A Case Report of Elective Bilateral Proximal Intercostal Blocks Used to Prevent Arrhythmia in Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disorder characterized by episodes of polymorphic ventricular tachycardia. Clinically, patients who have CPVT present with juvenile sudden death or stress-induced syncope. We present a case of an 18-year-old girl with CPVT resistant to traditional pharmacotherapies. Instead of a typical stellate ganglion block (SGB), the patient underwent bilateral continuous proximal intercostal blocks that successfully inhibited arrhythmogenic events. This therapeutic method may provide an alternative to SGBs and demonstrates proof of concept for an early elective intervention to be included in the diagnostic and therapeutic algorithm for patients with CPVT.

Post-total joint arthroplasty opioid prescribing practices vary widely and are not associated with opioid refill: an observational cohort study.

INTRODUCTION: Optimized health system approaches to improving guideline-congruent care require evaluation of multilevel factors associated with prescribing practices and outcomes after total knee and hip arthroplasty. MATERIALS AND METHODS: Electronic health data from patients who underwent a total knee or hip arthroplasty between January 2016-January 2020 in the Military Health System Data were retrospectively analyzed. A generalized linear mixed-effects model (GLMM) examined the relationship between fixed covariates, random effects, and the primary outcome (30-day opioid prescription refill). RESULTS: In the sample (N = 9151, 65% knee, 35% hip), the median discharge morphine equivalent dose was 660 mg [450, 892] and varied across hospitals and several factors (e.g., joint, race and ethnicity, mental and chronic pain conditions, etc.). Probability of an opioid refill was higher in patients who underwent total knee arthroplasty, were white, had a chronic pain or mental health condition, had a lower age, and received a presurgical opioid prescription (all p < 0.01). Sex assigned in the medical record, hospital duration, discharge non-opioid prescription receipt, discharge morphine equivalent dose, and receipt of an opioid-only discharge prescription were not significantly associated with opioid refill. CONCLUSION: In the present study, several patient-, care-, and hospital-level factors were associated with an increased probability of an opioid prescription refill within 30 days after arthroplasty. Future work is needed to identify optimal approaches to reduce unwarranted and inequitable healthcare variation within a patient-centered framework.

Opioid-Free Anesthesia in the Perioperative Setting-A Preliminary Retrospective Matched Cohort Study.

INTRODUCTION: Anesthesiologists have long used multimodal analgesia for effective pain control. Opioid-sparing anesthetics are gaining popularity among practitioners in light of increasing concerns for both immediate opioid side effects and the long-term opioid misuse among susceptible patients. Currently, there is a critical gap in knowledge regarding outcomes after an opioid-free anesthetic (OFA) during general anesthesia. We hypothesized that an opioid-free general anesthetic will not be inferior to a traditional opioid anesthetic (OA) as measured by the perioperative outcomes of postanesthesia care unit (PACU) duration, 12-hour postoperative summed pain intensity (SPI12) scores, total morphine equivalent doses (MEDs) utilized in the 12-hour postoperative inpatient (MED12) and total MEDs utilized in the 90-day outpatient periods (MED90). MATERIALS AND METHODS: Patients were included if they were ≥18 years old, met criteria for American Society of Anesthesiologists classification I-IV, received general endotracheal anesthesia from a single anesthesia provider for a surgical operation in 2016, did not receive intraoperative administration of opioids, and were recovered in the PACU. A total of 25 patients were included in the OFA group and 29 control patients in the OA group (n = 54). A retrospective chart review of intraoperative records, perioperative pain scores, and medication utilization (inpatient and outpatient) was performed to obtain the data for the analysis of the primary outcomes. RESULTS: In both OFA and OA groups, the continuous outcomes were not normally distributed. Subsequent bivariate tests of the indicated OA versus OFA age (d = 0.58), surgery duration (d = 0.24), and preoperative pain score (d = 0.51) warranted inclusion in the multinomial regression. Surgical duration was not significantly associated with the primary outcomes. However, the continuous variables of age and preoperative Defense and Veterans Pain Rating Scale score were associated with differences in primary outcomes. Every 1-year increase in the age was associated with a 5.06 increase in SPI12 and 5.73 mg increase in MED12. Every 1-point increase in the preoperative Defense and Veterans Pain Rating Scale score was associated with an 8.45 minutes increase in PACU duration, 11.25 increase in SPI12, 17.85 mg increase in MED12, and 20.83 mg increase in MED90. In regard to the primary outcomes, there was a lack of significant differences between the OFA and OA groups in all outcomes (PACU duration, mean SPI12, MED12, and MED90). CONCLUSIONS: To our knowledge, this is the first matched cohort study directly comparing an OFA with a traditional anesthetic for general anesthesia in a wide range of surgical and clinical scenarios. There was no significant difference in SPI12 between the OFA group and OA group, suggesting that patients' subjective pain was similar immediately after surgery whether or not they received intraoperative opioids. Concurrently, no "catch-up" effect was observed as the PACU duration; MED12 and MED90 were not different between the OFA and OA groups. However, there were many covariates identified in this study because of the small sample size or each group. Additional research is needed to explore if these findings can be extrapolated to a larger more heterogeneous population. Our preliminary work suggests that eliminating patient exposure to opioids in the intraoperative period does not have a deleterious effect on perioperative patient outcomes.

Quantifying Mitochondrial Dynamics in Patient Fibroblasts with Multiple Developmental Defects and Mitochondrial Disorders.

Mitochondria are dynamic organelles that undergo rounds of fission and fusion and exhibit a wide range of morphologies that contribute to the regulation of different signaling pathways and various cellular functions. It is important to understand the differences between mitochondrial structure in health and disease so that therapies can be developed to maintain the homeostatic balance of mitochondrial dynamics. Mitochondrial disorders are multisystemic and characterized by complex and variable clinical pathologies. The dynamics of mitochondria in mitochondrial disorders is thus worthy of investigation. Therefore, in this study, we performed a comprehensive analysis of mitochondrial dynamics in ten patient-derived fibroblasts containing different mutations and deletions associated with various mitochondrial disorders. Our results suggest that the most predominant morphological signature for mitochondria in the diseased state is fragmentation, with eight out of the ten cell lines exhibiting characteristics consistent with fragmented mitochondria. To our knowledge, this is the first comprehensive study that quantifies mitochondrial dynamics in cell lines with a wide array of developmental and mitochondrial disorders. A more thorough analysis of the correlations between mitochondrial dynamics, mitochondrial genome perturbations, and bioenergetic dysfunction will aid in identifying unique morphological signatures of various mitochondrial disorders in the future.

Evaluating Household Transmission of Invasive Group A Streptococcus Disease in the United States Using Population-based Surveillance Data, 2013-2016.

Using population-based surveillance data, we quantified the secondary invasive group A Streptococcus disease risk among household contacts. The disease risk in the 30 days postexposure to an index-case patient was highest among individuals aged ≥65 years, versus the annual background incidence of all ages.

Congenital Ocular Neuromyotonia with Partial Third Nerve Palsy.

PURPOSE: We report the first case of congenital ocular neuromyotonia (ONM) and the results of strabismus surgery for this patient's co-existing cranial nerve (CN) III palsy. PATIENTS AND METHOD: The patient presented at 18 months with strabismus that had reportedly been present since the time of birth. On exam, she had persistent exotropia (RXT) and hypertropia (RHT) with episodes of esotropia in the right eye that could be evoked by sustained left gaze. A diagnosis of ONM with partial CN III palsy was made. T1-weighted, T2-weighted, and fluid-attenuated inversion recovery magnetic resonance imaging failed to reveal intracranial pathology. RESULTS: Gaze induced intermittent esotropia resolved with carbamazepine. Surgery was performed to improve the patient's RXT and RHT. Post-operatively, the patient's RXT had improved from 12 to 15 prism diopters (∆) at near and 20∆ at a distance to 10∆ RXT at near with no horizontal deviation at distance. Her deviation has remained stable for 13 years, as has her neurological exam and good state of health. CONCLUSION: This case demonstrates that ONM may present congenitally and adds to the body of knowledge regarding surgical outcomes on concurrent CN palsies in these patients.

Discovery of N-arylpyrroles as agonists of GPR120 for the treatment of type II diabetes.

The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.

Discovery of an Isothiazole-Based Phenylpropanoic Acid GPR120 Agonist as a Development Candidate for Type 2 Diabetes.

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and ß-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

Design, synthesis and SAR of a novel series of heterocyclic phenylpropanoic acids as GPR120 agonists.

A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.

The multicopper ferroxidase hephaestin enhances intestinal iron absorption in mice.

Hephaestin is a vertebrate multicopper ferroxidase important for the transfer of dietary iron from intestinal cells to the blood. Hephaestin is mutated in the sex-linked anemia mouse, resulting in iron deficiency. However, sex-linked anemia mice still retain some hephaestin ferroxidase activity. They survive, breed, and their anemia improves with age. To gain a better understanding of the role of hephaestin in iron homeostasis, we used the Cre-lox system to generate knockout mouse models with whole body or intestine-specific (Villin promoter) ablation of hephaestin. Both types of mice were viable, indicating that hephaestin is not essential and that other mechanisms, multicopper ferroxidase-dependent or not, must compensate for hephaestin deficiency. The knockout strains, however, both developed a microcytic, hypochromic anemia, suggesting severe iron deficiency and confirming that hephaestin plays an important role in body iron acquisition. Consistent with this, the knockout mice accumulated iron in duodenal enterocytes and had reduced intestinal iron absorption. In addition, the similarities of the phenotypes of the whole body and intestine-specific hephaestin knockout mice clarify the important role of hephaestin specifically in intestinal enterocytes in maintaining whole body iron homeostasis. These mouse models will serve as valuable tools to study the role of hephaestin and associated proteins in iron transport in the small intestine and other tissues.

Innate immunity in free-ranging African buffalo (Syncerus caffer): associations with parasite infection and white blood cell counts.

Mammalian immunology has been studied in great detail in laboratory animals, but few of the tools and less of the insight derived from these studies have been placed in the context of natural, outbred wildlife populations subject to variable environments. We investigated patterns of innate immunity in free-ranging African buffalo in relation to host traits (age, reproductive status, body condition, white blood cell counts) and disease status (bovine tuberculosis [BTB], gastrointestinal nematodes, coccidia, ticks). We evaluated and used an in vitro assay measuring bactericidal competence of blood to assess a component of innate immunity in 200 female buffalo captured at Kruger National Park, South Africa, in June/July and October 2008. Animals with BTB had higher bactericidal competence of blood. Animals with higher neutrophil counts had higher bactericidal competence, whereas animals with lower lymphocyte counts had higher bactericidal competence. This pattern was driven by animals captured at the end of the dry season (October) and may be evidence of immune polarization, whereby individuals are unable to upregulate multiple components of immunity simultaneously. Bactericidal competence did not vary with host pregnancy status, body condition, age, lactation, tick infestation, nematode egg count, or coccidia oocyst count. Overall, we demonstrate that the bactericidal competence assay is practical and informative for field-based studies in wild bovids. Our results also show a correlation between bactericidal competence and bovine tuberculosis infection and reveal possible functional polarizations between different types of immune response in a free-ranging mammal.

Unsaturated fatty acids induce mesenchymal stem cells to increase secretion of angiogenic mediators.

Mesenchymal stem cells (MSC) represent emerging cell-based therapies for diabetes and associated complications. Ongoing clinical trials are using exogenous MSC to treat type 1 and 2 diabetes, cardiovascular disease and non-healing wounds due to diabetes. The majority of these trials are aimed at exploiting the ability of these multipotent mesenchymal stromal cells to release soluble mediators that reduce inflammation and promote both angiogenesis and cell survival at sites of tissue damage. Growing evidence suggests that MSC secretion of soluble factors is dependent on tissue microenvironment. Despite the contribution of fatty acids to the metabolic environment of type 2 diabetes, almost nothing is known about their effects on MSC secretion of growth factors and cytokines. In this study, human bone marrow-derived MSC were exposed to linoleic acid, an omega-6 polyunsaturated fatty acid, or oleic acid, a monounsaturated fatty acid, for seven days in the presence of 5.38 mM glucose. Outcomes measured included MSC proliferation, gene expression, protein secretion and chemotaxis. Linoleic and oleic acids inhibited MSC proliferation and altered MSC expression and secretion of known mediators of angiogenesis. Both unsaturated fatty acids induced MSC to increase secretion of interleukin-6, VEGF and nitric oxide. In addition, linoleic acid but not oleic acid induced MSC to increase production of interleukin-8. Collectively these data suggest that exposure to fatty acids may have functional consequences for MSC therapy. Fatty acids may affect MSC engraftment to injured tissue and MSC secretion of cytokines and growth factors that regulate local cellular responses to injury.