The potential for autonomic neuromodulation to reduce perioperative complications and pain: a systematic review and meta-analysis.

BACKGROUND: Autonomic dysfunction promotes organ injury after major surgery through numerous pathological mechanisms. Vagal withdrawal is a key feature of autonomic dysfunction, and it may increase the severity of pain. We systematically evaluated studies that examined whether vagal neuromodulation can reduce perioperative complications and pain. METHODS: Two independent reviewers searched PubMed, EMBASE, and the Cochrane Register of Controlled Clinical Trials for studies of vagal neuromodulation in humans. Risk of bias was assessed; I2 index quantified heterogeneity. Primary outcomes were organ dysfunction (assessed by measures of cognition, cardiovascular function, and inflammation) and pain. Secondary outcomes were autonomic measures. Standardised mean difference (SMD) using the inverse variance random-effects model with 95% confidence interval (CI) summarised effect sizes for continuous outcomes. RESULTS: From 1258 records, 166 full-text articles were retrieved, of which 31 studies involving patients (n=721) or volunteers (n=679) met the inclusion criteria. Six studies involved interventional cardiology or surgical patients. Indirect stimulation modalities (auricular [n=23] or cervical transcutaneous [n=5]) were most common. Vagal neuromodulation reduced pain (n=10 studies; SMD=2.29 [95% CI, 1.08-3.50]; P=0.0002; I2=97%) and inflammation (n=6 studies; SMD=1.31 [0.45-2.18]; P=0.003; I2=91%), and improved cognition (n=11 studies; SMD=1.74 [0.96-2.52]; P<0.0001; I2=94%) and cardiovascular function (n=6 studies; SMD=3.28 [1.96-4.59]; P<0.00001; I2=96%). Five of six studies demonstrated autonomic changes after vagal neuromodulation by measuring heart rate variability, muscle sympathetic nerve activity, or both. CONCLUSIONS: Indirect vagal neuromodulation improves physiological measures associated with limiting organ dysfunction, although studies are of low quality, are susceptible to bias and lack specific focus on perioperative patients.

Reducing the dose of neuromuscular blocking agents with adjuncts: a systematic review and meta-analysis.

BACKGROUND: Acute global shortages of neuromuscular blocking agents (NMBA) threaten to impact adversely on perioperative and critical care. The use of pharmacological adjuncts may reduce NMBA dose. However, the magnitude of any putative effects remains unclear. METHODS: We conducted a systematic review and meta-analysis of RCTs. We searched Medline, Embase, Web of Science, and Cochrane Database (1970-2020) for RCTs comparing use of pharmacological adjuncts for NMBAs. We excluded RCTs not reporting perioperative NMBA dose. The primary outcome was total NMBA dose used to achieve a clinically acceptable depth of neuromuscular block. We assessed the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) criteria. Data are presented as the standardised mean difference (SMD); I2 indicates percentage of variance attributable to heterogeneity. RESULTS: From 3082 records, the full texts of 159 trials were retrieved. Thirty-one perioperative RCTs met the inclusion criteria for meta-analysis (n=1962). No studies were conducted in critically ill patients. Reduction in NMBA dose was associated with use of magnesium (SMD: -1.10 [-1.44 to -0.76], P<0.001; I2=85%; GRADE=moderate), dexmedetomidine (SMD: -0.89 [-1.55 to -0.22]; P=0.009; I2=87%; GRADE=low), and clonidine (SMD: -0.67 [-1.13 to -0.22]; P=0.004; I2=0%; GRADE=low) but not lidocaine (SMD: -0.46 [-1.01 to -0.09]; P=0.10; I2=68%; GRADE=moderate). Meta-analyses for nicardipine, diltiazem, and dexamethasone were not possible owing to the low numbers of studies. We estimated that 30-50 mg kg-1 magnesium preoperatively (8-15 mg kg h-1 intraoperatively) reduces rocuronium dose by 25.5% (inter-quartile range, 14.7-31). CONCLUSIONS: Magnesium, dexmedetomidine, and clonidine may confer a clinically relevant sparing effect on the required dose of neuromuscular block ing drugs in the perioperative setting. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42020183969.

Preoperative lymphopaenia, mortality, and morbidity after elective surgery: systematic review and meta-analysis.

BACKGROUND: In the general adult population, lymphopaenia is associated with an increased risk for hospitalisation with infection and infection-related death. The quality of evidence and strength of association between perioperative lymphopaenia across different surgical procedures and mortality/morbidity has not been examined by systematic review or meta-analysis. METHODS: We searched MEDLINE, Embase, Web of Science, Google Scholar, and Cochrane databases from their inception to June 29, 2020 for observational studies reporting lymphocyte count and in-hospital mortality rate in adults. We defined preoperative lymphopaenia as a lymphocyte count 1.0-1.5×109 L-1. Meta-analysis was performed using either fixed or random effects models. Quality was assessed using the Newcastle-Ottawa Scale. The I2 index was used to quantify heterogeneity. The primary outcome was in-hospital mortality rate and mortality rate at 30 days. RESULTS: Eight studies met the inclusion criteria for meta-analysis, comprising 4811 patients (age range, 46-91 yr; female, 20-79%). These studies examined preoperative lymphocyte count exclusively. Studies were of moderate to high quality overall, ranking >7 using the Newcastle-Ottawa Scale. Preoperative lymphopaenia was associated with a threefold increase in mortality rate (risk ratio [RR]=3.22; 95% confidence interval [CI], 2.19-4.72; P<0.01, I2=0%) and more frequent major postoperative complications (RR=1.33; 95% CI, 1.21-1.45; P<0.01, I2=6%), including cardiovascular morbidity (RR=1.77; 95% CI, 1.45-2.15; P<0.01, I2=0%), infections (RR=1.45; 95% CI, 1.19-1.76; P<0.01, I2=0%), and acute renal dysfunction (RR=2.66; 95% CI, 1.49-4.77; P<0.01, I2=1%). CONCLUSION: Preoperative lymphopaenia is associated with death and complications more frequently, independent of the type of surgery. PROSPERO REGISTRY NUMBER: CRD42020190702.

mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy.

Large genes including several CRISPR-Cas modules like gene activators (CRISPRa) require dual adeno-associated viral (AAV) vectors for an efficient in vivo delivery and expression. Current dual AAV vector approaches have important limitations, e.g., low reconstitution efficiency, production of alien proteins, or low flexibility in split site selection. Here, we present a dual AAV vector technology based on reconstitution via mRNA trans-splicing (REVeRT). REVeRT is flexible in split site selection and can efficiently reconstitute different split genes in numerous in vitro models, in human organoids, and in vivo. Furthermore, REVeRT can functionally reconstitute a CRISPRa module targeting genes in various mouse tissues and organs in single or multiplexed approaches upon different routes of administration. Finally, REVeRT enabled the reconstitution of full-length ABCA4 after intravitreal injection in a mouse model of Stargardt disease. Due to its flexibility and efficiency REVeRT harbors great potential for basic research and clinical applications.

Neurocognitive development in HIV-positive children is correlated with plasma viral loads in early childhood.

Because of neurocognitive impairments in perinatally human immunodeficiency virus (HIV)-infected children and adolescents, this study aimed to demonstrate the effect of plasma viral loads and early initiation of sufficient combined antiretroviral therapy (cART) on neurocognitive development.In total, 14 perinatally infected HIV-positive children (median age 8.24 years [range: 6.0-16.74]) receiving lopinavir/ritonavir (LPV/r)-based ART underwent neurocognitive testing using the Wechsler Intelligence Score for Children, 4th Edition (WISC-IV). All 14 patients participated in a pharmacokinetic study in which they were hospitalized for an entire day. As a child's ability to concentrate varies over the course of the day, all tests were performed in the morning.The patients' neurocognitive development did not significantly differ from the normative collective pattern for any of the following composite scores that were examined: full-scale intelligence quotient (IQ) (mean: 106.5, P = .1060), verbal comprehension index (mean: 106.0, P = .1356), perceptual reasoning index (mean: 106.0, P = .1357), working memory index (mean: 106.3, P = .1171), and processing speed index (mean: 98.1, P = .6313). The overall full-scale IQ scores were significantly higher in children who began ART within the first year of life (P = .0379), whereas low lopinavir/r plasma levels (P = .0070) and high viral load area under the curves (AUCs) in the first 3 years of life, but not later, significantly correlated with reduced neurocognitive performance (Spearman r = -0.64, P = .0278).In this cohort of cART treated HIV-positive children and adolescents, neurocognitive performance correlated with early and sufficient viral load suppression within the first 3 years of life.