New local anesthetics

Local anesthetics are used for performing various regional anesthesia techniques to provide intraoperative anesthesia and analgesia, as well as for the treatment of acute and chronic pain. Older medications such as lidocaine and bupivacaine as well as newer ones such as mepivacaine and ropivacaine are being used successfully for decades. Routes of administration include neuraxial, perineural, intravenous, various infiltrative approaches, topical, and transdermal. There are new innovations with the use of older local anesthetics in a novel manner, in addition to the development and use of new formulations. This chapter seeks to summarize the pharmacokinetics of local anesthetics and address the role of newer local anesthetics, as well as clinical implications, safety profiles, and the future of local anesthetic research. Finally, some clinical pearls are highlighted

Loss of Notch1 disrupts the barrier repair in the corneal epithelium.

The corneal epithelium is the outermost layer of the cornea that directly faces the outside environment, hence it plays a critical barrier function. Previously, conditional loss of Notch1 on the ocular surface was found to cause inflammation and keratinization of the corneal epithelium. This was in part attributed to impaired vitamin A metabolism, loss of the meibomian glands and recurrent eyelid trauma. We hypothesized that Notch1 plays an essential role in the corneal epithelial barrier function and is a contributing factor in the pathologic changes in these mice. Notch1 was conditionally deleted in adult Notch1(flox/flox), K14-Cre-ERT(+/-) mice using hydroxy-tamoxifen. The results indicated that conditional deletion of Notch1 on the ocular surface leads to progressive impairment of the epithelial barrier function before the onset of corneal opacification and keratinization. Loss of the barrier was demonstrated both by an increase in in vivo corneal fluorescein staining and by enhanced penetration of a small molecule through the epithelium. Corneal epithelial wounding resulted in significant delay in recovery of the barrier function in conditional Notch1(-/-) mice compared to wild type. Mice with conditional deletion of Notch1 did not demonstrate any evidence of dry eyes based on aqueous tear production and had normal conjunctival goblet cells. In a calcium switch experiment in vitro, Notch1(-/-) cells demonstrated delayed membrane localization of the tight junction protein ZO-1 consistent with a defect in the epithelial tight junction formation. These findings highlight the role of Notch1 in epithelial differentiation and suggest that intrinsic defects in the corneal epithelial barrier recovery after wounding is an important contributing factor to the development of inflammatory keratinization in Notch1(-/-) mice

Notch1^-/- corneal epithelium is delayed in recovering its barrier function after wounding.

<p>Fluorescein staining of WT (A1-A4) and Notch1^-/- (B1-B4) eyes immediately (0 h), 24, 72 and 96 hours after 2.0 mm central corneal epithelial debridement wounds; indicating a delay in barrier recovery in Notch1^-/- eyes compared to WT. LC-biotin barrier function test at 96 hours post-wounding showing that the WT cornea is impermeable to LC-biotin (C1) while in the Notch1^-/- cornea LC-biotin has penetrated into the stroma (C2). LC-biotin staining showed penetration of the molecule into the stroma in 100% (7/7) of Notch1^-/- mice compared to only 28.6% (2/7) of WT littermates at 96 hours (<i>p</i>=0.021). (C3). Oil Red O staining confirmed the presence of oil producing meibomian glands (green arrow head) in both WT (D1) and Notch1^-/- (D2) at one week after 4-OHT treatment. Red: rhodamine, Blue: DAPI; scale bar: 100 µm.</p

Notch1^-/-mice develop progressive corneal opacification and keratinization.

<p>In WT (A) and Notch1 heterozygotes (N1^+/-) mice (B) corneal examination does not show any change after 4-OHT treatment and stays normal while conditional Notch1^-/- mice at 6 weeks after tamoxifen injection, demonstrate early corneal stromal opacification (C-1) which later progressed to keratinization and secondary neovascularization (white arrow head) (C-2). By 8 weeks after treatment almost 92% of Notch1^-/- mice developed corneal opacification/keratinization, while none of the WT or Notch1^+/- group showed this phenotype (<i>P</i> < 0.0001) (D). Wild type mouse corneal section showing normal histology on H&E staining (E) with no evidence of keratin 10 by immunostaining (F). On H&E staining, corneal lesions in Notch1^-/- mice demonstrate significant stromal infiltration (asterisk) with areas of keratinization and ulceration (black arrows) (G, H). The expression of keratin 10 (green) in the metaplastic epithelium confirms the skin-like epithelial phenotype (I). Green: FITC, Blue: DAPI; Scale bar: 50 µm.</p

Aqueous tear production is increased and goblet cells are intact in conditional Notch1^-/- mice.

<p>Aqueous tear measurement by phenol thread test in millimeters at baseline, 2 and 4 weeks after treatment with 4-OHT in Notch1^-/- and WT littermates. The mean aqueous tear production in Notch1^-/- eyes was found to be significantly higher than WT at 2 (7.4 ± 2.3 mm versus 3.6 ± 1.4, <i>P</i> = 0.001) (N=10 per group) and 4 weeks (10.5 ± 1.8 mm for Notch1^-/- compared to 2.7 ± 0.9 mm in WTs, <i>P</i> <0.001) after the treatment (A). Goblet cells (arrow heads) are visualized by H&E (B1, B2) and PAS (B3) staining in the conjunctival fornix of conditional Notch1^-/- mice which have developed keratinization (asterisk) of the central corneal epithelium (B4). Impression cytology of Notch1^-/- and WT lids showed no significant difference in the ratio of goblet to epithelial cells (mean ratio of 36.7±18% in N1^-/- and 25.1±16.6% in WT, <i>P</i> = 0.118). scale bar: 500 µm (B1), 100 µm (B2, B4, B5) and 200 µm (B3).</p

Notch1^-/-corneal epithelial cells have a delay in tight junction formation in vitro.

<p>After 12 hours in 1mM calcium, WT cells frequently showed continuous linear staining at the cell borders indicating more organized tight junctions (A). In contrast, Notch1^-/-cells exhibited predominantly non-continuous staining at the cell-cell junctions consistent with disorganized tight junction structures (B). Western blot confirmed deletion of Notch1 in knockout cells (C). The mean fluorescence intensity of ZO-1 staining at the cell membranes was measured and found to be higher for WT (arbitrarily set at 100%) compared to Notch1^-/- (56%) (D) (N = 119, <i>P</i> < 0.001); scale bar: 50 µm.</p

Notch1 deletion in the corneal epithelium leads to progressive barrier impairment.

<p>Notch1 knockout efficiency was evaluated by western blotting of pooled corneal epithelial sheets (N=8 per group) from conditional Notch1^-/- mice showing 64% to 70% decrease in Notch 1 expression comparing to epithelial sheets from WT littermates (A). Compared to WT (B1, B2), Notch1 deleted corneas demonstrate increased fluorescein staining at 2 (B3) and 6 (B4) weeks after 4-OHT treatment. LC-biotin (stained red with rhodamine) could not penetrate beyond the top few layers of the epithelium in WT mice (C) while it passed the epithelium and reached the stroma in Notch1^-/- mice at 4 weeks after Notch1 deletion (D). Red: rhodamine. Blue: DAPI; Scale bar: 50 µm.</p

Documenting Social Media Engagement as Scholarship: A New Model for Assessing Academic Accomplishment for the Health Professions.

BACKGROUND The traditional model of promotion and tenure in the health professions relies heavily on formal scholarship through teaching, research, and service. Institutions consider how much weight to give activities in each of these areas and determine a threshold for advancement. With the emergence of social media, scholars can engage wider audiences in creative ways and have a broader impact. Conventional metrics like the h-index do not account for social media impact. Social media engagement is poorly represented in most curricula vitae (CV) and therefore is undervalued in promotion and tenure reviews. OBJECTIVE The objective was to develop crowdsourced guidelines for documenting social media scholarship. These guidelines aimed to provide a structure for documenting a scholar's general impact on social media, as well as methods of documenting individual social media contributions exemplifying innovation, education, mentorship, advocacy, and dissemination. METHODS To create unifying guidelines, we created a crowdsourced process that capitalized on the strengths of social media and generated a case example of successful use of the medium for academic collaboration. The primary author created a draft of the guidelines and then sought input from users on Twitter via a publicly accessible Google Document. There was no limitation on who could provide input and the work was done in a democratic, collaborative fashion. Contributors edited the draft over a period of 1 week (September 12-18, 2020). The primary and secondary authors then revised the draft to make it more concise. The guidelines and manuscript were then distributed to the contributors for edits and adopted by the group. All contributors were given the opportunity to serve as coauthors on the publication and were told upfront that authorship would depend on whether they were able to document the ways in which they met the 4 International Committee of Medical Journal Editors authorship criteria. RESULTS We developed 2 sets of guidelines: Guidelines for Listing All Social Media Scholarship Under Public Scholarship (in Research/Scholarship Section of CV) and Guidelines for Listing Social Media Scholarship Under Research, Teaching, and Service Sections of CV. Institutions can choose which set fits their existing CV format. CONCLUSIONS With more uniformity, scholars can better represent the full scope and impact of their work. These guidelines are not intended to dictate how individual institutions should weigh social media contributions within promotion and tenure cases. Instead, by providing an initial set of guidelines, we hope to provide scholars and their institutions with a common format and language to document social media scholarship