Publications by authors named "Michael Robertson"

262 Publications

Drug discovery in the era of cryo-electron microscopy.

Trends Biochem Sci 2021 Jul 16. Epub 2021 Jul 16.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Structure-based drug discovery (SBDD) is an indispensable approach for the design and optimization of new therapeutic agents. Here, we highlight the rapid progress that has turned cryo-electron microscopy (cryoEM) into an exceptional SBDD tool, and the wealth of new structural information it is providing for high-value pharmacological targets. We review key advantages of a technique that directly images vitrified biomolecules without the need for crystallization; both in terms of a broader array of systems that can be studied and the different forms of information it can provide, including heterogeneity and dynamics. We discuss near- and far-future developments, working in concert towards achieving the resolution and throughput necessary for cryoEM to make a widespread impact on the SBDD pipeline.
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http://dx.doi.org/10.1016/j.tibs.2021.06.008DOI Listing
July 2021

Asymmetric activation of the calcium-sensing receptor homodimer.

Nature 2021 Jul 30;595(7867):455-459. Epub 2021 Jun 30.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders. CaSR is a family C G-protein-coupled receptor that functions as an obligate homodimer, with each protomer composed of a Ca-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor.
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http://dx.doi.org/10.1038/s41586-021-03691-0DOI Listing
July 2021

G-protein activation by a metabotropic glutamate receptor.

Nature 2021 Jul 30;595(7867):450-454. Epub 2021 Jun 30.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.
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http://dx.doi.org/10.1038/s41586-021-03680-3DOI Listing
July 2021

Agricultural Trauma causing Open Fractures: Is Antibiotic Coverage against Anaerobic Organisms Indicated?

J Orthop Trauma 2021 May 26. Epub 2021 May 26.

University of Iowa Hospital & Clinics, Department of Orthopedics & Rehabilitation, Iowa City, IA University of Mississippi Medical Center, Department of Orthopedic Surgery & Rehabilitation, Jackson, MS.

Objective: To compare deep infection rate and causative organisms in open fractures of the lower extremity from agricultural trauma to similar injuries in non-agricultural trauma.

Design: Retrospective.

Setting: Two tertiary-care institutions.

Methods: Open lower extremity fractures sustained between 2003-2018 by agriculture-related trauma in adult patients were reviewed. A non-agriculture open fracture control group was identified for comparison. Patient demographics and injury characteristics were assessed. Outcomes included occurrence of deep infection and causative organism.

Results: 178 patients were identified in the agriculture(AG) (n=89) and control(NAG) (n=89) groups. Among agricultural-injury patients, farm machinery was the most common mechanism in 69 (77.5%) patients. Open injuries of the foot (38.2%) were most common in the AG-group and tibial shaft (25.8%) in the NAG-group.Deep infection was seen in 21% of the AG-group compared to 10% in the NAG-group(p<0.05). AG-group anaerobic infection occurred in 44% of patients with deep infection versus 9.1% in NAG-group(p<0.05). Most common anaerobic organisms included Enterococcus, Pseudomonas aeruginosa, and Clostridium perfringens.

Conclusion: This study supports that open fractures due to agricultural trauma have a high infection rate, with anaerobic infection occurring at higher rates than in non-agricultural trauma. Prophylactic treatment with antibiotics directed against anaerobes is indicated in these injuries.

Level Of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000002192DOI Listing
May 2021

Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial.

Lancet HIV 2021 06 14;8(6):e324-e333. Epub 2021 May 14.

Merck, Kenilworth, NJ, USA. Electronic address:

Background: Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1.

Methods: We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov, NCT03272347.

Findings: Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI -14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, -1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, -17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI -12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, -12·2 to 24·6, for the 0·75 mg islatravir group; and -6·1%, -27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48.

Interpretation: Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development.

Funding: Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.
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http://dx.doi.org/10.1016/S2352-3018(21)00021-7DOI Listing
June 2021

Patterns of self-monitoring technology use and weight loss in people with overweight or obesity.

Transl Behav Med 2021 Apr 10. Epub 2021 Apr 10.

Department of Behavioral Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Mobile applications and paired devices allow individuals to self-monitor physical activity, dietary intake, and weight fluctuation concurrently. However, little is known regarding patterns of use of these self-monitoring technologies over time and their implications for weight loss. The objectives of this study were to identify distinct patterns of self-monitoring technology use and to investigate the associations between these patterns and weight change. We analyzed data from a 6-month weight loss intervention for school district employees with overweight or obesity (N = 225). We performed repeated measures latent profile analysis (RMLPA) to identify common patterns of self-monitoring technology use and used multiple linear regression to evaluate the relationship between self-monitoring technology use and weight change. RMLPA revealed four distinct profiles: minimal users (n = 65, 29% of sample), activity trackers (n = 124, 55%), dedicated all-around users (n = 25, 11%), and dedicated all-around users with exceptional food logging (n = 11, 5%). The dedicated all-around users with exceptional food logging lost the most weight (X2[1,225] = 5.27, p = .0217). Multiple linear regression revealed that, adjusting for covariates, only percentage of days of wireless weight scale use (B = -0.05, t(212) = -3.79, p < .001) was independently associated with weight loss. We identified distinct patterns in mHealth self-monitoring technology use for tracking weight loss behaviors. Self-monitoring of weight was most consistently linked to weight loss, while exceptional food logging characterized the group with the greatest weight loss. Weight loss interventions should promote self-monitoring of weight and consider encouraging food logging to individuals who have demonstrated consistent use of self-monitoring technologies.
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http://dx.doi.org/10.1093/tbm/ibab015DOI Listing
April 2021

The relation between individual-level factors and the implementation of classroom-based physical activity approaches among elementary school teachers.

Transl Behav Med 2021 04;11(3):745-753

Department of Health Promotion & Behavioral Sciences, Center for Health Promotion and Prevention Research, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.

Classroom-based physical activity approaches can improve students' physical activity; however, their implementation remains a challenge. This study examined teacher-level factors associated with implementing two classroom-based physical activity approaches (active learning and physical activity breaks). We collected cross-sectional survey data from classroom teachers (n = 133) from 20 elementary schools in an urban Texas school district. Surveys included questions about theoretical constructs (e.g., knowledge, self-efficacy), personal characteristics (e.g., age, gender), and the implementation of active learning and physical activity breaks. We used linear regression models to assess associations between independent variables and implementation outcomes. We also assessed variable importance by examining the unique variance explained. Knowledge (b = .31, p = .001), outcome expectations (b = .18, p = .015), self-efficacy (b = .40, p ≤ .001), and support (b = .22, p = .028) were directly associated with active learning implementation. Teacher physical activity level (b = .29, p = .004) and grade level (third to fifth had lower levels than kindergarten to second grade, b = -.45, p = .022) were also associated with active learning implementation. In fully adjusted models, self-efficacy explained the most variance (≈5%) in active learning implementation compared to other variables. Knowledge (b = .18, p = 0.026), attitudes (b = .18, p = .019), self-efficacy (b = .15, p = .036), and teacher grade level (third to fifth had lower levels than kindergarten to second grade, b = -.80, p < .001) were associated with activity break implementation. In fully adjusted models, teacher grade level explained the most variance (≈13%) in activity break implementation compared to other variables. Results suggest multiple theoretical constructs and personal characteristics are important to target/consider when developing implementation strategies for classroom-based physical activity approaches. Additionally, self-efficacy and teacher grade level are two factors to prioritize.
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http://dx.doi.org/10.1093/tbm/ibaa133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033594PMC
April 2021

Y-PATHS: A Conceptual Framework for Classifying the Timing, How, and Setting of Youth Physical Activity.

J Phys Act Health 2021 Feb 13;18(3):310-317. Epub 2021 Feb 13.

Background: Multiple models and frameworks exist for the measurement and classification of physical activity in adults that are applied broadly across populations but have limitations when applied to youth. The authors propose a conceptual framework specifically designed for classifying youth physical activity.

Methods: The Youth Physical Activity Timing, How, and Setting (Y-PATHS) framework is a conceptualization of the when (timing), how, and where (setting) of children's and adolescents' physical activity patterns. The authors developed Y-PATHS using the design thinking process, which includes 3 stages: inspiration, ideation, and implementation.

Results: The Y-PATHS includes 3 major components (timing, how, and setting) and 13 subcomponents. Timing subcomponents include (1) school days: in-school, (2) school days: out-of-school, and (3) nonschool days. How subcomponents include: (1) functional, (2) transportation, (3) organized, and (4) free play. Setting subcomponents include: (1) natural areas, (2) schools, (3) home, (4) recreational facilities, (5) shops and services, and (6) travel infrastructure.

Conclusions: The Y-PATHS is a comprehensive classification framework that can help researchers, practitioners, and policymakers to better understand youth physical activity. Specifically, Y-PATHS can help to identify the domains of youth physical activity for surveillance and research and to inform the planning/evaluation of more comprehensive physical activity programming.
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http://dx.doi.org/10.1123/jpah.2020-0603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035289PMC
February 2021

Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.

N Engl J Med 2021 01;384(1):11-19

From the Indiana University School of Medicine (S.S.F., M.A.Z., J.E.S., R.A., M.J.R., H.E.B., S.Z.), Indiana University Health (S.S.F., M.A.Z., J.E.S., T.C.T., R.A., M.J.R.), and Indiana University Simon Comprehensive Cancer Center (S.S.F., A.J.B., H.E.B.) - all in Indianapolis.

Background: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.

Methods: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.

Results: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.

Conclusions: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).
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http://dx.doi.org/10.1056/NEJMoa2027372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845486PMC
January 2021

Efficacy and safety of elbasvir/grazoprevir in treatment-naive Chinese adults with hepatitis C virus infection: A randomized trial.

JGH Open 2020 Dec 15;4(6):1065-1073. Epub 2020 Jul 15.

Department of Infectious Diseases Merck & Co., Inc. Kenilworth New Jersey USA.

Background And Aim: In China, clinical experience with direct-acting antiviral treatments for hepatitis C virus (HCV) infection is still emerging. C-CORAL is a phase 3, multinational, placebo-controlled, double-blind trial of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from the Asia-Pacific region and Russia. Here, we report the data from participants enrolled in China.

Methods: Treatment-naive participants with chronic HCV genotype (GT) 1, GT4, or GT6 infection were randomly assigned to receive 50 mg EBR/100 mg GZR for 12 weeks (immediate-treatment group, ITG) or placebo followed by deferred treatment with EBR/GZR (deferred-treatment group, DTG). The primary efficacy end-point was sustained virologic response at 12 weeks after completing treatment (SVR12), and the primary safety end-point was a comparison of safety between participants receiving EBR/GZR and placebo (NCT02251990; Protocol PN-5172-067).

Results: A total of 152 participants in China were randomly assigned (ITG, = 115; DTG, = 37). SVR12 was achieved in 96.7% (146/151) participants overall and in 97.3% (142/146) of those with GT1b infection. Four participants relapsed (GT1b, = 3; GT6a, = 1). Drug-related AEs were reported in 25 (21.7%) and 9 (24.3%) participants receiving EBR/GZR and placebo, respectively; no drug-related serious adverse events (AEs) occurred. Two (1.7%) participants receiving EBR/GZR had late hepatic transaminase elevations. Patient-reported outcomes indicate improved quality of life at follow-up week 4 in participants receiving EBR/GZR compared to placebo.

Conclusion: EBR/GZR administered for 12 weeks represents a highly effective and safe treatment option for Chinese individuals with HCV GT1 infection.
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http://dx.doi.org/10.1002/jgh3.12387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731814PMC
December 2020

Gamified Text Messaging Contingent on Device-Measured Steps: Randomized Feasibility Study of a Physical Activity Intervention for Cancer Survivors.

JMIR Mhealth Uhealth 2020 11 24;8(11):e18364. Epub 2020 Nov 24.

Department of Behavioral Science, University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Background: Physical activity can confer diverse benefits on cancer survivors. Unfortunately, many cancer survivors are not sufficiently active. The efficacy of physical activity interventions for this population may be increased by grounding them in Self-Determination Theory (SDT). Combining game design elements with wearable technologies may be a useful and scalable approach to targeting SDT constructs to promote cancer survivors' physical activity.

Objective: The primary aim of this study is to evaluate the feasibility and acceptability of Steps2Health, a physical activity intervention for cancer survivors. It also aims to investigate the effects of the intervention on motivation, physical activity, and step count.

Methods: We randomized 78 insufficiently active cancer survivors to an experimental or comparison group. All participants received a physical activity tracker. The experimental group participants also received a set sequence of multimedia messaging service messages that were triggered in real time by meeting predetermined cumulative step count totals. Messages presented information about a virtual journey and included photographs and vivid descriptions of locations to increase autonomous motivation. Additional messages targeted perceptions of relatedness (eg, role modeling) and competence (eg, facilitating mastery experiences). We administered pre- and postintervention surveys and conducted 15 individual interviews to evaluate the intervention. We performed directed content analysis of qualitative data and conducted mixed effects linear modeling to investigate participants' changes in motivation, self-reported physical activity, and device-measured step counts.

Results: There was minimal loss to follow-up (3/78, 4%), the device wear rate was high (2548/3044, 83.71% of days), and technical problems with messaging based on real-time step counts were limited. Our qualitative data analysis revealed 3 overarching themes: accessibility, autonomous motivation, and relatedness. Participants successfully navigated the technological aspects and game design elements of the intervention. Participants found messages targeting autonomous motivation and competence or self-efficacy to be enjoyable and compelling, but one feasibility criterion for participant engagement (response rate to text messages) was not met. Messages targeting relatedness were less highly rated than the messages targeting autonomous motivation and competence or self-efficacy. During the intervention, both groups increased their motivation for physical activity (B=0.16; 95% CI 0.01 to 0.30; P=.04; d=0.49), and assignment to the experimental group was associated with increased self-reported leisure activity score (B=10.78; 95% CI 3.54 to 18.02; P=.005; d=0.64). The experimental group had greater increases in daily step counts over time (B=322.08; 95% CI 54.01 to 590.15; P=.02; d=0.28).

Conclusions: This study supports the feasibility of using real-time game design elements to target SDT constructs and increase cancer survivors' physical activity. Overall, our findings support the acceptability of the Steps2Health intervention, but fostering active participant engagement and targeting relatedness may present additional challenges. Steps2Health may help cancer survivors increase their physical activity levels.
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http://dx.doi.org/10.2196/18364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723748PMC
November 2020

'True crime' stories and psychiatrists' ethical responsibilities.

Australas Psychiatry 2020 Nov 19:1039856220970046. Epub 2020 Nov 19.

Law and Psychiatry, University of Melbourne, Melbourne, VIC, Australia.

Objective: In May 2018, a small paperback book was published, which briefly described 10 cases of persons charged with murder whom an Australian psychiatrist had assessed for the court. This article considers the ethical issues raised by identifying both the persons charged with murder and their victims in newspaper articles and interviews to promote a book.

Conclusions: When persons who have committed homicide are named in a 'true crime' book, their recovery trajectory may be prejudiced and the families of their victims may be re-traumatised. Such publications may also contribute to the stigmatisation of persons with mental illness who commit serious offences. Respect for the dignity of the person is fundamental to the ethical practice of forensic report-writing. There can never be any implied agreement or consent that a psychiatrist who writes a report for the court can also use the material in a book written for profit. The Royal Australian and New Zealand College of Psychiatrists includes several principles relevant to psychiatrists who write medico-legal reports. Psychiatrists should carefully consider the ethical issues raised in publishing outside of textbooks and professional journals and engaging with the lay media.
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http://dx.doi.org/10.1177/1039856220970046DOI Listing
November 2020

A state-wide population-based evaluation of cervical cancers arising during opportunistic screening in the United States.

Gynecol Oncol 2020 11 22;159(2):344-353. Epub 2020 Sep 22.

Departments of Pathology and Obstetrics & Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.

Objective: Despite widespread cervical screening, an estimated 13,800 women will be diagnosed with cervical cancer in the United States in 2020. To inform improvements, the screening histories of women diagnosed with cervical cancer in New Mexico were assessed.

Methods: Data were collected on all cervical screening, diagnostic tests and treatment procedures for all women diagnosed with cervical cancer aged 25-64 yrs. in New Mexico from 2006 to 2016. Women were categorized by their screening attendance in the 5-40 months (screening interval) and 1-4 months (peri-diagnostic interval) prior to cancer diagnosis.

Results: Of the 504 women diagnosed between May 2009-December 2016, 64% were not screened or had only inadequate screening tests in the 5-40 months prior to diagnosis, and 90 of 182 screened women (49%) had only negative screens in this period. Only 32% (N = 162) of cervical cancers were screen-detected. Women with adenocarcinomas were more likely to have had a recent negative screen (41/57 = 722%) than women with squamous cancers (50/112 = 45%). Both older women (aged 45-64 years) and women with more advanced cancers were less likely to have been screened, and if screened, were more likely to have a false-negative outcome. Only 9% of cancers were diagnosed in women who did not attend biopsy or treatment after positive tests requiring clinical management. Screening currently prevents 35% of cancers, whereas full screening coverage could prevent 61% of cervical cancers.

Conclusion: Improved screening coverage has the largest potential for reducing cervical cancer incidence, though there is also a role for improved recall procedures and screening sensitivity.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594931PMC
November 2020

Structure of a Hallucinogen-Activated Gq-Coupled 5-HT Serotonin Receptor.

Cell 2020 09;182(6):1574-1588.e19

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7365, USA. Electronic address:

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.cell.2020.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593816PMC
September 2020

Health Behavior Changes During COVID-19 Pandemic and Subsequent "Stay-at-Home" Orders.

Int J Environ Res Public Health 2020 08 28;17(17). Epub 2020 Aug 28.

Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.

The COVID-19 pandemic, and resultant "Stay-at-Home" orders, may have impacted adults' positive health behaviors (sleep, physical activity) and negative health behaviors (alcohol consumption, drug use, and tobacco use). The purpose of this study was to investigate how these health behaviors changed (increased/improved or decreased/worsened) at the early stages of the pandemic, what participant characteristics were associated with health behavior changes, and why these behavioral changes may have occurred. A convenience sample of 1809 adults residing in the United States completed a 15-min self-report questionnaire in April and May 2020. Multinomial logistic regressions and descriptive statistics were used to evaluate how, for whom, and why these health behaviors changed. Participants were primarily female (67.4%), aged 35-49 years (39.8%), college graduates (83.3%), non-tobacco users (74.7%), and had previously used marijuana (48.6%). Overall, participants primarily reported a decrease in physical activity, while sleep and all of the negative health behaviors remained the same. Changes in negative health behaviors were related ( < 0.05) to sex, age, parental status, educational status, job status, BMI, and depression scores. Changes in positive health behaviors were related ( < 0.05) to sex, parental status, job status, and depression scores. Having more time available during the pandemic was the most commonly cited reason for changing health behaviors (negative and positive). Public health efforts should address the potential for long-term health consequences due to behavior change during COVID-19.
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http://dx.doi.org/10.3390/ijerph17176268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504386PMC
August 2020

Ipilimumab, nivolumab, and brentuximab vedotin combination therapies in patients with relapsed or refractory Hodgkin lymphoma: phase 1 results of an open-label, multicentre, phase 1/2 trial.

Lancet Haematol 2020 Sep;7(9):e660-e670

Division of Hematology, Mayo Clinic, Rochester MN, USA.

Background: Recognising that the immune suppressive microenvironment promotes tumour growth in Hodgkin lymphoma, we hypothesised that activating immunity might augment the activity of targeted chemotherapy. We evaluated the safety and activity of combinations of brentuximab vedotin with nivolumab or ipilimumab, or both in patients with relapsed or refractory Hodgkin lymphoma.

Methods: In this multicentre, open-label, phase 1/2 trial, patients with relapsed or refractory Hodgkin lymphoma aged 18 years or older who had relapsed after at least one line of therapy, with an Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ and marrow function, with no pulmonary dysfunction were eligible for inclusion. Phase 1 primary objectives were to determine the maximum tolerated dose and dose limiting toxicities of brentuximab vedotin combined with ipilimumab (ipilimumab group), nivolumab (nivolumab group), or both (triplet therapy group) using a 3 + 3 dose escalation design with expansion cohorts. During the dose escalation phase, patients were enrolled sequentially into one of six cohorts: in the ipilimumab group fixed brentuximab vedotin 1·8 mg/kg with ipilimumab 1 mg/kg (cohort A) or 3 mg/kg (cohort B); in the nivolumab group fixed nivolumab 3 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort D) or 1·8 mg/kg (cohort E); and in the triplet therapy group fixed nivolumab 3 mg/kg and ipilimumab 1 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort G) or 1·8 mg/kg (cohort H). Additional patients were enrolled in the expansion phase at the same doses of cohorts B, E, and H. All drugs were given intravenously; brentuximab vedotin and nivolumab were given every 3 weeks, ipilimumab was given every 6 weeks in the ipilimumab group and every 12 weeks in the triplet therapy group. All eligible and treated patients were included in the analysis. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01896999. The phase 2, randomised portion of the trial is still enrolling.

Findings: Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; two patients in the ipilimumab group and one patient in the nivolumab group were excluded due to ineligibility after enrolment and 61 were evaluable. A total of six dose limiting toxicities were reported in four patients, and the doses used in cohorts B, E, and H were established as maximum tolerated doses and patients were subsequently enrolled onto expansion cohorts (C, F, and I) with these schedules. There were ten (43%) grade 3-4 treatment related adverse events in the ipilimumab group, three (16%) in the nivolumab group, and 11 (50%) in the triplet therapy group including: eight (13%) of 64 patients reporting rash, and colitis, gastritis, pancreatitis and arthritis, and diabetic ketoacidosis each occurring in one (2%) patient. There were two (3%) treatment related deaths, one in the nivolumab group and one in the triplet therapy group. The overall response rate was 76% (95% CI 53-92) in the ipilimumab group, 89% (65-99) in the nivolumab group, and 82% (60-95) in the triplet therapy group, and the complete response rate was 57% (95% CI 34-78%) in the ipilimumab group, 61% (36-83%) in the nivolumab group, and 73% (50-89%) in the triplet therapy group. With a median follow-up of 2·6 years (IQR 1·8-2·9) in the ipilimumab group, 2·4 years (2·2-2·6) in the nivolumab group, and 1·7 years (1·6-1·9) in the triplet therapy group, median progression-free survival is 1·2 years (95% CI 1·7-not reached) in the ipilimumab group, but was not reached in the other two treatment groups. Median overall survival has not been reached in any of the groups.

Interpretation: There are clear differences in activity and toxicity of the three combination regimens. The tolerability and preliminary activity for the two most active regimens, brentuximab vedotin with nivolumab and the triplet therapy, are being compared in a randomised phase 2 trial (NCT01896999).

Funding: Eastern Cooperative Oncology Group-American College of Radiology Imaging Network and the National Cancer Institute of the National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3026(20)30221-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737486PMC
September 2020

Investigating the within-person relationships between activity levels and sleep duration using Fitbit data.

Transl Behav Med 2021 03;11(2):619-624

Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The advancement of wearable technologies provides opportunities to continuously track individuals' daily activity levels and sleep patterns over extended periods of time. These data are useful in examining the reciprocal relationships between physical activity and sleep at the intrapersonal level. The purpose of this study is to test the bidirectional relationships between daily activity levels and sleep duration. The current study analyzed activity and sleep data collected from a Fitbit device as part of a 6 month employer-sponsored weight loss program. A total of 105 overweight/obese adults were included (92% female, 70% obese, and 44% Hispanic). Multilevel models were used to examine (a) whether daily active and sedentary minutes predicted that night's sleep duration and (b) whether sleep duration predicted active and sedentary minutes the following day. Potential extended effects were explored by using a 2 day average of the activity minutes/sleep duration as the predictor. No significant relationships between active minutes and sleep duration were found on a daily basis. However, having less sleep over two nights than one's usual level was associated with an increased likelihood of engaging in some physical activity the following day. There was a significant bidirectional negative association between sedentary minutes and sleep duration for both the daily and 2 day models. Data from wearable trackers, such as Fitbit, can be used to investigate the daily within-person relationship between activity levels and sleep duration. Future studies should investigate other sleep metrics that may be obtained from wearable trackers, as well as potential moderators and mediators of daily activity levels and sleep.
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http://dx.doi.org/10.1093/tbm/ibaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963288PMC
March 2021

Effect of Sirolimus levels between days 11 and 20 after allogeneic stem cell transplantation on the risk of hepatic sinusoidal obstruction syndrome.

Bone Marrow Transplant 2021 01 4;56(1):121-128. Epub 2020 Jul 4.

Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12-58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21-30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57-8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.
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http://dx.doi.org/10.1038/s41409-020-0987-1DOI Listing
January 2021

Safety and tolerability of elbasvir/grazoprevir in chronic hepatitis C virus therapy: Integrated analysis from clinical trials.

J Viral Hepat 2020 11 10;27(11):1222-1233. Epub 2020 Aug 10.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA.

Direct-acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16-18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug-related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.
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http://dx.doi.org/10.1111/jvh.13357DOI Listing
November 2020

Structures of metabotropic GABA receptor.

Nature 2020 08 24;584(7820):310-314. Epub 2020 Jun 24.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Stimulation of the metabotropic GABA receptor by γ-aminobutyric acid (GABA) results in prolonged inhibition of neurotransmission, which is central to brain physiology. GABA belongs to family C of the G-protein-coupled receptors, which operate as dimers to transform synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins. However, GABA is unique in its function as an obligate heterodimer in which agonist binding and G-protein activation take place on distinct subunits. Here we present cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABA receptors. Complemented by cellular signalling assays and atomistic simulations, these structures reveal that extracellular loop 2 (ECL2) of GABA has an essential role in relaying structural transitions by ordering the linker that connects the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of each of the subunits of GABA caps and interacts with the hydrophilic head of a phospholipid that occupies the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G proteins. These results provide a starting framework through which to decipher the mechanistic modes of signal transduction mediated by GABA dimers, and have important implications for rational drug design that targets these receptors.
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http://dx.doi.org/10.1038/s41586-020-2469-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429364PMC
August 2020

Efficacy and safety of elbasvir/grazoprevir for 12 weeks in people with hepatitis C virus infection aged 35 years or younger compared with older people: a retrospective integrated analysis.

Curr Med Res Opin 2020 08 24;36(8):1325-1332. Epub 2020 Jun 24.

Department of Infectious Disease, Merck & Co. Inc., Kenilworth, NJ, USA.

In the United States, the number of new cases of hepatitis C virus infection has risen in recent years, driven largely by transmission among young white adults in their 20s and 30s. Herein, we report an integrated analysis of participants with hepatitis C virus infection aged ≤35 years from 12 phase II/III clinical trials of elbasvir/grazoprevir. Treatment-naive and -experienced adults with hepatitis C virus genotype 1 or 4 infection received elbasvir (50 mg/day)/grazoprevir (100 mg/day) for 12 weeks without ribavirin. Analyses were stratified according to participant age (≤35 years vs >35 years). The primary endpoint was sustained virologic response (hepatitis C virus RNA < lower limit of quantitation at 12 weeks after completion of therapy). Sustained virologic response was achieved by 98.9% (271/274) of participants aged ≤35 years and by 96.9% (2093/2160) aged >35 years. Three participants aged ≤35 years with genotype 1b infection relapsed. Eight participants with genotype 1a infection and baseline non-structural protein 5 A resistance-associated substitutions achieved sustained virologic response. Similarly, all 85 participants aged ≤35 years with genotype 1a infection and no baseline non-structural protein 5 A resistance-associated substitutions achieved sustained virologic response. Safety was favorable, with the incidence of drug-related adverse events similar in younger and older participants (30.1% vs 30.6%). One participant (0.4%) aged ≤35 years and 15 participants (0.7%) aged >35 years discontinued treatment owing to adverse events. Elbasvir/grazoprevir for 12 weeks was safe and highly effective in participants aged ≤35 years with hepatitis C virus genotype 1 or 4 infection.
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http://dx.doi.org/10.1080/03007995.2020.1775075DOI Listing
August 2020

GemSpot: A Pipeline for Robust Modeling of Ligands into Cryo-EM Maps.

Structure 2020 06 14;28(6):707-716.e3. Epub 2020 May 14.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Producing an accurate atomic model of biomolecule-ligand interactions from maps generated by cryoelectron microscopy (cryo-EM) often presents challenges inherent to the methodology and the dynamic nature of ligand binding. Here, we present GemSpot, an automated pipeline of computational chemistry methods that take into account EM map potentials, quantum mechanics energy calculations, and water molecule site prediction to generate candidate poses and provide a measure of the degree of confidence. The pipeline is validated through several published cryo-EM structures of complexes in different resolution ranges and various types of ligands. In all cases, at least one identified pose produced both excellent interactions with the target and agreement with the map. GemSpot will be valuable for the robust identification of ligand poses and drug discovery efforts through cryo-EM.
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http://dx.doi.org/10.1016/j.str.2020.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272260PMC
June 2020

Elbasvir/Grazoprevir for HCV Infection in Russia: A Randomized Trial.

Hepat Med 2020 21;12:61-68. Epub 2020 Apr 21.

Merck & Co., Inc., Kenilworth, NJ, USA.

Purpose: Hepatitis C virus (HCV) infection is a major healthcare concern in Russia, where almost 5 million individuals are viremic. Elbasvir/grazoprevir is a fixed-dose combination therapy for the treatment of HCV genotype 1 and genotype 4 infection. The present analysis aimed to assess the safety and efficacy of elbasvir/grazoprevir in individuals with HCV infection enrolled at Russian study sites in the C-CORAL study.

Patients And Methods: C-CORAL (Protocol PN-5172-067; NCT02251990) was a Phase 3, placebo-controlled, double-blind study conducted throughout Asia and Russia. Treatment-naive participants with chronic HCV infection were randomly assigned to receive immediate or deferred treatment with elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks. Participants in the immediate-treatment group received elbasvir/grazoprevir for 12 weeks, and those in the deferred-treatment group received placebo for 12 weeks, followed by open-label elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12).

Results: One hundred and nineteen Russian participants were randomized (immediate-treatment group, n=88; deferred-treatment group, n=31). Most participants were white (99%) with HCV genotype 1b infection (97%) and mild-to-moderate (F0-F2) fibrosis (70%). SVR12 was achieved by 98.9% participants in the immediate-treatment group and by 100% of those receiving deferred elbasvir/grazoprevir in the deferred-treatment group. One participant relapsed with nonstructural protein 5A (NS5A) L28M and Y93H resistance-associated substitutions at baseline and at time of failure. Drug-related adverse events were reported by 19% of participants receiving elbasvir/grazoprevir in the immediate-treatment group and by 16% of those receiving placebo in the deferred-treatment group. No serious adverse event or deaths occurred, and no participant discontinued treatment owing to an adverse event.

Conclusion: Elbasvir/grazoprevir for 12 weeks was highly effective in treatment-naive Russian individuals with HCV genotype 1b infection.
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http://dx.doi.org/10.2147/HMER.S241418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183329PMC
April 2020

Assessment of Biased Agonism among Distinct Synthetic Cannabinoid Receptor Agonist Scaffolds.

ACS Pharmacol Transl Sci 2020 Apr 4;3(2):285-295. Epub 2019 Nov 4.

Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.

Cannabinoid receptor 1 (CB) is a key drug target for a number of diseases, including metabolic syndromes and neuropathic pain. Most of the typical cannabinoid ligands provoke psychotropic side effects that impair their therapeutic utility. As of today, it is not yet clearly known which structural features of cannabinoid ligands determine a preference toward specific signaling pathways. Distinct bioassays are typically used to elucidate signaling preferences. However, these are often based on different cell lines and use different principles and/or read-outs, which makes straightforward assessment of "ligand bias" difficult. Within this context, this study is the first to investigate ligand bias among synthetic cannabinoid receptor agonists (SCRAs) in as closely analogous conditions as possible, by applying a new functional complementation-based assay panel to assess the recruitment of Gα protein or β-arrestin2 to CB. In a panel of 21 SCRAs, chosen to cover a broad diversity in chemical structures, distinct, although often subtle, preferences toward specific signaling pathways were observed. Relative to CP55940, here considered as a "balanced" reference agonist, most of the selected SCRAs (e.g., 5F-APINACA, CUMYL-PEGACLONE, among others) displayed preferred signaling through the β-arrestin2 pathway, whereas MMB-CHMICA could serve as a potential "balanced" agonist. Interestingly, EG-018 was the only SCRA showing a significant (10-fold) preference toward G protein over β-arrestin2 recruitment. While it is currently unclear what this exactly means in terms of abuse potential and/or toxicity, the approach proposed here may allow construction of a knowledge base that in the end may allow better insight into the structure-"functional" activity relationship of these compounds. This may aid the development of new therapeutics with less unwanted psychoactive effects.
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http://dx.doi.org/10.1021/acsptsci.9b00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155187PMC
April 2020

Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.

Nature 2020 03 16;579(7798):297-302. Epub 2020 Jan 16.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis. Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins. In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of β-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of β-arrestin 1 (βarr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-βarr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of βarr1 to phosphorylated receptor residues and insertion of the finger loop of βarr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric G protein complex. Moreover, the cryo-electron microscopy map reveals that the C-edge of βarr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of β-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.
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http://dx.doi.org/10.1038/s41586-020-1954-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367492PMC
March 2020

Structure of the neurotensin receptor 1 in complex with β-arrestin 1.

Nature 2020 03 16;579(7798):303-308. Epub 2020 Jan 16.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways. Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with βarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin-arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin-receptor interactions.
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http://dx.doi.org/10.1038/s41586-020-1953-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100716PMC
March 2020

School Staff's Perspectives on the Adoption of Elementary-School Physical Activity Approaches: A Qualitative Study.

Am J Health Educ 2020 19;51(6):395-405. Epub 2020 Oct 19.

The University of Texas Health Science Center at Houston School of Public Health, Center for Health Promotion and Prevention Research, 7000 Fannin St. Houston, TX, USA 77030.

Background: There is a need to understand how schools adopt physical activity approaches (curricula, programs and practices), but few studies report on this process.

Purpose: To obtain elementary school staff's perspectives regarding how their schools are currently adopting physical activity approaches.

Methods: We recruited 15 participants from four job types in an urban Texas school district to participate in semi-structured interviews. We coded and analyzed interviews using directed content analysis and iterative categorization.

Results: We identified four themes pertaining to how the district, schools, and teachers contribute to the adoption of approaches. Themes included: (1) Staff identify new approaches through numerous channels; (2) Adoption occurs at multiple organizational levels; (3) District staff fulfilled a supporting role in the adoption process; and (4) School staff's perceptions of approach characteristics influence adoption.

Discussion: We found that schools adopt physical activity approaches at both the district- and school-level. Additionally, multiple stakeholders played a role in the adoption process and those roles varied across approaches.

Translation To Health Education Practice: Time, money, space, staff, competing priorities, limited information, the school's mission, and the benefits an approach provides to children are factors that researches and practitioners should consider when starting a new physical activity approach.
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http://dx.doi.org/10.1080/19325037.2020.1822241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985910PMC
October 2020

Self-efficacy and Physical Activity in Overweight and Obese Adults Participating in a Worksite Weight Loss Intervention: Multistate Modeling of Wearable Device Data.

Cancer Epidemiol Biomarkers Prev 2020 04 23;29(4):769-776. Epub 2019 Dec 23.

Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Physical activity is associated with a reduced risk of numerous types of cancer and plays an important role in maintaining a healthy weight. Wearable physical activity trackers may supplement behavioral intervention and enable researchers to study how determinants like self-efficacy predict physical activity patterns over time.

Methods: We used multistate models to evaluate how self-efficacy predicted physical activity states among overweight and obese individuals participating in a 26-week weight loss program ( = 96). We specified five states to capture physical activity patterns: (i) active (i.e., meeting recommendations for 2 weeks), (ii) insufficiently active, (iii) nonvalid wear, (iv) favorable transition (i.e., improvement in physical activity over 2 weeks), and (v) unfavorable transition. We calculated HRs of transition probabilities by self-efficacy, body mass index, age, and time.

Results: The average prevalence of individuals in the active, insufficiently active, and nonvalid wear states was 13%, 44%, and 16%, respectively. Low self-efficacy negatively predicted entering an active state [HR, 0.51; 95% confidence interval (CI), 0.29-0.88]. Obesity negatively predicted making a favorable transition out of an insufficiently active state (HR, 0.61; 95% CI, 0.40-0.91). Older participants were less likely to transition to the nonvalid wear state (HR, 0.53; 95% CI, 0.30-0.93). Device nonwear increased in the second half of the intervention (HR, 1.73; 95% CI, 1.07-2.81).

Conclusions: Self-efficacy is an important predictor for clinically relevant physical activity change in overweight and obese individuals. Multistate modeling is useful for analyzing longitudinal physical activity data.

Impact: Multistate modeling can be used for statistical inference of covariates and allow for explicit modeling of nonvalid wear.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125025PMC
April 2020

Impact of screening on cervical cancer incidence: A population-based case-control study in the United States.

Int J Cancer 2020 08 31;147(3):887-896. Epub 2019 Dec 31.

Department of Pathology and Obstetrics & Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM.

Cervical cancer is widely preventable through screening, but little is known about the duration of protection offered by a negative screen in North America. A case-control study was conducted with records from population-based registries in New Mexico. Cases were women diagnosed with cervical cancer in 2006-2016, obtained from the Tumor Registry. Five controls per case from the New Mexico HPV Pap Registry were matched to cases by sex, age and place of residence. Dates and results of all cervical screening and diagnostic tests since 2006 were identified from the pap registry. We estimated the odds ratio of nonlocalized (Stage II+) and localized (Stage I) cervical cancer associated with attending screening in the 3 years prior to case-diagnosis compared to women not screened in 5 years. Of 876 cases, 527 were aged 25-64 years with ≥3 years of potential screening data. Only 38% of cases and 61% of controls attended screening in a 3-year period. Women screened in the 3 years prior to diagnosis had 83% lower risk of nonlocalized cancer (odds ratio [OR] = 0.17, 95% CI: 0.12-0.24) and 48% lower odds of localized cancer (OR = 0.52, 95% CI: 0.38-0.72), compared to women not screened in the 5 years prior to diagnosis. Women remained at low risk of nonlocalized cancer for 3.5-5 years after a negative screen compared to women with no negative screens in the 5 years prior to diagnosis. Routine cervical screening is effective at preventing localized and nonlocalized cervical cancers; 3 yearly screening prevents 83% of nonlocalized cancers, with no additional benefit of more frequent screening. Increasing screening coverage remains essential to further reduce cervical cancer incidence.
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http://dx.doi.org/10.1002/ijc.32826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282928PMC
August 2020