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The crystal packing of organic chromophores has a profound impact on their photophysical properties. Molecular crystal engineering is generally incapable of producing precisely spaced arrays of molecules for use in photovoltaics, light-emitting diodes, and sensors. A promising alternative strategy is the incorporation of chromophores into crystalline metal-organic frameworks (MOFs), leading to matrix coordination-induced emission (MCIE) upon confinement. However, it remains unclear how the precise arrangement of chromophores and defects dictates photophysical properties in these systems, limiting the rational design of well-defined photoluminescent materials. Herein, we report new, robust Zr-based MOFs constructed from the linker tetrakis(4-carboxyphenyl)ethylene (TCPE

Macrophages are present in every tissue of the body where they play crucial roles in maintaining tissue homeostasis and providing front line defence against pathogens. Arguably, this is most important at mucosal barrier tissues, such as the lung and gut, which are major ports of entry for pathogens. However, a common feature of inflammation, infection or injury is the loss of tissue resident macrophages and accumulation of monocytes from the circulation, which differentiate, to different extents, into macrophages. The exact fate and function of these elicited, monocyte-derived macrophages in infection, injury and inflammation remains contentious. While some studies have documented the indispensable nature of monocytes and their macrophage derivatives in combatting infection and restoration of lung homeostasis following insult, observations from clinical studies and preclinical models of lung infection/injury shows that monocytes and their progeny can become dysregulated in severe pathology, often perpetuating rather than resolving the insult. In this review, we aim to bring together these somewhat contradictory reports by discussing how the plasticity of monocytes allow them to assume distinct functions in different contexts in the lung, from health to infection, and effective tissue repair to fibrotic disease.

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

Chronic kidney disease (CKD) is a serious, progressive condition associated with significant patient morbidity. Hypertension control and use of renin-angiotensin system blockers are the cornerstones of treatment for CKD. However, even with these treatment strategies, many individuals will progress towards kidney failure. Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical trials with primary renal endpoints have firmly established SGLT2 inhibition, in addition to standard of care, as an effective strategy to slow down the progression of CKD and reduce some of its associated complications. The emergence of this new clinical evidence supports the use of SGLT2 inhibitors in the management of CKD in people with and without diabetes. As licensing and guidelines for SGLT2 inhibitors are updated, there is a need to adapt CKD treatment pathways and for this class of drugs to be included as part of standard care for CKD management. In this article, we have used consensus opinion alongside the available evidence to provide support for the healthcare community involved in CKD management, regarding the role of SGLT2 inhibitors in clinical practice. By highlighting appropriate prescribing and practical considerations, we aim to encourage greater and safe use of SGLT2 inhibitors for people with CKD, both with and without diabetes.

Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world’s population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD.

The clinical evidence base for evaluating modern type 2 diabetes interventions has expanded greatly in recent years, with numerous efficacious treatment options available (including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors). The cardiovascular safety of these interventions has been assessed individually versus placebo in numerous cardiovascular outcomes trials (CVOTs), statistically powered to detect differences in a composite endpoint of major adverse cardiovascular events. There have been growing calls to incorporate these data in the long-term modelling of type 2 diabetes interventions because current diabetes models were developed prior to the conduct of the CVOTs and therefore rely on risk equations developed in the absence of these data. However, there are numerous challenges and pitfalls to avoid when using data from CVOTs. The primary concerns are around the heterogeneity of the trials, which have different study durations, inclusion criteria, rescue medication protocols and endpoint definitions; this results in significant uncertainty when comparing two or more interventions evaluated in separate CVOTs, as robust adjustment for these differences is difficult. Analyses using CVOT data inappropriately can dilute clear evidence from head-to-head clinical trials, and blur healthcare decision making. Calibration of existing models may represent an approach to incorporating CVOT data into diabetes modelling, but this can only offer a valid comparison of one intervention versus placebo based on a single CVOT. Ideally, model development should utilize patient-level data from CVOTs to prepare novel risk equations that can better model modern therapies for type 2 diabetes.

The scientific landscape of treatments for type 2 diabetes (T2D) has changed rapidly in the last decade with newer treatments becoming available. However, a large proportion of people with T2D are not able to achieve glycaemic goals because of clinical inertia. The majority of T2D management is in primary care, where clinicians (medical, nursing and pharmacist staff) play an important role in addressing patient needs and achieving treatment goals. However, management of T2D is challenging because of the heterogeneity of T2D and complexity of comorbidity, time constraints, guidance overload and the evolving treatments. Additionally, the current coronavirus disease pandemic poses additional challenges to the management of chronic diseases such as T2D, including routine access to patients for monitoring and communication. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of agents that have evolved rapidly in recent years. These agents act in a glucose-dependent manner to promote insulin secretion and inhibit glucagon secretion, as well as enhancing satiety and reducing hunger. As a result, they are effective treatment options for people with T2D, achieving glycated haemoglobin reductions, weight loss and potential cardiovascular benefit, as monotherapy or as add-on to other glucose-lowering therapies. However, given the complexity of managing T2D, it is important to equip primary care clinicians with clear information regarding efficacy, safety and appropriate positioning of GLP-1 RA therapies in clinical practice. This review provides a summary of clinical and real-world evidence along with practical guidance, with the aim of aiding primary care clinicians in the initiation and monitoring of GLP-1 RAs to help ensure that desired outcomes are realised. Furthermore, a benefit/risk tool has been developed on the basis of current available evidence and guidelines to support primary care clinicians in selecting individuals who are most likely to benefit from GLP-1 RA therapies, in addition to indicating clinical situations where caution is needed.

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia., Diverse macrophage subsets are found in adipose tissue where they regulate its physiology. Here, the authors used single-cell RNA sequencing to analyse the effect of post-prandial lipids on adipose tissue macrophages and identify Tim4 as a regulator of ABCA1+ macrophage function and post-prandial cholesterol transport.

Background Aconitate decarboxylase 1 (ACOD1; also known as IRG-1) is the ubiquitous source of itaconate, which dampens inflammasome activation by preventing HIF1a production of IL-1b and prevents TNF production through NRF2 activation. We reasoned that expression of ACOD1 is an inhibitory pathway within monocytes to curtail their inflammatory function, which could be manipulated in IBD therapy. Methods We performed single-cell RNA sequencing of monocytes from colonoscopic biopsies of treatment naïve IBD patients, as well as complementary analysis of DSS treated C57BL/6J (WT) mice, using single-cell protein-mRNA (Primeflow) technologies for validation. To determine the role of ACOD1 in colitis, Acod1–/– mice were administered 2% DSS in drinking water for 6 days (acute colitis) or 4 days followed by 14 day recovery period (inflammation resolution) and assessed the colon myeloid compartment by multi-parameter flow cytometry. This was complemented with competitive bone marrow chimeric mice to assess the intrinsic role of ACOD1 controlling monocyte survival and proinflammatory status. Transcriptional profiling (Nanostring) was used to determine the molecular pathways influenced by ACOD1. Results We found that ACOD1/Acod1 represented an evolutionarily conserved of feature of inflammation-associated monocytes, with expression present in mucosal but not blood monocytes. Acod1–/– mice demonstrated increased susceptibility to acute intestinal injury with DSS compared to co-housed WT controls, characterised by increased weight loss and colon shortening with significant accumulation of colonic neutrophils and CD64+Ly6C+ MHC-II+/– monocytes. Consistent with Acod1 limiting inflammasome activation, Acod1–/– monocytes demonstrated significantly greater IL-1b producing capabilities than WT controls. To assess Acod1 deficient and sufficient haemopoietic cells in in the same environment, we generated competitive bone marrow chimeric mice. Acod1 deficiency conferred a significant advantage to monocyte recruitment to the colon, characterised by a 10fold increase in Ly6C+ MHC-II–colon monocytes in colitis. Transcriptional profiling of WT and Acod1–/– colonic monocytes revealed significantly greater expression of molecules required for monocyte extravasation, including Sell (CD62L), Icam1, Ccr2 and Itgal (CD11a). In addition, expression of genes indicative of macrophage maturation such as Itgax (CD11c), Cd163 and Cx3cr1 were lower in the context of Acod1 deficiency, suggesting that normal maturation of these cells may be perturbed by loss of Acod1. Conclusion ACOD1/Acod1 represents an evolutionarily conserved, monocyte specific immuno-metabolic pathway that acts to limit monocyte recruitment, fate and pro-inflammatory function within the inflamed intestine.

Aims Once-weekly semaglutide and dulaglutide represent two highly efficacious treatment options for type 2 diabetes. A recent indirect treatment comparison (ITC) has associated semaglutide 1 mg with similar and greater improvements in glycated haemoglobin (HbA1c) and body weight, respectively, vs. dulaglutide 3 mg and 4.5 mg. The present study aimed to evaluate the long-term cost-effectiveness of semaglutide 1 mg vs. dulaglutide 3 mg and 4.5 mg in the UK. Materials and methods The IQVIA CORE Diabetes Model (v9.0) was used to project outcomes over patients’ lifetimes. Baseline cohort characteristics were sourced from SUSTAIN 7, with changes in HbA1c and body mass index applied as per the ITC. Modelled patients received semaglutide or dulaglutide for 3 years, after which treatment was intensified to basal insulin. Costs (expressed in 2020 pounds sterling [GBP]) were accounted from a healthcare payer perspective. Results Semaglutide 1 mg was associated with improvements in quality-adjusted life expectancy of 0.05 and 0.04 quality-adjusted life years (QALYs) vs. dulaglutide 3 mg and 4.5 mg, respectively, due to a reduced incidence of diabetes-related complications with semaglutide. Direct costs were estimated to be GBP 76 lower and GBP 8 higher in the comparisons with dulaglutide 3 mg and 4.5 mg, respectively. Overall outcomes were similar, but favoured semaglutide, and based on modelled mean outcomes it was considered dominant vs. dulaglutide 3 mg and associated with an incremental cost-effectiveness ratio of GBP 228 per QALY gained vs. dulaglutide 4.5 mg. Conclusions Semaglutide 1 mg represents a cost-effective treatment vs. dulaglutide 3 mg and 4.5 mg for type 2 diabetes from a healthcare payer perspective in the UK.

The murine serous cavities contain a rare and enigmatic population of short-lived F4/80 loMHCII + macrophages but what regulates their development, survival, and fate is unclear. Here, we show that mature F4/80 loMHCII + peritoneal macrophages arise after birth, but that this occurs largely independently of colonization by microbiota. Rather, microbiota specifically regulate development of a subpopulation of CD11c + cells that express the immunoregulatory cytokine RELM-α, are reliant on the transcription factor EGR2, and develop independently of the growth factor CSF1. Furthermore, we demonstrate that intrinsic expression of RELM-α, a signature marker shared by CD11c + and CD11c – F4/80 loMHCII + cavity macrophages, regulates survival and differentiation of these cells in the peritoneal cavity in a sex-specific manner. Thus, we identify a previously unappreciated diversity in serous cavity F4/80 loMHCII + macrophages that is regulated by microbiota, and describe a novel sex and site-specific function for RELM-α in regulating macrophage endurance that reveals the unique survival challenge presented to monocyte-derived macrophages by the female peritoneal environment.

Introduction The glucagon-like peptide-1 receptor analogue (GLP-1RA) semaglutide is associated with improvements in glycaemia and cardiovascular risk factors in clinical trials. The aim of this study was to examine the real-world impact of semaglutide administered by injection in people with type 2 diabetes (T2D) across three secondary care sites in Wales. Methods A retrospective evaluation of 189 patients with T2D initiated on semaglutide between January 2019 and June 2020 with at least one follow-up visit was undertaken. Results At baseline, participants had a mean age of 61.1 years, mean glycated haemoglobin (HbA1c) of 77.8 mmol/mol (9.3%) and mean body weight of 101.8 kg. At 6 and 12 months of follow-up, mean HbA1c reductions of 13.3 mmol/mol (1.2%) and 16.4 mmol/mol (1.5%), respectively, were observed, and mean weight loss at 6 months was 3.0 kg (all p 35.0 kg/m2 or who had lower baseline HbA1c. Semaglutide was generally well tolerated, although adverse-effects limited use in 18 patients (9.5%). Conclusion Semaglutide provided clinically and statistically significant reductions in HbA1c, body weight, lipids and liver enzymes.

To detail the extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin dose adjustments in individuals with type 1 diabetes (T1D) using multiple daily injections of insulins aspart (IAsp) and degludec (IDeg).Sixteen individuals with T1D, completed a single-centred, randomised, four-period crossover trial consisting of 23-h inpatient phases. Participants administered either a regular (100%) or reduced (50%) dose (100%; 5.1 ± 2.4, 50%; 2.6 ± 1.2 IU, p 0.001) of individualised IAsp 1 h before and after 45-min of evening exercise at 60 ± 6% V̇OThese findings demonstrate the glycemic safety of peri-exercise bolus dose reduction strategies in minimising the prevalence of acute and nocturnal hypoglycemia following evening exercise in people with T1D on MDI. Use of newer background insulins with current bolus insulins demonstrates efficacy and advances current recommendations for safe performance of exercise.DRKS00013509.

The salivary glands often become damaged in individuals receiving radiotherapy for head and neck cancer, resulting in xerostomia, or chronic dry mouth. This leads to detrimental effects on their health and quality of life, for which there is no regenerative therapy. Macrophages are the predominant cell type in the salivary glands and are attractive therapeutic targets due to their unrivalled capacity to drive tissue repair and regeneration. Yet, the nature and role of macrophages in salivary gland homeostasis and whether or not they contribute to tissue repair/regeneration following injury is not well understood. Here, we have used single cell RNA-seq, multi-parameter flow cytometry and fluorescence microscopy to map the heterogeneity of the salivary gland macrophage compartment throughout development and following radiation-induced injury. We show that there are highly dynamic changes in the composition of the salivary gland macrophage compartment with age, in part due to changes in the ontogeny of these cells, determined using a suite of complementary fate mapping systems. A combination of mutant mice and antibody blockade demonstrates that salivary gland macrophages are dependent on CSF1, but not IL-34 or GM-CSF, for their development and maintenance. Finally, using an in vivo model of radiation-induced salivary gland injury combined with a novel Mafb-specific depletion system, we demonstrate an essential role for macrophages. Without macrophages the clearance of cells with DNA damage, and effective tissue repair following such injury, is severely comprised. Our data, therefore, indicate a strong case for exploring the therapeutic potential of manipulating macrophages in order to promote tissue repair and thus minimise salivary gland dysfunction after radiotherapy.

BACKGROUND AND AIMS Glucagon-like peptide-1 receptor agonists, such as semaglutide, have been associated with reductions in albuminuria, and may preserve estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (T2D). However, it has not been explored whether treatment with semaglutide affects a person's chronic kidney disease (CKD) risk category. The Kidney Disease: Improving Global Outcomes (KDIGO) risk category classification is a validated approach for defining the likelihood of CKD and cardiovascular (CV) disease progression, based on eGFR and urinary albumin-to-creatinine ratio (UACR). The aim of this analysis was to determine whether treatment with once-weekly (OW) semaglutide resulted in improvements in KDIGO risk category compared with placebo. METHOD The proportion of subjects with T2D moving to a lower KDIGO risk category, remaining in the same category or moving to a higher risk category between baseline and 2 years on treatment with OW subcutaneous semaglutide versus placebo was assessed post hoc using SUSTAIN 6 (NCT01720446) CV outcomes trial data. The endpoints were assessed for the overall population and by baseline KDIGO risk category (low, moderate, high and very high). Sensitivity analyses were conducted to investigate the contributions of UACR and eGFR to change in risk category. RESULTS Data from 2804 of the 3297 subjects randomized in SUSTAIN 6 were available for this post hoc analysis. At 2 years, in the overall population, subjects receiving OW semaglutide were more likely to move to a lower risk category (n = 183; 13.0%) than subjects receiving placebo (n = 114; 8.2%); odds ratio (OR; semaglutide versus placebo) 1.69 [95% confidence interval (CI) 1.32; 2.16, P < 0.0001) (Figure). Conversely, subjects receiving OW semaglutide were less likely to move to a higher risk category (n = 254; 18.1%) than those receiving placebo (n = 330; 23.6%); OR 0.71 (95% CI 0.59;0.86, P = 0.0003) (Figure). When the data were stratified by baseline KDIGO risk categories, across all categories, greater proportions of subjects receiving semaglutide than placebo moved to a lower risk category and lower proportions of subjects receiving semaglutide than placebo moved to a higher risk category (Figure). The effects of semaglutide on UACR and eGFR both contributed to the favourable change-in-risk-category profile compared with placebo (Table). CONCLUSION Subjects receiving semaglutide versus placebo were more likely to move to a lower KDIGO risk category and less likely to move to a higher risk category, both in the overall population and across KDIGO risk category subgroups. The potential kidney protective effects of semaglutide and the mechanisms underlying these are being investigated in subjects with T2D and CKD in the FLOW and REMODEL trials.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the largest global pandemic in living memory, with between 4.5 and 15M deaths globally from coronavirus disease 2019 (COVID-19). This has led to an unparalleled global, collaborative effort to understand the pathogenesis of this devastating disease using state-of-the-art technologies. A consistent feature of severe COVID-19 is dysregulation of pulmonary macrophages, cells that under normal physiological conditions play vital roles in maintaining lung homeostasis and immunity. In this article, we will discuss a selection of the pivotal findings examining the role of monocytes and macrophages in SARS-CoV-2 infection and place this in context of recent advances made in understanding the fundamental immunobiology of these cells to try to understand how key homeostatic cells come to be a central pathogenic component of severe COVID-19 and key cells to target for therapeutic gain.

The murine serous cavities contain a rare and enigmatic population of short-lived F4/80