PBIS and RTI : Best Practices and Practical Applications using Technology

This presentation will focus on the practical application of PBIS and RTI for Behavior within a Multi-Tiered System of Supports (MTSS) for K-12. The common challenges expressed by districts in establishing these systems will be reviewed, as will the requisite components and processes for a complete PBIS rollout. The presenters will discuss these challenges, and how districts have utilized available online tools to help overcome them, and have more successful processes and better outcomes for their students. Creating a positive climate more conducive to learning and more preventative of problem behaviors, establishing a systematic approach to discipline, identification of students who may be at-risk for behavioral issues, discovery and application of appropriate research based interventions, continuous progress monitoring, and data-driven decision making will be discussed, and presented within a single platform for management, analysis, professional development, screening and planning. Please join us as we look at how to take Behavior Improvement from theory to practice with real outcome data from schools districts in the field

Improvements in Awareness and Testing Have Led to a Threefold Increase Over 10 Years in the Identification of Monogenic Diabetes in the U.K

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordAims/hypothesis: Maturity Onset Diabetes of the Young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of UK cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve the awareness and detection of MODY including education initiatives (Genetic Diabetes Nurse (GDN) programme), the MODY probability calculator, and targeted next generation sequencing (tNGS). We aimed to examine how the estimated prevalence of MODY, and other forms of monogenic diabetes diagnosed outside the neonatal period, has changed over time and how the initiatives have impacted case finding. Research design and Methods: UK referrals for genetic testing for monogenic diabetes diagnosed >1y of age from 01/01/1996 to 31/12/2019 were examined. Positive-test rates were compared for referrals reporting involvement of the GDNs/MODY calculator with those that did not. Results: A diagnosis of monogenic diabetes was confirmed in 3860 individuals, >3-fold higher than 2009 (01/01/1996-28/02/2009; n=1177). Median age at diagnosis in probands was 21y. GDN involvement was reported in 21% of referrals; these referrals had a higher positive-test rate than those without GDN involvement (32% v 23%, p<0.001). MODY calculator usage was indicated on 74% of eligible referrals since 2014; these referrals had a higher positive-test rate than those not using the calculator (33% v 25%, p=0.001). 410 (10.6%) cases were identified through tNGS. Monogenic diabetes prevalence was estimated to be 248 cases/million (double that estimated in 2009 due to increased case-finding). 3 Conclusions: Since 2009, referral rates and case diagnosis have increased three-fold. This is likely to be the consequence of tNGS, GDN education and the MODY calculator

Patient preference for second- and third-line therapies in type 2 diabetes:a prespecified secondary endpoint of the TriMaster study

Patient preference is very important for medication selection in chronic medical conditions, like type 2 diabetes, where there are many different drugs available. Patient preference balances potential efficacy with potential side effects. As both aspects of drug response can vary markedly between individuals, this decision could be informed by the patient personally experiencing the alternative medications, as occurs in a crossover trial. In the TriMaster (NCT02653209, ISRCTN12039221), randomized double-blind, three-way crossover trial patients received three different second- or third-line once-daily type 2 diabetes glucose-lowering drugs (pioglitazone 30 mg, sitagliptin 100 mg and canagliflozin 100 mg). As part of a prespecified secondary endpoint, we examined patients’ drug preference after they had tried all three drugs. In total, 448 participants were treated with all three drugs which overall showed similar glycemic control (HbA1c on pioglitazone 59.5 sitagliptin 59.9, canagliflozin 60.5 mmol mol−1, P = 0.19). In total, 115 patients (25%) preferred pioglitazone, 158 patients (35%) sitagliptin and 175 patients (38%) canagliflozin. The drug preferred by individual patients was associated with a lower HbA1c (mean: 4.6; 95% CI: 3.9, 5.3) mmol mol−1 lower versus nonpreferred) and fewer side effects (mean: 0.50; 95% CI: 0.35, 0.64) fewer side effects versus nonpreferred). Allocating therapy based on the individually preferred drugs, rather than allocating all patients the overall most preferred drug (canagliflozin), would result in more patients achieving the lowest HbA1c for them (70% versus 30%) and the fewest side effects (67% versus 50%). When precision approaches do not predict a clear optimal therapy for an individual, allowing patients to try potential suitable medications before they choose long-term therapy could be a practical alternative to optimizing treatment for type 2 diabetes

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record.Objective: Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as Type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating Type 1 from non-Type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. Research Design and Methods: We studied patients diagnosed ≤30y, currently <50y, in two UK regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised 3 stages: 1) Assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) If UCPCR≥0.2nmol/mmol, measurement of GAD and IA2 islet autoantibodies; 3) If negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. Results: 1407 patients participated (1365 no known genetic cause, 34 monogenic diabetes, 8 cystic-fibrosis-related diabetes). 386/1365(28%) had UCPCR≥0.2nmol/mmol. 216/386(56%) of these patients were negative for GAD and IA2 and underwent molecular genetic testing. 17 new cases of monogenic diabetes were diagnosed (8 common MODY (Sanger sequencing), 9 rarer causes (next generation sequencing)) in addition to the 34 known cases (estimated prevalence of 3.6% (51/1407) (95%CI: 2.7-4.7%)). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. Conclusions: The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed ≤30y.This study was funded by the Department of Health and Wellcome Trust Health Innovation Challenge Award (HICF-1009-041; WT-091985). ATH and SE are Wellcome Trust Senior Investigators. ATH is an NIHR Senior Investigator. BS, ATH, MH, SE, and BK are core members of the NIHR Exeter Clinical Research Facility. EP is a Wellcome Trust New Investigator. TM is supported by NIHR CSO Fellowship. JP is partly funded by the NIHR Collaboration for Leadership in Applied Health Research and Care for the South West (PenCLAHRC)

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors:a systematic review

Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy.Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review.Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes.Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.</p

The impact of renal artery stenting on therapeutic aims

Renal artery stenosis manifests as poorly-controlled hypertension, impaired renal function or pulmonary oedema, therefore the success of treatment is dependent on indication. This study aims to determine the outcomes of patients undergoing renal artery stenting (RASt) based on therapeutic aim compared to criteria used in the largest randomised trial. Retrospective case-note review of patients undergoing RASt between 2008–2021 (n = 74). The cohort was stratified by indication for intervention (renal dysfunction, hypertension, pulmonary oedema) and criteria employed in the CORAL trial, with outcomes and adverse consequences reported. Intervention for hypertension achieved significant reduction in systolic blood pressure and antihypertensive agents at 1 year (median 43 mmHg, 1 drug), without detrimental impact on renal function. Intervention for renal dysfunction reduced serum creatinine by a median 124 μmol/L, sustained after 6 months. Intervention for pulmonary oedema was universally successful with significant reduction in SBP and serum creatinine sustained at 1 year. Patients who would have been excluded from the CORAL trial achieved greater reduction in serum creatinine than patients meeting the inclusion criteria, with equivalent blood pressure reduction. There were 2 procedure-related mortalities and 5 procedural complications requiring further intervention. 5 patients had reduction in renal function following intervention and 7 failed to achieve the intended therapeutic benefit. Renal artery stenting is effective in treating the indication for which it has been performed. Previous trials may have underestimated the clinical benefits by analysis of a heterogenous population undergoing a procedure rather than considering the indication, and excluding patients who would maximally benefit

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179

The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype

types: JOURNAL ARTICLEMutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined.This article presents independent research supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The research is funded by a Wellcome Trust Senior Investigator Award, (grant number 098395/Z/12/Z).Wellcome Trus

Market-dependent production set

A country’s production possibility frontier or PPF is defined as the boundary of its economy’s production set in the net output space for a given technology and fixed quantities of primary factors of production. In general equilibrium theory, exogenous changes in technology or primary-factor supplies alter equilibrium prices; however, government-policy induced domestic relative commodity price changes do not alter the shape of an economy’s production set. We show that, under international capital mobility, which is empirically significant, the shape of a country’s production set does, in fact, depend on market forces and this shape can be manipulated by government policy