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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.

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.

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.

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.

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.

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.

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.

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.

PURPOSE This study aimed to determine the glycemic responses to cardiopulmonary exercise testing (CPET) in individuals with type 1 diabetes (T1D) and to explore the influence of starting blood glucose (BG) concentrations on subsequent CPET outcomes. METHODS This study was a retrospective, secondary analysis of pooled data from three randomized crossover trials using identical CPET protocols. During cycling, cardiopulmonary variables were measured continuously, with BG and lactate values obtained minutely via capillary earlobe sampling. Anaerobic threshold was determined using ventilatory parameters. Participants were split into (i) euglycemic ([Eu] >3.9 to ≤10.0 mmol·L-1, n = 26) and (ii) hyperglycemic ([Hyper] >10.0 mmol·L-1, n = 10) groups based on preexercise BG concentrations. Data were assessed via general linear modeling techniques and regression analyses. P values of ≤0.05 were accepted as significant. RESULTS Data from 36 individuals with T1D (HbA1c, 7.3% ± 1.1% [56.0 ± 11.5 mmol·mol-1]) were included. BG remained equivalent to preexercise concentrations throughout CPET, with an overall change in BG of -0.32 ± 1.43 mmol·L-1. Hyper had higher HR at peak (+10 ± 2 bpm, P = 0.04) and during recovery (+9 ± 2 bpm, P = 0.038) as well as lower O2 pulse during the cool down period (-1.6 ± 0.04 mL per beat, P = 0.021). BG responses were comparable between glycemic groups. Higher preexercise BG led to greater lactate formation during exercise. HbA1c was inversely related to time to exhaustion (r = -0.388, P = 0.04) as well as peak power output (r = -0.355, P = 0.006) and O2 pulse (r = -0.308, P = 0.015). CONCLUSIONS This study demonstrated 1) stable BG responses to CPET in patients with T1D; 2) although preexercise hyperglycemia did not influence subsequent glycemic dynamics, it did potentiate alterations in various cardiac and metabolic responses to CPET; and 3) HbA1c was a significant factor in the determination of peak performance outcomes during CPET.

Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (

The randomized, double‐blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once‐weekly semaglutide (0.5‐1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P = .0136; SUSTAIN 6: 1.56 [1.14; 2.17], P = .0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease.

It is unknown if the cardioprotective and renal effects of glucagon-like peptide-1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P = .06 for MACE; P = .14 for nephropathy) or semaglutide (P = .40 for MACE; P = .27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP.

OBJECTIVE The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.

Aim: To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk. Methods: Post hoc analyses of individual patient-level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. Results: In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were 0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). Conclusions: In SUSTAIN and PIONEER combined, glucagon-like peptide-1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

Glucagon-like peptide-1 (GLP-1) receptor agonists have been available as glucose-lowering therapies for people with type 2 diabetes since 2006, when twice-daily exenatide was licenced. Since then, advances in peptide chemistry and delivery have allowed for once-daily and more recently once-weekly (QW) delivery of peptides in this class and there are currently three QW "long-acting" GLP-1 receptor agonists available in clinical practice. This short review describes the therapeutic landscape that is occupied by the modern type 2 diabetes glucose-lowering therapies with a particular focus on long-acting GLP-1 receptor agonists. The efficacy and side-effect profiles of the available QW GLP-1 receptor agonists are discussed, focusing on head-to-head clinical trial comparisons. There is also an appraisal of the cardiovascular outcome trials, for which there has been an assessment of each of the QW GLP-1 receptor agonists, leading to clinical conclusions regarding their comparative effectiveness.

Disease burden in people with diabetes is mainly driven by long-term complications such as cardiovascular disease, heart failure and chronic kidney disease. This is a consequence of the interconnection between the cardiovascular, renal and metabolic systems, through a continuous chain of events referred to as 'the cardiorenal metabolic continuum'. Increasing evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial effects across all stages of the cardiorenal metabolic continuum, reducing morbidity and mortality in a wide range of individuals, from those with diabetes and multiple risk factors to those with established heart failure and chronic kidney disease, regardless of the presence of diabetes. Despite this robust evidence base, the complexity of label indications and misconceptions concerning potential side effects have resulted in a lack of clear understanding in primary care regarding the implementation of SGLT2is in clinical practice. With this in mind, we provide an overview of the clinical and economic benefits of SGLT2is across the cardiorenal metabolic continuum together with practical considerations in order to help address some of these concerns and clearly define the role of SGLT2is in primary care as a holistic outcomes-driven treatment with the potential to reduce disease burden across the cardiorenal metabolic spectrum.

The last decade has been somewhat of a renaissance period for the field of macrophage biology. This renewed interest, combined with the advent of new technologies and development of novel model systems to assess different facets of macrophage biology, has led to major advances in our understanding of the diverse roles macrophages play in health, inflammation, infection and repair, and the dominance of tissue environments in influencing all of these areas. Here, we discuss recent developments in our understanding of lung macrophage heterogeneity, ontogeny, metabolism and function in the context of health and disease, and highlight core conceptual advances and key unanswered questions that we believe should be focus of work in the coming years.

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 dys- regulation 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 mac- rophages 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.

To identify key research questions where answers could improve care for older people living with diabetes (PLWD), and provide detailed recommendations for researchers and research funders on how best to address them.A series of online research workshops were conducted, bringing together a range of PLWD and an acknowledged group of academic and clinical experts in their diabetes care to identify areas for future research. Throughout the pre-workshop phase, during each workshop, and in manuscript preparation and editing, PLWD played an active and dynamic role in discussions as part of both an iterative and narrative process.The following key questions in this field were identified, and research recommendations for each were developed: How can we improve our understanding of the characteristics of older people living with diabetes (PLWD) and their outcomes, and can this deliver better person-centred care? How are services to care for older PLWD currently delivered, both for their diabetes and other conditions? How can we optimise and streamline the process and ensure everyone gets the best care, tailored to their individual needs? What tools might be used to evaluate the level of understanding of diabetes in the older population amongst non-specialist Healthcare Professionals (HCPs)? How can virtual experts or centres most effectively provide access to specialist multi-disciplinary team (MDT) expertise for older PLWD and the HCPs caring for them? Is a combination of exercise and a nutrition-dense, high protein diet effective in the prevention of the adverse effects of type 2 diabetes and deterioration in frailty, and how might this be delivered in a way which is acceptable to people with type 2 diabetes? How might we best use continuous glucose monitoring (CGM) in older people and, for those who require support, how should the data be shared? How can older PLWD be better empowered to manage their diabetes in their own home, particularly when living with additional long-term conditions? What are the benefits of models of peer support for older PLWD, both when living independently and when in care?This paper outlines recommendations supported by PLWD through which new research could improve their diabetes care and calls on the research community and funders to address them in future research programmes and strategies.