Ethnic differences in the severity and clinical management of type 2 diabetes at time of diagnosis: A cohort study in the UK Clinical Practice Research Datalink.

AIMS: To characterize ethnic differences in the severity and clinical management of type 2 diabetes at initial diagnosis. METHODS: An observational cohort study of 179,886 people with incident type 2 diabetes between 2004 and 2017 in the Clinical Practice Research Datalink was undertaken; 63.4% of the cohort were of white ethnicity, 3.9% south Asian, and 1.6% black. Ethnic differences in clinical profile at diagnosis, consultation rates, and risk factor recording were derived from linear and logistic regression. Cox-proportional hazards regression was used to determine ethnic differences in time to initiation of therapeutic and non-therapeutic management following diagnosis. All analyses adjusted for age, sex, deprivation, and clustering by practice. RESULTS: In the 12 months prior to diagnosis, non-white groups had fewer consultations compared to white groups, but risk factor recording was better than or equivalent to white groups for 9/10 risk factors for south Asian groups and 8/10 risk factors for black groups (p < 0.002). Blood pressure, BMI, cholesterol, eGFR, and CVD risk levels were more favourable in non-white groups, and prevalence of macrovascular disease was significantly lower (p < 0.003). Time to initiation of antidiabetic treatment and first risk assessment was faster in non-white groups relative to white groups, while time to risk factor measurement and diabetes review was slower. CONCLUSIONS: We find limited evidence of systematic ethnic inequalities around the time of type 2 diabetes diagnosis. Ethnic disparities in downstream consequences may relate to genetic risk factors, or manifest later in the care pathway, potentially in relation to long-term risk factor control.

Spinal navigation for minimally invasive thoracic and lumbosacral spine fixation: implications for radiation exposure, operative time, and accuracy of pedicle screw placement.

PURPOSE: Navigation is emerging as a useful adjunct in percutaneous, minimally invasive spinal surgery (MIS). The aim of this study was to compare C-Arm navigated, O-Arm navigated and conventional 2D-fluoroscopy assisted MIS thoracic and lumbosacral spine fixation techniques in terms of operating time, radiation exposure and accuracy of pedicle screw (PS) placement. METHODS: Retrospective observational study of 152 consecutive adults who underwent MIS fixations for spinal instability: 96 2D-fluoroscopy assisted, 39 3D-C-Arm navigated and 27 using O-Arm navigated. RESULTS: O-Arm navigation significantly reduced PS misplacement (1.23%, p) compared to 3D-C-Arm navigation (7.29%, p = 0.0082) and 2D-fluoro guided placement (5.16%, p = 0379). 3D-C-Arm navigation was associated with lower procedural radiation exposure of the patient (0.4 mSv) than O-Arm navigation (3.24 mSv) or 2D-fluoro guidance (1.5 mSv). Operative time was comparable between three modalities. CONCLUSIONS: O-Arm navigation provides greater accuracy of percutaneous instrumentation placement with an acceptable procedural radiation dose delivered to the patients and comparable operative times. These slides can be retrieved under Electronic Supplementary material.

Effect of Intravenous Administration of Cobalt Chloride to Horses on Clinical and Hemodynamic Variables.

BACKGROUND: Cobalt chloride (CoCl2 ) is administered to racehorses to enhance performance. The purpose of this study was to evaluate the clinical, cardiovascular, and endocrine effects of parenterally administered CoCl2 . OBJECTIVES: To describe the effects of weekly intravenous doses of CoCl2 on Standardbred horses. ANIMALS: Five, healthy Standardbred mares. METHODS: Prospective, randomized, experimental dose-escalation pilot. Five Standardbred mares were assigned to receive 1 of 5 doses of CoCl2 (4, 2, 1, 0.5, or 0.25 mg/kg) weekly IV for 5 weeks. Physical examination, blood pressure, cardiac output, and electrocardiography (ECG) were evaluated for 4 hours after administration of the first and fifth doses. Blood and urine samples were collected for evaluation of cobalt concentration, CBC and clinical chemistry, and hormone concentrations. RESULTS: All mares displayed pawing, nostril flaring, muscle tremors, and straining after CoCl2 infusion. Mares receiving 4, 2, or 1 mg/kg doses developed tachycardia after dosing (HR 60-126 bpm). Ventricular tachycardia was noted for 10 minutes after administration of the 4 mg/kg dose. Increases in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) occurred after administration of all doses (4, 2, 1, 0.5, and 0.25 mg/kg). Profound hypertension was observed after the 4 mg/kg dose (SAP/DAP, MAP [mmHg] = 291-300/163-213, 218-279). Hemodynamics normalized by 1-2 hours after administration. ACTH and cortisol concentrations increased within 30 minutes of administration of all CoCl2 doses, and cardiac troponin I concentration increased after administration of the 4 and 2 mg/kg doses. CONCLUSIONS AND CLINICAL IMPORTANCE: The degree of hypertension and arrhythmia observed after IV CoCl2 administration raises animal welfare and human safety concerns.

Time trends in breast cancer and menopause hormone therapy use in New Zealand.

OBJECTIVE: The publication of preliminary findings from the Women's Health Initiative (WHI) Study in 2002 suggested an increased risk of breast cancer among users of menopause hormone therapy (MHT). This resulted world-wide in a rapid and significant decline in the use of hormone therapy. It was later claimed that breast cancer incidence rates had fallen as a result of lower rates of hormone therapy use. Our aim was to investigate whether there was an association between changes in the use of hormone therapy and rates of breast cancer diagnosis in New Zealand subsequent to the publication of the WHI. METHOD: Validated prescription usage data along with breast cancer screening and cancer registration data were accessed. Time trends extending for 8 years after the publication of the WHI were assessed. RESULTS: The use of hormone therapy for managing menopausal symptoms fell by about 70% following the controversy about its safety. Breast cancer registration rates among women aged 50-59 years had started to fall in advance of this change in prescribing. Changes in other age groups appear to coincide with changes in the screening eligibility for the national breast screening program rather than use of hormone therapy. CONCLUSION: The time trend analysis does not support an association between changes in hormone therapy use and the incidence rate of breast cancer.

Decreased dose of radiation to dogs during acquisition of elbow radiographs using draped shielding.

Protective lead equivalent shielding of patients is not routinely used in veterinary radiology. The goal of this study was to determine whether the use of lead equivalent shielding results in a significant reduction in dose of radiation to dogs during acquisition of elbow radiographs. The authors measured radiation doses in the primary beam and over and under protective lead equivalent shielding that was placed at the level of the eyes, body and gonads during acquisition of elbow radiographs using 0.01 mSv sensitivity dosimetry badges. Shielding consisted of 0.5 mm lead equivalent aprons and thyroid shields placed over bodies and eyes, respectively. All badges in the primary beam-detected radiation. Shielding significantly decreased the dose of radiation with significantly less scatter and tube leakage radiation detected under compared with over shielding (P=0.0001). The dose of radiation detected over shielding was significantly greater than zero (P=0.0001), while that under shielding did not differ significantly from zero (P=0.09). Based on these results, the authors recommend protective shielding be used on veterinary patients during radiography.

Natural course of cannabis use disorders.

BACKGROUND: Despite its importance as a public health concern, relatively little is known about the natural course of cannabis use disorders (CUDs). The primary objective of this research was to provide descriptive data on the onset, recovery and recurrence functions of CUDs during the high-risk periods of adolescence, emerging adulthood and young adulthood based on data from a large prospective community sample. METHOD: Probands (n = 816) from the Oregon Adolescent Depression Project (OADP) participated in four diagnostic assessments (T1-T4) between the ages of 16 and 30 years, during which current and past CUDs were assessed. RESULTS: The weighted lifetime prevalence of CUDs was 19.1% with an average onset age of 18.6 years. Although gender was not significantly related to the age of initial CUD onset, men were more likely to be diagnosed with a lifetime CUD. Of those diagnosed with a CUD episode, 81.8% eventually achieved recovery during the study period. Women achieved recovery significantly more quickly than men. The recurrence rate (27.7%) was relatively modest, and most likely to occur within the first 36 months following the offset of the first CUD episode. CUD recurrence was uncommon after 72 months of remission and recovery. CONCLUSIONS: CUDs are relatively common, affecting about one out of five persons in the OADP sample prior to the age of 30 years. Eventual recovery from index CUD episodes is the norm, although about 30% of those with a CUD exhibit a generally persistent pattern of problematic use extending 7 years or longer.

Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate.

BACKGROUND: We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. METHODS: We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). RESULTS: We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. CONCLUSIONS: In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required.

Systemic lupus erythematosus prevalence in the UK: methodological issues when using the General Practice Research Database to estimate frequency of chronic relapsing-remitting disease.

PURPOSE: The purpose of this study was to calculate the prevalence of systemic lupus erythematosus (SLE) between 1992 and 1998 using the General Practice Research Database (GPRD) METHODS: We identified all individuals who had contributed at least 3 years of data to the GPRD and who had a diagnosis of SLE with supporting evidence of their diagnosis. We calculated the annual age- and sex-specific prevalence of SLE. Additionally, we stratified the prevalence by years of data contributed to the GRPD. RESULTS: In males the point estimate of the prevalence of SLE increased from 7.5/100,000 (CI(95) 6.3, 8.8) to 10.1/100,000 (CI(95) 7.8, 12.2) but this rise was not statistically significant. However, prevalence appeared to increase significantly amongst females from 42.6/100,000 (CI(95) 39.6, 45.6) in 1992 to 70.8/100,000 (CI(95) 65.1, 76.6) in 1998. This increase was mainly amongst women aged 50-79 and in those contributing more than 5 years of data and could not be explained by increasing incidence of SLE or decreasing mortality during the study period. CONCLUSIONS: We found an increasing prevalence of SLE that could not be explained by increasing incidence or decreasing mortality. This is almost certainly an artefact caused by the increased likelihood of detecting or confirming cases of chronic relapsing-remitting diseases with increasing time contributed to the GPRD.

Simvastatin did not prevent nor restore ovariectomy-induced bone loss in adult rats.

Current published results on whether statins have beneficial effects on bone metabolism have been conflicting so far. In order to further investigate if statins were promising candidates for the treatment for osteoporosis, we conducted a study in which rats were ovariectomized (OVX) at 6 months of age, allowed to lose bone for 60 days and followed by oral administration of simvastatin at the dose levels of 0.3-10 mg/kg/d for 60 days. PGE2 (6 mg/kg) was used as a positive control. Study endpoints included bone histomorphometry on the proximal tibial metaphysis (PTM) and the tibial diaphysis (TX), dual-energy X-ray absorptiometry on the right femur and micro computed tomography (ICT) on the 5th lumbar vertebra (LV). After 120 days of OVX, cancellous bone lost by 80% in the PTM and 18% in the LV accompanied by increased bone formation and resorption. Simvastatin at all dose levels did not affect bone volume, bone formation rate and bone erosion surface when compared to 120 day ovariectomized animals at all bone sites studied. By contrast, PGE2 restored cancellous and cortical bone area to sham control levels. In conclusion, this study demonstrated that unlike PGE2, oral administration of simvastatin did not have effects on cancellous or cortical bone formation and resorption; and consequently was not able to prevent further bone loss or restore bone mass in the osteopenic, OVX rats.

Myocardial infarction risk and hormone replacement: differences between products.

OBJECTIVES: To establish the risk of myocardial infarction (MI) in users of hormone replacement therapy (HRT) compared with non-users and to compare the risk between different HRT regimens. METHODS: A population-based cohort and case-control study, and a case-control study nested within a cohort of HRT users, using the UK General Practice Research Database. Differences between HRT regimen, mode of administration and duration and recency of use were examined whilst adjusting for confounding. RESULTS: In the cohort and case-control study, 4537 cases of MI were identified in 2.62 million observed women years, cases were age-matched to 27,220 controls. In both studies, current and past HRT use were associated with reduced risk estimates for MI compared with no prior use. MIs were less likely to be fatal amongst women who had used HRT than amongst never users (OR(adj) 0.58; 95% CI 0.45-0.75). No difference in risk was seen between current and past use, oral and transdermal HRT or between different regimens (p>0.44). In the nested study, no difference was found in the association with MI risk between different oestrogen-progestogen combinations or between different combinations and tibolone. Unopposed oestrogen use was not associated with a decrease in risk compared with combined HRT. CONCLUSIONS: These results are consistent with previous observational studies in supporting the hypothesis that use of postmenopausal HRT is associated with a decrease in risk of acute myocardial infarction (AMI). Case fatality differed between HRT users and non-users, suggesting a protective effect of HRT. This study does not demonstrate a difference between regimens.

Detection and evaluation of intracranial aneurysms with 16-row multislice CT angiography.

AIM: The aim of this study was to assess the usefulness of 16-row multislice CT angiography (CTA) in evaluating intracranial aneurysms, by comparison with conventional digital subtraction angiography (DSA) and intraoperative findings. METHODS: A consecutive series of 57 patients, scheduled for DSA for suspected intracranial aneurysm, was prospectively recruited to have CTA. This was performed with a 16-detector row machine, detector interval 0.75 mm, 0.5 rotation/s, table speed 10mm/rotation and reconstruction interval 0.40 mm. CTA studies were independently and randomly assessed by two neuroradiologists and a vascular neurosurgeon blinded to the DSA and surgical findings. Review of CTA was performed on workstations with an interactive 3D volume-rendered algorithm. RESULTS: DSA or intraoperative findings or both confirmed 53 aneurysms in 44 patients. For both independent readers, sensitivity and specificity per aneurysm of DSA were 96.2% and 100%, respectively. Sensitivity and specificity of CTA were also 96.2% and 100%, respectively. Mean diameter of aneurysms was 6.3mm (range 1.9 to 28.1 mm, SD 5.2 mm). For aneurysms of less than 3 mm, CTA had a sensitivity of 91.7% for each reader. Although the neurosurgeon would have been happy to proceed to surgery on the basis of CTA alone in all cases, he judged that DSA might have provided helpful additional anatomical information in 5 patients. CONCLUSION: The diagnostic accuracy of 16-slice CTA is promising and appears equivalent to that of DSA for detection and evaluation of intracranial aneurysms. A strategy of using CTA as the primary imaging method, with DSA reserved for cases of uncertainty, appears to be practical and safe.

Venous thromboembolism associated with cyproterone acetate in combination with ethinyloestradiol (Dianette): observational studies using the UK General Practice Research Database.

PURPOSE: To derive risk estimates for venous thromboembolism (VTE) in women prescribed cyproterone acetate combined with ethinyloestradiol (CPA/EE), a drug licensed in the UK for the treatment of women with acne or hirsutism. CPA/EE provides a treatment option for women with polycystic ovary syndrome (PCOS). CPA/EE has been associated with an increased risk of VTE. METHODS: Using the General Practice Research Database, we conducted cohort and case-control analyses in all women aged 15-39 and then nested in a population of women of the same age with acne, hirsutism or PCOS. RESULTS: The incidence rate ratio (IRR) for VTE in women exposed to CPA/EE versus conventional combined oral contraceptives (COCs) was significantly raised (all women: 1.92; 95% CI: 1.22,2.88; nested: 2.51; 95% CI: 1.07,5.75). Using exposure to conventional COCs as the reference, the adjusted odds ratio (ORadj) for VTE associated with CPA/EE was 1.45 (95% CI: 0.80,2.64) in all women and 1.71 (95% CI: 0.31,9.49) in women with acne, hirsutism or PCOS. CONCLUSIONS: The risk of VTE associated with CPA/EE use does not differ significantly from that associated with the use of conventional COCs. These data are reassuring and together with knowledge of the risks associated with other treatments for acne, in particular, should influence prescribing practice.

Utilisation of hormone replacement therapy in the United Kingdom. A descriptive study using the general practice research database.

OBJECTIVE: To determine prevalence and patterns of hormone replacement therapy (HRT) utilisation in women in the UK. DESIGN: Prospective observational study. SETTING: UK general practice. POPULATION: Women from general practices throughout the UK. METHODS: The study period was 1 January 1992 to 31 December 1998. Age-specific prevalence was calculated for each year. Trends in prescribing patterns were described over time. A sub-cohort of 'new starters' on HRT was identified to establish patterns of use, including duration of use and switching of preparations. Characteristics of the sub-cohort were compared with a reference group of non-HRT users. MAIN OUTCOME MEASURES: Prevalence, prescribing patterns and differences in characteristics between HRT users and non-HRT users. RESULTS: Among women aged 45-64, prevalence of HRT use increased from 18.6% in 1992 to 27.7% in 1998. Secular trends were observed away from prescribing combined-sequential preparations and towards use of combined-continuous preparations. Among the prescriptions for combined HRT products, only 4.3% contained medroxyprogesterone acetate (MPA). A total of 45.7% of women without a record of a hysterectomy and 53.8% of women with a record of a hysterectomy used HRT for at least three years. When women were partitioned by year of starting HRT, there was a trend of increasing duration of use across the seven years. Some women without a record of a hysterectomy were receiving unopposed oestrogen without progestogen supplementation. CONCLUSIONS: Within the past decade, use of HRT has increased among women in the UK with large numbers of women using HRT for long periods and treatment often tailored to the individual.

The risk of liver disorders in women prescribed cyproterone acetate in combination with ethinyloestradiol (Dianette): a nested case-control study using the GPRD.

PURPOSE: To explore the risk of liver disorders associated with cyproterone acetate combined with ethinyloestradiol (CPA/EE). CPA/EE is licensed in the UK for the treatment of women with acne and hirsutism and is a treatment option for polycystic ovary syndrome (PCOS). It acts as a contraceptive also. METHODS: Using the General Practice Research Database, we conducted a cohort analysis and case-control study in women aged 15-39 with acne, hirsutism or PCOS to estimate the risk of liver disorders associated with CPA/EE. RESULTS: Compared with cases exposed to conventional combined oral contraceptives (COCs), the age-adjusted incidence rate ratio for liver disorders in women using CPA/EE was 1.7 (95% CI: 0.9, 3.4) and compared with no use it was 1.5 (95% CI: 0.8, 2.8). In the case-control study, the adjusted odds ratio (OR) for liver disorders in women exposed to CPA/EE was 1.6 (95% CI: 0.7, 3.5) and 0.8 (95% CI: 0.5, 1.3) for exposure to conventional COCs, compared with no use. The risk of liver disorders in women prescribed CPA/EE was not significantly greater than that in women prescribed conventional COCs (OR: 2.1 [95% CI: 0.9, 4.8]). CONCLUSION: Our results do not indicate an increased risk for liver disorders associated with CPA/EE use in women with acne, hirsutism or PCOS after adjusting for potential confounding. This may be due to lack of statistical power.

Differences in the use of combined oral contraceptives amongst women with and without acne.

BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) provides a treatment option for women with acne, hirsutism or polycystic ovary syndrome (PCOS). CPA/EE may be prescribed as an oral contraceptive (OC), but is not licensed as such in the UK. The use of CPA/EE steadily increased after its introduction to the UK market in 1987, but there was a marked increase in its share of the OC market after 1995. METHODS: Using the General Practice Research Database, utilization patterns of CPA/EE and conventional oral contraceptives were compared in women aged 15-39 years, with or without acne or PCOS. RESULTS: Between 1994 and 1998, CPA/EE accounted for an increasing proportion of all OC use. The proportion of CPA/EE prescribed to women with acne declined between 1994 and 1998, whereas that prescribed to women with PCOS remained constant. The age-specific use of CPA/EE by women with acne or PCOS almost doubled. After 1995, there was a marked increase in the use of products containing levonorgestrel by women with acne or PCOS. CONCLUSIONS: A large proportion of CPA/EE is prescribed to women with acne and/or PCOS, although this proportion decreased between 1992 and 1998. This has important implications in CPA/EE risk assessment studies.

The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case-control study.

BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) is licensed in the UK for the treatment of women with acne and hirsutism and is also a treatment option for polycystic ovary syndrome (PCOS). Previous studies have demonstrated an increased risk of venous thromboembolism (VTE) associated with CPA/EE compared with conventional combined oral contraceptives (COCs). We believe the results of those studies may have been affected by residual confounding. METHODS: Using the General Practice Research Database we conducted a cohort analysis and case-control study nested within a population of women aged between 15 and 39 years with acne, hirsutism or PCOS to estimate the risk of VTE associated with CPA/EE. RESULTS: The age-adjusted incidence rate ratio for CPA/EE versus conventional COCs was 2.20 [95% confidence interval (CI) 1.35-3.58]. Using as the reference group women who were not using oral contraception, had no recent pregnancy or menopausal symptoms, the case-control analysis gave an adjusted odds ratio (OR(adj)) of 7.44 (95% CI 3.67-15.08) for CPA/EE use compared with an OR(adj) of 2.58 (95% CI 1.60-4.18) for use of conventional COCs. CONCLUSIONS: We have demonstrated an increased risk of VTE associated with the use of CPA/EE in women with acne, hirsutism or PCOS although residual confounding by indication cannot be excluded.