J Dennis

High-dose Nitrogen Mustard Therapy with Intermittent Aortic Occlusion

possibility in advance, but it was never felt to contraindicate treatment, as the hair regrows during maintenance therapy. Nauisea and vomiting may occur, but this depends on the dosage and susceptibility of the patient. The severity and incidence of this side-effect is, in our opinion, less than that seen using comparable doses of muistine (HN2) or thiotepa. Cyclophosphamide has been used by other workers as a prophylactic measure in conjunction with surgery. Denk et al. (1961) report a series of 282 cases of carcinoma of the bronchus which have been treated chemotherapeutically for two years after radical operation, and claim that at 18 months the survival rate was 81 % compared with 42% without the drug. This form of treatment has not been used in this series. The long-term results are not encouraging in the present series despite continued treatment. Only two patients, both with carcinoma of the breast, responded for more than one year and only one of these remained symptom-free after 18 months.

Precision Medicine in Type 2 Diabetes: Clinical Markers of Insulin Resistance Are Associated With Altered Short- and Long-term Glycemic Response to DPP-4 Inhibitor Therapy

OBJECTIVE A precision approach to type 2 diabetes therapy would aim to target treatment according to patient characteristics. We examined if measures of insulin resistance and secretion were associated with glycemic response to dipeptidyl peptidase 4 (DPP-4) inhibitor therapy. RESEARCH DESIGN AND METHODS We evaluated whether markers of insulin resistance and insulin secretion were associated with 6-month glycemic response in a prospective study of noninsulin-treated participants starting DPP-4 inhibitor therapy (Predicting Response to Incretin Based Agents [PRIBA] study; n = 254), with replication for routinely available markers in U.K. electronic health care records (Clinical Practice Research Datalink [CPRD]; n = 23,001). In CPRD, we evaluated associations between baseline markers and 3-year durability of response. To test the specificity of findings, we repeated analyses for glucagon-like peptide 1 (GLP-1) receptor agonists (PRIBA, n = 339; CPRD, n = 4,464). RESULTS In PRIBA, markers of higher insulin resistance (higher fasting C-peptide [P = 0.03], HOMA2 insulin resistance [P = 0.01], and triglycerides [P < 0.01]) were associated with reduced 6-month HbA1c response to DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA1c response (both P < 0.01). A subgroup defined by obesity (BMI ≥30 kg/m2) and high triglycerides (≥2.3 mmol/L) had reduced 6-month response in both data sets (PRIBA HbA1c reduction 5.3 [95% CI 1.8, 8.6] mmol/mol [0.5%] [obese and high triglycerides] vs. 11.3 [8.4, 14.1] mmol/mol [1.0%] [nonobese and normal triglycerides]; P = 0.01). In CPRD, the obese, high- triglycerides subgroup also had less durable response (hazard ratio 1.28 [1.16, 1.41]; P < 0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists. CONCLUSIONS Markers of higher insulin resistance are consistently associated with reduced glycemic response to DPP-4 inhibitors. This finding provides a starting point for the application of a precision diabetes approach to DPP-4 inhibitor therapy.

Time trends and geographical variation in prescribing of drugs for diabetes in England from 1998 to 2017.

To measure the variation in prescribing of second‐line non‐insulin diabetes drugs.

Sex and BMI Alter the Benefits and Risks of Sulfonylureas and Thiazolidinediones in Type 2 Diabetes: A Framework for Evaluating Stratification Using Routine Clinical and Individual Trial Data

OBJECTIVE The choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones. RESEARCH DESIGN AND METHODS We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2,725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2,222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1,977). RESULTS In CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups. CONCLUSIONS Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.

Heart rate turbulence after ventricular premature beats in healthy Doberman pinschers and those with dilated cardiomyopathy

OBJECTIVESnTo describe the measurement of heart rate turbulence (HRT) after ventricular premature beats and compare HRT in healthy Doberman pinschers and those with dilated cardiomyopathy (DCM), with and without congestive heart failure (CHF).nnnANIMALSnSixty-five client-owned Dobermans: 20 healthy (NORMAL), 31 with preclinical DCM and 14 with DCM and CHF (DCMxa0+xa0CHF).nnnMETHODSnA retrospective study of data retrieved from clinical records and ambulatory ECG (Holter) archives, including data collected previously for a large-scale prospective study of Dobermans with preclinical DCM. Holter data were reanalysed quantitatively, including conventional time-domain heart rate variabilityxa0and the HRT parameters turbulence onsetxa0and turbulence slope.nnnRESULTSnHeart rate turbulence could be measured in 58/65 dogs. Six Holter recordings had inadequate ventricular premature contractions (VPCs) and one exhibited VPCs too similar to sinus morphology. Heart rate turbulence parameter, turbulence onset, was significantly reduced in DCM dogs, whereas conventional heart rate variability measures were not. Heart rate variability and HRT markers were reduced in DCMxa0+xa0CHF dogs as expected.nnnCONCLUSIONSnHeart rate turbulence can be measured from the majority of good quality standard canine 24-hour Holter recordings with >5 VPCs. Turbulence onset is significantly reduced in Dobermans with preclinical DCM which indicates vagal withdrawal early in the course of disease. Heart rate turbulence is a powerful prognostic indicator in human cardiac disease which can be measured from standard 24-hour ambulatory ECG (Holter) recordings using appropriate computer software. Further studies are warranted to assess whether HRT may be of prognostic value in dogs with preclinical DCM and in other canine cardiac disease.

Parliamentary privilege—mortality in members of the Houses of Parliament compared with the UK general population: retrospective cohort analysis, 1945-2011

Objective To examine mortality in members of the two UK Houses of Parliament compared with the general population, 1945-2011. Design Retrospective cohort analysis of death rates and predictors of mortality in Members of Parliament (MPs) and members of the House of Lords (Lords). Setting UK. Participants 4950 MPs and Lords first joining the UK parliament in 1945-2011. Main outcome measure Standardised mortality ratios, comparing all cause death rates of MPs and Lords from first election or appointment with those in the age, sex, and calendar year matched general population. Results Between 1945 and 2011, mortality was lower in MPs (standardised mortality ratio 0.72, 95% confidence interval 0.67 to 0.76) and Lords (0.63, 0.60 to 0.67) than in the general population. Over the same period, death rates among MPs also improved more quickly than in the general population. For every 100 expected deaths, 22 fewer deaths occurred among MPs first elected in 1990-99 compared with MPs first elected in 1945-49. Labour party MPs had 19% higher death rates compared with the general population than did Conservative MPs (relative mortality ratio 1.19, 95% confidence interval 1.01 to 1.40). The effect of political party on mortality disappeared when controlling for education level. Conclusions From 1945 to 2011, MPs and Lords experienced lower mortality than the UK general population, and, at least until 1999, the mortality gap between newly elected MPs and the general population widened. Even among MPs, educational background was an important predictor of mortality, and education possibly explains much of the mortality difference between Labour and Conservative MPs. Social inequalities are alive and well in UK parliamentarians, and at least in terms of mortality, MPs are likely to have never had it so good.