Integrated multi-omic characterization of congenital heart disease.

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer2. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.

Hippo pathway deletion in adult resting cardiac fibroblasts initiates a cell state transition with spontaneous and self-sustaining fibrosis.

Cardiac fibroblasts (CFs) respond to injury by transitioning through multiple cell states, including resting CFs, activated CFs, and myofibroblasts. We report here that Hippo signaling cell-autonomously regulates CF fate transitions and proliferation, and non-cell-autonomously regulates both myeloid and CF activation in the heart. Conditional deletion of Hippo pathway kinases, Lats1 and Lats2, in uninjured CFs initiated a self-perpetuating fibrotic response in the adult heart that was exacerbated by myocardial infarction (MI). Single cell transcriptomics showed that uninjured Lats1/2 mutant CFs spontaneously transitioned to a myofibroblast cell state. Through gene regulatory network reconstruction, we found that Hippo-deficient myofibroblasts deployed a network of transcriptional regulators of endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) consistent with elevated secretory activity. We observed an expansion of myeloid cell heterogeneity in uninjured Lats1/2 CKO hearts with similarity to cells recovered from control hearts post-MI. Integrated genome-wide analysis of Yap chromatin occupancy revealed that Yap directly activates myofibroblast cell identity genes, the proto-oncogene Myc, and an array of genes encoding pro-inflammatory factors through enhancer-promoter looping. Our data indicate that Lats1/2 maintain the resting CF cell state through restricting the Yap-induced injury response.

Perioperative Considerations for Patients Exposed to Psychostimulants.

Concerns regarding the perioperative management of acute psychostimulant intoxication have been recognized for decades, but novel and diverse substances in this class continue to be developed. Despite the similarities in mechanisms of action among psychostimulants, each subclass within this broad category has unique receptor specificity and different mechanisms that play a role in patient clinical presentation. These issues present challenges to anesthesia providers when caring for patients with either acute or chronic exposure to psychostimulants during the perioperative period. Challenges result from both physiological and psychological effects that influence the action of the primary anesthetic agent, adjuvant anesthetics, and analgesics used for perioperative management of pain. The epidemiology, pharmacology, and perioperative implications of psychostimulant use are presented for amphetamines and similar acting nonamphetamines, cocaine, and, finally, the mixed-action drugs known as entactogens that share stimulant and psychedelic properties. This information is then used as the foundation for safe and effective perioperative management of patients exposed to psychostimulants.

Statewide Emergency Medical Services Protocols for Status Epilepticus Management.

Although seizures are common in prehospital settings, standardized emergency medical services (EMS) treatment algorithms do not exist nationally. We examined nationwide variability in status epilepticus treatment by analyzing 33 publicly available statewide EMS protocols. All adult protocols recommend intravenous benzodiazepines (midazolam, n = 33; lorazepam, n = 23; diazepam, n = 24), 30 recommend intramuscular benzodiazepines (midazolam, n = 30; lorazepam, n = 8; diazepam, n = 3), and 27 recommend intranasal benzodiazepines (midazolam, n = 27; lorazepam, n = 3); pediatric protocols also frequently recommend rectal diazepam (n = 14). Recommended dosages vary widely, and first- and second-line agents are designated in only 18 and 2 states, respectively. Given this degree of variability, standardized national EMS guidelines are needed. ANN NEUROL 2021;89:604-609.

Unjustified Administration in Liberal Use of Tranexamic Acid in Trauma Resuscitation.

BACKGROUND: Early administration of tranexamic acid (TXA) has been widely implemented for the treatment of presumed hyperfibrinolysis in hemorrhagic shock. We aimed to characterize the liberal use of TXA and whether unjustified administration was associated with increased venous thrombotic events (VTEs). METHODS: We identified injured patients who received TXA between January 2016 and January 2018 by querying our Level 1 trauma center's registry. We retrospectively reviewed medical records and radiologic images to classify whether patients had a hemorrhagic injury that would have benefited from TXA (justified) or not (unjustified). RESULTS: Ninety-five patients received TXA for traumatic injuries, 42.1% were given by emergency medical services. TXA was considered unjustified in 35.8% of the patients retrospectively and in 52% of the patients when given by emergency medical services. Compared with unjustified administration, patients in the justified group were younger (47.6 versus 58.4; P = 0.02), more hypotensive in the field (systolic blood pressure: 107 ± 31 versus 137 ± 32 mm Hg; P < 0.001) and in the emergency department (systolic blood pressure: 97 ± 27 versus 128 ± 27; P < 0.001), and more tachycardic in emergency department (heart rate: 99 ± 29 versus 88 ± 19; P = 0.04). The justified group also had higher injury severity score (median 24 versus 11; P < 0.001), was transfused more often (81.7% versus 20.6%; P < 0.001), and had higher in-hospital mortality (39.3% versus 2.9%; P < 0.001), but there was no difference in the rate of VTE (8.2% versus 5.9%). CONCLUSIONS: Our results highlight a high rate of unjustified administration, especially in the prehospital setting. Hypotension and tachycardia were indications of correct use. Although we did not observe a difference in VTE rates between the groups, though, our study was underpowered to detect a difference. Cautious implementation of TXA in resuscitation protocols is encouraged in the meantime. Nonetheless, adverse events associated with unjustified TXA administration should be further evaluated.

Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells.

Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

Cannabinoid Modulation of Food-Cocaine Choice in Male Rhesus Monkeys.

Marijuana and other cannabinoid compounds are widely used by cocaine users. Preclinical animal studies suggest that these compounds can increase the reinforcing effects of cocaine under some schedules of cocaine self-administration and reinstatement, but not in all cases. To date, no studies have used a food-cocaine concurrent choice procedure, which allows for assessment of drug effects on response allocation, not just changes in cocaine self-administration. The goal of the present study was to examine the effects of compounds differing in their efficacy at the cannabinoid receptor (CBR) on cocaine self-administration using a food-drug choice procedure in monkeys. Four adult male rhesus monkeys were trained to self-administer cocaine in the context of an alternative food (1.0-g banana-flavored pellets) reinforcer, such that complete cocaine dose-response curves (0, 0.003-0.1 mg/kg per injection) were determined each session. Monkeys were tested acutely with the CBR full agonist CP 55,940 (0.001-0.01 mg/kg); the CBR partial agonist Δ9-tetrahydrocannabinol (THC; 0.03-0.3 mg/kg), which is also the primary active ingredient in marijuana and the CBR antagonist rimonabant (0.3-3.0 mg/kg). Cocaine choice increased in a dose-dependent manner. Acute treatment with CP 55,940 decreased cocaine choice, whereas THC and rimonabant enhanced the reinforcing effects of cocaine. Chronic (7-day) treatment with CP 55,940 resulted in tolerance to the decreases in cocaine choice. These findings with Δ9-THC provide support for a potential mechanism for co-abuse of marijuana and cocaine. Additional research with chronic treatment with full CBR agonists on attenuating the reinforcing strength of cocaine is warranted. SIGNIFICANCE STATEMENT: Co-abuse of tetrahydrocannabinol and cocaine is a significant public health problem. The use of animal models allows for the determination of how cannabinoid receptor stimulation or blockade influences the reinforcing strength of cocaine.

Chemical and Toxicological Characterization of Vaping Emission Products from Commonly Used Vape Juice Diluents.

Recent reports have linked severe lung injuries and deaths to the use of e-cigarettes and vaping products. Nevertheless, the causal relationship between exposure to vaping emissions and the observed health outcomes remains to be elucidated. Through chemical and toxicological characterization of vaping emission products, this study demonstrates that during vaping processes, changes in chemical composition of several commonly used vape juice diluents (also known as cutting agents) lead to the formation of toxic byproducts, including quinones, carbonyls, esters, and alkyl alcohols. The resulting vaping emission condensates cause inhibited cell proliferation and enhanced cytotoxicity in human airway epithelial cells. Notably, substantial formation of the duroquinone and durohydroquinone redox couple was observed in the vaping emissions from vitamin E acetate, which may be linked to acute oxidative stress and lung injuries reported by previous studies. These findings provide an improved molecular understanding and highlight the significant role of toxic byproducts in vaping-associated health effects.

Seasonality of postoperative pneumonia after coronary artery bypass grafting: A national inpatient sample study.

BACKGROUND: The development of postoperative pneumonia following cardiac surgery is associated with significant morbidity and mortality. However, seasonal variation as a risk factor for the development of postoperative pneumonia remains to be investigated. We sought to investigate whether patients undergoing coronary artery bypass grafting (CABG) during "flu season" (Fall and Winter months) at increased risk of postoperative pneumonia. MATERIALS AND METHODS: A retrospective cohort study of patients undergoing CABG in the National Inpatient Sample between 2005 and 2015 was completed. Concomitant diagnosis of pneumonia was defined as the primary outcome. Secondary outcomes were defined to include pneumonia secondary to several known pathogens. Outcomes with significant differences between Fall/Winter and Spring/Summer groups were further analyzed with additive time series decomposition. Odds ratios were generated and adjusted for age, sex, elective status, and 29 other Agency for Healthcare Research and Quality comorbidity measures. RESULTS: A total of 238 757 and 277 941 patients undergoing CABG during Fall/Winter and Spring/Summer, respectively, were identified. A significantly increased risk of postoperative pneumonia (adjusted odds ratio [aOR] = 1.15) and infection with influenza (aOR = 4.08), Haemophilus influenzae (aOR = 1.40), and Streptococcus pneumoniae (aOR = 1.47) was observed among patients receiving CABG in Q1 (January-March) compared to Q3 (July-September). CONCLUSIONS: There is a strong seasonality in the incidence of postoperative pneumonia after CABG which may persist across other cardiothoracic surgeries. In addition to optimizing infection control and perioperative care, cardiac surgeons should consider preoperative vaccination against seasonal influenza, H. influenzae, and S. pneumoniae to improve outcomes among high-risk patients.

PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer's disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0-120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the "test" and "retest" data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

Law and Disorder: Special Stacking Units-Building the Intergrowth Ce6Co5Ge16.

A new structure type of composition Ce6Co5Ge16 was grown out of a molten Sn flux. Ce6Co5Ge16 crystallizes in the orthorhombic space group Cmcm, with highly anisotropic lattice parameters of a = 4.3293(5) Å, b = 55.438(8) Å, and c = 4.3104(4) Å. The resulting single crystals were characterized by X-ray diffraction, and the magnetic and transport properties are presented. The Sn-stabilized structure of Ce6Co5Ge16 is based on the stacking of disordered Ce cuboctahedra and is an intergrowth of existing structure types including AlB2, BaNiSn3, and AuCu3. The stacking of structural subunits has previously been shown to be significant in the fields of superconductivity, quantum materials, and optical materials. Herein, we present the synthesis, characterization, and complex magnetic behavior of Ce6Co5Ge16 at low temperature, including three distinct magnetic transitions.

Chronic Δ9-THC in Rhesus Monkeys: Effects on Cognitive Performance and Dopamine D2/D3 Receptor Availability.

Cannabis-related impairments to cognitive function may represent novel therapeutic targets for cannabis-use disorder, although the nature, persistence, and reversibility of such deficits remain unclear. Adult male rhesus monkeys (N = 6) responded in the morning on tasks designed to assess different cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) touchscreens followed by responding maintained under a fixed-ratio (FR) 10 schedule of food presentation in different operant chambers. First, the acute effects of Δ9-tetrahydrocannabinol (THC; 0.01-0.56 mg/kg, i.v.) on cognitive performance, FR responding, and body temperature were determined. Next, THC (1.0-2.0 mg/kg, s.c.) was administered daily after FR 10 sessions for 12 weeks, during which the residual effects of THC (i.e., 22 hours after administration) on cognition were examined and the acute effects of THC were redetermined. In a subgroup of monkeys, dopamine D2/D3 receptor availability was assessed after 4 weeks of chronic THC exposure and compared with drug-naive controls using positron emission tomography and [11C]-raclopride (N = 4/group). Acute THC pretreatments dose-dependently decreased FR responding and body temperature, and impairment to cognitive performance was task specific. During chronic treatment, THC produced persistent residual impairment only to working memory; tolerance differentially developed to acute cognitive impairments. There was recovery from residual cognitive impairments to working memory within 2 weeks of abstinence. Compared with controls, D2/D3 receptor availability was not altered during chronic THC treatment. In conclusion, THC-induced disruptions in cognition were task-specific, as was tolerance development, and not related to changes in D2/D3 receptor availability. Intervention strategies for cannabis-use disorder that enhance working memory performance may facilitate positive treatment outcomes.

Incisional Nociceptive Input Impairs Attention-related Behavior and Is Associated with Reduced Neuronal Activity in the Prefrontal Cortex in Rats.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Cognitive capacity may be reduced from inflammation, surgery, anesthesia, and pain. In this study, we hypothesized that incision-induced nociceptive input impairs attentional performance and alters neuronal activity in the prefrontal cortex. METHODS: Attentional performance was measured in rats by using the titration variant of the 5-choice serial reaction time to determine the effect of surgical incision and anesthesia in a visual attention task. Neuronal activity (single spike and local field potentials) was measured in the medial prefrontal cortex in animals during the task. RESULTS: Incision significantly impaired attention postoperatively (area under curve of median cue duration-time 97.2 ± 56.8 [n = 9] vs. anesthesia control 25.5 ± 14.5 s-days [n = 9], P = 0.002; effect size, η = 0.456). Morphine (1 mg/kg) reduced impairment after incision (area under curve of median cue duration-time 31.6 ± 36.7 [n = 11] vs. saline 110 ± 64.7 s-days [n = 10], P < 0.001; η = 0.378). Incision also decreased cell activity (n = 24; 1.48 ± 0.58 vs. control, 2.93 ± 2.02 bursts/min; P = 0.002; η = 0.098) and local field potentials (n = 28; η = 0.111) in the medial prefrontal cortex. CONCLUSIONS: These results show that acute postoperative nociceptive input from incision reduces attention-related task performance and decreases neuronal activity in the medial prefrontal cortex. Decreased neuronal activity suggests nociceptive input is more than just a distraction because neuronal activity increases during audiovisual distraction with similar behavioral impairment. This suggests that nociceptive input and the medial prefrontal cortex may contribute to attentional impairment and mild cognitive dysfunction postoperatively. In this regard, pain may affect postoperative recovery and return to normal activities through attentional impairment by contributing to lapses in concentration for routine and complex tasks.

Assessment of Behavioral Disruption in Rats with Abdominal Inflammation Using Visual Cue Titration and the Five-choice Serial-reaction Time Task.

BACKGROUND: Both acute and chronic pain result in a number of behavioral symptoms in patients, including cognitive effects such as decreased attention and working memory. Intraperitoneal administration of dilute lactic acid in rodents has been used to induce abdominal inflammation and produce effects in behavioral assays of both sensory-discriminative and affective pain modalities. METHODS: Intraperitoneal injection of dilute lactic acid was used to study the impact of abdominal inflammation on an operant task requiring sustained visual attention in rats (N = 7 to 15/group) that adapts dynamically to performance ability. The effects of ketoprofen and morphine on lactic acid-induced impairment were compared with those on the disruptive effects of scopolamine. RESULTS: Lactic acid impaired performance in a concentration-dependent manner, increasing the duration of cue presentation required to maintain optimal performance from 0.5 ± 0.2 s (mean ± SD) to 17.2 ± 11.4 s after the administration of 1.8% (v/v) (N = 13). The latency to emit correct responses and to retrieve the food reward were both increased by lactic acid. All effects of lactic acid injection were reversed by both ketoprofen and morphine in a dose-dependent manner. Scopolamine, however, produced dose-dependent, nonpain-related disruption in sustained attention that was not altered by either ketoprofen or morphine. CONCLUSIONS: These data demonstrate that abdominal inflammation induced by lactic acid produces robust disruption in a visual attention-based operant task and that this disruption is reversed by analgesics. Future studies will focus on pain-related circuitry and its impact on both limbic forebrain and frontal cortical mechanisms.

Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat.

BACKGROUND: Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models. METHODS: CPM was assessed in individual rats and correlated with each animal's time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine ß-hydroxylase-conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation. RESULTS: The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine ß-hydroxylase-saporin. Dopamine ß-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine ß-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery. CONCLUSION: Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Differential suppression of intracranial self-stimulation, food-maintained operant responding, and open field activity by paw incision and spinal nerve ligation in rats.

BACKGROUND: Detection of ongoing spontaneous pain behaviors in laboratory animals remains a research challenge. Most preclinical pain studies measure elicited behavioral responses to an external noxious stimulus; however, ongoing spontaneous pain in humans and animals may be unrelated to hypersensitivity, and likely diminishes many behaviors, particularly motivated behaviors, that we hypothesize will decrease after induction of acute and chronic pain. METHODS: In this study, 201 male rats were subjected to paw incision (INC), L5/L6 spinal nerve ligation (SNL), or INC in SNL rats, and the effects on paw withdrawal threshold (PWT) were assessed. For comparison, the behavioral-decreasing effects on nonevoked measures, including lever pressing for rewarding electrical stimulation of the ventral tegmental area intracranial self-stimulation (VTA ICSS) or food reinforcement (FR), and open field activity (OFA), were also assessed in these same rats. RESULTS: INC decreased PWT for 4 days, decreased VTA ICSS for 2 days, and FR for 1 day but did not alter OFA. SNL decreased PWT similarly to INC but did not decrease VTA ICSS or FR; SNL did however decrease OFA. INC in SNL rats reduced PWT, VTA ICSS, and FR similarly to INC alone and did not decrease OFA compared with SNL alone. CONCLUSIONS: The acute effects of INC on decreasing lever pressing for VTA ICSS and FR (1-2 days after incision) correspond to the timeframe in which ongoing spontaneous pain is expected to occur after INC. Therefore, these decreases are likely mediated by ongoing spontaneous pain, which may be unrelated to mechanical hypersensitivity that persists for up to 4 days after INC. PWT is decreased similarly by SNL, yet operant behavior (lever pressing for VTA ICSS and FR) was not decreased by SNL. SNL, but not INC, decreased rearing behavior but not total distance traveled during OFA. This further indicates that the presence and the extent of hypersensitivity are not predictive of many behavioral changes in rats thought to be mediated by the presence of ongoing pain. Surprisingly, the behavioral effects of INC are not exacerbated in SNL rats. These data support the growing belief that acute pain models produce short-lived spontaneous pain behaviors that are often less pronounced or absent in neuropathic pain models, and highlight the need for assessment of both evoked and nonevoked pain behaviors in developing future therapies for acute and chronic pain.

Nonterpenoid Chemical Diversity of Cannabis Phenotypes Predicts Differentiated Aroma Characteristics.

The recent increase in legality of Cannabis Sativa L. has led to interest in developing new varieties with unique aromatic or effect-driven traits. Selectively breeding plants for the genetic stability and consistency of their secondary metabolite profiles is one application of phenotyping. While this horticultural process is used extensively in the cannabis industry, few studies exist examining the chemical data that may differentiate phenotypes aromatically. To gain insight into the diversity of secondary metabolite profiles between progeny, we analyzed five ice water hash rosin extracts created from five different phenotypes of the same crossing using comprehensive 2-dimensional gas chromatography coupled to time-of-flight mass spectrometry, flame ionization detection, and sulfur chemiluminescence detection. These results were then correlated to results from a human sensory panel, which revealed specific low-concentration compounds that strongly influence sensory perception. We found aroma differences between certain phenotypes that are driven by key minor, nonterpenoid compounds, including the newly reported 3-mercaptohexyl hexanoate. We further report the identification of octanoic and decanoic acids, which are implicated in the production of cheese-like aromas in cannabis. These results establish that even genetically similar phenotypes can possess diverse and distinct aromas arising not from the dominant terpenes, but rather from key minor volatile compounds. Moreover, our study underscores the value of detailed chemical analyses in enhancing cannabis selective breeding practices, offering insights into the chemical basis of aroma and sensory differences.

Crosstalk between bone metastatic cancer cells and sensory nerves in bone metastatic progression.

Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene-related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron-derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis.

Comparison of surgical stabilization of rib fractures vs epidural analgesia on in-hospital outcomes.

INTRODUCTION: Surgical stabilization of rib fractures (SSRF) improves functional outcomes compared to controls, partly due to reduction in pain. We investigated the impact of early SSRF on pulmonary complications, mortality, and length of stay compared to non-operative analgesia with epidural analgesia (EA). METHODS: Retrospective cohort study of the Trauma Quality Improvement Program (TQIP) 2017 dataset for adults with rib fractures, excluding those with traumatic brain injury or death within twenty-four hours. Early SSRF and EA occurred within 72 h, and we excluded those who received both or neither intervention. Our primary outcome was a composite of pulmonary complications including acute respiratory distress syndrome (ARDS) or ventilator-associated pneumonia (VAP). Additional outcomes included unplanned endotracheal intubation, in-hospital mortality, and hospital and intensive care unit (ICU) length of stay (LOS) for those surviving to discharge. Multiple logistic and linear regressions were controlled for variables including age, sex, flail chest (FC), injury severity, additional procedures, and medical comorbidities. RESULTS: We included 1,024 and 1,109 patients undergoing early SSRF and EA, respectively. SSRF patients were more severely injured with higher rates of FC (42.8 vs 13.3%, p<0.001), Injury Severity Score (ISS) > 16 (56.9 vs 36.1%, p<0.001), and Abbreviated Injury Scale (AIS) Thorax > 3 (33.3 vs 12.2%, p<0.001). Overall, 49 (2.3%) of patients developed ARDS or VAP, 111 (5.2%) required unplanned intubation, and 58 (2.7%) expired prior to discharge. On multivariable analysis, SSRF was not associated with the primary composite outcome (OR: 1.65, 95%CI: 0.85-3.21). Early SSRF significantly predicted decreased risk of unplanned intubation (OR:0.59, 95%CI: 0.38-0.92) compared with early EA alone, however, was not a significant predictor of in-hospital mortality (OR: 1.27, 95%CI: 0.68-2.39). SSRF was associated with significantly longer hospital (Exp(ß): 1.06, 95%CI: 1.00-1.12, p = 0.047) and ICU LOS (Exp(ß): 1.17, 95%CI: 1.08-1.27, p<0.001). CONCLUSIONS: Aside from unplanned intubation, we observed no statistically significant difference in the adjusted odds of in-hospital pulmonary morbidity or mortality for patients undergoing early SSRF compared with early EA. Chest wall injury patients may benefit from referral to trauma centers where both interventions are available and appropriate surgical candidates may receive timely intervention.