The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists.

Analgesic and Respiratory Depressant Effects of R-dihydroetorphine: A Pharmacokinetic-Pharmacodynamic Analysis in Healthy Male Volunteers.

BACKGROUND: There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the µ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. METHODS: The authors performed a population pharmacokinetic-pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. RESULTS: R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. CONCLUSIONS: Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures.

The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. Previous work has implicated R2.60(190), N3.43(240), Q7.49(394), and H6.52(363) as key residues involved in peptide-mediated biased agonism, with R2.60(190), N3.43(240), and Q7.49(394) predicted to form a polar interaction network. In this study, we used novel insight gained from recent crystal structures of the transmembrane domains of the glucagon and corticotropin releasing factor 1 (CRF1) receptors to develop improved models of the GLP-1 receptor that predict additional key molecular interactions with these amino acids. We have introduced E6.53(364)A, N3.43(240)Q, Q7.49(394)N, and N3.43(240)Q/Q7.49(394)N mutations to probe the role of predicted H-bonding and charge-charge interactions in driving cAMP, calcium, or extracellular signal-regulated kinase (ERK) signaling. A polar interaction between E6.53(364) and R2.60(190) was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49(394), but not R2.60(190)/E6.53(364) was critical for calcium mobilization for all three peptides. Mutation of N3.43(240) and Q7.49(394) had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events.

Redox-induced controllable engineering of MnO2-MnxCo3-xO4 interface to boost catalytic oxidation of ethane.

Multicomponent oxides are intriguing materials in heterogeneous catalysis, and the interface between various components often plays an essential role in oxidations. However, the underlying principles of how the hetero-interface affects the catalytic process remain largely unexplored. Here we report a unique structure design of MnCoOx catalysts by chemical reduction, specifically for ethane oxidation. Part of the Mn ions incorporates with Co oxides to form spinel MnxCo3-xO4, while the rests stay as MnO2 domains to create the MnO2-MnxCo3-xO4 interface. MnCoOx with Mn/Co ratio of 0.5 exhibits an excellent activity and stability up to 1000 h under humid conditions. The synergistic effects between MnO2 and MnxCo3-xO4 are elucidated, in which the C2H6 tends to be adsorbed on the interfacial Co sites and subsequently break the C-H bonds on the reactive lattice O of MnO2 layer. Findings from this study provide valuable insights for the rational design of efficient catalysts for alkane combustion.

Fluoroscopy-guided high-intensity focused ultrasound neurotomy of the lumbar zygapophyseal joints: a prospective, open-label study.

OBJECTIVE: The objective of this study is to investigate safety and effectiveness of a fluoroscopy-guided high-intensity focused ultrasound (HIFU) system for thermal ablation of the lumbar medial branch nerves. METHODS: This dual center prospective cohort study enrolled 30 participants with lumbar zygapophyseal joint syndrome. Each participant previously had a positive response to either a single diagnostic analgesic block or radiofrequency ablation (RFA). The primary effectiveness outcome was individual responder rate, defined as a reduction of two points or more on the pain intensity numerical rating scale without an increase in opioid intake, or a reduction in opioid intake without an increase in pain at 6 months after the intervention. The primary safety outcome was procedure-related or device-related adverse events (AEs). Secondary outcome variables included MRI evidence of tissue ablation, Oswestry Disability Index, 12-Item Short Form Health Survey, Brief Pain Inventory, and Patient Global Impression of Change. RESULTS: The individual responder rate was 89.7% at 2 days, 89.7% at 7 days, 72.4% at 14 days, 82.1% at 30 days, 59.3% at 90 days and 82.6% at 180 days. The average Numeric Rating Scale for pain severity decreased from 7.1 at baseline to 3.0 (N=29) after 2 days, 3.0 (N=29) after 7 days, 3.1 (N=29) after 14 days, 3.2 (N=28) after 30 days, 4.3 (N=27) after 90 days, and 3.3 (N=23) after 180 days. All participants tolerated the procedure well with no significant side effects or complications. CONCLUSIONS: Fluoroscopy-guided HIFU neurotomy achieved clinical responses comparable with RFA, and there were no significant device-related or procedure-related AEs. TRIAL REGISTRATION NUMBER: NCT04129034.

New molten metal catalysts for CO2 and CH4 conversion to 2 : 1 H2 : CO syngas.

Activity trends for 22 metals and metal alloys are reported for the conversion of CO2 and CH4 to 2 : 1 H2 : CO syngas and carbon. A correlation is observed between CO2 conversion and the free energy of oxidation by CO2 on pure metal catalysts. Indium and indium alloys activate CO2 at the highest rates. We identify a new bifunctional 20 : 80 mol% Sn-In alloy that activates both CO2 and CH4 while catalyzing both reactions.

Chronic pain management during the COVID-19 pandemic: Can telemedicine replace in-person consultation? A prospective clinical study.

Introduction: The COVID-19 pandemic forced numerous pain clinics to suspend their services. For chronic pain patients, even a temporary closure and inability to connect with their healthcare providers may result in adverse outcomes. There are serious concerns regarding worsening of physical and emotional suffering and a surge in substance abuse. Therefore, telemedicine, also called telehealth, would seem to be a reasonable alternative to in-person clinic visits during the lockdowns. However, it remains unclear whether a telemedicine consultation is adequate for diagnostic purposes and subsequent intervention planning. Methods: This study was conducted as an open-label cohort study on new patients referred to an interdisciplinary community pain clinic focused on image-guided interventions. The primary outcome was to determine whether a video consultation was sufficient to make an initial diagnosis and plan subsequent interventions. Secondary variables included technical feasibility, patient satisfaction, calculated nonincurred cost and time-saving. Video consultations were performed using a secure videoconference system consistent with routine clinic practice. Results: Sixty-five participants were recruited, and 49 (75.4%) completed the study. Patients for whom interventional approaches were not recommended elected not to continue with clinic visits. The intra-observer agreement rate between the telemedicine and in-person encounter was 93.9% (95% CI 87.2-100) for the diagnostic codes and treatment plan. The median satisfaction score from the telemedicine encounter was seven on a scale of 0-7, and it remained 6 when the remote care experience was later compared with the in-person visit. There were considerable savings in travel time and expenses. Discussion: The study experimentally validated the ability of telemedicine encounters to establish a diagnosis and formulate an interventional pain management plan of care. The validity of virtual consultation for complex pain care remains to be determined. It is unreasonable to expect telemedicine to completely replace clinic visits in the foreseeable future. However, judicious use of technology may facilitate timely scheduling, save time and resources, and improve satisfaction without jeopardizing the quality of care.

Heuristic evaluation and usability testing of a computerized patient-reported outcomes survey for headache sufferers.

OBJECTIVE: The aim of this study was to evaluate usability of a prototype tablet PC-administered computerized adaptive test (CAT) of headache impact and patient feedback report, referred to as HEADACHE-CAT. MATERIALS AND METHODS: Heuristic evaluation specialists (n = 2) formed a consensus opinion on the application's strengths and areas for improvement based on general usability principles and human factors research. Usability testing involved structured interviews with headache sufferers (n = 9) to assess how they interacted with and navigated through the application, and to gather input on the survey and report interface, content, visual design, navigation, instructions, and user preferences. RESULTS: Specialists identified the need for improved instructions and text formatting, increased font size, page setup that avoids scrolling, and simplified presentation of feedback reports. Participants found the tool useful, and indicated a willingness to complete it again and recommend it to their healthcare provider. However, some had difficulty using the onscreen keyboard and autoadvance option; understanding the difference between generic and headache-specific questions; and interpreting score reports. CONCLUSIONS: Heuristic evaluation and user testing can help identify usability problems in the early stages of application development, and improve the construct validity of electronic assessments such as the HEADACHE-CAT. An improved computerized HEADACHE-CAT measure can offer headache sufferers an efficient tool to increase patient self-awareness, monitor headaches over time, aid patient-provider communications, and improve quality of life.

Electrocatalytic Hydrogenation of Guaiacol in Diverse Electrolytes Using a Stirred Slurry Reactor.

Electrocatalytic hydrogenation (ECH) of guaiacol was performed in a stirred slurry electrochemical reactor (SSER) using 5 wt % Pt/C catalyst in the cathode compartment. Different pairs of acid (H2 SO4 ), neutral (NaCl), and alkaline (NaOH) catholyte-anolyte combinations separated by a Nafion® 117 cation exchange membrane, were investigated by galvanostatic and potentiostatic electrolysis to probe the electrolyte and proton concentration effect on guaiacol conversion, product distribution, and Faradaic efficiency. The acid-acid and neutral-acid pairs were found to be the most effective. In the case of the neutral-acid pair, proton diffusion and migration through the membrane from the anolyte to the catholyte supplies the protons required for ECH. Typically, the two major hydrogenation products were cyclohexanol and 2-methoxycyclohexanol. However, ECH at constant cathode superficial current density (-182 mA cm-2 ) and higher temperature (i.e., 60 °C) favored a pathway leading mainly to cyclohexanone. The guaiacol conversion routes were affected by temperature- and cathode potential-dependent surface coverage of adsorbed hydrogen radicals generated through electroreduction of protons.

A hybrid cohort individual sampling natural history model of age-related macular degeneration: assessing the cost-effectiveness of screening using probabilistic calibration.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness. It is likely that treatment of AMD at earlier stages is more effective than later treatment; thus, screening for AMD should be considered. The aim of this study was to develop a natural history model of AMD to estimate the cost-effectiveness of screening. METHODS: A hybrid cohort/individual sampling decision analytic model was developed. Primary data sets, expert elicitation, and data from the literature were used to populate the model. To incorporate joint parameter uncertainty, and to populate unobservable parameters, an innovative form of probabilistic calibration was applied to a range of output parameters. RESULTS: In the reference case, annual screening from age 60 y is the most cost-effective option, although this is subject to high levels of uncertainty. Alternative, age-specific utility values show that screening is predicted to be less cost-effective, assuming interventions that reduce progression to wet AMD moderately improve the cost-effectiveness of screening, whereas the addition of anti-vascular endothelial growth factor therapy for juxtafoveal or subfoveal wet AMD lesions improves the cost-effectiveness of screening significantly. CONCLUSIONS: The extent of the uncertainty around the mean results, and the additional resources and possible reorganization of services required to implement screening, indicate that it may be preferable to reduce the level of uncertainty before implementing screening for AMD. Initial actions may be best targeted at assessing how routine data may be used to describe clinical presentation, a screening pilot study, and a secondary costing study.

Esterification over Acid-Treated Mesoporous Carbon Derived from Petroleum Coke.

Multistep activation of a Canadian oilsands petroleum coke that yields an acidified mesoporous carbon catalyst is reported. Microporous-activated carbon (APC; ∼2000 m2/g), obtained by thermochemical activation of petroleum coke using KOH, was impregnated with ammonium heptamolybdate and activated by carbothermal hydrogen reduction (CHR). The resulting Mo2C, supported on high-mesopore volume (V meso ∼0.4 cm3/g) carbon, yields the desired mesoporous carbon catalyst (V meso ∼0.7 cm3/g) following acid washing. The effect of CHR temperature and the benefit of Mo2C loading on mesopore development is reported, and pore development models are discussed. The mesoporous carbons are active for the esterification of acetic acid and 1-butanol at 77 °C, and the butanol conversion correlates with the catalyst acidity, as measured by NH3-TPD.

Body satisfaction effect on thorough skin self-examination.

BACKGROUND: Melanoma and obesity have both increased in recent years. Given the propensity of body dissatisfaction among the obese, the objectives of this paper were to determine how body satisfaction might influence skin examination and to examine differences in this relationship by gender among the participants of Check-It-Out, a study to increase thorough skin self-examination (TSSE). METHODS: Through primary care offices, 2126 participants were recruited from April 2000 to November 2001 for the baseline cross-sectional telephone data from the Check-It-Out study. TSSE was defined as the self-reported examination of all seven key areas of the body. Body satisfaction was reported based on the degree of disagreement or agreement with the statement I like the way my body looks. Analyses were conducted in 2005 and 2006. RESULTS: Among participants, 18% reported performing TSSE, 34% were normal or underweight, 36% were overweight, and 30% were obese. Overall, 23% strongly agreed, 45% somewhat agreed, 19% somewhat disagreed, and 12% strongly disagreed with the statement I like the way my body looks. Body satisfaction was less common among women than men. The odds of conducting TSSE were 1.6 for the total sample (1.9 for women and 1.2 for men) for those with strong agreement that they like the way their body looks. In multivariate analysis, body satisfaction was associated with TSSE performance for women and both genders together, along with the availability of a partner (both genders together and men), the availability of a wall mirror, the advice of a physician, and the use of glasses or contacts(women only). CONCLUSIONS: Body satisfaction is an important factor in TSSE performance, especially among women, and should be considered along with other risk factors.

Cost-utility analysis of screening high-risk groups for anal cancer.

OBJECTIVES: Cost-utility analysis of screening for anal cancer in high-risk groups from a UK perspective. METHODS: Criteria for the assessment of screening programmes were combined in a Markov model representing the natural history of anal cancer and HIV infection in the UK population of men who have sex with men (MSM). Alternative screening programmes were overlaid on the natural history model to evaluate their impact. The model was populated using data derived from a systematic review of the literature, and calibrated probabilistically to represent joint uncertainty in the input parameters. RESULTS: Reference case results showed screening is unlikely to be cost-effective. Sensitivity analyses identified two important parameters: regression from low-grade anal intra-epithelial neoplasia (AIN) and utility effects. Increased AIN regression rates resulted in a minimum incremental cost per QALY gained of 39,405 pounds, whereas a best case scenario reduced the ratio to 20,996 pounds. CONCLUSIONS: There are major areas of uncertainty. New analyses of existing primary data, undertaken specifically to inform regression rates may usefully update key parameters at little additional cost. If these analyses increase the likelihood that screening is cost-effective, further studies of the utility effects of treatment for high-grade AIN, and potential screening attendance rates may be justified.

Innovations in curriculum design: a multi-disciplinary approach to teaching statistics to undergraduate medical students.

BACKGROUND: Statistics is relevant to students and practitioners in medicine and health sciences and is increasingly taught as part of the medical curriculum. However, it is common for students to dislike and under-perform in statistics. We sought to address these issues by redesigning the way that statistics is taught. METHODS: The project brought together a statistician, clinician and educational experts to re-conceptualize the syllabus, and focused on developing different methods of delivery. New teaching materials, including videos, animations and contextualized workbooks were designed and produced, placing greater emphasis on applying statistics and interpreting data. RESULTS: Two cohorts of students were evaluated, one with old style and one with new style teaching. Both were similar with respect to age, gender and previous level of statistics. Students who were taught using the new approach could better define the key concepts of p-value and confidence interval (p < 0.001 for both). They were more likely to regard statistics as integral to medical practice (p = 0.03), and to expect to use it in their medical career (p = 0.003). There was no significant difference in the numbers who thought that statistics was essential to understand the literature (p = 0.28) and those who felt comfortable with the basics of statistics (p = 0.06). More than half the students in both cohorts felt that they were comfortable with the basics of medical statistics. CONCLUSION: Using a variety of media, and placing emphasis on interpretation can help make teaching, learning and understanding of statistics more people-centred and relevant, resulting in better outcomes for students.

Mesoporous Silica-Supported Nanostructured PdO/CeO2 Catalysts for Low-Temperature Methane Oxidation.

Nanostructured PdO/CeO2 supported on mesoporous SBA-15 silica was synthesized using a combination of incipient wetness impregnation and surface-assisted reduction. After calcination, the materials showed good activity as catalysts for the low-temperature oxidation of methane, with a sample having 5 wt % Pd loading showing 50% conversion to CO2 at ∼290 °C and complete conversion below 360 °C. The stability of catalysts in the presence of water was studied. The formation of Pd(0) during the methane oxidation reaction increases the oxygen vacancies on the surface of catalysts, improving the catalytic activity.

Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor.

Class B GPCRs can activate multiple signalling effectors with the potential to exhibit biased agonism in response to ligand stimulation. Previously, we highlighted key TM domain polar amino acids that were crucial for the function of the GLP-1 receptor, a key therapeutic target for diabetes and obesity. Using a combination of mutagenesis, pharmacological characterisation, mathematical and computational molecular modelling, this study identifies additional highly conserved polar residues located towards the TM helical boundaries of Class B GPCRs that are important for GLP-1 receptor stability and/or controlling signalling specificity and biased agonism. This includes (i) three positively charged residues (R3.30227, K4.64288, R5.40310) located at the extracellular boundaries of TMs 3, 4 and 5 that are predicted in molecular models to stabilise extracellular loop 2, a crucial domain for ligand affinity and receptor activation; (ii) a predicted hydrogen bond network between residues located in TMs 2 (R2.46176), 6 (R6.37348) and 7 (N7.61406 and E7.63408) at the cytoplasmic face of the receptor that is important for stabilising the inactive receptor and directing signalling specificity, (iii) residues at the bottom of TM 5 (R5.56326) and TM6 (K6.35346 and K6.40351) that are crucial for receptor activation and downstream signalling; (iv) residues predicted to be involved in stabilisation of TM4 (N2.52182 and Y3.52250) that also influence cell signalling. Collectively, this work expands our understanding of peptide-mediated signalling by the GLP-1 receptor.

How absent negativity relates to affect and motivation: an integrative relief model.

The present paper concerns the motivational underpinnings and behavioral correlates of the prevention or stopping of negative stimulation - a situation referred to as relief. Relief is of great theoretical and applied interest. Theoretically, it is tied to theories linking affect, emotion, and motivational systems. Importantly, these theories make different predictions regarding the association between relief and motivational systems. Moreover, relief is a prototypical antecedent of counterfactual emotions, which involve specific cognitive processes compared to factual or mere anticipatory emotions. Practically, relief may be an important motivator of addictive and phobic behaviors, self destructive behaviors, and social influence. In the present paper, we will first provide a review of conflicting conceptualizations of relief. We will then present an integrative relief model (IRMO) that aims at resolving existing theoretical conflicts. We then review evidence relevant to distinctive predictions regarding the moderating role of various procedural features of relief situations. We conclude that our integrated model results in a better understanding of existing evidence on the affective and motivational underpinnings of relief, but that further evidence is needed to come to a more comprehensive evaluation of the viability of IRMO.

Mesoporous Mn- and La-doped cerium oxide/cobalt oxide mixed metal catalysts for methane oxidation.

New precious-metal-free mesoporous materials were investigated as catalysts for the complete oxidation of methane to carbon dioxide. Mesoporous cobalt oxide was first synthesized using KIT-6 mesoporous silica as a hard template. After removal of the silica, the cobalt oxide was itself used as a hard template to construct cerium oxide/cobalt oxide composite materials. Furthermore, cerium oxide/cobalt oxide composite materials doped with manganese and lanthanum were also prepared. All of the new composite materials retained the hierarchical long-range order of the original KIT-6 template. Temperature-programmed oxidation measurements showed that these cerium oxide/cobalt oxide and doped cerium oxide/cobalt oxide materials are effective catalysts for the total oxidation of methane, with a light-off temperature (T50%) of ∼400 °C observed for all of the nanostructured materials.

Nanostructured Materials Prepared by Surface-Assisted Reduction: New Catalysts for Methane Oxidation.

Cerium formate hollow spheres and cerium hydroxycarbonate nanorods with residual formate groups are effective for reducing palladium(II) salts onto their surfaces. Calcination of the new materials obtained by this surface-assisted reduction method gives highly active PdO/CeO2 nanostructures with Pd well dispersed on the substrate. Temperature-programmed oxidation experiments showed that these nanomaterials are good catalysts for the low-temperature oxidation of methane, with 50% conversion temperatures (T(50%)) at ∼300 °C.

The unique role of transdermal buprenorphine in the global chronic pain epidemic.

Pain is a global epidemic, exacerbated by barriers to access of opioid analgesics. Regulations about opioids attempt to protect public health from the risks of harmful use of opioids, diversion, and dependence. Transdermal buprenorphine is an effective opioid analgesic agent with unique properties that may make it particularly well suited for more widespread use. It is a versatile analgesic product with demonstrated safety and effectiveness in cancer and noncancer pain populations. Its pharmacological properties make it a first-line opioid analgesic for geriatric patients and patients with renal dysfunction; no dosing adjustments need to be made. The 7-day transdermal delivery system is convenient for patients and promotes compliance. A low dose of buprenorphine can provide effective and well-tolerated pain relief. Although buprenorphine has been associated with certain opioid-related adverse effects, such as dizziness and nausea, it is associated with a lower rate of constipation than many other opioid analgesics. The potential for nonmedical use of buprenorphine is relatively low compared with other opioid agents. Buprenorphine has a relatively low likeability for nonmedical use and the transdermal matrix patch renders the substance particularly difficult to extract for illicit purposes.