Current Controversy Related to Glucocorticoid and Insulin Therapy in the Intensive Care Unit

ObjectiveTo review the controversy related to the widespread use of intensive insulin treatment (IIT) to maintain normoglycemia and of glucocorticoid replacement therapy in patients with sepsis in the intensive care unit (ICU).MethodsWe performed a MEDLINE search of the literature using a combination of words (critical/intensive care, endocrinology/endocrine, glucocorticoid/adrenal, insulin) to identify original studies and reviews on glucocorticoid therapy and IIT in the ICU.ResultsGlucocorticoid replacement therapy is advocated for patients with sepsis who have relative adrenal insufficiency. The current definition of relative adrenal insufficiency is poorly supported, and validated endocrine criteria that consistently identify ICU patients likely to benefit from glucocorticoid therapy are not yet available. IIT benefits postoperative patients at high risk of infection and patients who remain in the ICU more than 3 days. Potential harm caused by early IIT administration in medical ICU patients remains controversial. The role of early nutritional supplementation in major studies about IIT is largely unexplored. Improvements in insulin infusion protocols are needed to reduce the risk of hypoglycemia related to IIT.ConclusionEndocrine therapy in the ICU is entering a new era. Controversies remain related to glucocorticoid and insulin therapy even as interest in new, and old, endocrine therapies is being revived. (Endocr Pract. 2007;13:542-549)     

Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study

BackgroundGlucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases.Methods and findingsWe conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998–2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person–years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0–14.9 mg, 1.6% for 15.0–24.9 mg, and 1.2% for ≥25.0 mg.Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64–1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54–1.85) for atrial fibrillation, 1.75 (95% CI 1.56–1.97) for heart failure, 1.76 (95% CI 1.51–2.05) for acute myocardial infarction, 1.78 (95% CI 1.53–2.07) for peripheral arterial disease, 1.32 (95% CI 1.15–1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47–2.53) for abdominal aortic aneurysm.The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose–response estimates.ConclusionsIn this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.

Mar Pujades-Rodriguez and colleagues investigate whether low dose steroids are associated with increased risks of cardiovascular diseases.     

Modeling inter-sex and inter-individual variability in response to chronopharmacological administration of synthetic glucocorticoids

ABSTRACT

Endogenous glucocorticoids have diverse physiological effects and are important regulators of metabolism, immunity, cardiovascular function, musculoskeletal health and central nervous system activity. Synthetic glucocorticoids have received widespread attention for their potent anti-inflammatory activity and have become an important class of drugs used to augment endogenous glucocorticoid activity for the treatment of a host of chronic inflammatory conditions. Chronic use of synthetic glucocorticoids is associated with a number of adverse effects as a result of the persistent dysregulation of glucocorticoid sensitive pathways. A failure to consider the pronounced circadian rhythmicity of endogenous glucocorticoids can result in either supraphysiological glucocorticoid exposure or severe suppression of endogenous glucocorticoid secretion, and is thought be a causal factor in the incidence of adverse effects during chronic glucocorticoid therapy. Furthermore, given that synthetic glucocorticoids have potent feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis, physiological factors which can give rise to individual variability in HPA axis activity such as sex, age, and disease state might also have substantial implications for therapy. We use a semi-mechanistic mathematical model of the rodent HPA axis to study how putative sex differences and individual variability in HPA axis regulation can influence the effects of long-term synthetic exposure on endogenous glucocorticoid circadian rhythms. Model simulations suggest that for the same drug exposure, simulated females exhibit less endogenous suppression than males considering differences in adrenal sensitivity and negative feedback to the hypothalamus and pituitary. Simulations reveal that homeostatic regulatory variability and chronic stress-induced regulatory adaptations in the HPA axis network can result in substantial differences in the effects of synthetic exposure on the circadian rhythm of endogenous glucocorticoids. In general, our results provide insight into how the dosage and exposure profile of synthetic glucocorticoids could be manipulated in a personalized manner to preserve the circadian dynamics of endogenous glucocorticoids during chronic therapy, thus potentially minimizing the incidence of adverse effects associated with long-term use of glucocorticoids     

Community water fluoridation, bone mineral density, and fractures: prospective study of effects in older women

ObjectiveTo determine whether fluoridation influences bone mineral density and fractures in older women.DesignMulticentre prospective study on risk factors for osteoporosis and fractures.SettingFour community based centres in the United States.Participants9704 ambulatory women without bilateral hip replacements enrolled during 1986-8; 7129 provided information on exposure to fluoride.ResultsWomen were classified as exposed or not exposed or having unknown exposure to fluoride for each year from 1950 to 1994. Outcomes were compared in women with continuous exposure to fluoridated water for the past 20 years (n=3218) and women with no exposure during the past 20 years (n=2563). In women with continuous exposure mean bone mineral density was 2.6% higher at the femoral neck (0.017 g/cm², P<0.001), 2.5% higher at the lumbar spine (0.022 g/cm², P<0.001), and 1.9% lower at the distal radius (0.007 g/cm², P=0.002). In women with continuous exposure the multivariable adjusted risk of hip fracture was slightly reduced (risk ratio 0.69, 95% confidence interval 0.50 to 0.96, P=0.028) as was the risk of vertebral fracture (0.73, 0.55 to 0.97, P=0.033). There was a non-significant trend toward an increased risk of wrist fracture (1.32, 1.00 to 1.71, P=0.051) and no difference in risk of humerus fracture (0.85, 0.58 to 1.23, P=0.378).ConclusionsLong term exposure to fluoridated drinking water does not increase the risk of fracture.     

Congenital Anomalies in Children Exposed to Antithyroid Drugs In-Utero: A Meta-Analysis of Cohort Studies

BackgroundHyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is commonly managed with antithyroid drugs (ATDs). However, previous studies about the effects of ATDs on congenital anomalies are controversial. Therefore, the present meta-analysis was performed to explore the risk of congenital anomalies in children exposed to ATDs in-utero.MethodsEmbase, Pubmed, Web of Knowledge, and BIOSIS Citation Index were searched to find out studies about congenital anomalies in children exposed to ATDs in-utero reported up to May 2014. The references cited by the retrieved articles were also searched. The relative risks (RRs) and confidence intervals (CIs) for the individual studies were pooled by fixed effects models, and heterogeneity was analyzed by chi-square and I² tests.ResultsEight studies met the inclusion criteria. Exposure to propylthiouracil (PTU), methimazole/carbimazole (MMI/CMZ), and PTU & MMI/CMZ was investigated in 7, 7 and 2 studies, respectively. The pooled RR was 1.20 (95%CI: 1.02-1.42), 1.64 (95%CI: 1.39-1.92), and 1.83 (95%CI: 1.30-2.56) for congenital anomalies after exposure to PTU, MMI/CMZ, and PTU & MMI/CMZ, respectively.ConclusionsThe meta-analysis suggests that exposure to ATDs in-utero increases the risk of congenital anomalies. The use of ATDs in pregnancy should be limited when possible. Further research is needed to delineate the exact teratogenic risk for particular congenital anomaly.     

Submitting articles to the BMJ

ObjectiveTo determine whether people whose marital partners have depression, diabetes, hypertension, ischaemic heart disease, stroke, hyperlipidaemia, peptic ulcer disease, or asthma or chronic obstructive pulmonary disease are at increased risk of the same disease.DesignCross sectional study.Setting10 practices from the Trent Focus Collaborative Research Practice Network.Participants8386 married couples (16 772 individuals) from a population of 29 014 participants aged 30-74 years.OutcomesRisk of disease in participants whose marital partner had that disease compared with those whose partner did not.ResultsAfter both partners'' age, smoking, and obesity and which general practice they attend were adjusted for, participants whose marital partner had asthma, depression, hypertension, hyperlipidaemia, and peptic ulcer disease were at increased risk of having the same disease. The adjusted odds ratios were 1.69 (95% confidence interval 1.43 to 2.98) for asthma, 2.08 (1.71 to 2.54) for depression, 1.32 (1.04 to 1.67) for hypertension, 1.44 (1.19 to 1.75) for hyperlipidaemia, and 2.01 (1.48 to 2.73) for peptic ulcer disease.ConclusionPartners of people with specific diseases are at increased risk of the disease themselves—at least 70% increased risk for asthma, depression, and peptic ulcer disease. This implicates shared environmental causes in some diseases in addition to any genetic or distant exposure or shared behaviours with respect to seeking health care.

What is already known on this topic

People whose spouses have hypertension are at increased risk of hypertensionLittle is known about the risks of disease for spouses of patients with diseases other than hypertension

What this study adds

People whose marital partner had asthma, depression, and peptic ulcer disease were at increased risk of having the same diseaseShared environmental factors contribute to the risk of diseasesThe costs and benefits of screening people for diseases of their spouses needs to be considered     

Socioeconomic variations in responses to chest pain: qualitative study

ObjectiveTo explore and explain socioeconomic variations in perceptions of and behavioural responses to chest pain.DesignQualitative interviews.SettingCommunity based study in Glasgow, Scotland.Participants30 respondents (15 men and 15 women) from a socioeconomically deprived area of Glasgow and 30 respondents (15 men and 15 women) from an affluent area of Glasgow.ResultsResidents of the deprived area reported greater perceived vulnerability to heart disease, stemming from greater exposure to heart disease in family members and greater identification with high risk groups and stereotypes of cardiac patients. This greater perceived vulnerability was not associated with more frequent reporting of presenting to a general practitioner. People from the deprived area reported greater exposure to ill health, which allowed them to normalise their chest pain, led to confusion with other conditions, and gave rise to a belief that they were overusing medical services. These factors were associated with a reported tendency not to present with chest pain. Anxiety about presenting among respondents in the deprived area was heightened by self blame and fear that they would be chastised by their general practitioner for their risk behaviours.ConclusionsImportant socioeconomic variations in responses to chest pain may contribute to the known inequities in uptake of secondary cardiology services. Primary care professionals and health promoters should be aware of the ways in which perceptions of symptoms and illness behaviour are shaped by social and cultural factors.

What is already known on this topic

Socioeconomic variations in rates of angiography and revascularisation existAmong socioeconomically deprived patients with a diagnosis of angina, barriers to accessing services include fear, denial, low expectations, and diagnostic confusion

What this study adds

Perceived vulnerability to heart disease is associated with socioeconomic deprivation and is underpinned by positive family history and identification with high risk groups and stereotypesGreater perceived vulnerability to heart disease does not lead to reported presentation in deprived patientsIllness behaviour is influenced by normalisation of chest pain, comorbidity, and poor experience and low expectations of health care, which are more prominent in deprived patients     

Exposure to Fluoride in Drinking Water and Hip Fracture Risk: A Meta-Analysis of Observational Studies

BackgroundMany observational studies have shown that exposure to fluoride in drinking water is associated with hip fracture risk. However, the findings are varied or even contradictory. In this work, we performed a meta-analysis to assess the relationship between fluoride exposure and hip fracture risk.MethodsPubMed and EMBASE databases were searched to identify relevant observational studies from the time of inception until March 2014 without restrictions. Data from the included studies were extracted and analyzed by two authors. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were pooled using random- or fixed-effects models as appropriate. Sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Finally, publication bias was assessed.ResultsFourteen observational studies involving thirteen cohort studies and one case-control study were included in the meta-analysis. Exposure to fluoride in drinking water does not significantly increase the incidence of hip fracture (RRs, 1.05; 95% CIs, 0.96–1.15). Sensitivity analyses based on adjustment for covariates, effect measure, country, sex, sample size, quality of Newcastle–Ottawa Scale scores, and follow-up period validated the strength of the results. Meta-regression showed that country, gender, quality of Newcastle–Ottawa Scale scores, adjustment for covariates and sample size were not sources of heterogeneity. Little evidence of publication bias was observed.ConclusionThe present meta-analysis suggests that chronic fluoride exposure from drinking water does not significantly increase the risk of hip fracture. Given the potential confounding factors and exposure misclassification, further large-scale, high-quality studies are needed to evaluate the association between exposure to fluoride in drinking water and hip fracture risk.     

Effect of radiation exposure on survival after first solid cancer diagnosis in A-bomb survivors

BackgroundComparison of the estimated effect of atomic bomb radiation exposure on solid cancer incidence and solid cancer mortality in the RERF Life Span Study (LSS) reveals a difference in the magnitude and shape of the excess relative risk dose response. A possible contributing factor to this difference is pre-diagnosis radiation effect on post-diagnosis survival. Pre-diagnosis radiation exposure theoretically could influence post-diagnosis survival by affecting the genetic makeup and possibly aggressiveness of cancer, or by compromising tolerance for aggressive treatment for cancer.MethodsWe analyze the radiation effect on post-diagnosis survival in 20,463 LSS subjects diagnosed with first-primary solid cancer between 1958 and 2009 with particular attention to whether death was caused by the first-primary cancer, other cancer, or non-cancer diseases.ResultsFrom multivariable Cox regression analysis of cause-specific survival, the excess hazard at 1 Gy (EH_1Gy) for death from the first primary cancer was not significantly different from zero – p = 0.23, EH_1Gy = 0.038 (95 % CI: −0.023, 0.104). Death from other cancer and death from non-cancer diseases both were significantly associated with radiation dose: other cancer EH_1Gy = 0.38 (95 % CI: 0.24, 0.53); non-cancer EH_1Gy = 0.24 (95 % CI: 0.13, 0.36), both p < 0.001.ConclusionThere is no detectable large effect of pre-diagnosis radiation exposure on post-diagnosis death from the first primary cancer in A-bomb survivors.ImpactA direct effect of pre-diagnosis radiation exposure on cancer prognosis is ruled out as an explanation for the difference in incidence and mortality dose response in A-bomb survivors.     

Qualitative study of decisions about infant feeding among women in east end of London

ObjectiveTo improve understanding of how first time mothers who belong to a socioeconomic group with particularly low rates of breast feeding decide whether or not to initiate breast feeding.DesignQualitative semistructured interviews early in pregnancy and 6-10 weeks after birth.SettingWomen’s homes in east end of London.Subjects21 white, low income women expecting their first baby were interviewed mostly at home, often with their partner or a relative. Two focus groups were conducted.ResultsWomen who had regularly seen a relative or friend successfully breast feed and described this experience positively were more confident about and committed to breast feeding. They were also more likely to succeed. Exposure to breast feeding, however, could be either a positive or a negative influence on the decision to breast feed, depending on the context. Women who had seen breast feeding only by a stranger often described this as a negative influence, particularly if other people were present. All women knew that breast feeding has health benefits. Ownership of this knowledge, however, varied according to the woman’s experience of seeing breast feeding.ConclusionsThe decision to initiate breast feeding is influenced more by embodied knowledge gained from seeing breast feeding than by theoretical knowledge about its benefits. Breast feeding involves performing a practical skill, often with others present. The knowledge, confidence, and commitment necessary to breast feed may be more effectively gained through antenatal apprenticeship to a breastfeeding mother than from advice given in consultations or from books.

Key messages

• Women who have seen successful breast feeding as part of their daily lives and perceive this as a positive experience are more likely to initiate breast feeding
• Embodied knowledge gained through seeing breast feeding may be more influential than theoretical knowledge about the health benefits for women of lower social class
• Listening to pregnant women talking about breast feeding could help clinicians assess the relative importance of theoretical and embodied knowledge for each woman
• Women hoping to breast feed but with little exposure to breast feeding may benefit from an antenatal apprenticeship with a breastfeeding mother
• Ideally apprenticeship would be with a breastfeeding mother from her social network to minimise the potential barriers of embarrassment and lack of confidence with strangers

     

Smoking and dementia in male British doctors: prospective study

ObjectiveTo assess the possible association between smoking and dementia.DesignProspective study.SettingCohort of British male doctors followed up since 1951.Subjects34 439 male British doctors, with 24 133 deaths recorded.ResultsFor all types of dementia combined the relative risk was 0.96 (95% confidence interval 0.78 to 1.18), based on 473 deaths at a mean age of 81 years. For probable or definite Alzheimer''s disease, the relative risk in continuing smokers was 0.99 (0.78 to 1.25), based on 370 deaths at a mean age of 82 years. In aggregate, however, the other prospective studies indicate a direct, although not clearly significant, association between smoking and the onset of dementia in general and of Alzheimer''s disease in particular. ConclusionsContrary to previous suggestions persistent smoking does not substantially reduce the age specific onset rate of Alzheimer''s disease or of dementia in general. If anything, it might increase rather than decrease the rate, but any net effect on severe dementia cannot be large in either direction.     

Assisted reproductive technology and the risk of pediatric cancer: A population based study and a systematic review and meta analysis

BackgroundThere is controversy whether exposure to assisted reproductive technology (ART) is associated with increased risk of pediatric cancer.We aimed at calculating the overall risk of pediatric cancers after ART in a large cohort of exposed women; and to conduct a systematic review and meta- analysis of cohort studies examining overall risk of pediatric cancers after ART.MethodsAll children born in Israel who were members of Maccabi Health Services (MHS) between 1999 and 2016 after ART, were linked to the Israeli Registry of Childhood Cancer (IGS) to identify those with cancer diagnosed before 16 years of age. In parallel we conducted a systematic review and meta-analysis of observational cohort studies with more than 5000 ART- exposed cases that measured pediatric cancer after ART.ResultsIn the cohort study, the risk ratio for pediatric cancer after ART in general was 0.95 (95% CI, 0.76–1.19). The RR was 1.09 (95% CI, 0.79–1.48) for IVF treatments. Meta- analysis of 13 cohort studies with a total of 750,138 women exposed to ART (with 1152 pediatric cancers) and 214,008,000 unexposed controls (with 30,458 pediatric cancers) did not reveal increased risk for pediatric cancers (RR 0.99; 95% CI, 0.85–1.15).ConclusionsBased on very large numbers, ART in general, and IVF in particular, are not associated with overall increased risk of pediatric cancer.     

Association of driver air bags with driver fatality: a matched cohort study

ObjectiveTo estimate the association of driver air bag presence with driver fatality in road traffic crashes.DesignMatched pair cohort study.SettingAll passenger vehicle crashes in the United States during 1990-2000 inclusive.Subjects51 031 driver-passenger pairs in the same vehicle.ResultsDrivers with an air bag were less likely to die than drivers without an air bag (adjusted relative risk 0.92 (95% confidence interval 0.88 to 0.96)). This estimate was nearly the same whether drivers wore a seat belt (adjusted relative risk 0.93) or not (0.91). Air bags were associated with more protection for women (0.88 (0.82 to 0.93)), than for men (0.94 (0.90 to 0.99)). Drivers wearing a seat belt were less likely to die than unbelted drivers (0.35 (0.33 to 0.36)). Belted drivers with an air bag were less likely to die than unbelted drivers without an air bag (0.32 (0.30 to 0.34)).ConclusionsIf the associations are causal the average risk of driver death was reduced 8% (95% confidence interval 4% to 12%) by an air bag. Benefit was similar for belted and unbelted drivers and was slightly greater for women. However, seat belts offered much more protection than air bags.

What is already known on this topic

Studies have estimated that driver air bags reduce the risk of death in a road vehicle crash by 10-14%These studies disagree as to whether benefit is greater for drivers wearing a seat belt or for unbelted drivers

What this study adds

Having an air bag was associated with an 8% reduction in the risk of death, whether the driver was belted or notThe reduction in risk was greater for women (12%) than for men (6%)Seat belts provided much greater protection, with seat belt use reducing the risk of death by 65% (or by 68% in combination with an air bag)     

Comparison of estimates and calculations of risk of coronary heart disease by doctors and nurses using different calculation tools in general practice: cross sectional study

ObjectiveTo assess the effect of using different risk calculation tools on how general practitioners and practice nurses evaluate the risk of coronary heart disease with clinical data routinely available in patients'' records.DesignSubjective estimates of the risk of coronary heart disease and results of four different methods of calculation of risk were compared with each other and a reference standard that had been calculated with the Framingham equation; calculations were based on a sample of patients'' records, randomly selected from groups at risk of coronary heart disease.SettingGeneral practices in central England.Participants18 general practitioners and 18 practice nurses.ResultsOnly a minority of patients'' records contained all of the risk factors required for the formal calculation of the risk of coronary heart disease (concentrations of high density lipoprotein (HDL) cholesterol were present in only 21%). Agreement of risk calculations with the reference standard was moderate (κ=0.33-0.65 for practice nurses and 0.33 to 0.65 for general practitioners, depending on calculation tool), showing a trend for underestimation of risk. Moderate agreement was seen between the risks calculated by general practitioners and practice nurses for the same patients (κ=0.47 to 0.58). The British charts gave the most sensitive results for risk of coronary heart disease (practice nurses 79%, general practitioners 80%), and it also gave the most specific results for practice nurses (100%), whereas the Sheffield table was the most specific method for general practitioners (89%).ConclusionsRoutine calculation of the risk of coronary heart disease in primary care is hampered by poor availability of data on risk factors. General practitioners and practice nurses are able to evaluate the risk of coronary heart disease with only moderate accuracy. Data about risk factors need to be collected systematically, to allow the use of the most appropriate calculation tools.

What is already known on this topic

Recent guidelines have recommended determining the risk of coronary heart disease for targeting patients at high risk for primary preventionEstimates of risk have been shown to be inaccurateGeneral practitioners and practice nurses can use risk calculation tools accurately when given patient data in the form of scenarios

What this study adds

Many patients do not have adequate information in their records to allow the risk of coronary heart disease to be calculatedWhen data about risk factors were available, risk calculations made by general practitioners and practice nurses were moderately accurate compared to a reference calculationWhen adequate information about risk factors is not available, subjective estimates are a reasonable alternative to calculating risk     

Pasireotide and Mifepristone: New Options in the Medical Management of Cushing's Disease

ObjectiveTo review and evaluate medical therapies for Cushing’s disease (CD), with an emphasis on recent clinical trial experience with pasireotide and mifepristone, and to discuss the therapeutic potential and appropriate selection of these compounds in this patient population.MethodsRecently published Phase III trial data for each compound are reviewed and assessed, and relative benefits and risks are examined and compared where possible.ResultsMifepristone and pasireotide are both potentially beneficial for CD patients but have greatly dissimilar mechanisms of action and adverse event (AE) profiles. Pasireotide acts at the level of the pituitary adenoma, reducing cortisol levels through inhibition of adrenocorticotropic hormone (ACTH) release. However, pasireotide reduces insulin secretion and incretin hormone response and is associated with significant risk for new or worsening hyperglycemia. Mifepristone ameliorates the signs and symptoms of hypercortisolemia via glucocorticoid receptor (GR2) blockade, but this approach raises serum cortisol levels and increases risk for adrenal insufficiency (AI), hypokalemia, and endometrial thickening. While response to pasireotide can be monitored via measurements of serum, urine, or late-night salivary cortisol, evaluation of response to mifepristone is solely based on changes in clinical parameters (e.g., hyperglycemia, hypertension, body weight/composition).ConclusionManagement of persistent CD is challenging, and the decision to initiate medical treatment hinges on many factors. Pasireotide may be a more attractive option for most patients due to its action at the underlying tumor and the ability to monitor biochemical responses. However, mifepristone may be more appropriate when it is necessary to avoid or minimize risk for hyperglycemiarelated complications. (Endocr Pract. 2014;20:84-93)     

Effect of postal prompts to patients and general practitioners on the quality of primary care after a coronary event (POST): randomised controlled trial

ObjectivesTo determine whether postal prompts to patients who have survived an acute coronary event and to their general practitioners improve secondary prevention of coronary heart disease.DesignRandomised controlled trial.Setting52 general practices in east London, 44 of which had received facilitation of local guidelines for coronary heart disease.Participants328 patients admitted to hospital for myocardial infarction or unstable angina.InterventionsPostal prompts sent 2 weeks and 3 months after discharge from hospital. The prompts contained recommendations for lowering the risk of another coronary event, including changes to lifestyle, drug treatment, and making an appointment to discuss these issues with the general practitioner or practice nurse.ResultsPrescribing of β bockers (odds ratio 1.7, 95% confidence interval 0.8 to 3.0, P>0.05) and cholesterol lowering drugs (1.7, 0.8 to 3.4, P>0.05) did not differ between intervention and control groups. A higher proportion of patients in the intervention group (64%) than in the control group (38%) had their serum cholesterol concentrations measured (2.9, 1.5 to 5.5, P<0.001). Secondary outcomes were significantly improved for consultations for coronary heart disease, the recording of risk factors, and advice given. There were no significant differences in patients’ self reported changes to lifestyle or to the belief that it is possible to modify the risk of another coronary event.ConclusionsPostal prompts to patients who had had acute coronary events and to their general practitioners in a locality where guidelines for coronary heart disease had been disseminated did not improve prescribing of effective drugs for secondary prevention or self reported changes to lifestyle. The prompts did increase consultation rates related to coronary heart disease and the recording of risk factors in the practices. Effective secondary prevention of coronary heart disease requires more than postal prompts and the dissemination of guidelines.

Key messages

• Postal prompts to patients and their general practitioners about effective secondary prevention after a myocardial infarction did not improve the prescribing of cholesterol lowering drugs and β blockers
• The prompts did improve general practice recording of cardiovascular risk factors and lifestyle advice given to patients, but they made no difference to patients’ reports of changes to lifestyle
• Other methods are needed to improve the quality of secondary prevention of coronary heart disease in general practice

     

Benzodiazepines and hip fractures in elderly people: case-control study

ObjectiveTo determine whether benzodiazepines are associated with an increased risk of hip fracture.DesignCase-control study.ParticipantsAll incident cases of hip fracture not related to traffic accidents or cancer in patients over 65 years of age. 245 cases were matched to 817 controls.SettingEmergency department of a university hospital.ResultsThe use of benzodiazepines as determined from questionnaires, medical records, or plasma samples at admission to hospital was not associated with an increased risk of hip fracture (odds ratio 0.9, 95% confidence interval 0.5 to 1.5). Hip fracture was, however, associated with the use of two or more benzodiazepines, as determined from questionnaires or medical records but not from plasma samples. Of the individual drugs, only lorazepam was significantly associated with an increased risk of hip fracture (1.8, 1.1 to 3.1).ConclusionExcept for lorazepam, the presence of benzodiazepines in plasma was not associated with an increased risk of hip fracture. The method used to ascertain exposure could influence the results of case-control studies.

What is already known on this topic

Benzodiazepines increase the risk of elderly people falling in a dose dependent wayTheir role in hip fracture remains disputed, with increased risk sometimes attributed to drugs with a longer half life or those used to induce sleep

What this study adds

Benzodiazepines were not associated with hip fracture either as a group or according to half life or to characterisation as hypnotic or anxiolyticPatients using two or more benzodiazepines may be at higher riskPatients using lorazepam or certain other benzodiazepines may also be at a higher risk of fracture     

Projection of cancer risks from the Japanese atomic bomb survivors to the England and Wales population taking into account uncertainty in risk parameters

Generalized relative risk models, with adjustments to the relative risk for time after exposure and age at exposure and incorporating a linear-quadratic dose response, were fitted to the latest (Life Span Study Report 12) Japanese atomic bomb survivor cancer mortality data using Bayesian Markov Chain Monte Carlo methods, taking account of random errors in the DS86 dose estimates. The resulting uncertainty distributions in the relative risk model parameters were used to derive uncertainties in population cancer risks for a current UK population. Following an assumed administered dose of 1 Sv, leukaemia mortality risks were estimated to be 1.93×10^–2 Sv^–1 (95% CI 1.14, 3.38), or 0.44 years of life lost Sv^–1 (95% CI 0.22, 0.94). Following an assumed administered dose of 1 Sv, solid cancer mortality risks were calculated to be 10.36×10^–2 Sv^–1 (95% CI 8.41, 12.42), or 1.38 years of life lost Sv^–1 (95% CI 1.11, 1.68). In general, solid cancer risks were very similar to those predicted by classical likelihood-based methods; however, leukaemia risks were somewhat higher, by 10–35%, than those predicted by classical likelihood-based methods. This is so in both cases, irrespective of whether or not adjustments are made in these likelihood-based fits for the effects of measurement errors, and the discrepancy for leukaemia tends to be greater at higher doses. Overall, cancer risks predicted by Bayesian Markov Chain Monte Carlo methods are similar to those derived by classical likelihood-based methods and which form the basis of established estimates of radiation-induced cancer risk. Received: 28 September 1999 / Accepted: 21 August 2000