Acute Postoperative Pain Due to Dental Extraction in the Adult Population: A Systematic Review and Network Meta-analysis.

This study compares the effectiveness of pharmacological treatments to develop guidelines for the management of acute pain after tooth extraction. We searched Medline, EMBASE, CENTRAL, and US Clinical Trials registry on November 21, 2020. We included randomized clinical trials (RCTs) of participants undergoing dental extractions comparing 10 interventions, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and combinations to placebo. After duplicate screening and data abstraction, we conducted a frequentist network meta-analysis for each outcome at 6 h (i.e., pain relief, total pain relief [TOTPAR], summed pain intensity difference [SPID], global efficacy rating, rescue analgesia, and adverse effects). We assessed the risk of bias using a modified Cochrane RoB 2.0 tool and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. We implemented the analyses in RStudio version 3.5.3 and classified interventions from most to least beneficial or harmful. We included 82 RCTs. Fifty-six RCTs enrolling 9,095 participants found moderate- and high-certainty evidence that ibuprofen 200 to 400 mg plus acetaminophen 500 to 1,000 mg (mean difference compared to placebo [MDp], 1.68; 95% confidence interval [CI], 1.06-2.31), acetaminophen 650 mg plus oxycodone 10 mg (MDp, 1.19; 95% CI, 0.85-1.54), ibuprofen 400 mg (MDp, 1.31; 95% CI, 1.17-1.45), and naproxen 400-440 mg (MDp, 1.44; 95% CI, 1.07-1.80) were most effective for pain relief on a 0 to 4 scale. Oxycodone 5 mg, codeine 60 mg, and tramadol 37.5 mg plus acetaminophen 325 mg were no better than placebo. The results for TOTPAR, SPID, global efficacy rating, and rescue analgesia were similar. Based on low- and very low-certainty evidence, most interventions were classified as no more harmful than placebo for most adverse effects. Based on moderate- and high-certainty evidence, NSAIDs with or without acetaminophen result in better pain-related outcomes than opioids with or without acetaminophen (except acetaminophen 650 mg plus oxycodone 10 mg) or placebo.

Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus.

OBJECTIVE: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vivo and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation. SUMMARY BACKGROUND DATA: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long-lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance. METHODS: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection. RESULTS: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in viral clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus. CONCLUSIONS: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.

Genetically engineered grafts to study xenoimmunity: a role for indirect antigen presentation in the destruction of major histocompatibility complex antigen deficient xenografts.

BACKGROUND: The genetic engineering of xenogeneic donor species for transplantation may provide a means of attenuating the potent immune response elicited by tissues from foreign species. Because of their well-established role in allograft rejection, a logical target for genetic manipulation is the genes encoded by the major histocompatibility complex (MHC). In the current study we examined whether skin, heart, or pancreatic islet xenografts harvested from lines of transgenic mice rendered deficient in MHC antigen expression by gene disruption would exhibit a survival benefit when transplanted to xenogeneic rat recipients. In addition, we characterized the in vitro response of rat T cells to normal and MHC-deficient mouse cells. METHODS: Skin, heart, and pancreatic islet grafts were harvested from control C57Bl/6 and each of three lines of mice deficient in MHC antigen expression. MHC-deficient lines included (1) mice selectively lacking MHC class I antigens (CID), produced by disruption of the beta-2 microglobulin gene; (2) mice lacking MHC class II expression (CIID), produced by targeting the I-A beta-chain gene; and (3) mice devoid of both class I and class II molecules (CI,IID). RESULTS: In contrast to the prolonged survival that has been observed for certain allografts deficient in MHC antigen expression, we did not detect significant extension of survival in the case of xenografts. Using in vitro assays of T-cell function, we demonstrated that rats that rejected grafts lacking MHC expression evidenced sensitization of T cells specific for graft antigens presented by rat antigen-presenting cells. CONCLUSIONS: The strategies of gene targeting of donor species to produce less immunogenic xenografts may be hampered by the presence of a strong response through the indirect pathway of immunity. Immune intervention directed at the indirect antigen presentation pathway may be of benefit in xenotransplantation.