Type 2 diabetes (T2D) is caused by loss of pancreatic β-cell mass and failure of the remaining β-cells to deliver sufficient insulin to meet demand. β-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on β-cell function and survival, contributes to T2D-associated β-cell failure. Drugs and mechanisms that protect β-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking low-molecular-weight compounds that protected β-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured β-cell–protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLT-induced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve β-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment.

Progression from the initial vascular response upon hyperglycemia to a proliferative stage with neovacularizations is the hallmark of proliferative diabetic retinopathy. Here, we report on the novel diabetic pdx1^–/– zebrafish mutant as a model for diabetic retinopathy that lacks the transcription factor pdx1 through CRISPR-Cas9–mediated gene knockout leading to disturbed pancreatic development and hyperglycemia. Larval pdx1^–/– mutants prominently show vasodilation of blood vessels through increased vascular thickness in the hyaloid network as direct developmental precursor of the adult retinal vasculature in zebrafish. In adult pdx1^–/– mutants, impaired glucose homeostasis induces increased hyperbranching and hypersprouting with new vessel formation in the retina and aggravation of the vascular alterations from the larval to the adult stage. Both vascular aspects respond to antiangiogenic and antihyperglycemic pharmacological interventions in the larval stage and are accompanied by alterations in the nitric oxide metabolism. Thus, the pdx1^–/– mutant represents a novel model to study mechanisms of hyperglycemia-induced retinopathy wherein extensive proangiogenic alterations in blood vessel morphology and metabolic alterations underlie the vascular phenotype.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA_1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA_1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m², higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.

Approximately 40% of patients with diabetic macular edema (DME) are resistant to anti–vascular endothelial growth factor (VEGF) therapy (rDME). Here, we demonstrate that significant correlations between inflammatory cytokines and VEGF, as observed in naive DME, are lost in patients with rDME. VEGF overexpression in the mouse retina caused delayed inflammatory cytokine upregulation, monocyte/macrophage infiltration (CD11b⁺ Ly6C⁺ CCR2⁺ cells), macrophage/microglia activation (CD11b⁺ CD80⁺ cells), and blood-retinal barrier disruption due to claudin-5 redistribution, which did not recover with VEGF blockade alone. Phosphorylated protein analysis of VEGF-overexpressed retinas revealed rho-associated coiled-coil–containing protein kinase (ROCK) activation. Administration of ripasudil, a selective ROCK inhibitor, attenuated retinal inflammation and claudin-5 redistribution. Ripasudil also contributed to the stability of claudin-5 expression by both transcriptional enhancement and degradation suppression in inflammatory cytokine–stimulated endothelium. Notably, the anti-VEGF agent and the ROCK inhibitor were synergic in suppressing cytokine upregulation, monocyte/macrophage infiltration, macrophage/microglia activation, and claudin-5 redistribution. Furthermore, in vitro analysis confirmed that claudin-5 redistribution depends on ROCK2 but not on ROCK1. This synergistic effect was also confirmed in human rDME cases. Our results suggest that ROCK-mediated claudin-5 redistribution by inflammation is a key mechanism in the anti-VEGF resistance of DME.

As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3⁺ Treg-cell expansion in the spleen of wild-type mice but not in Gitr^–/– mice. G3C/cps also induced the expansion of nonconventional Cd4⁺Cd25^–/lowFoxp3^lowGitr^int/high (GITR single-positive [sp]) Tregs. Both Cd4⁺Cd25⁺Gitr^highFoxp3⁺ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant INS gene–induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in β-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.

Inadequate insulin secretion in response to glucose is an important factor for β-cell failure in type 2 diabetes (T2D). Although HMG-CoA reductase degradation 1 (HRD1), a subunit of the endoplasmic reticulum–associated degradation complex, plays a pivotal role in β-cell function, HRD1 elevation in a diabetic setting contributes to β-cell dysfunction. We report in this study the excessive HRD1 expression in islets from humans with T2D and T2D mice. Functional studies reveal that β-cell–specific HRD1 overexpression triggers impaired insulin secretion that will ultimately lead to severe hyperglycemia; by contrast, HRD1 knockdown improves glucose control and response in diabetic models. Proteomic analysis results reveal a large HRD1 interactome, which includes v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), a master regulator of genes implicated in the maintenance of β-cell function. Furthermore, mechanistic assay results indicate that HRD1 is a novel E3 ubiquitin ligase that targets MafA for ubiquitination and degradation in diabetic β-cells, resulting in cytoplasmic accumulation of MafA and in the reduction of its biological function in the nucleus. Our results not only reveal the pathological importance of excessive HRD1 in β-cell dysfunction but also establish the therapeutic importance of targeting HRD1 in order to prevent MafA loss and suppress the development of T2D.

Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and DLL4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult β-cells display improved glucose tolerance, increased glucose-stimulated insulin secretion, and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that Notch ligands play specific roles in the adult pancreas and highlight a novel function of the Delta/Notch pathway in β-cell insulin secretion.

Studies implicating sodium–glucose cotransporter 2 (SGLT2) inhibitors in glucagon secretion by pancreatic α-cells reported controversial results. We hypothesized that interindividual heterogeneity in SGLT2 expression and regulation may affect glucagon secretion by human α-cells in response to SGLT2 inhibitors. An unbiased RNA-sequencing analysis of 207 donors revealed an unprecedented level of heterogeneity of SLC5A2 expression. To determine heterogeneity of SGLT2 expression at the protein level, the anti-SGLT2 antibody was first rigorously evaluated for specificity, followed by Western blot and immunofluorescence analysis on islets from 10 and 12 donors, respectively. The results revealed a high interdonor variability of SGLT2 protein expression. Quantitative analysis of 665 human islets showed a significant SGLT2 protein colocalization with glucagon but not with insulin or somatostatin. Moreover, glucagon secretion by islets from 31 donors at low glucose (1 mmol/L) was also heterogeneous and correlated with dapagliflozin-induced glucagon secretion at 6 mmol/L glucose. Intriguingly, islets from three donors did not secrete glucagon in response to either 1 mmol/L glucose or dapagliflozin, indicating a functional impairment of the islets of these donors to glucose sensing and SGLT2 inhibition. Collectively, these data suggest that heterogeneous expression of SGLT2 protein and variability in glucagon secretory responses contribute to interindividual differences in response to SGLT2 inhibitors.

An aging global population combined with sedentary lifestyles and unhealthy diets has contributed to an increasing incidence of obesity and type 2 diabetes. These metabolic disorders are associated with perturbations to nitric oxide (NO) signaling and impaired glucose metabolism. Dietary inorganic nitrate, found in high concentration in green leafy vegetables, can be converted to NO in vivo and demonstrates antidiabetic and antiobesity properties in rodents. Alongside tissues including skeletal muscle and liver, white adipose tissue is also an important physiological site of glucose disposal. However, the distinct molecular mechanisms governing the effect of nitrate on adipose tissue glucose metabolism and the contribution of this tissue to the glucose-tolerant phenotype remain to be determined. Using a metabolomic and stable-isotope labeling approach, combined with transcriptional analysis, we found that nitrate increases glucose uptake and oxidative catabolism in primary adipocytes and white adipose tissue of nitrate-treated rats. Mechanistically, we determined that nitrate induces these phenotypic changes in primary adipocytes through the xanthine oxidoreductase–catalyzed reduction of nitrate to NO and independently of peroxisome proliferator–activated receptor-α. The nitrate-mediated enhancement of glucose uptake and catabolism in white adipose tissue may be a key contributor to the antidiabetic effects of this anion.

Subjects with low serum HDL cholesterol levels are reported to be susceptible to diabetes, with insulin resistance believed to be the underlying pathological mechanism. Apolipoprotein M (apoM) is a carrier of sphingosine-1-phosphate (S1P), a multifunctional lipid mediator, on HDL, and the pleiotropic effects of HDL are believed to be mediated by S1P. In the current study, we attempted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the serum levels of apoM were lower in patients with type 2 diabetes and that they were negatively correlated with BMI and the insulin resistance index. While deletion of apoM in mice was associated with worsening of insulin resistance, overexpression of apoM was associated with improvement of insulin resistance. Presumably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also by improving the mitochondrial functions through upregulation of SIRT1 protein levels. These actions of apoM/S1P appear to be mediated via activation of S1P1 and/or S1P3. These results suggest that apoM/S1P exerts protective roles against the development of insulin resistance.

Accumulation of lipid in skeletal muscle is thought to be related to the development of insulin resistance and type 2 diabetes. Initial work in this area focused on accumulation of intramuscular triglyceride; however, bioactive lipids such as diacylglycerols and sphingolipids are now thought to play an important role. Specific species of these lipids appear to be more negative toward insulin sensitivity than others. Adding another layer of complexity, localization of lipids within the cell appears to influence the relationship between these lipids and insulin sensitivity. This article summarizes how accumulation of total lipids, specific lipid species, and localization of lipids influence insulin sensitivity in humans. We then focus on how these aspects of muscle lipids are impacted by acute and chronic aerobic and resistance exercise training. By understanding how exercise alters specific species and localization of lipids, it may be possible to uncover specific lipids that most heavily impact insulin sensitivity.

The coordinated electrical activity of β-cells within the pancreatic islet drives oscillatory insulin secretion. A recent hypothesis postulates that specially equipped "hub" or "leader" cells within the β-cell network drive islet oscillations and that electrically silencing or optically ablating these cells suppresses coordinated electrical activity (and thus insulin secretion) in the rest of the islet. In this Perspective, we discuss this hypothesis in relation to established principles of electrophysiological theory. We conclude that whereas electrical coupling between β-cells is sufficient for the propagation of excitation across the islet, there is no obvious electrophysiological mechanism that explains how hyperpolarizing a hub cell results in widespread inhibition of islet electrical activity and disruption of their coordination. Thus, intraislet diffusible factors should perhaps be considered as an alternate mechanism.

Advances in small RNA sequencing have revealed the enormous diversity of small noncoding RNA (sRNA) classes in mammalian cells. At this point, most investigators in diabetes are aware of the success of microRNA (miRNA) research and appreciate the importance of posttranscriptional gene regulation in glycemic control. Nevertheless, miRNAs are just one of multiple classes of sRNAs and likely represent only a minor fraction of sRNA sequences in a given cell. Despite the widespread appreciation of sRNAs, very little research into non-miRNA sRNA function has been completed, likely due to some major barriers that present unique challenges for study. To emphasize the importance of sRNA research in cardiometabolic diseases, we highlight the success of miRNAs and competitive endogenous RNAs in cholesterol and glucose metabolism. Moreover, we argue that sequencing studies have demonstrated that miRNAs are just the tip of the iceberg for sRNAs. We are likely standing at the precipice of immense discovery for novel sRNA-mediated gene regulation in cardiometabolic diseases. To realize this potential, we must first address critical barriers with an open mind and refrain from viewing non-miRNA sRNA function through the lens of miRNAs, as they likely have their own set of distinct regulatory factors and functional mechanisms.

Impaired insulin secretion from the pancreatic β-cells is central in the pathogenesis of type 2 diabetes (T2D), and microRNAs (miRNAs) are fundamental regulatory factors in this process. Differential expression of miRNAs contributes to β-cell adaptation to compensate for increased insulin resistance, but deregulation of miRNA expression can also directly cause β-cell impairment during the development of T2D. miRNAs are small noncoding RNAs that posttranscriptionally reduce gene expression through translational inhibition or mRNA destabilization. The nature of miRNA targeting implies the presence of complex and large miRNA–mRNA regulatory networks in every cell, including the insulin-secreting β-cell. Here we exemplify one such network using our own data on differential miRNA expression in the islets of T2D Goto-Kakizaki rat model. Several biological processes are influenced by multiple miRNAs in the β-cell, but so far most studies have focused on dissecting the mechanism of action of individual miRNAs. In this Perspective we present key islet miRNA families involved in T2D pathogenesis including miR-200, miR-7, miR-184, miR-212/miR-132, and miR-130a/b/miR-152. Finally, we highlight four challenges and opportunities within islet miRNA research, ending with a discussion on how miRNAs can be utilized as therapeutic targets contributing to personalized T2D treatment strategies.

Nayeli G. Reyes-Nava, Hung-Chun Yu, Curtis R. Coughlin II, Tamim H. Shaikh, and Anita M. Quintana

We used whole-exome sequencing (WES) to determine the genetic etiology of a patient with a multi-system disorder characterized by a seizure phenotype. WES identified a heterozygous de novo missense mutation in the GABRA1 gene (c.875C>T). GABRA1 encodes the alpha subunit of the gamma-aminobutyric acid receptor A (GABA_AR). The GABA_AR is a ligand gated ion channel that mediates the fast inhibitory signals of the nervous system, and mutations in the subunits that compose the GABA_AR have been previously associated with human disease. To understand the mechanisms by which GABRA1 regulates brain development, we developed a zebrafish model of gabra1 deficiency. gabra1 expression is restricted to the nervous system and behavioral analysis of morpholino injected larvae suggests that the knockdown of gabra1 results in hypoactivity and defects in the expression of other subunits of the GABA_AR. Expression of the human GABRA1 protein in morphants partially restored the hypomotility phenotype. In contrast, the expression of the c.875C>T variant did not restore these behavioral deficits. Collectively, these results represent a functional approach to understand the mechanisms by which loss-of-function alleles cause disease.

Chalongrat Noree and Naraporn Sirinonthanawech

Previously, we have developed an extramitochondrial assembly system, where mitochondrial targeting signal (MTS) can be removed from a given mitochondrial enzyme, which could be used to characterize the regulatory factors involved in enzyme assembly/disassembly in vivo. Here, we demonstrate that addition of exogenous acetaldehyde can quickly induce the supramolecular assembly of MTS-deleted aldehyde dehydrogenase Ald4p in yeast cytoplasm. Also, by using PCR-based modification of the yeast genome, cytoplasmically targeted Ald4p cannot polymerize into long filaments when key functional amino acid residues are substituted, as shown by N192D, S269A, E290K and C324A mutations. This study has confirmed that extramitochondrial assembly could be a powerful external system for studying mitochondrial enzyme assembly, and its regulatory factors outside the mitochondria. In addition, we propose that mitochondrial enzyme assembly/disassembly is coupled to the regulation of a given mitochondrial enzyme activity.

Manoella Gemaque Cavalcante, Cleusa Yoshiko Nagamachi, Julio Cesar Pieczarka, and Renata Coelho Rodrigues Noronha

Eukaryotic genomes exhibit substantial accumulation of repetitive DNA sequences. These sequences can participate in chromosomal reorganization events and undergo molecular cooption to interfere with the function and evolution of genomes. In turtles, repetitive DNA sequences appear to be accumulated at probable break points and may participate in events such as non-homologous recombination and chromosomal rearrangements. In this study, repeated sequences of 5S rDNA, U2 snRNA and Tc1/Mariner transposons were amplified from the genomes of the turtles, Podocnemis expansa and Podocnemis unifilis, and mapped by fluorescence in situ hybridization. Our data confirm the 2n=28 chromosomes for these species (the second lowest 2n in the order Testudines). We observe high conservation of the co-located 5S rDNA and U2 snRNA genes on a small chromosome pair (pair 13), and surmise that this represents the ancestral condition. Our analysis reveals a wide distribution of the Tc1/Mariner transposons and we discuss how the mobility of these transposons can act on karyotypic reorganization events (contributing to the 2n decrease of those species). Our data add new information for the order Testudines and provide important insights into the dynamics and organization of these sequences in the chelonian genomes.

Soojeong Kim and Isabel K. Darcy

An experimental technique called difference topology combined with the mathematics of tangle analysis has been used to unveil the structure of DNA bound by the Mu transpososome. However, difference topology experiments can be difficult and time consuming. We discuss a modification that greatly simplifies this experimental technique. This simple experiment involves using a topoisomerase to trap DNA crossings bound by a protein complex and then running a gel to determine the crossing number of the knotted product(s). We develop the mathematics needed to analyze the results and apply these results to model the topology of DNA bound by 13S condensin and by the condensin MukB.

Sonu Shrestha Baral, Molly E. Lieux, and Patrick J. DiMario

Different stem cells or progenitor cells display variable threshold requirements for functional ribosomes. This is particularly true for several human ribosomopathies in which select embryonic neural crest cells or adult bone marrow stem cells, but not others, show lethality due to failures in ribosome biogenesis or function (now known as nucleolar stress). To determine if various Drosophila neuroblasts display differential sensitivities to nucleolar stress, we used CRISPR-Cas9 to disrupt the Nopp140 gene that encodes two splice variant ribosome biogenesis factors (RBFs). Disruption of Nopp140 induced nucleolar stress that arrested larvae in the second instar stage. While the majority of larval neuroblasts arrested development, the mushroom body (MB) neuroblasts continued to proliferate as shown by their maintenance of deadpan, a neuroblast-specific transcription factor, and by their continued EdU incorporation. MB neuroblasts in wild-type larvae appeared to contain more fibrillarin and Nopp140 in their nucleoli as compared to other neuroblasts, indicating that MB neuroblasts stockpile RBFs as they proliferate in late embryogenesis while other neuroblasts normally enter quiescence. A greater abundance of Nopp140 encoded by maternal transcripts in Nopp140-/- MB neuroblasts of 1­­­–2-day-old larvae likely rendered these cells more resilient to nucleolar stress.

This article has an associated First Person interview with the first author of the paper.

BackgroundSelf-harm is a serious risk factor for suicide, a major public health concern, and a significant burden on the NHS. Rates of self-harm presentation in primary care are rising and GPs interact with patients both before and after they have self-harmed. There is significant public and political interest in reducing rates of self-harm, but there has been no robust synthesis of the existing literature on the role of GPs in the management of patients who self-harm.AimThis study aimed to explore the role of the GP in the management of patients with self-harm behaviour.Design and settingA systematic review and narrative synthesis of primary care literature.MethodThis systematic review was conducted and is reported in line with PRISMA guidance. Electronic databases systematically searched were MEDLINE, PsycINFO, EMBASE, CINAHL, Web of Science, and AMED. Two independent reviewers conducted study screening and selection, data extraction, and quality appraisal of all included studies. Thematic analysis was conducted.ResultsFrom 6976 unique citations, 12 studies met eligibility criteria and were included. These 12 studies, published from 1997–2016, of 789 GPs/family medicine physicians from Europe, the US, and Australia were of good methodological quality. Five themes were identified for facilitating GP management of self-harm: GP training, improved communication, service provision, clinical guidelines, and young people. Four barriers for GP management of self-harm were identified: assessment, service provision, local, and systemic factors.ConclusionGPs recognise self-harm as a serious risk factor for suicide, but some feel unprepared for managing self-harm. The role of the GP is multidimensional and includes frontline assessment and treatment, referral to specialist care, and the provision of ongoing support.

BackgroundA brief intervention whereby GPs opportunistically facilitate an NHS-funded referral to a weight loss programme is clinically and cost-effective.AimTo test the acceptability of a brief intervention and attendance at a weight loss programme when GPs facilitate a referral that requires patients to pay for the service.Design and settingAn observational study of the effect of a GP encouraging attendance at a weight loss programme requiring self-payment in the West Midlands from 16 October 2018 to 30 November 2018, to compare with a previous trial in England in which the service was NHS-funded.MethodSixty patients with obesity who consecutively attended primary care appointments received an opportunistic brief intervention by a GP to endorse and offer a referral to a weight loss programme at the patient’s own expense. Participants were randomised to GPs who either stated the weekly monetary cost of the programme (basic cost) or who compared the weekly cost to an everyday discretionary item (cost comparison). Participants were subsequently asked to report whether they had attended a weight loss programme.ResultsOverall, 47% of participants (n = 28) accepted the referral; 50% (n = 15) in the basic cost group and 43% (n = 13) in the cost comparison group. This was significantly less than in a previous study when the programme was NHS-funded (77%, n = 722/940; P<0.0001). Most participants reported the intervention to be helpful/very helpful and appropriate/very appropriate (78%, n = 46/59 and 85%, n = 50/59, respectively) but scores were significantly lower than when the programme was NHS-funded (92% n = 851/922 and 88% n = 813/922, respectively; P = 0.004). One person (2%) attended the weight loss programme, which is significantly lower than the 40% of participants who attended when the programme was NHS-funded (P<0.0001).ConclusionGP referral to a weight loss programme that requires patients to pay rather than offering an NHS-funded programme is acceptable; however, it results in almost no attendance.

BackgroundAwareness of the importance of shared decision making (SDM) is widespread; however, little research has focused on discussions surrounding investigations, despite increasing laboratory testing in primary care.AimTo explore the discussion of blood tests in routine primary care consultations.Design and settingA secondary analysis of 50 video-recorded routine primary care consultations, linked surveys, and records data (all from the One in a Million [OiaM] archive). The consultations were taken by 22 GPs across 12 practices.MethodA coding scheme was developed, using qualitative content analysis, to explore discussion of blood tests in transcripts of recorded consultations. Codes focused on instigating testing, the extent of SDM, and how results were explained. Survey data were used to compare patients’ pre-visit expectations with consultation content. Medical records were reviewed to compare tests discussed with those ordered.ResultsIn 36 out of 50 consultations that discussed ordering blood tests, 11 patients (31%) hinted that they wanted a blood test; however, none asked explicitly. Only four patients (11%) were offered alternative options. In 29 cases (81%) the GP gave some explanation of the indication, but only in six cases (17%) were the limitations of testing explained. Only 10 out of 31 patients (32%) were informed about all blood tests ordered. Of the 23 out of 50 consultations in which results were conveyed, the GP gave no explanation of the results in six cases (26%). Thirteen patients (57%) were only informed of an assessment of the results (for example, ‘normal’), rather than the actual results.ConclusionA lack of information dissemination and SDM exists around ordering tests and conveying results. Promoting SDM could reduce unnecessary testing and improve patient-centred care.

BackgroundUrinary tract infections (UTIs) are one of the most common bacterial infections managed in general practice. Many women with symptoms of uncomplicated UTI may not benefit meaningfully from antibiotic treatment, but the evidence base is complex and there is no suitable shared decision-making resource to guide antibiotic treatment and symptomatic care for use in general practice consultations.AimTo develop an evidence-based, shared decision-making intervention leaflet to optimise management of uncomplicated UTI for women aged <65 years in the primary care setting.Design and settingQualitative telephone interviews with GPs and patient focus group interviews.MethodIn-depth interviews were conducted to explore how consultation discussions around diagnosis, antibiotic use, self-care, safety netting, and prevention of UTI could be improved. Interview schedules were based on the Theoretical Domains Framework.ResultsBarriers to an effective joint consultation and appropriate prescribing included: lack of GP time, misunderstanding of depth of knowledge and miscommunication between the patient and the GP, nature of the consults (such as telephone consultations), and a history of previous antibiotic therapy.ConclusionConsultation time pressures combined with late symptom presentation are a challenge for even the most experienced of GPs: however, it is clear that enhanced patient–clinician shared decision making is urgently required when it comes to UTIs. This communication should incorporate the provision of self-care, safety netting, and preventive advice to help guide patients when to consult. A shared decision-making information leaflet was iteratively co-produced with patients, clinicians, and researchers at Public Health England using study data.

BackgroundPolycystic ovary syndrome (PCOS) is a common lifelong metabolic condition with serious associated comorbidities. Evidence points to a delay in diagnosis and inconsistency in the information provided to women with PCOS.AimTo capture women’s experiences of how PCOS is diagnosed and managed in UK general practice.Design and settingThis was a mixed-methods study with an online questionnaire survey and semi-structured telephone interviews with a subset of responders.MethodAn online survey to elicit women’s experiences of general practice PCOS care was promoted by charities and BBC Radio Leicester. The survey was accessible online between January 2018 and November 2018. A subset of responders undertook a semi-structured telephone interview to provide more in-depth data.ResultsA total of 323 women completed the survey (average age 35.4 years) and semi-structured interviews were conducted with 11 women. There were five key themes identified through the survey responses. Participants described a variable lag time from presentation to PCOS diagnosis, with a median of 6–12 months. Many had experienced mental health problems associated with their PCOS symptoms, but had not discussed these with the GP. Many were unable to recall any discussion about associated comorbidities with the GP. Some differences were identified between the experiences of women from white British backgrounds and those from other ethnic backgrounds.ConclusionFrom the experiences of the women in this study, it appears that PCOS in general practice is not viewed as a long-term condition with an increased risk of comorbidities including mental health problems. Further research should explore GPs’ awareness of comorbidities and the differences in PCOS care experienced by women from different ethnic backgrounds.

BackgroundIn the context of a variable condition such as asthma, patient recognition of deteriorating control and knowing what prompt action to take is crucial. Yet, implementation of recommended self-management strategies remains poor.AimTo explore how patients with asthma and parents/carers of children with asthma develop and establish recommended self-management strategies for living with asthma, and how clinicians can best support the process.Design and settingA qualitative study in UK primary care.MethodPatients with asthma and parents/carers of children with asthma from 10 general practices were purposively sampled (using age, sex, and duration of asthma) to participate in focus groups or interviews between May 2016 and August 2016. Participants’ experiences of health care, management of asthma, and views on supported self-management were explored. Interviews and focus group sessions were audio-recorded and transcribed verbatim. Iterative thematic analysis was conducted, guided by the research questions and drawing on habit theory in discussion with a multidisciplinary research team.ResultsA total of 49 participants (45 patients; 4 parents/carers) took part in 32 interviews and five focus groups. Of these, 11 reported using an action plan. Patients learnt how to self-manage over time, building knowledge from personal experience and other sources, such as the internet. Some regular actions, for example, taking medication, became habitual. Dealing with new or unexpected scenarios required reflective abilities, which may be supported by a tailored action plan.ConclusionPatients reported learning intuitively how to self-manage. Some regular actions became habitual; dealing with the unexpected required more reflective cognitive skills. In order to support implementation of optimal asthma self- management, clinicians should consider both these aspects of self-management and support, and educate patients proactively.