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0.25% Bupivacaine vs 0.5% Bupivacaine vs Mepivicaine/Bupivacaine: Comparisons of 3 local anesthetic regimens used in nerve blocks
(2022-09-17) Lange, Michael; Yeap, Yar; Ice, Kelsea
Background: Nerve blocks are a vital component of postoperative pain management. There are many local anesthetics (LA) that are utilized in providing nerve blocks. This study aims to gather information regarding the efficacy of 0.25% Bupivacaine vs 0.5% Bupivacaine vs Mepivacaine/Bupivacaine nerve blocks. Methods: Over a period of 4 months, patients who received a peripheral nerve block for postoperative pain were called within 48hrs of their surgery via telephone and asked standardized questions regarding their pain status. The data was then sorted according to what type of block was performed (Upper extremity[UE]{Supraclavicular, Interscalene, Intercostobrachial,}, Lower extremity[LE]{Femoral, Sciatic, Adductor Canal, Popliteal, Fascia Iliaca}, and other{TAP, PECs I & II, ESP, QL}) and the type of LA that was used (0.25% Bupivacaine, 0.5% Bupivacaine, Mepivacaine/Bupivacaine). Results: Overall, 35.54% of patients experienced pain in the Post Anesthesia Care Unit (PACU) with an average pain score of 6.5/10 (n=127). 47.54% of patients who received a block with 0.25% Bupivacaine experienced pain in the PACU with an average pain score of 6.8/10 (n=60). 32.14% of patients who received a block with 0.5% Bupivacaine experienced pain in the PACU with an average pain score of 5.8/10 (n=27). 0% of patients who received a block with Mepivacaine/Bupivacaine pain in the PACU experienced pain (n=10). The median pain return for 0.5% Bupivacaine, 0.25% Bupivacaine, and Mepivacaine/Bupivacaine were 23.5hrs, 9.5hrs, and 8.83hrs respectively (n=62). The median pain return for LE, UE, and Other blocks was 24.92hrs, 13.67hrs, and 11.87hrs respectively (n=74). The median motor function return for LE and UE blocks was 24.6hrs and 18.73hrs respectively (n=33). The median pain return for LE blocks which used 0.25% Bupivacaine and 0.5% Bupivacaine was 3hrs and 25.21hrs respectively (n=11). The median pain return for UE blocks that used 0.5% Bupivacaine and Mepivacaine/Bupivacaine was 19.83hrs and 8.83hrs respectively (n=13). The median pain return for Other blocks that used 0.25% Bupivacaine and 0.5% Bupivacaine was 9.5hrs and 23.5hrs respectively (n=33). The median motor function return for LE and UE blocks that used 0.5% Bupivacaine was 24.6hrs and 21.83hrs respectively (n=15). The median motor function return of UE blocks that used Mepivacaine/Bupivacaine was 15.96hrs (n=8). Conclusions: 0.5% Bupivacaine provided longer pain control in comparison to 0.25% Bupivacaine and Mepivacaine/Bupivacaine. (0.5% Bupivacaine is the superior local anesthetic for both upper and lower extremity nerve blocks). We conclude that as long as LA toxicity is not a problem, anesthesiologists should use 0.5% Bupivacaine for all nerve blocks to provide patients the maximum benefit from their regional anesthesia.
07. The Mechanism of NGF Signaling In Innervation-dependent Corneal Epithelial Renewal: New Topical Treatment For Neurotrophic Keratopathy
(Wolters Kluwer, 2024-04-19) Hussain, Arif; Mirmoeini, Kaveh; Mulenga, Chilando; Crabtree, Jordan; Tajdaran, Kiana; Henrique, Mario; Blum, Noam; Shalom-Feuerstein, Ruby; Borschel, Gregory; Feinberg, Konstantin; Surgery, School of Medicine
Background: Corneal clarity is essential for vision. Limbal stem cells (LSCs), the source of transparent corneal epithelial cells, are located in the basal epithelium of the limbus at the corneal-conjunctival interface, where they interact with corneal sensory nerves. Besides protection, corneal nerves may stimulate LSC activity. Pathological corneal denervation can lead to ulcers, scarring, and opacification due to impaired healing from repetitive wounds. This condition, termed Neurotrophic Keratopathy (NK), a major cause of corneal blindness, and lacks a definitive cure. Corneal nerves release various trophic factors that regulate epithelial renewal. Nerve growth factor (NGF) has shown positive effects on corneal healing and maintenance in vivo. Topical recombinant human NGF is the only FDA-approved treatment for NK. However, NGF is not efficacious in 30% of cases, requires very frequent dosing, and costs $100k per course. Moreover, NGF’s ability to heal corneal ulcers is limited. Prior studies showed NGF stimulates proliferation and maintenance of cultured human LSCs, which express TrkA and p75NTR receptors, but didn’t establish a link between NGF signaling and corneal sensory innervation-mediated trophic regulation of epithelial renewal. Furthermore, the role and molecular mechanism of NGF signaling in LSC activity remains unidentified. We hypothesize that NGF, locally expressed in its mature and premature (proNGF) forms, regulates LSC activity-dependent homeostatic and wound-induced corneal epithelial renewal via differential activation of its receptors TrkA and p75NTR, a process dependent on corneal sensory innervation. Methods: A) We conducted in vivo experiments in wild-type and mutant mice and rats to elucidate the NGF signaling mechanism in corneal innervation-dependent epithelial renewal. We examined the effect of combinations of TrkA and p75NTR agonists and antagonists on the healing of experimentally wounded corneas, both intact and surgically denervated. B) To understand the role and mechanism of NGF signaling in LSC activity and its relevance to humans, we assessed the clonogenicity of cultured human LSCs (hLSCs) by pharmacologically modulating NGF receptors, as described in (A). Results: A) While inactivation of TrkA completely prevents healing of normally innervated cornea, inactivation of p75NTR combined with a single daily dose of NGF induces complete and rapid healing of denervated de-epithelialized corneas. B) NGF or specific p75NTR inhibitor THX-B supported colonies’ formation by hLSCs that were further augmented by combination of the two compounds. Conclusions: Corneal sensory nerve-associated expression of NGF in its both forms (NGF and proNGF) regulates the proliferation and differentiation of LSCs by differentially stimulating the activity of the NGF receptors. Combined pharmacological activation and inhibition of TrkA and p75NTR, respectively, will be applied in the development of a superior NGF-based treatment of NK.
1,25-Dihydroxyvitamin D3 enhances glucose-stimulated insulin secretion in mouse and human islets: a role for transcriptional regulation of voltage-gated calcium channels by the vitamin D receptor
(Elsevier, 2018) Kjalarsdottir, Lilja; Tersey, Sarah A.; Vishwanath, Mridula; Chuang, Jen-Chieh; Posner, Bruce A.; Mirmira, Raghavendra G.; Repa, Joyce J.; Pediatrics, School of Medicine
Aim Vitamin D deficiency in rodents negatively affects glucose-stimulated insulin secretion (GSIS) and human epidemiological studies connect poor vitamin D status with type 2 diabetes. Previous studies performed primarily in rat islets have shown that vitamin D can enhance GSIS. However the molecular pathways linking vitamin D and insulin secretion are currently unknown. Therefore, experiments were undertaken to elucidate the transcriptional role(s) of the vitamin D receptor (VDR) in islet function. Methods Human and mouse islets were cultured with vehicle or 1,25-dihydroxyvitamin-D3 (1,25D3) and then subjected to GSIS assays. Insulin expression, insulin content, glucose uptake and glucose-stimulated calcium influx were tested. Microarray analysis was performed. In silico analysis was used to identify VDR response elements (VDRE) within target genes and their activity was tested using reporter assays. Results Vdr mRNA is abundant in islets and Vdr expression is glucose-responsive. Preincubation of mouse and human islets with 1,25D3 enhances GSIS and increases glucose-stimulated calcium influx. Microarray analysis identified the R-type voltage-gated calcium channel (VGCC) gene, Cacna1e, which is highly upregulated by 1,25D3 in human and mouse islets and contains a conserved VDRE in intron 7. Results from GSIS assays suggest that 1,25D3 might upregulate a variant of R-type VGCC that is resistant to chemical inhibition. Conclusion These results suggest that the role of 1,25D3 in regulating calcium influx acts through the R-Type VGCC during GSIS, thereby modulating the capacity of beta cells to secrete insulin.
1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10
(Elsevier, 2016-12) Wang, Xiaoliang; Wang, Hongwei; Shen, Bing; Overholser, Brian R.; Cooper, Bruce R.; Lu, Yinghao; Tang, Huamei; Zhou, Chongzhi; Sun, Xing; Zhong, Lin; Favus, Murray J.; Decker, Brian S.; Liu, Wanqing; Peng, Zhihai; Department of Medicine, IU School of Medicine
Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity.
1-year mortality following contrast-induced nephropathy
(2013) Mitchell, Alice M; Jones, Alan E; Tumlin, James A; Kline, Jeffrey A.
Objective: The aim of this study was to determine the 1-year mortality risk subsequent to Contrast-Induced Nephropathy (CIN) following CECT imaging, relative to other well-recognized predictors of mortality. Methods: We followed a prospective, consecutive cohort of ambulatory patients who received intravenous contrast for CECT for the outcome of death from any cause within 1 year. In a multivariate analysis, we compared CIN with other predictors of mortality: active malignancy, coronary artery disease (CAD), congestive heart failure (CHF) and age ≥70 years. Anticipating that terminal cancers would account for the majority of deaths in this population, we also analyzed the subset of patients without an active malignancy at the time of enrollment. Results: We followed 633 patients and 46 died (7%, 95%CI: 5-9%) within 1 year. The incidence of CIN was 11% (95%CI: 8-14%). Active malignancy (HR 9.2, 95%CI: 5.1-16.8), CIN (HR 2.4, 95%CI: 1.3-4.6), CHF (HR 2.1, 95%CI: 1.0-4.2), CAD (HR 2.2, 95%CI: 1.0-5.5) and age ≥70 years (HR 1.8, 95%CI: 1.0-3.8) were significant predictors of all-cause mortality. Among patients without active malignancies, the mortality rate was 4% (25/580, 95%CI: 3-6%) and CIN (HR 4.0, 95%CI: 1.7-9.6) and age ≥70 years (HR 3.7, 95%CI: 1.4-9.7) were significantly associated with death, whereas CAD (HR 2.5, 95%CI: 0.8-7.7) and CHF (HR 1.8, 95%CI: 0.6-5.3) were not. Conclusions: The development of CIN following CECT is associated with an increased likelihood of death at 1 year among patients with and without active malignancies, comparable to CAD, CHF and advanced age.
100 years of insulin: celebrating the past, present and future of diabetes therapy
(Springer Nature, 2021) Sims, Emily K.; Carr, Alice L.J.; Oram, Richard A.; DiMeglio, Linda A.; Evans-Molina, Carmella; Pediatrics, School of Medicine
The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.
100% of People Who Confuse Correlation With Causation Eventually Die
(Sage, 2024-10-03) Schwalb, Jason M.; Neurological Surgery, School of Medicine
1021. VP22 Mediates Tumor Vasculature Specific Targeting
(Elsevier, 2004-05-01) Raikwar, Sudhanshu P.; Gardner, Thomas A.; Kao, Chinghai; Urology, School of Medicine
105. Long Term Surgical and Patient Reported Outcomes After Cross Face Nerve Graft Reconstruction in Pediatric Facial Paralysis
(Wolters Kluwer, 2022) Zuo, Kevin J.; Heinelt, Martina; Ho, Emily; Borschel, Gregory; Zuker, Ronald; Surgery, School of Medicine
Purpose: Free functioning muscle transfer is the gold standard for pediatric facial paralysis reconstruction and using the contralateral facial nerve for neurotization via a cross face nerve graft enables spontaneous smile restoration. Outcomes of pediatric facial reanimation beyond 10 years are not known, including how smiles change with aging and how adult patients report their facial function and quality of life. This study evaluated long term surgical and patient-reported outcomes for adults who underwent facial reanimation as children. Methods: This cross-sectional study enrolled patients who underwent facial reanimation with a staged cross face nerve graft and free gracilis muscle transfer as children at least 10 years ago. FACE-Gram software was used to quantify commissure excursion on frontal photographs in repose and maximal smile at three time points: preoperative, early postoperative within 2 years, and current (long term follow up). Patient-reported outcomes were evaluated quantitatively using the FaCE Scale and FACE-Q instruments for patient satisfaction, and qualitatively with semi-structured interviews. Results are reported as mean ± SD and parametric statistical analysis was performed with alpha of 0.05. Results: Eighteen patients who underwent facial reanimation as children more than 10 years ago were included (14 females, 5 males; 10 congenital, 8 acquired; age at stage 1 surgery 7.4 ± 3.6 years). Commissure excursion was measured as -1.3 ± 3.5 mm preoperatively, 5.9 ± 2.3 mm postoperatively within 2 years, and 7.6 ± 3.5 mm at long term follow up (mean 20.5 ± 6.9 years). Commissure excursion increased 7.2 ± 4.9 mm from preoperative to early postoperative time points (p<0.0001) and did not significantly increase or decrease at long term follow up (p>0.05). For patient reported outcomes, mean FaCE scale score for facial movement was 44/100 when including eyebrow function and 79/100 when excluding eyebrow function. Mean FaCE scale scores were 63/100 for eye comfort and 81/100 for social function. On the FACE-Q Satisfaction with Outcome scale, 17/18 respondents somewhat agreed or definitely agreed with the statement, “I am pleased with the result.” On the FACE-Q Social Function scale, 16/18 respondents somewhat agreed or definitely agreed with the statement, “I feel confident when I meet a new person.” Conclusions: Pediatric facial reanimation with cross face nerve grafting improves commissure excursion and this is maintained with aging. Adult patients report overall high satisfaction and social functioning. Ongoing ocular issues remains a problem for many patients, underscoring the importance of refining techniques for reanimation of the eye.
1082. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial Infections: A Multicenter Evaluation
(Oxford University Press, 2021-12-04) Morrisette, Taylor; Alosaimy, Sara; Lagnf, Abdalhamid M.; Philley, Julie V.; Sigler, Carly; Butt, Saira; Kaip, Emily A.; MacDougall, Conan; Mejia-Chew, Carlos; Bouchard, Jeannette; Frens, Jeremy J.; Gore, Tristan; Hamad, Yasir; Howard, Catessa; Barger, Melissa; Cabanilla, M. Gabriela; Ong, Aaron; Veve, Michael P.; Webb, Andrew J.; Stevens, Ryan W.; Cohen, Keira A.; Rybak, Michael J.; Medicine, School of Medicine
Background: Nontuberculous mycobacteria (NTM) are resistant to numerous antibiotics and lead to significant morbidity and mortality. Omadacycline (OMC) is an aminomethylcycline antibiotic that is Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Furthermore, OMC has shown in vitro activity against NTM. Given that real-world evidence is lacking, our primary objective was to evaluate the clinical success and tolerability of OMC when used for a variety of NTM infections. Methods: This was a multicenter, retrospective, observational study conducted from January 2020 to June 2021. We included all patients ≥ 18 years of age that received OMC of any indication for Mycobacterium spp. The primary outcome was clinical success, defined as a lack of all-cause mortality, lack of persistence or re-emergence of infection during or after therapy, and lack of alteration of OMC. Incidence of adverse effects potentially attributable to OMC and reasons for OMC utilization were also analyzed. Results: A total of 31 patients were included from 12 geographically distinct academic health systems (median age: 57 (IQR, 45-63) years; 45% male; 81% Caucasian). The majority of isolated pathogens were Mycobacterium abscessus complex (84%) and of those with subspeciation performed (54%), the majority (86%) were subsp. abscessus. The primary infections were of pulmonary origin (67%) and the median (IQR) duration of OMC therapy was 5.3 (3.2-9.4) months. Most isolates did not have OMC susceptibility conducted (87%), while the majority did for tigecycline (90%). Clinical success was reported in 81% of the population. Most patients were on combination antimicrobial therapy, and 39% of patients reported an adverse effect while on OMC (58% gastrointestinal distress). The majority of patients were prescribed OMC due to ease of administration (61%) and antimicrobial resistance to previous antibiotics (42%). Conclusion: OMC may be a potential option for the therapy of NTM infections. Prospective, randomized clinical trials are needed to confirm our preliminary findings.

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