John-Michael Gamble

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and consider how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture...

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OBJECTIVES: To examine the associations between COVID-19 pandemic waves (1-4) and prevalent antipsychotic, antidepressant, benzodiazepine, anticonvulsant, and opioid use among assisted living (AL) residents, by setting (dementia care vs other). DESIGN: Population-based, repeated cross-sectional study. SETTING AND PARTICIPANTS: Linked clinical and health administrative databases for residents of all publicly subsidized AL homes (N = 256) in Alberta, Canada, examined from January 2018 to December 2021...

AIMS: To assess post-initiation predictors of discontinuation of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared to dipeptidyl-peptidase-4 (DPP-4) inhibitors in the United Kingdom. MATERIALS AND METHODS: We conducted a comparative population-based retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) with linked data to hospital and death records. We included new metformin users who initiated either SGLT2 inhibitors or DPP-4 inhibitors between January 2013 and October 2019...

OBJECTIVE: Evidence of an increased dementia risk with insulin use in type 2 diabetes is weakened by confounding by indication and disease severity. Herein we reassess this association, while accounting for confounding through design and analysis. RESEARCH DESIGN AND METHODS: Using administrative health care data from British Columbia, Canada, we identified patients diagnosed with type 2 diabetes in 1998-2016. To adjust for confounding by diabetes severity through design, we compared new users of insulin to new users of a noninsulin class, both from a restricted cohort of those who previously received two noninsulin antihyperglycemic classes...

The aim of this work was to develop approaches to utilize whole particle distributions for both particle size and particle shape parameters to map the full range of particle properties in a curated dataset. It is hoped that such an approach may enable a more complete understanding of the particle landscape as a step towards improving the link between particle properties and processing behaviour. A 1-dimensional principal component analysis (PCA) approach was applied to create a 'morphological distribution landscape'...

OBJECTIVE: Severe hypoglycemia is associated with an increased risk of dementia. We examined if the association is consistently present in mid- and late-life hypoglycemia. RESEARCH DESIGN AND METHODS: Using health care data from Population Data BC, we created a base cohort of patients age ≥40 years with incident type 2 diabetes. Exposure was the first occurrence of severe hypoglycemia (hospitalization or physician visit). We assessed exposure versus no exposure in mid- (age 45-64 years) and late-life (age 65-84 years) cohorts...

OBJECTIVES: Landmark clinical trials have shown the sodium-glucose cotransporter-2 (SGLT-2) inhibitors to have cardiorenal benefits beyond their glucose-lowering effect. Clinical guidelines now recommend their use in patients with chronic kidney disease or heart failure, with or without type 2 diabetes, potentially affecting prescribing patterns among physician specialties. METHODS: Using monthly projected total retail dispensed prescription data from IQVIA's CompuScript database, we assessed trends in prescribing SGLT-2 inhibitors among 6 prescriber specialities from 2015 to 2021 in Canada...

Computational modeling, machine learning, and statistical data analysis are increasingly utilized to mitigate chemistry, manufacturing, and control failures related to particle properties in solid dosage form manufacture. Advances in particle characterization techniques and computational approaches provide unprecedented opportunities to explore relationships between particle morphology and drug product manufacturability. Achieving this, however, has numerous challenges such as producing and appropriately curating robust particle size and shape data...

Seven preregistered studies ( N = 2,890, adult participants) conducted in the field, in the lab, and online documented opportunity neglect: a tendency to reject opportunities with low probability of success even when they come with little or no objective cost (e.g., time, money, reputation). Participants rejected a low-probability opportunity in an everyday context (Study 1). Participants also rejected incentive-compatible gambles with positive expected value-for both goods (Study 2) and money (Studies 3-7)-even with no possibility of monetary loss and nontrivial rewards (e...

BACKGROUND: Previous studies have shown hypoglycaemia to be associated with an increased risk of dementia; however, there are several design challenges to consider. The objective of this study is to assess the association between hypoglycaemia and dementia while addressing these challenges using a lag period, exposure density sampling (EDS) and inverse probability of treatment weighting (IPTW). METHODS: This was a population-based cohort using data (1996-2018) from British Columbia, Canada...

Purpose: Despite ample evidence underpinning the efficacy of β2 -agonists in asthma and chronic obstructive pulmonary disease (COPD), the occurrence of β1 - and β2 -adrenoceptors in the heart suggests that β2 -agonists may have deleterious cardiac effects. We investigated the association between new users of long-or short-acting β2 -agonists (LABA or SABA) or ICS (inhaled corticosteroids)/LABA and major adverse cardiovascular events (MACE). Methods: A nested case-control analysis was conducted using the UK Clinical Practice Research Datalink of patients with asthma, COPD or asthma-COPD overlap with initial treatment of LABA, SABA, ICS/LABA, ICS, long-or short-acting muscarinic antagonist (LAMA or SAMA) between 01 January 1998 and 31 July 2018...

OBJECTIVES: Sodium-glucose cotransporter-2 (SGLT2) inhibitor-induced glycosuria is hypothesized to increase the risk of urinary tract infections (UTIs). We assessed the risk of UTIs associated with SGLT2 inhibitor initiation in type 2 diabetes. METHODS: We conducted a population-based cohort study using primary care data from the United Kingdom's Clinical Practice Research Datalink (CPRD) and administrative health-care data from Alberta, Canada. From a base cohort of new metformin users, we constructed 5 comparative cohorts, wherein the exposure contrast was defined as new use of SGLT2 inhibitors or 1 of 5 active comparators: dipeptidylpeptidase-4 (DPP-4) inhibitors, sulfonylureas (SU), glucagon-like peptide-1 receptor agonists (GLP-1 RA), thiazolidinediones (TZD) and insulin...

OBJECTIVES: Our aim in this study was to quantify the prevalence over time and identify determinants of acetylsalicylic acid (ASA) use in patients with diabetes with and without cardiovascular disease (CVD) in a representative Canadian sample from 2005 to 2014, and to determine whether the use of ASA among patients with diabetes changed after Diabetes Canada guidelines updates. METHODS: Data from the Canadian Community Health Survey were used. Respondents who were at least 35 years of age and diagnosed with diabetes---not during pregnancy---were included and categorized into secondary prevention (previous heart disease or stroke) or primary prevention (high or low CVD risk) groups...

AIM: To assess the association between SGLT2-i initiation and genital tract infections (GTIs) among patients with type 2 diabetes. METHODS: A population-based cohort study using administrative healthcare data from Alberta, Canada and primary care data from the UK's Clinical Practice Research Datalink (CPRD). Among new metformin users, we identified new users of SGLT2-i and five active comparator cohorts (new users of dipeptidyl peptidase-4 inhibitor (DPP4-i) Sulfonylureas (SU), glucagon-like peptide-1 receptor agonists (GLP-1 RA), thiazolidinediones (TZD) and insulin)...

OBJECTIVE: To assess the variation in bleeding risk estimates and risk stratification among Web and mobile applications for patients with atrial fibrillation. DESIGN: Cross-sectional study. SETTING: Simulated patient population. PARTICIPANTS: Hypothetical patient cohorts that encompassed all possible binary risk factor combinations for each clinical prediction model. INTERVENTIONS: Twenty-five bleeding risk calculators (18 Web and 7 mobile apps), each of which used 1 of 4 clinical prediction models to predict an individual's 12-month bleed risk: ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), HAS-BLED (hypertension [systolic blood pressure >160 mm Hg], abnormal renal or liver function, stroke [caused by bleeding], bleeding, labile international normalized ratio, elderly [age >65 years], drugs [acetylsalicylic acid or nonsteroidal anti-inflammatory drugs] or alcohol [≥8 drinks per week]), HEMORR2 HAGES (hepatic or renal disease, ethanol abuse, malignancy, older [age >75 years], reduced platelet count or function, rebleeding risk [history of past bleeding], hypertension [uncontrolled], anemia, genetic factors, excessive fall risk, and stroke), and mOBRI (modified Outpatient Bleeding Risk Index)...

AIMS: Disproportionality analysis is a common pharmacovigilance tool to detect safety signals of type 2 diabetes medications from spontaneous drug reporting databases. The aim was to demonstrate the impact of using active-comparator restricted disproportionality analysis (ACR-DA), wherein the reference group is restricted to reports with a clinically appropriate active comparator. METHODS: Using reports from the Food and Drug Administration Adverse Event Reporting System, we assessed if sodium/glucose cotransporter 2 (SGLT2) inhibitors are associated with higher reporting of 5 potential adverse events: acute kidney injury, genitourinary tract infections, diabetic ketoacidosis, fractures, and amputations...

Consistent buckling distortions of a large membrane patch (200 × 200 Å) are observed during molecular dynamics (MD) simulations using the Monte-Carlo (MC) barostat in combination with a hard Lennard-Jones (LJ) cutoff. The buckling behavior is independent of both the simulation engine and the force field but requires the MC barostat-hard LJ cutoff combination. Similar simulations of a smaller patch (90 × 90 Å) do not show buckling, but do show a small, systematic reduction in the surface area accompanied by ~1 Å thickening suggestive of compression...

INTRODUCTION: To assess the comparative effectiveness and safety of renal-related outcomes associated with sodium-glucose cotransporter-2 inhibitors (SGLT2-i) initiation among patients with type 2 diabetes using real-world data. RESEARCH DESIGN AND METHODS: We conducted a population-based cohort study using administrative healthcare data from Alberta (AB), Canada and primary care data from the Clinical Practice Research Datalink (CPRD), UK. From a cohort of new metformin users, we identified initiators of a SGLT2-i or dipeptidyl peptidase-4 inhibitor (DPP4-i) between January 1, 2014 and March 30, 2018 (AB) or between January 1, 2013 and November 29, 2018 (CPRD)...

AIM: We assessed the risk of all-cause hospitalization and all-cause death associated with the use of Sodium Glucose Cotransporter-2 inhibitors (SGLT2i). METHODS: Population-based propensity scores-matched cohort study of new users of metformin who subsequently initiated SGLT2i compared to those who initiated dipeptidyl peptidase-4 inhibitors (DPP4i) (primary comparison), sulfonylureas, thiazolidinediones, GLP1-Receptors agonists, and insulin, respectively. Alberta (Canada) health administrative data and United Kingdom Clinical Practice Research Datalink (CPRD) data were used to assess the study outcomes...