The analgesic benefit of Pericapsular Nerve Group (PENG) block in hip arthroscopic surgery: a retrospective pragmatic analysis at an academic health center.

INTRODUCTION: The novel pericapsular nerve group (PENG) block has recently been reported to provide effective motor-sparing local anesthetic-based analgesia to the hip joint. We aimed to evaluate the analgesic efficacy and safety of a preoperative PENG block among patients undergoing ambulatory hip arthroscopic surgery where systemic analgesia is the gold standard. METHODS: We conducted a single-center, retrospective pragmatic exploratory cohort study of consecutive outpatient hip arthroscopic surgery cases from January 2017 to March 2019. We identified 164 cases in which patients received general anesthesia with or without a preoperative PENG block. The primary analgesic outcome measures were time to first postoperative analgesic request, intraoperative and postoperative opioid consumption (intravenous morphine equivalent), and postoperative pain severity (visual analog scale 10 cm scale ranging from 0=no pain to 10=severe pain) in hospital. Secondary outcomes included duration of stay in the postanesthesia care unit, opioid-related side effects, time to discharge readiness, and block-related complications. RESULTS: Seventy-five cases received a preoperative PENG block and 89 cases received systemic analgesia alone. The addition of a PENG block reduced intraoperative (6.6 mg vs 7.5 mg, difference: 0.9 mg; 95% CI 0.2 to 1.7; p=0.01) and postoperative (10.7 mg vs 13.9 mg, difference: 3.2 mg; 95% CI 0.9 to 5.5; p=0.01) intravenous morphine consumption, as well as the mean (3.5 vs 4.2, difference: 0.7; 95% CI 0.1 to 1.3; p=0.03) and highest (5.5 vs 6.5, difference: 1.0; 95% CI 0.2 to 1.7; p=0.02) postoperative pain severity scores in hospital. The PENG block did not prolong the time to first analgesic request (15.8 min vs 12.3 min, difference: 3.5 min; 95% CI -9.0 to 2.0; p=0.23). Fewer patients in the PENG group experienced postoperative nausea and vomiting compared with systemic analgesia alone (36% vs 52%, OR 1.9; 95% CI 1.0 to 3.6; p=0.02), while the PENG block expedited discharge readiness (165.0 min vs 202.8 min, difference: 37.8 min; 95% CI 2.9 to 72.3; p=0.04). No block-related complications were noted in any patient. DISCUSSION: Based on our retrospective dataset, this pragmatic exploratory cohort study suggests that a preoperative PENG block is associated with questionable improvements in postoperative in-hospital analgesic outcomes which may or may not prove to be clinically relevant when compared with systemic analgesia alone for patients undergoing hip arthroscopic surgery. This small signal should be investigated in a prospective randomized trial.

Identification of the global miR-130a targetome reveals a role for TBL1XR1 in hematopoietic stem cell self-renewal and t(8;21) AML.

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed in t(8;21) acute myeloid leukemia (AML), where it is critical for maintaining the oncogenic molecular program mediated by the AML1-ETO complex. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of genes and molecular networks underpinning stemness properties of normal and leukemic cells.

Mapping the cellular origin and early evolution of leukemia in Down syndrome.

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.

The Complex Landscape of PTEN mRNA Regulation.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a key tumor suppressor in the development and progression of different tumor types. Emerging data indicate that small reductions in PTEN protein levels can promote cancer. PTEN protein levels are tightly controlled by a plethora of mechanisms beginning with epigenetic and transcriptional regulation and ending with control of protein synthesis and stability. PTEN messenger RNA (mRNA) is also subject to exquisite regulation by microRNAs, coding and long noncoding RNAs, and RNA-binding proteins. Additionally, PTEN mRNA is markedly influenced by alternative splicing and variable polyadenylation. Herein we provide a synoptic description of the current understanding of the complex regulatory landscape of PTEN mRNA regulation including several specific processes that modulate its stability and expression, in the context of PTEN loss-associated cancers.

microRNAs and Acute Myeloid Leukemia Chemoresistance: A Mechanistic Overview.

Up until the early 2000s, a functional role for microRNAs (miRNAs) was yet to be elucidated. With the advent of increasingly high-throughput and precise RNA-sequencing techniques within the last two decades, it has become well established that miRNAs can regulate almost all cellular processes through their ability to post-transcriptionally regulate a majority of protein-coding genes and countless other non-coding genes. In cancer, miRNAs have been demonstrated to play critical roles by modifying or controlling all major hallmarks including cell division, self-renewal, invasion, and DNA damage among others. Before the introduction of anthracyclines and cytarabine in the 1960s, acute myeloid leukemia (AML) was considered a fatal disease. In decades since, prognosis has improved substantially; however, long-term survival with AML remains poor. Resistance to chemotherapy, whether it is present at diagnosis or induced during treatment is a major therapeutic challenge in the treatment of this disease. Certain mechanisms such as DNA damage response and drug targeting, cell cycling, cell death, and drug trafficking pathways have been shown to be further dysregulated in treatment resistant cancers. miRNAs playing key roles in the emergence of these drug resistance phenotypes have recently emerged and replacement or inhibition of these miRNAs may be a viable treatment option. Herein, we describe the roles miRNAs can play in drug resistant AML and we describe miRNA-transcript interactions found within other cancer states which may be present within drug resistant AML. We describe the mechanisms of action of these miRNAs and how they can contribute to a poor overall survival and outcome as well. With the precision of miRNA mimic- or antagomir-based therapies, miRNAs provide an avenue for exquisite targeting in the therapy of drug resistant cancers.

The pharmacology of medieval sedatives: the "Great Rest" of the Antidotarium Nicolai.

ETHNOPHARMACOLOGICAL RELEVANCE: Past practices of compound drugs from different plant ingredients enjoyed remarkable longevity over centuries yet are largely dismissed by modern science as subtherapeutic, lethal or fanciful. AIM OF THE STUDY: To examine the phytochemical content of a popular medieval opiate drug called the "Great Rest" and gauge the bioavailability and combined effects of its alkaloid compounds (morphine, codeine, hyoscyamine, scopolamine) on the human body according to modern pharmacokinetic and pharmacodynamic parameters established for these compounds. CALCULATIONS AND THEORY: We reviewed the most recent studies on the pharmacodynamics of morphine, codeine, hyoscyamine and scopolamine to ascertain plasma concentrations required for different physiological effects and applied these findings to dosage of the Great Rest. RESULTS: Given the proportional quantities of the alkaloid rich plants, we calculate the optimal dose of Great Rest to be 3.1±0.1-5.3±0.76 g and reveal that the lethal dose of Great Rest is double the therapeutic concentration where all three alkaloid compounds are biologically active. CONCLUSION: This study helps establish the effective dose (ED50), toxic dose (TD50) and lethal dose (LD50) rates for the ingestion of raw opium, henbane and mandrake, and describes their probable combined effects, which may be applied to similar types of pre-modern pharmaceuticals to reveal the empirical logic behind past practices.