Variation in Intraoperative Opioid Administration by Patient, Clinician, and Hospital Contribution.

Importance: The opioid crisis has led to scrutiny of opioid exposures before and after surgical procedures. However, the extent of intraoperative opioid variation and the sources and contributing factors associated with it are unclear. Objective: To analyze attributable variance of intraoperative opioid administration for patient-, clinician-, and hospital-level factors across surgical and analgesic categories. Design, Setting, and Participants: This cohort study was conducted using electronic health record data collected from a national quality collaborative database. The cohort consisted of 1 011 268 surgical procedures at 46 hospitals across the US involving 2911 anesthesiologists, 2291 surgeons, and 8 surgical and 4 analgesic categories. Patients without ambulatory opioid prescriptions or use history undergoing an elective surgical procedure between January 1, 2014, and September 11, 2020, were included. Data were analyzed from January 2022 to July 2023. Main Outcomes and Measures: The rate of intraoperative opioid administration as a continuous measure of oral morphine equivalents (OMEs) normalized to patient weight and case duration was assessed. Attributable variance was estimated in a hierarchical structure using patient, clinician, and hospital levels and adjusted intraclass correlations (ICCs). Results: Among 1 011 268 surgical procedures (mean [SD] age of patients, 55.9 [16.2] years; 604 057 surgical procedures among females [59.7%]), the mean (SD) rate of intraoperative opioid administration was 0.3 [0.2] OME/kg/h. Together, clinician and hospital levels contributed to 20% or more of variability in intraoperative opioid administration across all analgesic and surgical categories (adjusting for surgical or analgesic category, ICCs ranged from 0.57-0.79 for the patient, 0.04-0.22 for the anesthesiologist, and 0.09-0.26 for the hospital, with the lowest ICC combination 0.21 for anesthesiologist and hosptial [0.12 for the anesthesiologist and 0.09 for the hospital for opioid only]). Comparing the 95th and fifth percentiles of opioid administration, variation was 3.3-fold among anesthesiologists (surgical category range, 2.7-fold to 7.7-fold), 4.3-fold among surgeons (surgical category range, 3.4-fold to 8.0-fold), and 2.2-fold among hospitals (surgical category range, 2.2-fold to 4.3-fold). When adjusted for patient and surgical characteristics, mean (square error mean) administration was highest for cardiac surgical procedures (0.54 [0.56-0.52 OME/kg/h]) and lowest for orthopedic knee surgical procedures (0.19 [0.17-0.21 OME/kg/h]). Peripheral and neuraxial analgesic techniques were associated with reduced administration in orthopedic hip (51.6% [95% CI, 51.4%-51.8%] and 60.7% [95% CI, 60.5%-60.9%] reductions, respectively) and knee (48.3% [95% CI, 48.0%-48.5%] and 60.9% [95% CI, 60.7%-61.1%] reductions, respectively) surgical procedures, but reduction was less substantial in other surgical categories (mean [SD] reduction, 13.3% [8.8%] for peripheral and 17.6% [9.9%] for neuraxial techniques). Conclusions and Relevance: In this cohort study, clinician-, hospital-, and patient-level factors had important contributions to substantial variation of opioid administrations during surgical procedures. These findings suggest the need for a broadened focus across multiple factors when developing and implementing opioid-reducing strategies in collaborative quality-improvement programs.

Salivary gland cell aggregates are derived from self-organization of acinar lineage cells.

OBJECTIVE: The objective of this study was to characterize the mechanism by which salivary gland cells (SGC) aggregate in vitro. DESIGN: Timelapse microscopy was utilized to analyze the process of salivary gland aggregate formation using both primary murine and human salivary gland cells. The role of cell density, proliferation, extracellular calcium, and secretory acinar cells in aggregate formation was investigated. Finally, the ability of cells isolated from irradiated glands to form aggregates was also evaluated. RESULTS: Salivary gland cell self-organization rather than proliferation was the predominant mechanism of aggregate formation in both primary mouse and human salivary gland cultures. Aggregation was found to require extracellular calcium while acinar lineage cells account for ∼80% of the total aggregate cell population. Finally, aggregation was not impaired by irradiation. CONCLUSIONS: The data reveal that aggregation occurs as a result of heterogeneous salivary gland cell self-organization rather than from stem cell proliferation and differentiation, contradicting previous dogma. These results suggest a re-evaluation of aggregate formation as a criterion defining salivary gland stem cells.

Murine Salivary Functional Assessment via Pilocarpine Stimulation Following Fractionated Radiation.

Hyposalivation is commonly observed in the autoimmune reaction of Sjögren's syndrome or following radiation injury to the major salivary glands. In these cases, questions remain regarding disease pathogenesis and effective interventions. An optimized technique that allows functional assessment of the salivary glands is invaluable for investigating exocrine gland biology, dysfunction, and therapeutics. Here, we present a step by step approach to performing pilocarpine stimulated saliva secretion, including tracheostomy and the dissection of the three major murine salivary glands. We also detail the appropriate murine head and neck anatomy accessed during these techniques. This approach is scalable, allowing for multiple mice to be processed simultaneously, thus improving the efficiency of the work flow. We aim to improve the reproducibility of these methods, each of which has further applications within the field. In addition to saliva collection, we discuss metrics for quantifying and normalizing functional capacity of these tissues. Representative data are included from submandibular glands with depressed salivary gland function 2 weeks following fractionated radiation (4 doses of 6.85 Gy).

The Effects of Biological Fluids on Colloidal Stability and siRNA Delivery of a pH-Responsive Micellar Nanoparticle Delivery System.

Nanoparticles (NPs) interact with complex protein milieus in biological fluids, and these interactions have profound effects on NP physicochemical properties and function. Surprisingly, most studies neglect the impact of these interactions, especially with respect to NP-mediated siRNA delivery. Here, the effects of serum on colloidal stability and siRNA delivery of a pH-responsive micellar NP delivery system were characterized. Results show cationic NP-siRNA complexes aggregate in ≥2% serum in buffer, but are stable in serum-free media. Furthermore, nonaggregated NP-siRNA delivered in serum-free media result in 4-fold greater siRNA uptake in vitro, compared to aggregated NP-siRNA. Interestingly, pH-responsive membrane lysis behavior, which is required for endosomal escape, and NP-siRNA dissociation, necessary for gene knockdown, are significantly reduced in serum. Consistent with these data, nonaggregated NP-siRNA in serum-free conditions result in highly efficient gene silencing, even at doses as low as 5 nM siRNA. NP-siRNA diameter was measured at albumin and IgG levels mimicking biological fluids. Neither albumin nor IgG alone induces NP-siRNA aggregation, implicating other serum proteins in NP colloidal instability. Finally, as a proof-of-principle that stability is maintained in established in vivo models, transmission electron microscopy reveals NP-siRNA are taken up by ductal epithelial cells in a nonaggregated state when injected retroductally into mouse salivary glands in vivo. Overall, this study shows serum-induced NP-siRNA aggregation significantly diminishes efficiency of siRNA delivery by reducing uptake, pH-responsive membrane lysis activity, and NP-siRNA dissociation. Moreover, these results highlight the importance of local NP-mediated drug delivery and are broadly applicable to other drug delivery systems.

Retroductal Nanoparticle Injection to the Murine Submandibular Gland.

Two common goals of salivary gland therapeutics are prevention and cure of tissue dysfunction following either autoimmune or radiation injury. By locally delivering bioactive compounds to the salivary glands, greater tissue concentrations can be safely achieved versus systemic administration. Furthermore, off target tissue effects from extra-glandular accumulation of material can be dramatically reduced. In this regard, retroductal injection is a widely used method for investigating both salivary gland biology and pathophysiology. Retroductal administration of growth factors, primary cells, adenoviral vectors, and small molecule drugs has been shown to support gland function in the setting of injury. We have previously shown the efficacy of a retroductally injected nanoparticle-siRNA strategy to maintain gland function following irradiation. Here, a highly effective and reproducible method to administer nanomaterials to the murine submandibular gland through Wharton's duct is detailed (Figure 1). We describe accessing the oral cavity and outline the steps necessary to cannulate Wharton's duct, with further observations serving as quality checks throughout the procedure.

Salvage of venous congestion using medicinal leeches for traumatic nasal flap.

Medicinal leeches are extremely useful and safe in the salvage of venous outflow compromised tissue, particularly in digit replants and various forms of flaps. Although it is unusual for a partial soft tissue avulsion of the face to require medicinal leech therapy, situations may occur in which there is adequate arterial inflow but inadequate venous outflow. In such cases, medicinal leeches may play a very important role in salvaging the soft tissue segment. We report a case of a 34-year-old gentleman who showed signs of venous congestion following primary management for a traumatic nasal flap. Successful salvage of venous congestion was done using medicinal leech therapy, once daily, for 5 days. His recovery deemed satisfactory and uncomplicated. Medicinal leeches are well-known in the treatment of venous congestion or complete venous outflow obstruction in larger pedicled flaps and microvascular transfers. In trauma, it is well established that medicinal leeches are invaluable in treating venous congestion in digit replants and replantation of totally avulsed external ear segments. A limited number of other reports have demonstrated the use of medicinal leeches for salvage of other partially avulsed facial structures. Medicinal leeches have a significant role in the management of traumatic and microvascular flaps, the oral and maxillofacial surgeon should weigh the benefits of such treatment before instituting other expensive or complex treatment modalities.

Autogenous Reconstructive Modalities of TMJ Ankylosis-A Retrospective Analysis of 45 Cases.

The study reports the authors' experience in managing temporomandibular joint (TMJ) ankylosis in Chennai, India (1995-2006) and compares the surgical modalities used. Forty-five patients (67 joints) were reviewed in this retrospective study. Pre- and post-operative assessment included history, radiological, physical examination, and range of mouth opening. Age, gender, aetiology, joint(s) affected, surgical modality, complications and follow-up periods were evaluated. Various types (fibrous, fibroosseous and bony) of TMJ ankylosis were diagnosed. Trauma was the commonest aetiology. The patients' age range was 2-50 years, 51.1 % were males and the follow-up period ranged from 14 to 96 months. Average mouth opening was significantly increased to 32 mm 12 months post-operatively. Mouth opening was compared following different interpositional materials like temporalis interpositioning (33 mm), costochondral graft (30.6 mm) and autograft (30 mm). Minor and major complications were encountered in 37.4 % of cases, including 6.7 % recurrence rate. Early release of TMJ ankylosis; reconstruction of the ramus height with distraction osteogenesis or bone grafting combined with interpositional arthroplasty, followed by vigorous physiotherapy is a successful strategy for the management of TMJ ankylosis.