects meta-analyses for the primary outcome of intubation rate. We used moderator analysis and meta-regressions to assess sources of heterogeneity. We used the standard and modified Newcastle-Ottawa Scales (NOS) to assess studies' quality. Results: Our search identified 1043 articles. We included 16 studies from the original search and 2 in-press as of October 2020 in our analysis. All were observational studies. Our analysis included 364 patients; mean age was 56.8 (SD 7.12) years, and 68% were men. The intubation rate was 28% (95% CI 20%-38%, I 2 = 63%). The mortality rate among patients who underwent awake PP was 14% (95% CI 7.4%-24.4%). Potential sources of heterogeneity were study design and setting (practice and geographic). Conclusions: Our study demonstrated an intubation rate of 28% among hypoxic patients with COVID-19 who underwent awake PP. Awake PP in COVID-19 is feasible and practical, and more rigorous research is needed to confirm this promising intervention.
IntroductionEx vivo gene therapy for treatment of Inborn errors of Immunity (IEIs) have demonstrated significant clinical benefit in multiple Phase I/II clinical trials. Current approaches rely on engineered retroviral vectors to randomly integrate copy(s) of gene-of-interest in autologous hematopoietic stem/progenitor cells (HSPCs) genome permanently to provide gene function in transduced HSPCs and their progenies. To circumvent concerns related to potential genotoxicities due to the random vector integrations in HSPCs, targeted correction with CRISPR-Cas9-based genome editing offers improved precision for functional correction of multiple IEIs. MethodsWe compare the two approaches for integration of IL2RG transgene for functional correction of HSPCs from patients with X-linked Severe Combined Immunodeficiency (SCID-X1 or XSCID); delivery via current clinical lentivector (LV)-IL2RG versus targeted insertion (TI) of IL2RG via homology-directed repair (HDR) when using an adeno-associated virus (AAV)-IL2RG donor following double-strand DNA break at the endogenous IL2RG locus. Results and discussionIn vitro differentiation of LV- or TI-treated XSCID HSPCs similarly overcome differentiation block into Pre-T-I and Pre-T-II lymphocytes but we observed significantly superior development of NK cells when corrected by TI (40.7% versus 4.1%, p = 0.0099). Transplants into immunodeficient mice demonstrated robust engraftment (8.1% and 23.3% in bone marrow) for LV- and TI-IL2RG HSPCs with efficient T cell development following TI-IL2RG in all four patients’ HSPCs. Extensive specificity analysis of CRISPR-Cas9 editing with rhAmpSeq covering 82 predicted off-target sites found no evidence of indels in edited cells before (in vitro) or following transplant, in stark contrast to LV’s non-targeted vector integration sites. Together, the improved efficiency and safety of IL2RG correction via CRISPR-Cas9-based TI approach provides a strong rationale for a clinical trial for treatment of XSCID patients.
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