BACKGROUND

Sex differences have been described in diabetes cardiovascular outcome trials (CVOTs).

OBJECTIVE

Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes.

OBJECTIVE

Diabetes is a chronic health condition contributing to a substantial burden of disease. According to the Robert Wood Johnson Foundation, 10.9 million people were newly insured by Medicaid between 2013 and 2016. Considering this coverage expansion, the Affordable Care Act (ACA) could significantly affect people with diabetes in their management of the disease. This study evaluates the impact of the Medicaid expansion under the ACA on diabetes management.

OBJECTIVE

Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population.

OBJECTIVE

Suboptimal adherence to insulin treatment is a main issue in adolescents with type 1 diabetes. However, to date, there are no available data on adherence to adjunct noninsulin medications in this population. Our aim was to assess adherence to ACE inhibitors and statins and explore potential determinants in adolescents with type 1 diabetes.

OBJECTIVE

With rising health care costs and finite health care resources, understanding the population needs of different type 2 diabetes mellitus (T2DM) patient subgroups is important. Sparse data exist for the application of population segmentation on health care needs among Asian T2DM patients. We aimed to segment T2DM patients into distinct classes and evaluate their differential health care use, diabetes-related complications, and mortality patterns.

OBJECTIVE

Type 2 diabetes is characterized by increased death rate. In order to tackle this dramatic event, it becomes essential to discover novel biomarkers capable of identifying high-risk patients to be exposed to more aggressive preventive and treatment strategies. hs-CRP and serum amyloid P component (SAP) are two acute-phase inflammation proteins, which interact physically and share structural and functional features. We investigated their combined role in associating with and improving prediction of mortality in type 2 diabetes.

OBJECTIVE

The prevalence of type 2 diabetes is increasing among adults under age 45. Onset of type 2 diabetes at a younger age increases an individual’s risk for diabetes-related complications. Given the lasting benefits conferred by early glycemic control, we compared glycemic control and initial care between adults with younger onset (21–44 years) and mid-age onset (45–64 years) of type 2 diabetes.

OBJECTIVE

No study has reported global disability burden estimates for individual diabetes-related lower-extremity complications (DRLECs). The Global Burden of Disease (GBD) study presents a robust opportunity to address this gap.

In patients with cancer-associated venous thromboembolism, knowledge of the estimated rate of recurrent events is important for clinical decision-making regarding anticoagulant therapy. The Ottawa score is a clinical prediction rule designed for this purpose, stratifying patients according to their risk of recurrent venous thromboembolism during the first six months of anticoagulation. We conducted a systematic review and meta-analysis of studies validating either the Ottawa score in its original or modified versions. Two investigators independently reviewed the relevant articles published from 1st June 2012 to 15th December 2018 and indexed in MEDLINE and EMBASE. Nine eligible studies were identified; these included a total of 14,963 patients. The original score classified 49.3% of the patients as high-risk, with a sensitivity of 0.7 [95% confidence interval (CI): 0.6-0.8], a 6-month pooled rate of recurrent venous thromboembolism of 18.6% (95%CI: 13.9-23.9). In the low-risk group, the recurrence rate was 7.4% (95%CI: 3.4-12.5). The modified score classified 19.8% of the patients as low-risk, with a sensitivity of 0.9 (95%CI: 0.4-1.0) and a 6-month pooled rate of recurrent venous thromboembolism of 2.2% (95%CI: 1.6-2.9). In the high-risk group, recurrence rate was 10.2% (95%CI: 6.4-14.6). Limitations of our analysis included type and dosing of anticoagulant therapy. We conclude that new therapeutic strategies are needed in patients at high risk for recurrent cancer-associated venous thromboembolism. Low-risk patients, as per the modified score, could be good candidates for oral anticoagulation. (This systematic review was registered with the International Prospective Registry of Systematic Reviews as: PROSPERO CRD42018099506).

Sepsis causes an activation of the human contact system, an inflammatory response mechanism against foreign surfaces, proteins and pathogens. The serine proteases of the contact system, factor XII and plasma kallikrein, are decreased in plasma of septic patients, which was previously associated with an unfavorable outcome. However, the precise mechanisms and roles of contact system factors in bacterial sepsis are poorly understood. We, therefore, studied the physiological relevance of factor XII and plasma kallikrein in a mouse model of experimental sepsis. We show that decreased plasma kallikrein concentration in septic mice is a result of reduced mRNA expression plasma prekallikrein gene, indicating that plasma kallikrein belong to negative acute phase proteins. Investigations regarding the pathophysiological function of contact system proteases during sepsis revealed different roles for factor XII and plasma kallikrein. In vitro, factor XII decelerated bacteria induced fibrinolysis, whereas plasma kallikrein supported it. Remarkably, depletion of plasma kallikrein (but not factor XII) by treatment with antisense-oligonucleotides, dampens bacterial dissemination and growth in multiple organs in the mouse sepsis model. These findings identify plasma kallikrein as a novel host pathogenicity factor in Streptococcus pyogenes sepsis.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 μmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (P=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.

1q21 amplification is an important prognostic marker in multiple myeloma. In this study we identified that IL6R (the interleukin-6 membrane receptor) and ADAR1 (an RNA editing enzyme) are critical genes located within the minimally amplified 1q21 region. Loss of individual genes caused suppression to the oncogenic phenotypes, the magnitude of which was enhanced when both genes were concomitantly lost. Mechanistically, IL6R and ADAR1 collaborated to induce a hyper-activation of the oncogenic STAT3 pathway. High IL6R confers hypersensitivity to interleukin-6 binding, whereas, ADAR1 forms a constitutive feed-forward loop with STAT3 in a P150-isoform-predominant manner. In this respect, ADAR1-P150 acts as a direct transcriptional target for STAT3 and this STAT3-induced-P150 in turn directly interacts with and stabilizes the former protein, leading to a larger pool of proteins acting as oncogenic transcription factors for pro-survival genes. The importance of both IL6R and ADAR1-P150 in STAT3 signaling was further validated when concomitant knockdown of both genes impeded IL6-induced-STAT3 pathway activation. Clinical evaluation of various datasets of myeloma patients showed that low expression of either one or both genes was closely associated with a compromised STAT3 signature, confirming the involvement of IL6R and ADAR1 in the STAT3 pathway and underscoring their essential role in disease pathogenesis. In summary, our findings highlight the complexity of the STAT3 pathway in myeloma, in association with 1q21 amplification. This study therefore reveals a novel perspective on 1q21 abnormalities in myeloma and a potential therapeutic target for this cohort of high-risk patients.

B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma (DLBCL). In in vitro and in vivo model systems, a subset of DLBCLs depend upon BCR survival signals and respond to proximal BCR/phosphoinositide 3 kinase (PI3K) blockade. However, single-agent BCR pathway inhibitors have had more limited activity in patients with DLBCL, underscoring the need for indicators of sensitivity to BCR blockade and insights into potential resistance mechanisms. Here, we report highly significant transcriptional upregulation of C-X-C chemokine receptor 4 (CXCR4) in BCR-dependent DLBCL cell lines and primary tumors following chemical spleen tyrosine kinase (SYK) inhibition, molecular SYK depletion or chemical PI3K blockade. SYK or PI3K inhibition also selectively upregulated cell surface CXCR4 protein expression in BCR-dependent DLBCLs. CXCR4 expression was directly modulated by fork-head box O1 via the PI3K/protein kinase B/forkhead box O1 signaling axis. Following chemical SYK inhibition, all BCR-dependent DLBCLs exhibited significantly increased stromal cell-derived factor-1α (SDF-1α) induced chemotaxis, consistent with the role of CXCR4 signaling in B-cell migration. Select PI3K isoform inhibitors also augmented SDF-1α induced chemotaxis. These data define CXCR4 upregulation as an indicator of sensitivity to BCR/PI3K blockade and identify CXCR4 signaling as a potential resistance mechanism in BCR-dependent DLBCLs.

Tlarge granular lymphocyte leukemia (T-LGLL) is characterized by the expansion of several large granular lymphocyte clones, among which a subset of large granular lymphocytes showing constitutively activated STAT3, a specific CD8⁺/CD4^– phenotype and the presence of neutropenia has been identified. Although STAT3 is an inducer of transcription of a large number of oncogenes, so far its relationship with miRNAs has not been evaluated in T-LGLL patients. Here, we investigated whether STAT3 could carry out its pathogenetic role in T-LGLL through an altered expression of miRNAs. The expression level of 756 mature miRNA was assessed on purified T large granular lymphocytes (T-LGLs) by using a TaqMan Human microRNA Array. Hierarchical Clustering Analysis of miRNA array data shows that the global miRNome clusters with CD8 T-LGLs. Remarkably, CD8 T-LGLs exhibit a selective and STAT3-dependent repression of miR-146b expression, that significantly correlated with the absolute neutrophil counts and inversely correlated with the expression of Fas ligand (FasL), that is regarded as the most relevant factor in the pathogenesis of neutropenia. Experimental evidence demonstrates that the STAT3-dependent reduction of miR-146b expression in CD8 T-LGLs occurs as a consequence of miR-146b promoter hypermethylation and results in the disruption of the HuR-mediated post-transcriptional machinery controlling FasL mRNA stabilization. Restoring miR-146b expression in CD8 T-LGLs lead to a reduction of HuR protein and, in turn, of FasL mRNA expression, thus providing mechanistic insights for the existence of a STAT3-miR146b-FasL axis and neutropenia in T-LGLL.

Identifying gene variants causing monogenic diabetes (MD) increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of MD in youth with diabetes in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young-adult patients with diabetes in Lithuania (n = 1,209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients (n = 153) using targeted high-throughput sequencing of >300 potential candidate genes. In this group, 40.7% had MD, with the highest percentage (100%) in infants (diagnosis at ages 0–12 months), followed by those diagnosed at ages >1–18 years (40.3%) and >18–25 years (22.2%). The overall prevalence of MD in youth with diabetes in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with MD. Prospective treatment change was successful in >50% of eligible candidates, with C-peptide >252 pmol/L emerging as the best prognostic factor.

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.

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.

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.

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.

Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. In addition to its role in the regulation of glucose metabolism, glucagon has been described to promote ketosis in the fasted state. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs that act primarily in the kidney, but some reports have described direct effects of SGLT2i on α-cells to stimulate glucagon secretion. Interestingly, SGLT2 inhibition also results in increased endogenous glucose production and ketone production, features common to glucagon action. Here, we directly test the ketogenic role of glucagon in mice, demonstrating that neither fasting- nor SGLT2i-induced ketosis is altered by interruption of glucagon signaling. Moreover, any effect of glucagon to stimulate ketogenesis is severely limited by its insulinotropic actions. Collectively, our data suggest that fasting-associated ketosis and the ketogenic effects of SGLT2 inhibitors occur almost entirely independent of glucagon.

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.

Yuta Sakae, Akira Oikawa, Yuki Sugiura, Masatoshi Mita, Shuhei Nakamura, Toshiya Nishimura, Makoto Suematsu, and Minoru Tanaka

The teleost fish, medaka (Oryzias latipes), employs the XX/XY genetic sex determination system. We show here that the phenotypic sex of medaka is affected by changes in lipid metabolism. Medaka larvae subjected to 5 days of starvation underwent female-to-male sex reversal. Metabolomic and RT-qPCR analyses indicated that pantothenate metabolism was suppressed by starvation. Consistently, inhibiting the pantothenate metabolic pathway caused sex reversal. The final metabolite in this pathway is coenzyme A, an essential factor for lipogenesis. Inhibiting fatty acid synthesis, the first step of lipogenesis, also caused sex reversal. The expression of dmrt1, a critical gene for male development, was suppressed by starvation, and a dmrt1 (13) mutant did not show sex reversal under starvation. Collectively, these results indicate that fatty acid synthesis is involved in female-to-male sex reversal through ectopic expression of male gene dmrt1 under starvation.

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.

BackgroundAutistic people are at increased risk of developing mental health problems. To reduce the negative impact of living with autism in a non-autistic world, efforts to improve take-up and access to care, and support in early years, which will typically start with a GP appointment, must be grounded in the accounts of autistic young adults.AimTo explore how autistic young adults understand and manage mental health problems; and to consider help seeking as a focus.Design and settingA cross-sectional, qualitative study. Autistic participants were purposively selected to represent a range of mental health conditions including anxiety and depression. A subsample were recruited from a population cohort screened for autism in childhood. The study concerns access to primary care.MethodNineteen autistic young adults without learning disabilities, aged 23 or 24 years, were recruited. In-depth, semi-structured interviews explored how they understood and managed mental health problems. Data were analysed thematically.ResultsYoung adults preferred self-management strategies. Multiple factors contributed to a focus on self-management, including: beliefs about the aetiology of mental health difficulties and increased vulnerability with the context of a diagnosis of autism, knowledge of self-management, and a view that formal support was unavailable or inadequate. Families had limited awareness of professional support.ConclusionYoung autistic adults without learning disabilities, and their families, may hold erroneous beliefs about autism and mental health. This may affect help seeking and contribute to an exacerbation of symptoms. GPs need to be alert to the fact that autistic young adults in their care may be experiencing mental health difficulties but may not recognise them as such.

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.

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.