Factors associated with long-term opioid use among patients with axial spondyloarthritis or psoriatic arthritis who initiated opioids.

OBJECTIVE: Up to one in five patients with axial spondyloarthritis (AxSpA) or psoriatic arthritis (PsA) newly initiated on opioids transition to long-term use within the first year. This study aimed to investigate individual factors associated with long-term opioid use among opioid new users with AxSpA/PsA. METHODS: Adult patients with AxSpA/PsA and without prior cancer who initiated opioids between 2006-2021 were included from Clinical Practice Research Datalink Gold, a national UK primary care database. Long-term opioid use was defined as having ≥3 opioid prescriptions issued within 90 days, or ≥ 90 days of opioid supply, in the first year of follow-up. Individual factors assessed included sociodemographic, lifestyle factors, medication use and comorbidities. A mixed-effects logistic regression model with patient-level random intercept was used to examine the association of individual characteristics with the odds of long-term opioid use. RESULTS: In total 10 300 opioid initiations were identified from 8,212 patients (3037 AxSpA; 5175 PsA). The following factors were associated with long-term opioid use: being a current smoker (OR : 1.62; 95%CI : 1.38,1.90), substance use disorder (OR : 2.34, 95%CI : 1.05,5.21), history of suicide/self-harm (OR : 1.84; 95%CI : 1.13,2.99), co-existing fibromyalgia (OR : 1.62; 95%CI : 1.11,2.37), higher Charlson Comorbidity Index (OR : 3.61; 95%CI : 1.69,7.71 for high scores), high MME/day at initiation (OR : 1.03; 95%CI : 1.02,1.03) and gabapentinoid (OR : 2.35; 95%CI : 1.75,3.16) and antidepressant use (OR : 1.69; 95%CI : 1.45,1.98). CONCLUSIONS: In AxSpA/PsA patients requiring pain relief, awareness of lifestyle, sociodemographic and prescribing characteristics associated with higher risk of long-term opioid use can prompt timely interventions such as structured medication reviews and smoking cessation to promote safer prescribing and better patient outcomes.

Machine learning identifies risk factors associated with long-term opioid use in fibromyalgia patients newly initiated on an opioid.

OBJECTIVES: Fibromyalgia is frequently treated with opioids due to limited therapeutic options. Long-term opioid use is associated with several adverse outcomes. Identifying factors associated with long-term opioid use is the first step in developing targeted interventions. The aim of this study was to evaluate risk factors in fibromyalgia patients newly initiated on opioids using machine learning. METHODS: A retrospective cohort study was conducted using a nationally representative primary care dataset from the UK, from the Clinical Research Practice Datalink. Fibromyalgia patients without prior cancer who were new opioid users were included. Logistic regression, a random forest model and Boruta feature selection were used to identify risk factors related to long-term opioid use. Adjusted ORs (aORs) and feature importance scores were calculated to gauge the strength of these associations. RESULTS: In this study, 28 552 fibromyalgia patients initiating opioids were identified of which 7369 patients (26%) had long-term opioid use. High initial opioid dose (aOR: 31.96, mean decrease accuracy (MDA) 135), history of self-harm (aOR: 2.01, MDA 44), obesity (aOR: 2.43, MDA 36), high deprivation (aOR: 2.00, MDA 31) and substance use disorder (aOR: 2.08, MDA 25) were the factors most strongly associated with long-term use. CONCLUSIONS: High dose of initial opioid prescription, a history of self-harm, obesity, high deprivation, substance use disorder and age were associated with long-term opioid use. This study underscores the importance of recognising these individual risk factors in fibromyalgia patients to better navigate the complexities of opioid use and facilitate patient-centred care.

Comparing Predictive Performance of Time Invariant and Time Variant Clinical Prediction Models in Cardiac Surgery.

Clinical prediction models are increasingly used across healthcare to support clinical decision making. Existing methods and models are time-invariant and thus ignore the changes in populations and healthcare practice that occur over time. We aimed to compare the performance of time-invariant with time-variant models in UK National Adult Cardiac Surgery Audit data from Manchester University NHS Foundation Trust between 2009 and 2019. Data from 2009-2011 were used for initial model fitting, and data from 2012-2019 for validation and updating. We fitted four models to the data: a time-invariant logistic regression model (not updated), a logistic model which was updated every year and validated it in each subsequent year, a logistic regression model where the intercept is a function of calendar time (not updated), and a continually updating Bayesian logistic model which was updated with each new observation and continuously validated. We report predictive performance over the complete validation cohort and for each year in the validation data. Over the complete validation data, the Bayesian model had the best predictive performance.

Trends for opioid prescribing and the impact of the COVID-19 pandemic in patients with rheumatic and musculoskeletal diseases between 2006 and 2021.

OBJECTIVE: To investigate opioid prescribing trends and assess the impact of the COVID-19 pandemic on opioid prescribing in rheumatic and musculoskeletal diseases (RMDs). METHODS: Adult patients with RA, PsA, axial spondyloarthritis (AxSpA), SLE, OA and FM with opioid prescriptions between 1 January 2006 and 31 August 2021 without cancer in UK primary care were included. Age- and gender-standardized yearly rates of new and prevalent opioid users were calculated between 2006 and 2021. For prevalent users, monthly measures of mean morphine milligram equivalents (MME)/day were calculated between 2006 and 2021. To assess the impact of the pandemic, we fitted regression models to the monthly number of prevalent opioid users between January 2015 and August 2021. The time coefficient reflects the trend pre-pandemic and the interaction term coefficient represents the change in the trend during the pandemic. RESULTS: The study included 1 313 519 RMD patients. New opioid users for RA, PsA and FM increased from 2.6, 1.0 and 3.4/10 000 persons in 2006 to 4.5, 1.8 and 8.7, respectively, in 2018 or 2019. This was followed by a fall to 2.4, 1.2 and 5.9, respectively, in 2021. Prevalent opioid users for all RMDs increased from 2006 but plateaued or dropped beyond 2018, with a 4.5-fold increase in FM between 2006 and 2021. In this period, MME/day increased for all RMDs, with the highest for FM (≥35). During COVID-19 lockdowns, RA, PsA and FM showed significant changes in the trend of prevalent opioid users. The trend for FM increased pre-pandemic and started decreasing during the pandemic. CONCLUSION: The plateauing or decreasing trend of opioid users for RMDs after 2018 may reflect the efforts to tackle rising opioid prescribing in the UK. The pandemic led to fewer people on opioids for most RMDs, providing reassurance that there was no sudden increase in opioid prescribing during the pandemic.

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study. FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12). INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF. FUNDING: Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, and National Institutes of Health National Heart, Lung, and Blood Institute.

Mortality in People with Type 2 Diabetes Following SARS-CoV-2 Infection: A Population Level Analysis of Potential Risk Factors.

INTRODUCTION: Research is ongoing to increase our understanding of how much a previous diagnosis of type 2 diabetes mellitus (T2DM) affects someone's risk of becoming seriously unwell following a COVID-19 infection. In this study we set out to determine the relative likelihood of death following COVID-19 infection in people with T2DM when compared to those without T2DM. This was conducted as an urban population study and based in the UK. METHODS: Analysis of electronic health record data was performed relating to people living in the Greater Manchester conurbation (population 2.82 million) who had a recorded diagnosis of T2DM and subsequent COVID-19 confirmed infection. Each individual with T2DM (n = 13,807) was matched with three COVID-19-infected non-diabetes controls (n = 39,583). Data were extracted from the Greater Manchester Care Record (GMCR) database for the period 1 January 2020 to 30 June 2021. Social disadvantage was assessed through Townsend scores. Death rates were compared in people with T2DM to their respective non-diabetes controls; potential predictive factors influencing the relative likelihood of admission were ascertained using univariable and multivariable logistic regression. RESULTS: For individuals with T2DM, their mortality rate after a COVID-19 positive test was 7.7% vs 6.0% in matched controls; the relative risk (RR) of death was 1.28. From univariate analysis performed within the group of individuals with T2DM, the likelihood of death following a COVID-19 recorded infection was lower in people taking metformin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 (GLP-1) agonist. Estimated glomerular filtration rate (eGFR) and hypertension were associated with increased mortality and had odds ratios of 0.96 (95% confidence interval 0.96-0.97) and 1.92 (95% confidence interval 1.68-2.20), respectively. Likelihood of death following a COVID-19 infection was also higher in those people with a diagnosis of chronic obstructive pulmonary disease (COPD) or severe enduring mental illness but not with asthma, and in people taking aspirin/clopidogrel/insulin. Smoking in people with T2DM significantly increased mortality rate (odds ratio of 1.46; 95% confidence interval 1.29-1.65). In a combined analysis of patients with T2DM and controls, multiple regression modelling indicated that the factors independently relating to a higher likelihood of death (accounting for 26% of variance) were T2DM, age, male gender and social deprivation (higher Townsend score). CONCLUSION: Following confirmed infection with COVID-19 a number of factors are associated with mortality in individuals with T2DM. Prescription of metformin, SGLT2is or GLP-1 agonists and non-smoking status appeared to be associated with a reduced the risk of death for people with T2DM. Age, male sex and social disadvantage are associated with an increased risk of death.

Dasatinib does not exacerbate dexamethasone-induced osteonecrosis in murine models of acute lymphoblastic leukemia therapy.

INTRODUCTION: There are clinical reports that the incorporation of dasatinib may increase the frequency of osteonecrosis in acute lymphoblastic leukemia (ALL) treatment regimens. No rigorous testing of this hypothesis is available to guide clinicians. METHODS: We tested whether oral dasatinib increased the frequency of dexamethasone-induced osteonecrosis in a murine model and tested its effects on dexamethasone's antileukemic efficacy in a murine BCR-ABL+ model of ALL. RESULTS: Dasatinib did not change the frequency of osteonecrosis (p = .99) nor of arteriopathy (p = .36) in dexamethasone-treated mice when given at dosages that achieved clinically relevant steady-state dasatinib plasma concentrations of 53.1 ng/ml (95% CI: 43.5-57.3 ng/ml). These dasatinib exposures were not associated with increased dexamethasone plasma exposure in nonleukemia-bearing mice. These same dosages were not associated with any decrement in antileukemic efficacy of dexamethasone in a responsive BCR-ABL+ model of ALL. CONCLUSIONS: Based on the results of our preclinical murine studies, we conclude that dasatinib is unlikely to increase the osteonecrotic effects of dexamethasone in ALL regimens.

Effects of zoledronic acid on osteonecrosis and acute lymphoblastic leukemia treatment efficacy in preclinical models.

BACKGROUND: Osteonecrosis is a devastating side effect of acute lymphoblastic leukemia (ALL) therapy. Associations between bone density loss and osteonecrosis have sparked interest in using bisphosphonates to reduce this complication. PROCEDURE: We assessed the impact of zoledronic acid (ZA) on the development of osteonecrosis in murine models when used either throughout therapy (continuous administration) or late in therapy after vascular lesions have developed but before osteonecrosis has occurred. Effects on bone density were measured using microcomputed tomography (µCT)-assessed tibial cortical thickness, while osteonecrosis was assessed histologically in the distal femur. Effects on antileukemic efficacy of chemotherapy were evaluated in both immunocompetent/syngeneic and patient-derived xenograft (PDX) models. RESULTS: Continuous administration of ZA with chemotherapy prevented chemotherapy-associated bone loss (p < .001) and reduced osteonecrosis (p = .048). Late initiation of ZA diminished bone loss (p < .001) but had no impact on the development of osteonecrosis (p = .93). In the immunocompetent murine ALL model, mice treated with ZA and chemotherapy succumbed to leukemia sooner than mice treated with chemotherapy alone (p = .046). Analysis using PDX showed a nonsignificant decrease in survival with ZA (p = .17). CONCLUSION: Our data indicate ZA may prevent osteonecrosis if begun with chemotherapy but showed no benefit when administered later in therapy. However, ZA may also reduce the antileukemic efficacy of chemotherapy.

Estimating the causal effect of BMI on mortality risk in people with heart disease, diabetes and cancer using Mendelian randomization.

BACKGROUND: Observational data have reported that being overweight or obese, compared to being normal weight, is associated with a lower risk for death - the "obesity paradox". We used Mendelian randomization (MR) to estimate causal effects of body mass index (BMI) on mortality risks in people with coronary heart disease (CHD), type 2 diabetes mellitus (T2DM) or malignancy in whom this paradox has been often reported. METHODS: We studied 457,746 White British UK Biobank participants including three subgroups with T2DM (n = 19,737), CHD (n = 21,925) or cancer (n = 42,612) at baseline and used multivariable-adjusted Cox models and MR approaches to describe relationships between BMI and mortality risk. RESULTS: Observational Cox models showed J-shaped relationships between BMI and mortality risk including within disease subgroups in which the BMI values associated with minimum mortality risk were within overweight/obese ranges (26.5-32.5 kg/m2). In all participants, MR analyses showed a positive linear causal effect of BMI on mortality risk (HR for mortality per unit higher BMI: 1.05; 95% CI: 1.03-1.08), also evident in people with CHD (HR: 1.08; 95% CI: 1.01-1.14). Point estimates for hazard ratios across all BMI values in participants with T2DM and cancer were consistent with overall positive linear effects but confidence intervals included the null. CONCLUSION: These data support the idea that population efforts to promote intentional weight loss towards the normal BMI range would reduce, not enhance, mortality risk in the general population including, importantly, individuals with CHD.

Fenofibrate reduces osteonecrosis without affecting antileukemic efficacy in dexamethasone-treated mice.

Recent clinical trials in children with acute lymphoblastic leukemia (ALL) indicate that severe hypertriglyceridemia (> 1000 mg/dL) during therapy is associated with increased frequency of symptomatic osteonecrosis. Interventions to lower triglycerides have been considered, but there have been no pre-clinical studies investigating impact of lowering triglycerides on osteonecrosis risk, nor whether such interventions interfere with the antileukemic efficacy of ALL treatment. We utilized our clinically relevant mouse model of dexamethasone-induced osteonecrosis to determine if fenofibrate decreased osteonecrosis. To test whether fenofibrate affected the antileukemic efficacy of dexamethasone, we utilized a BCR-ABL+ model of ALL. Serum triglycerides were reduced with fenofibrate throughout treatment, with the most pronounced 4.5-fold decrease at week 3 (p<1x10-6). Both frequency (33% versus 74%, p=0.006) and severity (median necrosis score of 0 versus 75; p=6x10-5) of osteonecrosis were reduced with fenofibrate. Fenofibrate had no impact on BCR-ABL+ ALL survival (p=0.65) nor on the antileukemic properties of dexamethasone (p=0.49). These data suggest that lowering triglycerides with fenofibrate reduces dexamethasone-induced osteonecrosis while maintaining antileukemic efficacy, and thus may be considered for clinical trials.

Diagnosis of physical and mental health conditions in primary care during the COVID-19 pandemic: a retrospective cohort study.

BACKGROUND: To date, research on the indirect impact of the COVID-19 pandemic on the health of the population and the health-care system is scarce. We aimed to investigate the indirect effect of the COVID-19 pandemic on general practice health-care usage, and the subsequent diagnoses of common physical and mental health conditions in a deprived UK population. METHODS: We did a retrospective cohort study using routinely collected primary care data that was recorded in the Salford Integrated Record between Jan 1, 2010, and May 31, 2020. We extracted the weekly number of clinical codes entered into patient records overall, and for six high-level categories: symptoms and observations, diagnoses, prescriptions, operations and procedures, laboratory tests, and other diagnostic procedures. Negative binomial regression models were applied to monthly counts of first diagnoses of common conditions (common mental health problems, cardiovascular and cerebrovascular disease, type 2 diabetes, and cancer), and corresponding first prescriptions of medications indicative of these conditions. We used these models to predict the expected numbers of first diagnoses and first prescriptions between March 1 and May 31, 2020, which were then compared with the observed numbers for the same time period. FINDINGS: Between March 1 and May 31, 2020, 1073 first diagnoses of common mental health problems were reported compared with 2147 expected cases (95% CI 1821 to 2489) based on preceding years, representing a 50·0% reduction (95% CI 41·1 to 56·9). Compared with expected numbers, 456 fewer diagnoses of circulatory system diseases (43·3% reduction, 95% CI 29·6 to 53·5), and 135 fewer type 2 diabetes diagnoses (49·0% reduction, 23·8 to 63·1) were observed. The number of first prescriptions of associated medications was also lower than expected for the same time period. However, the gap between observed and expected cancer diagnoses (31 fewer; 16·0% reduction, -18·1 to 36·6) during this time period was not statistically significant. INTERPRETATION: In this deprived urban population, diagnoses of common conditions decreased substantially between March and May 2020, suggesting a large number of patients have undiagnosed conditions. A rebound in future workload could be imminent as COVID-19 restrictions ease and patients with undiagnosed conditions or delayed diagnosis present to primary and secondary health-care services. Such services should prioritise the diagnosis and treatment of these patients to mitigate potential indirect harms to protect public health. FUNDING: National Institute of Health Research.

TRIM37 controls cancer-specific vulnerability to PLK4 inhibition.

Centrosomes catalyse the formation of microtubules needed to assemble the mitotic spindle apparatus1. Centrosomes themselves duplicate once per cell cycle, in a process that is controlled by the serine/threonine protein kinase PLK4 (refs. 2,3). When PLK4 is chemically inhibited, cell division proceeds without centrosome duplication, generating centrosome-less cells that exhibit delayed, acentrosomal spindle assembly4. Whether PLK4 inhibitors can be leveraged as a treatment for cancer is not yet clear. Here we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase TRIM37. Low TRIM37 levels accelerate acentrosomal spindle assembly and improve proliferation following PLK4 inhibition, whereas high TRIM37 levels inhibit acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the TRIM37 gene is frequently amplified in neuroblastoma and in breast cancer5-8, rendering these cancer types highly sensitive to PLK4 inhibition. We find that inactivating TRIM37 improves acentrosomal mitosis because TRIM37 prevents PLK4 from self-assembling into centrosome-independent condensates that serve as ectopic microtubule-organizing centres. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly through a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is an essential determinant of mitotic vulnerability to PLK4 inhibition. Linkage of TRIM37 to prevalent cancer-associated genomic changes-including 17q gain in neuroblastoma and 17q23 amplification in breast cancer-may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers.

Asparaginase combined with discontinuous dexamethasone improves antileukemic efficacy without increasing osteonecrosis in preclinical models.

INTRODUCTION: Combination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule. METHODS: Using the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts. RESULTS: The addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied. CONCLUSIONS: When discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase.

Potential prognostic factors for delayed healing of common, non-traumatic skin ulcers: A scoping review.

Healing of non-traumatic skin ulcers is often suboptimal. Prognostic tools that identify people at high risk of delayed healing within the context of routine ulcer assessments may improve this, but robust evidence on which factors to include is lacking. Therefore, we scoped the literature to identify which potentially prognostic factors may warrant future systematic reviews and meta-analyses. We conducted electronic searches in MEDLINE and Embase to identify studies in English published between 1997 and 2017 that tested the association between healing of the three most common non-traumatic skin ulcers encountered by health care professionals (venous leg, diabetic foot, and pressure ulcers) and patient characteristics, ulcer characteristics, and results from clinical investigations. We included 42 studies that investigated factors which may be associated with the healing of venous leg ulcers (n = 17), diabetic foot ulcers (n = 15), and pressure ulcers (n = 10). Across ulcer types, ulcer characteristics were most commonly reported as potential prognostic factors for healing (n = 37), including the size of the ulcer area (n = 29) and ulcer duration at first assessment (n = 16). A total of 35 studies investigated the prognostic value of patient characteristics (n = 35), including age (n = 31), gender (n = 30), diabetes (n = 22), smoking status (n = 15), and history of deep vein thrombosis (DVT) (n = 13). Of these studies, 23 reported results from clinical investigations as potential prognostic factors, with the majority regarding vessel quality. Age, gender, diabetes, smoking status, history of DVT, ulcer area, and ulcer duration at time of first assessment warrant a systematic review and meta-analysis to quantify their prognostic value for delayed ulcer healing.

Adiposity-Mortality Relationships in Type 2 Diabetes, Coronary Heart Disease, and Cancer Subgroups in the UK Biobank, and Their Modification by Smoking.

OBJECTIVE: The obesity paradox in which overweight/obesity is associated with mortality benefits is believed to be explained by confounding and reverse causality rather than by a genuine clinical benefit of excess body weight. We aimed to gain deeper insights into the paradox through analyzing mortality relationships with several adiposity measures; assessing subgroups with type 2 diabetes, with coronary heart disease (CHD), with cancer, and by smoking status; and adjusting for several confounders. RESEARCH DESIGN AND METHODS: We studied the general UK Biobank population (N = 502,631) along with three subgroups of people with type 2 diabetes (n = 23,842), CHD (n = 24,268), and cancer (n = 45,790) at baseline. A range of adiposity exposures were considered, including BMI (continuous and categorical), waist circumference, body fat percentage, and waist-to-hip ratio, and the outcome was all-cause mortality. We used Cox regression models adjusted for age, smoking status, deprivation index, education, and disease history. RESULTS: For BMI, the obesity paradox was observed among people with type 2 diabetes (adjusted hazard ratio for obese vs. normal BMI 0.78 [95% CI 0.65, 0.95]) but not among those with CHD (1.00 [0.86, 1.17]). The obesity paradox was pronounced in current smokers, absent in never smokers, and more pronounced in men than in women. For other adiposity measures, there was less evidence for an obesity paradox, yet smoking status consistently modified the adiposity-mortality relationship. CONCLUSIONS: The obesity paradox was observed in people with type 2 diabetes and is heavily modified by smoking status. The results of subgroup analyses and statistical adjustments are consistent with reverse causality and confounding.

Phenotypic Screening for Inhibitors of a Mutant Thrombopoietin Receptor.

An inhibitor for the thrombopoietin receptor (TpoR) would be more specific for the treatment of myeloproliferative neoplasms (MPNs) due to constitutively active mutant TpoR compared to the current treatment approach of inhibiting Janus kinase 2 (JAK2). We describe a cell-based high-throughput phenotypic screening approach to identify inhibitors for constitutively active mutant TpoR. A stepwise elimination process is used to differentiate generally cytotoxic compounds from compounds that specifically inhibit growth of cells expressing wild-type TpoR and/or mutant TpoR. We have systematically optimized the phenotypic screening assay and documented in this chapter critical parameters for a successful phenotypic screen, such as cell growth and seeding optimization, plate reproducibility and uniformity studies, and an assay robustness analysis with a pilot screen.

Plasma fatty acid changes following consumption of dietary oils containing n-3, n-6, and n-9 fatty acids at different proportions: preliminary findings of the Canola Oil Multicenter Intervention Trial (COMIT).

BACKGROUND: The Canola Oil Multicenter Intervention Trial (COMIT) was a randomized controlled crossover study designed to evaluate the effects of five diets that provided different oils and/or oil blends on cardiovascular disease (CVD) risk factors in individuals with abdominal obesity. The present objective is to report preliminary findings on plasma fatty acid profiles in volunteers with abdominal obesity, following the consumption of diets enriched with n-3, n-6 and n-9 fatty acids. METHODS: COMIT was conducted at three clinical sites, Winnipeg, Manitoba, Canada, Québec City, Québec, Canada and University Park, Pennsylvania, United States. Inclusion criteria were at least one of the followings: waist circumference (≥90 cm for males and ≥84 cm for females), and at least one other criterion: triglycerides ≥1.7 mmol/L, high density lipoprotein cholesterol <1 mmol/L (males) or <1.3 mmol/L (females), blood pressure ≥130 mmHg (systolic) and/or ≥85 mmHg (diastolic), and glucose ≥5.5 mmol/L. Weight-maintaining diets that included shakes with one of the dietary oil blends were provided during each of the five 30-day dietary phases. Dietary phases were separated by four-week washout periods. Treatment oils were canola oil, high oleic canola oil, high oleic canola oil enriched with docosahexaenoic acid (DHA), flax oil and safflower oil blend, and corn oil and safflower oil blend. A per protocol approach with a mixed model analysis was decided to be appropriate for data analysis. RESULTS: One hundred and seventy volunteers were randomized and 130 completed the study with a dropout rate of 23.5%. The mean plasma total DHA concentrations, which were analyzed among all participants as a measure of adherence, increased by more than 100% in the DHA-enriched phase, compared to other phases, demonstrating excellent dietary adherence. CONCLUSIONS: Recruitment and retention strategies were effective in achieving a sufficient number of participants who completed the study protocol to enable sufficient statistical power to resolve small differences in outcome measures. It is expected that the study will generate important data thereby enhancing our understanding of the effects of n-3, n-6, and n-9 fatty acid-containing oils on CVD risks. TRIAL REGISTRATION: ClinicalTrials.gov NCT01351012.

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo.

Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An alpha-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 micromol/L in the screening biochemical assay and an EC50 of 0.025 micromol/L in HeLa cell-based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non-small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent.