Structural determinants of dual incretin receptor agonism by tirzepatide.

SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.

Barriers to and enablers of type 2 diabetes screening among women with prior gestational diabetes: A systematic review update and qualitative synthesis applying the Theoretical Domains Framework.

AIMS: Women with prior gestational diabetes have nearly 10 times the risk of developing type 2 diabetes. Postpartum screening for type 2 diabetes is recommended for early diagnosis and management, yet uptake is low. This work updates a previous systematic review and advances it through the application of the Theoretical Domains Framework (TDF) to synthesise personal-level factors impacting type 2 diabetes screening and the Capability, Opportunity, Motivation-Behaviour model (COM-B), to develop messaging recommendations for use in clinical practice and screening promotion interventions. METHODS: We searched seven academic databases from September 2017 (prior review) to April 2021, reference lists and grey literature. Two reviewers independently screened articles against inclusion criteria (qualitative studies exploring factors impacting postpartum diabetes screening, any language) and extracted data. Using an inductive-deductive model, we coded determinants to the TDF and mapped onto the COM-B model. RESULTS: We identified 38 eligible papers from 34 studies (N = 1291 participants). Most (71%) reported sample sizes of N ≥ 16. The ratio of barriers to enablers was three to one. Eight key TDF domains were identified. Evidence-based recommendations include addressing knowledge, risk perception, fear of diabetes diagnosis, low prioritisation of personal health and fatalism. The risk of bias was low and confidence in findings was moderate to high. A limitation was conceptual overlap between TDF domains, which we addressed via the study procedure. CONCLUSIONS: The theoretical categorisation of determinants enables the development of messaging and interventions at the personal level, to promote women's uptake of postpartum type 2 diabetes screening.

Barriers to and enablers of postpartum health behaviours among women from diverse cultural backgrounds with prior gestational diabetes: A systematic review and qualitative synthesis applying the theoretical domains framework.

AIMS: Racial and ethnic disparities exist in gestational diabetes prevalence and risk of subsequent type 2 diabetes mellitus (T2DM). Postpartum engagement in healthy behaviours is recommended for prevention and early detection of T2DM, yet uptake is low among women from diverse cultural backgrounds. Greater understanding of factors impacting postpartum health behaviours is needed. Applying the Theoretical Domains Framework (TDF) and Capability, Opportunity, Motivation-Behaviour (COM-B) model, our aim was to synthesise barriers to and enablers of postpartum health behaviours among women from diverse cultural backgrounds with prior GDM and identify relevant intervention components. METHODS: Databases, reference lists and grey literature were searched from September 2017 to April 2021. Two reviewers screened articles independently against inclusion criteria and extracted data. Using an inductive-deductive model, themes were mapped to the TDF and COM-B model. RESULTS: After screening 5148 citations and 139 full texts, we included 35 studies (N = 787 participants). The main ethnicities included Asian (43%), Indigenous (15%) and African (11%). Barriers and enablers focused on Capability (e.g. knowledge), Opportunity (e.g. competing demands, social support from family, friends and healthcare professionals, culturally appropriate education and resources) and Motivation (e.g. negative emotions, perceived consequences and necessity of health behaviours, social/cultural identity). Five relevant intervention functions are identified to link the barriers and enablers to evidence-based recommendations for communications to support behaviour change. CONCLUSIONS: We provide a conceptual model to inform recommendations regarding the development of messaging and interventions to support women from diverse cultural backgrounds in engaging in healthy behaviours to reduce risk of T2DM.

Effectiveness of nutrition and dietary interventions for people with serious mental illness: systematic review and meta-analysis.

OBJECTIVE: To review recent published trials of nutrition and dietary interventions for people with serious mental illness; to assess their effectiveness in improving metabolic syndrome risk factors. STUDY DESIGN: Systematic review and meta-analysis of randomised and non-randomised controlled trials of interventions with a nutrition/diet-related component delivered to people with serious mental illness, published 1 January 2010 - 6 September 2021. Primary outcomes were weight, body mass index (BMI), and waist circumference. Secondary outcomes were total serum cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglyceride, and blood glucose levels. DATA SOURCES: MEDLINE, EMBASE, PsycINFO, CINAHL, and CENTRAL databases. In addition, reference lists of relevant publications were examined for further additional studies. DATA SYNTHESIS: Twenty-five studies encompassing 26 intervention arms were included in our analysis. Eight studies were at low or some risk of bias, seventeen were deemed to be at high risk. Eight of seventeen intervention arms found statistically significant intervention effects on weight, ten of 24 on BMI, and seven of seventeen on waist circumference. The pooled effects of nutrition interventions on metabolic syndrome risk factors were statistically non-significant. However, we identified small size effects on weight for interventions delivered by dietitians (five studies; 262 intervention, 258 control participants; standardised mean difference [SMD], -0.28; 95% CI, -0.51 to -0.04) and interventions consisting of individual sessions only (three studies; 141 intervention, 134 control participants; SMD, -0.30; 95% CI, -0.54 to -0.06). CONCLUSIONS: We found only limited evidence for nutrition interventions improving metabolic syndrome risk factors in people with serious mental illness. However, they may be more effective when delivered on an individual basis or by dietitians. PROSPERO REGISTRATION: CRD42021235979 (prospective).

Should antidiabetic medicines be considered to reduce cardiometabolic risk in patients with serious mental illness?

Substantially reduced life expectancy for people with serious mental illness compared with the general population is primarily driven by physical health issues, of which cardiovascular disease is the leading cause. In this narrative review, we examine the evidence base for use of metformin and other antidiabetic agents as a means for reducing this excess cardiometabolic disease burden. Evidence from randomised controlled trials (RCTs) suggests substantial potential for metformin to prevent or manage weight gain and glycaemic impairment induced by atypical antipsychotic medications, whereas the impact of metformin on other cardiometabolic risk factors is less consistent. Evidence from RCTs also suggests potential benefits from glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly for addressing cardiometabolic risk factors in people using atypical antipsychotic medications, but this is based on a small number of trials and remains an emerging area of research. Trials of both metformin and GLP-1RAs suggest that these medications are associated with a high prevalence of mild-moderate gastrointestinal side effects. The heterogeneous nature of participant eligibility criteria and of antipsychotic and antidiabetic drug regimens, alongside short trial durations, small numbers of participants and paucity of clinical endpoints as trial outcomes, warrants investment in definitive trials to determine clinical benefits for both metformin and GLP-1RAs. Such trials would also help to confirm the safety profile of antidiabetic agents with respect to less common but serious adverse effects. The weight of RCT evidence suggests that an indication for metformin to address antipsychotic-induced weight gain is worth considering in Australia. This would bring us into line with other countries.

Peer-facilitated interventions for improving the physical health of people with schizophrenia spectrum disorders: systematic review and meta-analysis.

OBJECTIVES: To evaluate the efficacy of peer-facilitated interventions for improving the physical health of people with schizophrenia spectrum disorders. STUDY DESIGN: Systematic review and random effects meta-analysis of peer-facilitated interventions for people with serious mental illness, including schizophrenia spectrum disorders, in which physical health outcomes were assessed. DATA SOURCES: MEDLINE, PsycINFO, EMBASE, CINAHL, Web of Science, Scopus, CENTRAL, and PubMed. In addition, reference lists of reviews were examined for further relevant studies published to 10 November 2021. DATA SYNTHESIS: We included fourteen publications (thirteen randomised controlled trials of ten peer-facilitated interventions, and one secondary analysis; total of 2099 participants) that assessed physical health outcomes for people with mental health conditions, including schizophrenia spectrum disorders. Intervention duration ranged from three to eighteen months; peers were involved as sole or co-leaders of the programs in group or individual sessions. Meta-analysis identified a statistically significant pooled effect on physical activity and capacity (various measures; six studies; 468 intervention, 461 control participants; standardised mean difference, +0.19 standard deviation [SD]; 95% CI, +0.06-0.32 SD; I2  = 0%); overall GRADE certainty of evidence was low. Marked study heterogeneity precluded secure conclusions regarding intervention effects on self-rated physical health, healthy eating, and body mass index. CONCLUSIONS: Peer-facilitated interventions for improving physical outcomes are feasible for people with schizophrenia spectrum disorders, a group at particular risk of certain physical health conditions. Further research is required to assess the effects of such interventions on other health-related parameters. PROSPERO REGISTRATION: CRD42021283578 (retrospective).

Shared medical appointments for weight loss: a systematic review.

PURPOSE: Shared medical appointments (SMAs) may help mitigate some of the barriers for managing obesity in primary care. The primary aim of this systematic review was to measure the effect of weight loss SMAs. METHODS: Systematic searches using keywords and Medical Subject Headings for overweight, obesity, and SMAs were conducted in the CENTRAL, Medline Complete, PsycINFO, Scopus, CINAHL, EMBASE, and Web of Science databases with no date limits. Risk of bias was assessed using the Effective Health Practice Project Quality Assessment Tool for Quantitative Studies. RESULTS: Fifteen studies involving weight loss SMAs in adults and children were identified. Six studies had controls. Inconsistency in reporting weight loss or weight change in controlled studies meant that data could not be pooled for meta-analysis. Results from individual studies indicated that SMAs can support adult patients to achieve significant weight loss. Women and older adults were more likely to take up SMA invitations. Results from the 5 studies involving children were less conclusive. Studies involving participants of a higher socioeconomic status tended to report lower attrition than studies involving participants who experienced disadvantage. These findings should be interpreted with caution as all but 1 included study was assessed as being weak in quality. CONCLUSIONS: Overall, SMAs may be of benefit to address obesity in primary care, particularly for women and older adults. Appropriately designed prospective and controlled studies are required to engage their target audience and to assess whether SMAs are superior to other weight loss options in primary care.

Implementing primary care diabetes prevention for women with previous gestational diabetes: a mixed-methods study.

BACKGROUND: The implementation of diabetes prevention for women with previous gestational diabetes (GDM) has been stymied by many barriers that are located within routine general practice (GP). We aimed to unpack the GP factors and understand the mechanisms that explain why a diabetes prevention intervention for this population succeeds or fails. METHODS: We performed a mixed-methods study with a Normalization Process Theory framework that included clinical audits, semistructured interviews, and focus groups within mixed urban and rural primary care practices in Victoria, Australia. Staff of primary care practices and external support staff who provide services to women with previous GDM participated in a 12-month quality improvement collaborative intervention. We compared diabetes screening and prevention activity planning with the strategies and factors identified through a process evaluation of full-, moderate-, and low-active participating practices. RESULTS: The intervention doubled screening rates (26%-61%) and 1-in-10 women received a diabetes prevention planning consultation. Critical improvement factors were: mothers being seen as participants in the quality improvement work; staff collectively building care strategies; staff taking a long-term care of a community perspective rather than episodic service delivery; and feedback processes being provided and acted on across the practice. The observable factors from the external perspective were: leadership by identified practice staff, reminder systems in action and practice staff driving the process collectively. CONCLUSIONS: Successful engagement in diabetes prevention for women with previous GDM requires proactive building of the critical improvement factors and audit feedback into routine GP.

The effect of a diabetes prevention program on dietary quality in women with previous gestational diabetes.

BACKGROUND: Women with gestational diabetes have low diet quality. We evaluated the effectiveness of a group-based lifestyle modification program for improvement of dietary quality in women with previous gestational diabetes predominantly within their first postnatal year. METHODS: Women were randomised to intervention (n = 284) or usual care (n = 289). Dietary data was collected at baseline and twelve months using a food frequency questionnaire and recoded into the Australian Recommended Food Score (ARFS). Mixed model analyses investigated the intervention effect on ARFS (per-protocol-set (PPS) excluded women without the minimum intervention exposure). RESULTS: Baseline mean total ARFS was low (31.8 ± 8.9, maximum score = 74) and no significant changes were seen in total ARFS (Cohen's D = - 0.06). 2% reduction in alcohol for intervention (0.05, 0.26) compared with - 1% for usual care (Odds ratio: 0.68; 95%CI 0.46, 0.99). Dairy ARFS sub-category significantly improved (low fat/saturated fat foods) in the intervention group over time compared with usual care for the PPS analysis (dairy + 0.28 in intervention (95%CI 0.08, 0.48) compared with + 0.02 in usual care (95%CI -0.14, 0.18) (group-by-treatment interaction p = 0.05, Cohen's D = 0.14)). CONCLUSIONS: Engaging with the intervention improved aspects of diet quality that aligned with minimum intervention exposure, but the total diet quality remains low. Further research is needed to improve diabetes prevention program engagement. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ANZCTRN12610000338066 , April 2010.

Sphinx: merging knowledge-based and ab initio approaches to improve protein loop prediction.

Motivation: Loops are often vital for protein function, however, their irregular structures make them difficult to model accurately. Current loop modelling algorithms can mostly be divided into two categories: knowledge-based, where databases of fragments are searched to find suitable conformations and ab initio, where conformations are generated computationally. Existing knowledge-based methods only use fragments that are the same length as the target, even though loops of slightly different lengths may adopt similar conformations. Here, we present a novel method, Sphinx, which combines ab initio techniques with the potential extra structural information contained within loops of a different length to improve structure prediction. Results: We show that Sphinx is able to generate high-accuracy predictions and decoy sets enriched with near-native loop conformations, performing better than the ab initio algorithm on which it is based. In addition, it is able to provide predictions for every target, unlike some knowledge-based methods. Sphinx can be used successfully for the difficult problem of antibody H3 prediction, outperforming RosettaAntibody, one of the leading H3-specific ab initio methods, both in accuracy and speed. Availability and Implementation: Sphinx is available at http://opig.stats.ox.ac.uk/webapps/sphinx. Contact: deane@stats.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

Big Data in Drug Discovery.

Interpretation of Big Data in the drug discovery community should enhance project timelines and reduce clinical attrition through improved early decision making. The issues we encounter start with the sheer volume of data and how we first ingest it before building an infrastructure to house it to make use of the data in an efficient and productive way. There are many problems associated with the data itself including general reproducibility, but often, it is the context surrounding an experiment that is critical to success. Help, in the form of artificial intelligence (AI), is required to understand and translate the context. On the back of natural language processing pipelines, AI is also used to prospectively generate new hypotheses by linking data together. We explain Big Data from the context of biology, chemistry and clinical trials, showcasing some of the impressive public domain sources and initiatives now available for interrogation.

SAbPred: a structure-based antibody prediction server.

SAbPred is a server that makes predictions of the properties of antibodies focusing on their structures. Antibody informatics tools can help improve our understanding of immune responses to disease and aid in the design and engineering of therapeutic molecules. SAbPred is a single platform containing multiple applications which can: number and align sequences; automatically generate antibody variable fragment homology models; annotate such models with estimated accuracy alongside sequence and structural properties including potential developability issues; predict paratope residues; and predict epitope patches on protein antigens. The server is available at http://opig.stats.ox.ac.uk/webapps/sabpred.

ANARCI: antigen receptor numbering and receptor classification.

MOTIVATION: Antibody amino-acid sequences can be numbered to identify equivalent positions. Such annotations are valuable for antibody sequence comparison, protein structure modelling and engineering. Multiple different numbering schemes exist, they vary in the nomenclature they use to annotate residue positions, their definitions of position equivalence and their popularity within different scientific disciplines. However, currently no publicly available software exists that can apply all the most widely used schemes or for which an executable can be obtained under an open license. RESULTS: ANARCI is a tool to classify and number antibody and T-cell receptor amino-acid variable domain sequences. It can annotate sequences with the five most popular numbering schemes: Kabat, Chothia, Enhanced Chothia, IMGT and AHo. AVAILABILITY AND IMPLEMENTATION: ANARCI is available for download under GPLv3 license at opig.stats.ox.ac.uk/webapps/anarci. A web-interface to the program is available at the same address. CONTACT: deane@stats.ox.ac.uk.

Health professional perspectives on the management of multimorbidity and polypharmacy for older patients in Australia.

Background: delivering appropriate care for patients with multimorbidity and polypharmacy is increasingly challenging. Challenges for individual healthcare professions are known, but only little is known about overall healthcare team implementation of best practice for these patients. Objective: to explore current approaches to multimorbidity management, and perceived barriers and enablers to deliver appropriate medications management for community-dwelling patients with multimorbidity and polypharmacy, from a broad range of healthcare professional (HCP) perspectives in Australia. Methods: this qualitative study used semi-structured interviews to gain in-depth understanding of HCPs' perspectives on the management of multimorbidity and polypharmacy. The interview guide was based on established principles for the management of multimorbidity in older patients. HCPs in rural and metropolitan Victoria and South Australia were purposefully selected to obtain a maximum variation sample. Twenty-six HCPs, from relevant medical, dentistry, nursing, pharmacy and allied health backgrounds, were interviewed between October 2013 and February 2014. Fourteen were prescribers and 12 practiced in primary care. Interviews were digitally audio-taped, transcribed verbatim and analysed using a constant comparison approach. Results: most participants did not routinely use structured approaches to incorporate patients' preferences in clinical decision-making, address conflicting prescriber advice, assess patients' adherence to treatment plans or seek to optimise care plans. Most HCPs were either unaware of medical decision aids and measurements tools to support these processes or disregarded them as not being user-friendly. Challenges with coordination and continuity of care, pressures of workload and poorly defined individual responsibilities for care, all contributed to participants' avoiding ownership of multimorbidity management. Potential facilitators of improved care related to improved culture, implementation of electronic health records, greater engagement of pharmacists, nurses and patients, families in care provision, and the use of care coordinators. Conclusion: extensive shortcomings exist in team-based care for the management of multimorbidity. Delegating coordination and review responsibilities to specified HCPs may support improved overall care.

Recent improvements to Binding MOAD: a resource for protein-ligand binding affinities and structures.

For over 10 years, Binding MOAD (Mother of All Databases; http://www.BindingMOAD.org) has been one of the largest resources for high-quality protein-ligand complexes and associated binding affinity data. Binding MOAD has grown at the rate of 1994 complexes per year, on average. Currently, it contains 23,269 complexes and 8156 binding affinities. Our annual updates curate the data using a semi-automated literature search of the references cited within the PDB file, and we have recently upgraded our website and added new features and functionalities to better serve Binding MOAD users. In order to eliminate the legacy application server of the old platform and to accommodate new changes, the website has been completely rewritten in the LAMP (Linux, Apache, MySQL and PHP) environment. The improved user interface incorporates current third-party plugins for better visualization of protein and ligand molecules, and it provides features like sorting, filtering and filtered downloads. In addition to the field-based searching, Binding MOAD now can be searched by structural queries based on the ligand. In order to remove redundancy, Binding MOAD records are clustered in different families based on 90% sequence identity. The new Binding MOAD, with the upgraded platform, features and functionalities, is now equipped to better serve its users.

Cardiovascular Disease Risk Assessment in Australian Community Pharmacy.

BACKGROUND: Population screening and monitoring of cardiovascular risk is suboptimal in Australian primary care. The role of community pharmacy has increased considerably, but without any policy framework for development. The aim of this study was to explore the nature of community pharmacy-based screening models in Australia, capacity to increase delivery of pharmacy screening, and barriers and enablers to increasing capacity. METHODS: An online survey weblink was emailed to pharmacy managers at every quality-accredited pharmacy in Australia by the Quality Pharmacy Care Program. The 122-item survey explored the nature of screening services, pharmacy capacity to deliver services, and barriers and enablers to service delivery in considerable detail. Adaptive questioning was used extensively to reduce the participant burden. Pharmacy location details were requested to facilitate geo-coding and removal of duplicate entries. A descriptive analysis of responses was undertaken. RESULTS: There were 294 valid responses from 4890 emails, a 6% response rate. Most pharmacies (79%) had private counselling areas. Blood pressure assessment was nearly universal (96%), but other common risk factor assessments were offered by a minority. Most did not charge for assessments, and 59% indicated capacity to provide multiple risk factor assessments. Fewer than one in five (19%) reported any formal arrangements with general practice for care coordination. Financial viability was perceived as a key barrier to service expansion, amid concerns of patient willingness to pay. Support from government and non-governmental organisations for their role was seen as necessary. CONCLUSION: There appears to be a critical mass of pharmacies engaging in evidence-based and professional services. Considerable additional support appears required to optimise performance across the profession.

Using local clinical educators and shared resources to deliver simulation training activities across rural and remote South Australia and south-west Victoria: A distributed collaborative model.

PROBLEM: There is a lack of access to simulation-based education (SBE) for professional entry students (PES) and health professionals at rural and remote locations. DESIGN: A descriptive study. SETTING: Health and education facilities in regional South Australia and south-west Victoria. KEY MEASURES FOR IMPROVEMENT: Number of training recipients who participated in SBE; geographical distribution and locations where SBE was delivered; number of rural clinical educators providing SBE. STRATEGIES FOR CHANGE: A distributed model to deliver SBE in rural and remote locations in collaboration with local health and community services, education providers and the general public. Face-to-face meetings with health services and education providers identified gaps in locally delivered clinical skills training and availability of simulation resources. Clinical leadership, professional development and community of practice strategies were implemented to enhance capacity of rural clinical educators to deliver SBE. EFFECTS OF CHANGE: The number of SBE participants and training hours delivered exceeded targets. The distributed model enabled access to regular, localised training for PES and health professionals, minimising travel and staff backfill costs incurred when attending regional centres. The skills acquired by local educators remain in rural areas to support future training. LESSONS LEARNT: The distributed collaborative model substantially increased access to clinical skills training for PES and health professionals in rural and remote locations. Developing the teaching skills of rural clinicians optimised the use of simulation resources. Consequently, health services were able to provide students with flexible and realistic learning opportunities in clinical procedures, communication techniques and teamwork skills.