Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.

A Dynamic Model for Estimating the Retention Duration of Neutralizing Antibody Titers After Vaccination in a COVID-19 Convalescent Population.

We measured neutralizing antibodies (nAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a cohort of 235 convalescent patients (representing 384 analytic samples). They were followed for up to 588 days after the first report of onset in Taiwan. A proposed Bayesian approach was used to estimate nAb dynamics in patients postvaccination. This model revealed that the titer reached its peak (1819.70 IU/mL) by 161 days postvaccination and decreased to 154.18 IU/mL by day 360. Thus, the nAb titers declined in 6 months after vaccination. Protection, against variant B.1.1.529 (ie, Omicron) may only occur during the peak period.

Mapping the Geographical Distribution of the Mucosa-Associated Gut Microbiome in GI-Symptomatic Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by cognitive, behavioral, and communication impairments. In the last few years, it has been proposed that alterations in the gut microbiota may contribute to an aberrant communication between the gut and brain in children with ASD. Consistent with this notion, several studies have demonstrated that children with ASD have an altered fecal microbiota compared to typically developing (TD) children. However, it is unclear where along the length of the gastrointestinal (GI) tract these alterations in microbial communities occur. Additionally, the variation between specific mucosa-associated communities remains unknown. To address this gap in knowledge of the microbiome associated with ASD, biopsies from the antrum, duodenum, ileum, ascending colon, and rectum of children with ASD and age- and sex-matched TD children were examined by 16s rRNA sequencing. We observed an overall elevated abundance of Bacillota and Bacteroidota and decreased abundance of Pseudomonadota in all GI tract regions of both male and female ASD children compared to TD children. Further analysis at the genera level revealed unique differences in the microbiome in the different regions of the GI tract in ASD children compared to TD children. We also observed sex-specific differences in the gut microbiota composition in children with ASD. These data indicate that the microbiota of ASD children is altered at multiple regions of the GI tract and that different anatomic locations have unique alterations in mucosa-associated bacterial genera.

Methods for estimating insulin resistance from untargeted metabolomics data.

CONTEXT: Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming. OBJECTIVE: Develop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data. DESIGN: Insulin Resistance Atherosclerosis Family Study (IRASFS). SETTING: Community based. PARTICIPANTS: Mexican Americans (MA) and African Americans (AA). MAIN OUTCOME: Estimation models for measures of insulin resistance, i.e. SI and HOMA-IR. RESULTS: Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build insulin resistance estimation models from 1274 metabolites combined with clinical data, e.g. age, sex, body mass index (BMI). Metabolite data were transformed using three approaches, i.e. inverse normal transformation, standardization, and Box Cox transformation. The analysis was performed in one MA recruitment site (San Luis Valley, Colorado (SLV); N = 450) and tested in another MA recruitment site (San Antonio, Texas (SA); N = 473). In addition, the two MA recruitment sites were combined and estimation models tested in the AA recruitment sample (Los Angeles, California; N = 495). Estimated and empiric SI were correlated in the SA (r2 = 0.77) and AA (r2 = 0.74) testing datasets. Further, estimated and empiric SI were consistently associated with BMI, low-density lipoprotein cholesterol (LDL), and triglycerides. We applied similar approaches to estimate HOMA-IR with similar results. CONCLUSIONS: We have developed a method for estimating insulin resistance with metabolomics data that has the potential for application to a wide range of biomedical studies and conditions.

Characterizing the Impact of Clinical Exposure to Patients with Opioid Use Disorder on Medical Students' Perceptions of Stigma and Patient Care.

PHENOMENON: Opioid use disorder (OUD) is a growing public health crisis. Many residents and physicians do not feel comfortable working with patients with OUD. Social stigma promotes negative attitudes toward these patients and is a roadblock to delivering equitable and effective care. This study sought to (1) characterize medical students' experiences with patients with OUD, (2) understand the features that make a patient encounter memorable, (3) explore factors that influence future practice, and (4) describe the influence on stigma toward patients with OUD. Approach: A study was conducted using qualitative descriptive theory and purposive sampling of fourth-year medical students (M4s) enrolled at Wake Forest School of Medicine (WFSOM). Data collection consisted of a free-text question as a part of a larger survey to M4s in the Class of 2019 and 2020, followed by semi-structured interviews. The goal of the survey was to gain a broad understanding of student encounters with patients with OUD. The goal of the interviews was to gain a deeper understanding of the impact of these encounters on future practice and stigma. Thematic analysis was used to analyze all data. Findings: One-hundred-seventy out of 237 students (RR = 71.7%) completed the free text question describing a memorable encounter with a patient with OUD. Twelve students then completed interviews. Patient encounters occurred in three primary settings: Emergency department, inpatient clerkship, or Intensive Outpatient Program (IOP) meetings during psychiatry clerkship. Clinical encounters were memorable when there was: (1) conflict with patients or teams, (2) complicated care, (3) inadequate care, and (4) relevance to the student's future career. Memorable encounters influenced future practice by changing students' approaches to: (1) future treatment, (2) future communication, or (3) allowing students to practice professionalism. Regarding opioid stigma, students reported that these encounters made them: (1) more aware of stereotypes in medicine, (2) stereotypes in their personal lives, and (3) generated actions that students want to take in the future. Insights: A single, influential clinical encounter has the potential to substantially influence medical students' approach to patients with OUD, including both clinical management and attitudes toward care. Affecting encounters increased knowledge of OUD and fostered empathy and perspective-taking. Not all encounters had a defining impact on students' stigma toward OUD. Medical schools need to create opportunities that will have lasting impact by encouraging students to fully engage with patients with OUD.Supplemental data for this article is available online at https://doi.org/10.1080/10401334.2022.2038175 .

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

HIPEC after neoadjuvant chemotherapy is associated with acceptable toxicity and favorable quality of life in newly diagnosed advanced ovarian cancer patients.

OBJECTIVE: To evaluate toxicity, quality of life and PFS in patients with advanced ovarian cancer who underwent neoadjuvant chemotherapy (NAC) followed by CRS and HIPEC with carboplatin. METHODS: Patients with stage IIIC or IVA epithelial ovarian cancer, who were not candidates for primary CRS, were enrolled in this phase two trial. Patients received 3-6 cycles of NAC with an IV carboplatin doublet followed by CRS with HIPEC (carboplatin 800 mg/m2 for 90 min). They were followed for at least 12 months to assess for adverse events, quality of life (QOL) and disease progression. QOL was measured using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaires prior to CRS and post-operatively at 6 weeks, 3 months, and 6 months after CRS. RESULTS: Twenty patients were enrolled. HIPEC was completed successfully in all twenty patients, and there was no peri-operative mortality. Twelve (70.6%) patients experienced a grade 3 or 4 toxicity; most commonly anemia (59%), thrombocytopenia (29%), and hypokalemia (24%). There was no significant change between the pre-operative and postoperative 6 weeks, 3 month, and 6 month FACT-O, NTX, and AD scores. Nine (45%) patients have experienced disease recurrence to date. The median progression free survival in this cohort is 11.2 months (2.5-23.7 months). CONCLUSION: The addition of HIPEC with carboplatin to interval CRS was well tolerated in patient population. Myelosuppression was the most common adverse event. CRS with HIPEC did not adversely impact these patients' QOL indices. The efficacy of this regimen should be further evaluated in a larger clinical trial.

Constant Pressure Convection-Enhanced Delivery Increases Volume Dispersed With Catheter Movement in Agarose.

Convection-enhanced delivery (CED) has been extensively studied for drug delivery to the brain due to its inherent ability to bypass the blood-brain barrier. Unfortunately, CED has also been shown to inadequately distribute therapeutic agents over a large enough targeted tissue volume to be clinically beneficial. In this study, we explore the use of constant pressure infusions in addition to controlled catheter movement as a means to increase volume dispersed (Vd) in an agarose gel brain tissue phantom. Constant flow rate and constant pressure infusions were conducted with a stationary catheter, a catheter retracting at a rate of 0.25 mm/min, and a catheter retracting at a rate of 0.5 mm/min. The 0.25 mm/min and 0.5 mm/min retracting constant pressure catheters resulted in significantly larger Vd compared to any other group, with a 105% increase and a 155% increase compared to the stationary constant flow rate catheter, respectively. These same constant pressure retracting infusions resulted in a 42% and 45% increase in Vd compared to their constant flow rate counterparts. Using constant pressure infusions coupled with controlled catheter movement appears to have a beneficial effect on Vd in agarose gel. Furthermore, constant pressure infusions reveal the fundamental limitation of flow-driven infusions in both controlled catheter movement protocols as well as in stationary protocols where maximum infusion volume can never be reliably obtained.

Comparing data-driven and hypothesis-driven MRI-based predictors of cognitive impairment in individuals from the Atherosclerosis Risk in Communities (ARIC) study.

INTRODUCTION: A data-driven index of dementia risk based on magnetic resonance imaging (MRI), the Alzheimer's Disease Pattern Similarity (AD-PS) score, was estimated for participants in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: AD-PS scores were generated for 839 cognitively non-impaired individuals with a mean follow-up of 4.86 years. The scores and a hypothesis-driven volumetric measure based on several brain regions susceptible to AD were compared as predictors of incident cognitive impairment in different settings. RESULTS: Logistic regression analyses suggest the data-driven AD-PS scores to be more predictive of incident cognitive impairment than its counterpart. Both biomarkers were more predictive of incident cognitive impairment in participants who were White, female, and apolipoprotein E gene (APOE) ε4 carriers. Random forest analyses including predictors from different domains ranked the AD-PS scores as the most relevant MRI predictor of cognitive impairment. CONCLUSIONS: Overall, the AD-PS scores were the stronger MRI-derived predictors of incident cognitive impairment in cognitively non-impaired individuals.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Plasma metabolomic profiling in subclinical atherosclerosis: the Diabetes Heart Study.

BACKGROUND: Incidence rates of cardiovascular disease (CVD) are increasing, partly driven by the diabetes epidemic. Novel prediction tools and modifiable treatment targets are needed to enhance risk assessment and management. Plasma metabolite associations with subclinical atherosclerosis were investigated in the Diabetes Heart Study (DHS), a cohort enriched for type 2 diabetes (T2D). METHODS: The analysis included 700 DHS participants, 438 African Americans (AAs), and 262 European Americans (EAs), in whom coronary artery calcium (CAC) was assessed using ECG-gated computed tomography. Plasma metabolomics using liquid chromatography-mass spectrometry identified 853 known metabolites. An ancestry-specific marginal model incorporating generalized estimating equations examined associations between metabolites and CAC (log-transformed (CAC + 1) as outcome measure). Models were adjusted for age, sex, BMI, diabetes duration, date of plasma collection, time between plasma collection and CT exam, low-density lipoprotein cholesterol (LDL-C), and statin use. RESULTS: At an FDR-corrected p-value < 0.05, 33 metabolites were associated with CAC in AAs and 36 in EAs. The androgenic steroids, fatty acid, phosphatidylcholine, and bile acid metabolism subpathways were associated with CAC in AAs, whereas fatty acid, lysoplasmalogen, and branched-chain amino acid (BCAA) subpathways were associated with CAC in EAs. CONCLUSIONS: Strikingly different metabolic signatures were associated with subclinical coronary atherosclerosis in AA and EA DHS participants.

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates.

BACKGROUND: Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and µ receptors produces analgesia with reduced side effects in nonhuman primates. METHODS: The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with µ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. RESULTS: Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] µg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] µg/kg). Pretreatment with antagonists selective for nociceptin and µ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 µg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 µg; 3,009 ± 1,474 scratches). CONCLUSIONS: In nonhuman primates, the µ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/µ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol.

A pilot study of aquatic prehabilitation in adults with knee osteoarthritis undergoing total knee arthroplasty - short term outcome.

BACKGROUND: Knee osteoarthritis (KOA) is increasingly more prevalent and significant number of patients require knee arthroplasty. Although knee arthroplasty is generally successful, it takes months to recover physical function. Preoperative physical function is known to predict postoperative outcomes and exercise can improve preoperative physical function. However, patients with KOA have difficulty exercise on land due to pain and stiffness, while water exercise can be better tolerated. We hypothesized that preoperative water exercise to improve preoperative physical function will improve postoperative outcomes after total knee arthroplasty (TKA). METHODS: We enrolled 43 participants who were scheduled for elective TKA in 4-8 weeks and scored at or below 50th percentile in mobility assessment tool-sf (MAT-sf). All enrolled participants were assessed on 1) clinical osteoarthritis symptom severity using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 2) physical function using Short Physical Performance Battery (SPPB), 3) self-reported mobility using Mobility Assessment Tool-short form (MAT-sf), 4) depression using Geriatric Depression Scale-short form (GDS-sf), 5) cognitive function using Montreal Cognitive Assessment (MoCA). Blood samples for high-sensitivity-C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were stored at - 80 °C then all samples were analyzed together. All the enrolled participants were randomly assigned to the aquatic exercise intervention (AEI) or usual care group. Sixty minute sessions of AEI was conducted three times a week for 4-8 weeks. Participants in both groups were evaluated within 1 week before their scheduled surgery, as well as 4 weeks after the surgery. RESULTS: The mean age was 67.1 (±6.2), 44% were female, 74% were White. There is no statistically significant difference in combined outcome of any complication, unscheduled ER visit, and disposition to nursing home or rehab facility by AEI. However, AEI was associated with more favorable outcomes: WOMAC scores (p < 0.01), chair-stand (p = 0.019), MAT-sf as well as improved depression (p = 0.043) and cognition (p = 0.008). CONCLUSION: 4-8 weeks of aquatic exercise intervention resulted in improved functional outcomes as well as improved depression and cognition in elderly patients undergoing TKA. A larger study is warranted to explore the role of water exercise in clinical and functional outcomes of TKA.

Feasibility and accuracy of 3D printed patient-specific skull contoured brain biopsy guides.

OBJECTIVE: Design 3D printed skull contoured brain biopsy guides (3D-SCGs) from computed tomography (CT) or T1-weighted magnetic resonance imaging (T1W MRI). STUDY DESIGN: Feasibility study. SAMPLE POPULATION: Five beagle dog cadavers and two client-owned dogs with brain tumors. METHODS: Helical CT and T1W MRI were performed on cadavers. Planned target point was the head of the caudate nucleus. Three-dimensional-SCGs were created from CT and MRI using commercially available open-source software. Using 3D-SCGs, biopsy needles were placed into the caudate nucleus in cadavers, and CT was performed to assess needle placement accuracy, followed by histopathology. Three-dimensional-SCGs were then created and used to perform in vivo brain tumor biopsies. RESULTS: No statistical difference was found between the planned target point and needle placement. Median needle placement error for all planned target points was 2.7 mm (range: 0.86-4.5 mm). No difference in accuracy was detected between MRI and CT-designed 3D-SCGs. Median needle placement error for the CT was 2.8 mm (range: 0.86-4.5 mm), and 2.2 mm (range: 1.7-2.7 mm) for MRI. Biopsy needles were successfully placed into the target in the two dogs with brain tumors and biopsy was successfully acquired in one dog. CONCLUSION: Three-dimensional-SCGs designed from CT or T1W MRI allowed needle placement within 4.5 mm of the intended target in all procedures, resulting in successful biopsy in one of two live dogs. CLINICAL SIGNIFICANCE: This feasibility study justifies further evaluation of 3D-SCGs as alternatives in facilities that do not have access to stereotactic brain biopsy.

Neuromuscular ultrasound for taxane peripheral neuropathy in breast cancer.

BACKGROUND: Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent. METHODS: This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD). RESULTS: A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm2 smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R2 0.30; P = .04). CONCLUSIONS: These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.

Antinociceptive, reinforcing, and pruritic effects of the G-protein signalling-biased mu opioid receptor agonist PZM21 in non-human primates.

BACKGROUND: A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent Gi/o activator with minimal ß-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates. METHODS: Antinociceptive, reinforcing, and pruritic effects of PZM21 were compared with those of the clinically used MOP receptor agonists oxycodone and morphine in assays of acute thermal nociception, capsaicin-induced thermal allodynia, itch scratching responses, and drug self-administration in gonadally intact, adult rhesus macaques (10 males, six females). RESULTS: After subcutaneous administration, PZM21 (1.0-6.0 mg kg-1) and oxycodone (0.1-0.6 mg kg-1) induced dose-dependent thermal antinociceptive effects (P<0.05); PZM21 was 10 times less potent than oxycodone. PZM21 exerted oxycodone-like reinforcing effects and strength as determined by two operant schedules of reinforcement in the intravenous drug self-administration assay. After intrathecal administration, PZM21 (0.03-0.3 mg) dose-dependently attenuated capsaicin-induced thermal allodynia (P<0.05). Although intrathecal PZM21 and morphine induced MOP receptor-mediated antiallodynic effects, both compounds induced robust, long-lasting itch scratching. CONCLUSIONS: PZM21 induced antinociceptive, reinforcing, and pruritic effects similar to clinically used MOP receptor agonists in primates. Although structure-based discovery of PZM21 identified a novel avenue for studying G-protein signalling-biased ligands, biasing an agonist towards G-protein signalling pathways did not determine or alter reinforcing (i.e. abuse potential) or pruritic effects of MOP receptor agonists in a translationally relevant non-human primate model.

Symptoms Suggestive of Gastroparesis in a Community-Based Cohort of European Americans and African Americans with Type 2 Diabetes Mellitus.

BACKGROUND: Although gastroparesis is seen in patients with type 2 diabetes mellitus (T2DM), the prevalence of symptoms suggestive of gastroparesis in patients with T2DM is unknown, particularly among African Americans. AIMS: To determine the prevalence of symptoms associated with gastroparesis in a large community-based population of European Americans and African Americans with T2DM. METHODS: Individuals with T2DM in the Diabetes Heart Study were asked to complete the gastroparesis cardinal symptom index (GCSI) and other GI-related questionnaires. GCSI total score ≥ 18 represented moderate or worse symptoms suggestive of gastroparesis. RESULTS: A total of 1253 participants (700 female, 553 male) completed the GCSI: 750 were European American and 503 African American. GCSI scores ≥ 18 were recorded in 72 participants: 38 (5%) of European Americans and 34 (7%) of African Americans. The average GCSI was 24.1 in European Americans and 24.6 in African Americans, indicating moderate to severe symptoms. Compared to European Americans with GCSI scores ≥ 18, African Americans were younger (59.4 vs. 53.3 years, p = 0.004), had earlier onset of T2DM (46.3 vs. 40.1 years, p = 0.01), higher HbA1c (7.6 vs. 9.1, p = 0.0009), underwent fewer upper endoscopies (55.3% vs. 26.5%, p = 0.02), and had more anxiety and depression (p < 0.001). CONCLUSIONS: Moderate or greater symptoms suggestive of gastroparesis are present in 5-7% of European and African American patients with T2DM in community-based populations. Symptoms suggestive of gastroparesis may be underappreciated in patients with T2DM and account for upper gastrointestinal symptoms, unexplained glycemic control issues, and decreased quality of life.

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates.

BACKGROUND: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. METHODS: A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. RESULTS: After systemic administration, BU10038 (0.001-0.01 mg kg-1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10-30-fold higher dose (0.01-0.1 mg kg-1). After intrathecal administration, BU10038 (3 µg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. CONCLUSIONS: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.

Prognostic and predictive factors for clinical and radiographic responses in patients with painful bone metastasis treated with magnetic resonance-guided focused ultrasound surgery.

Background: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an alternative local therapy for patients with painful bone metastasis. However, little is known about the prognostic and predictive factors of MRgFUS in treating bone metastasis. Materials and methods: This retrospective study analyzed the performance status, treated site, pretreatment pain score, pretreatment tumor volume and lesion coverage volume factor (CVF) of 31 patients who underwent MRgFUS. A numerical rating scale for pain was used at the same time to assess the clinical response. Radiographic responses were evaluated using a modified version of The University of Texas MD Anderson Cancer Center criteria and reference to the MR imaging or computed tomography scans obtained 3 months after treatment. Univariate and multivariate logistic regression analyses were conducted to examine the effect of variables on clinical and radiographic responses. Results: The overall clinical response rate was 83.9% and radiographic response rate was 67.7%. Multivariate logistic regression analysis revealed that the better pretreatment Karnofsky performance status (KPS) (odds ratio: 1.220, 95% confidence interval (CI): 1.033-1.440; p = 0.019) was significantly associated with a more positive clinical response, and that the lesion CVF (odds ratio: 1.183, 95% CI: 1.029-1.183; p = 0.0055) was an independent prognostic factor for radiographic responses. The radiographic response of patients with lesion CVF ≥70% and CVF <70% were 91.7% and 52.6%, respectively (p = 0.0235). Conclusion: The pretreatment KPS was an independent prognostic factor for clinical responses, and lesion CVF was an independent prognostic factor for radiographic responses.