Can the introduction of a 12-lead ECG help reduce mortality in those presenting with foot ulceration to multidisciplinary diabetic foot clinics? An observational evaluation of a real-world implementation pilot in England.

Aims/hypothesis: The risk of dying within 2 years of presentation with diabetic foot ulceration is over six times the risk of amputation, with CVD the major contributor. Using an observational evaluation of a real-world implementation pilot, we aimed to assess whether for those presenting with diabetic foot ulceration in England, introducing a 12-lead ECG into routine care followed by appropriate clinical action was associated with reduced mortality.

Methods: Between July 2014 and December 2017, ten multidisciplinary diabetic foot services in England participated in a pilot project introducing 12-lead ECGs for new attendees with foot ulceration.

Study protocol for a multicentre comparative diagnostic accuracy study of tools to establish the presence and severity of peripheral arterial disease in people with diabetes mellitus: the DM PAD study.

Introduction: Peripheral arterial disease (PAD) is a key risk factor for cardiovascular disease, foot ulceration and lower limb amputation in people with diabetes. Early diagnosis of PAD can enable optimisation of therapies to manage these risks. Its diagnosis is fundamental, though challenging in the context of diabetes.

Microbiological evaluation of resection margins of the infected diabetic foot ulcer.

Aim: To evaluate the impact of surgical debridement on the microbiology of resection margins of an infected diabetic foot ulcer and to compare the use of marginal sampling as a guide for antimicrobial therapy.

Methods: Forty consecutive participants were studied. Tissue samples from infected diabetic foot ulcers were obtained at first contact by podiatrists.

Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify , a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model.

Residual Adrenal Function in Autoimmune Addison's Disease-Effect of Dual Therapy With Rituximab and Depot Tetracosactide.

Context: In autoimmune Addison's disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy, and poorer quality of life.

Objective: The objective of this article is to restore adrenocortical steroidogenic function in recent-onset AAD.

Discovery and Optimization of Quinolinone Derivatives as Potent, Selective, and Orally Bioavailable Mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors.

Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1.

Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas.

Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening.

Synthesis and evaluation of triazolones as checkpoint kinase 1 inhibitors.

Checkpoint kinase 1 (Chk1, CHEK1) is a Ser/Thr protein kinase that plays a key role in mediating the cellular response to DNA-damage. Synthesis and evaluation of a previously described class of Chk1 inhibitors, triazoloquinolones/triazolones (TZs) is further described herein. Our investigation of structure-activity relationships led to the identification of potent inhibitors 14c, 14h and 16e.

Multi-professional clinical medication reviews in care homes for the elderly: study protocol for a randomised controlled trial with cost effectiveness analysis.

Background: Evidence demonstrates that measures are needed to optimise therapy and improve administration of medicines in care homes for older people. The aim of this study is to determine the clinical and cost effectiveness of a novel model of multi-professional medication review.

Methods: A cluster randomised controlled trial design, involving thirty care homes.

Discovery of a novel class of triazolones as checkpoint kinase inhibitors--hit to lead exploration.

Checkpoint Kinase-1 (Chk1, CHK1, CHEK1) is a Ser/Thr protein kinase that mediates cellular responses to DNA-damage. A novel class of Chk1 inhibitors, triazoloquinolones/triazolones (TZ's) was identified by high throughput screening. The optimization of these hits to provide a lead series is described.

Strategies towards more effective anticancer therapies: targeting DNA damage response pathways.

The last decade has seen a tremendous increase in the understanding of the cellular mechanisms that underlie the detection and repair of DNA damage. This gave rise to the hypothesis that inhibition of DNA repair may result in increased efficacy of existing therapies and, more recently, to the idea that some tumor cells may carry additional defects that make them hypersensitive to DNA repair inhibitors as single agents. In order to minimize the potential to cause lesions in normal tissue, strategies have been directed to specific targets or pathways where selectivity for tumor over normal tissue is possible, thus to date most emphasis has been placed on a relatively small number of targets such as the poly(ADP-ribose) polymerase and the checkpoint kinases.

Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents.

Purpose: Pharmacokinetic/pharmacodynamic (PK/PD) models have been shown to be useful in predicting tumor growth rates in mouse xenografts. We applied novel PK/PD models to the published anticancer combination therapies of tumor growth inhibition to simulate synergistic changes in tumor growth rates. The parameters from the PK/PD model were further used to estimate clinical doses of the combination.

An exploratory study of the effect of using high-mix biphasic insulin aspart in people with type 2 diabetes.

Objective: To compare blood glucose control when using biphasic insulin aspart (BIAsp) three times a day (using 70/30 high-mix before breakfast and lunch), with biphasic human insulin (BHI, 30/70) twice daily in adults with type 2 diabetes already treated with insulin.

Research Design And Methods: In a 60-day, open-label, crossover study, people with insulin-treated type 2 diabetes [n = 38, baseline haemoglobin A1c 8.3 +/- 0.

Checkpoint kinase inhibitors: a review of the patent literature.

Background: The checkpoint kinases, Chk1 and Chk2 are Ser/Thr protein kinases, which function as key regulatory kinases in cellular DNA damage response pathways limiting cell-cycle progression in the presence of DNA damage. The development of checkpoint kinase inhibitors for the treatment of cancer has been a major objective in drug discovery over the past decade, as evidenced by three checkpoint kinase inhibitors entering clinic trials since late 2005.

Objectives: This review describes and discusses the most recent inhibitors of checkpoint kinases Chk1 and Chk2, as reported in the patent literature, including an evaluation of chemical structure and biological activity.

AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies.

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death.

Keeping checkpoint kinases in line: new selective inhibitors in clinical trials.

Background: Checkpoint kinase 1 (Chk1), a serine/threonine kinase, functions as a regulatory kinase in cell cycle progression and is a critical effector of the DNA-damage response. Inhibitors of Chk1 are known to sensitise tumours to a variety of DNA-damaging agents and increase efficacy in preclinical models.

Objective: The most advanced agents are now in Phase I clinical trials; the preclinical profiles of these drugs are compared and contrasted, together with a discussion of some of the opportunities and challenges facing this potentially revolutionary approach to cancer therapy.

DNA damage detection and repair pathways--recent advances with inhibitors of checkpoint kinases in cancer therapy.

Insights from cell cycle research have led to the hypothesis that tumors may be selectivity sensitized to DNA-damaging agents, resulting in improved antitumor activity and a wider therapeutic margin. The theory relies primarily on the observation that the majority of tumors are deficient in the G(1)-DNA damage checkpoint pathway, resulting in reliance on S and G(2) phase checkpoints for DNA repair and cell survival. The S and G(2) phase checkpoints are predominantly regulated by checkpoint kinase 1; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death.

Discovery of a novel class of 2-ureido thiophene carboxamide checkpoint kinase inhibitors.

Checkpoint kinase-1 (Chk1, CHEK1) is a Ser/Thr protein kinase that mediates the cellular response to DNA-damage. A novel class of 2-ureido thiophene carboxamide urea (TCU) Chk1 inhibitors is described. Inhibitors in this chemotype were optimized for cellular potency and selectivity over Cdk1.

Treatment satisfaction and quality of life with insulin glargine plus insulin lispro compared with NPH insulin plus unmodified human insulin in individuals with type 1 diabetes.

Objective: The purpose of this study was to compare quality of life (QoL) and treatment satisfaction using insulin glargine plus insulin lispro with that using NPH insulin plus unmodified human insulin in adults with type 1 diabetes managed with multiple injection regimens.

Research Design And Methods: As part of a 32-week, five-center, two-way crossover study in 56 individuals with type 1 diabetes randomized to evening insulin glargine plus mealtime insulin lispro or to NPH insulin (once or twice daily) plus mealtime unmodified human insulin, the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Audit of Diabetes Dependent Quality of Life questionnaire were completed at baseline and at weeks 16 and 32, with additional interim DTSQ measurements.

Results: For all patients combined, the mean baseline present QoL score was 1.

Inhibitors of checkpoint kinases: from discovery to the clinic.

Checkpoint kinase 1 (CHK1) is a member of the serine/ threonine kinase family. CHK1 functions as a regulatory kinase in cell-cycle progression and is the main effector of theDNA-damage response within the cell. Over the past few years, a large number of novel inhibitors of CHK1 have been discovered that encompass an enormous area of chemical space and diversity and, in more recent reports, many of these inhibitors have been demonstrated preclinically to sensitize tumors to a wide variety of DNA-damaging agents.

Insulin glargine in combination with nateglinide in people with Type 2 diabetes: a randomized placebo-controlled trial.

Objective: To determine the effect of adding nateglinide to therapy with insulin glargine in adults with Type 2 diabetes previously treated with insulin and with poor blood glucose control.

Research Design And Methods: In this 16-week, double-blind, placebo-controlled study, people with Type 2 diabetes [n = 55, HbA(1c) 8.2 +/- 1.

Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.

Aim: To compare blood glucose control when using insulin glargine twice daily at breakfast- and dinner-times with insulin glargine once daily at dinner time, in unselected people with Type 1 diabetes using insulin aspart at meal-times.

Methods: In this 8-week, two-way, cross-over study, 20 people with Type 1 diabetes were randomized to insulin glargine injection once daily at dinner-time or twice daily at breakfast- and dinner-times, both plus meal-time insulin aspart. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile.

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes.

Aims: To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen.

Methods: In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.

Optimal timing of injection of once-daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal-times.

Aims: To compare blood glucose control when insulin glargine is given at lunch-time, dinner-time, and bed-time in people with Type 1 diabetes using insulin lispro at meal-times.

Methods: In this 16-week, three-way, cross-over study, 23 people with Type 1 diabetes were randomized to insulin glargine injection at lunch-time (L) [mean 12.37 +/- 00.