Background: Statins represent the largest selling class of cardiovascular drug in the world. Previous randomized trials (RCTs) have demonstrated important clinical benefits with statin therapy. Aim: We combined evidence from all RCTs comparing a statin with placebo or usual care among patients with and without prior coronary heart disease (CHD) to determine clinical outcomes. Design: We searched independently, in duplicate, 12 electronic databases (from inception to August 2010), including full text journal content databases, to identify all statin versus inert control RCTs. We included RCTs of any statin versus any non-drug control in any populations. We abstracted data in duplicate on reported major clinical events and adverse events. We performed a random-effects meta-analysis and meta-regression. We performed a mixed treatment comparison using Bayesian methods. Results: We included a total of 76 RCTs involving 170 255 participants. There were a total of 14 878 deaths. Statin therapy reduced all-cause mortality, Relative Risk (RR) 0.90 [95% confidence interval (CI) 0.86-0.94, P <= 0.0001, I-2 = 17%]; cardiovascular disease (CVD) mortality (RR 0.80, 95% CI 0.74-0.87, P < 0.0001, I-2 = 27%); fatal myocardial infarction (MI) (RR 0.82, 95% CI 0.75-0.91, P < 0.0001, I-2 = 21%); non-fatal MI (RR 0.74, 95% Cl 0.67-0.81, P <= 0.001, I-2 = 45%); revascularization (RR 0.76, 95% CI 0.70-0.81, P <= 0.0001); and a composite of fatal and non-fatal strokes (0.86, 95% CI 0.78-0.95, P=0.004, I-2 = 41%). Adverse events were generally mild, but 17 RCTs reported on increased risk of development of incident diabetes [Odds Ratio (OR) 1.09; 95% CI 1.02-1.17, P=0.001, I-2 = 11%]. Studies did not yield important differences across populations. We did not find any differing treatment effects between statins. Discussion: Statin therapies offer clear benefits across broad populations. As generic formulations become more available efforts to expand access should be a priority.
Background: the clinical frailty scale (CFS) was validated as a predictor of adverse outcomes in community-dwelling older people. In our hospital, the use of the CFS in emergency admissions of people aged >= 75 years was introduced under the Commissioning for Quality and Innovation payment framework. Aim: we retrospectively studied the association of the CFS with patient characteristics and outcomes. Design: retrospective observational study in a large tertiary university National Health Service hospital in UK. Methods: the CFS was correlated with transfer to specialist Geriatric ward, length of stay (LOS), in-patient mortality and 30-day readmission rate. Results: between 1st August 2013 and 31st July 2014, there were 11 271 emergency admission episodes of people aged >= 75 years (all specialties), corresponding to 7532 unique patients (first admissions); of those, 5764 had the CFS measured by the admitting team (81% of them within 72 hr of admission). After adjustment for age, gender, Charlson comorbidity index and history of dementia and/or current cognitive concern, the CFS was an independent predictor of in-patient mortality [ odds ratio (OR) >= 1.60, 95% confidence interval (CI): 1.48 to 1.74, P= 10 days (OR = 1.19, 95% CI: 1.14 to 1.23, P<0.001). The CFS was not a multivariate predictor of 30-day readmission. Conclusions: the CFS may help predict in-patient mortality and target specialist geriatric resources within the hospital. Usual hospital metrics such as mortality and LOS should take into account measurable patient complexity.
Background: The supply of recreational drugs has changed and users increasingly buy 'legal highs' over the Internet. Use of these is common and there is a potential for significant toxicity associated with their use. Aim: To determine the content of legal highs available for purchase in the UK and whether the content of these remains consistent. Methods: Twenty-six legal highs were purchased monthly from five different Internet sites over 6 months. These were analysed to determine the drugs in the products and whether there were any changes in their content over this time period. Results: All products were supplied initially, but there was a decline in supply of products month by month. The following drug classes were detected: piperazines, cathinones, caffeine/ephedrine or products in which no psychoactive drugs were detected. Of the products supplied on more than one occasion, 15 (75%) contained the same compounds on each occasion. In three products there was a change in the piperazine detected, with 1-benzylpiperazine being substituted for 1-methyl-4-benzylpiperazine or vice versa. In two other products there was a cathinone [4-fluorophenylpiperazine (pFPP) or 3-fluromethcathinone (3FMC)] detected in products purchased in Month 1 that was not present in the products purchased in subsequent months. Conclusions: Whilst there was no variation in the composition of most legal highs supplied over 6 month, there was significant variation in the piperazine or cathinone content of one quarter of the products. This variation could be of clinical significance as the cathinone and piperazine products can be associated with significant toxicity.
Aim: To perform a systematic review and meta-analysis of the available evidence to establish if female sex is a risk factor for stroke/thromboembolism among patients with AF. Methods: A systematic literature search was conducted using Medline. The search term 'atrial fibrillation' was used in combination with 'stroke risk', 'thromboembolism', 'female' and 'gender differences' and returned 735 articles, of which 17 were appraised and included. Females with AF were compared with males with AF for the outcome of stroke/thromboembolism. Results: Seventeen studies, 5 randomized-controlled trials and 12 prospective observational studies were included; 10 demonstrated an increased risk of stroke in women. Meta-analysis of the 17 studies revealed a 1.31-fold (95% confidence intervals (CIs) 1.18-1.46) elevated risk of stroke in women with AF; the risk appearing greatest for women aged a parts per thousand yen75 years. Only three studies compared entirely anticoagulated populations; stroke rates among these patients varied from 1.2-1.44% per-patient year for men and 2.08-2.43% per-patient year for women. Risk of stroke in women appeared similar regardless of oral anticoagulation therapy [risk ratio (95% CI 1.29 (1.09-1.52) and 1.49 (1.17-1.90) in non-anticogulated vs. anticoagulated/mixed cohorts, respectively). Conclusions: Women with AF are at increased risk of stroke, particularly elderly women. Comprehensive stroke risk assessment, including sex as a risk factor, should be undertaken in all AF patients.
Background: Mild hyponatremia is the commonest electrolyte imbalance in the older population and has been shown to be associated with gait and attention deficits resulting in higher frequency of falls. The association of mild hyponatremia and bone fracture is still unknown. Objective: To determine if mild hyponatremia is associated with increased risk of bone fracture in ambulatory elderly. Design, setting and participants: Case control study of 513 cases of bone fracture after incidental fall in ambulatory patients aged 65 or more in general university hospital. Controls were age and sex matched randomly selected ambulatory patients without history of bone fracture. Main exposure measures: Odds ratio (OR) of bone fracture after incidental fall associated with presence of hyponatremia. Results: Prevalence of hyponatremia (serum sodium <135 mEq/l,) in patients with bone fracture and in controls patient was, respectively, 13.06% and 3.90%. Hyponatremia was mild and asymptomatic in all patients (mean serum sodium 131 mEq/l) and was found to be associated with bone fracture after incidental fall in ambulatory elderly (unadjusted OR: 3.47, 95% CI: 2.09-5.79, and adjusted OR: 4.16 95% CI: 2.24-7.71). Hyponatremia was either drug induced (36% diuretics, 17% selective serotonin reuptake inhibitors) or resulted from idiopathic syndrome of inappropriate antidiuretic hormone secretion (37%). Hyponatremia was associated with 9.20% of all bone fractures. Conclusions: Mild asymptomatic hyponatremia is associated with bone fracture in ambulatory elderly and avoiding iatrogenic hyponatremia or treating hyponatremia may decrease the number of bone fractures in this population.
Background: The installation of drug databases on personal digital assistants (PDAs) allows for rapid detection of adverse drug interactions at the point of care. Aim: To test the ability of a drug interaction database (ePocrates RX) to correctly identify clinically significant adverse drug interactions in an out-patient setting. Design: Retrospective file review of 1801 drug prescriptions in out-patients consulting a medical walk-in clinic. Methods: Each prescription was assessed independently by a clinical pharmacologist using drug-drug interaction compendia, and by a general internist using the drug interaction database. Discrepant results were systematically reviewed by both, using published literature, and a consensus was then reached. This consensus was used as the criterion against which the PDA drug interaction database was judged. Results: The prevalence of potential adverse drug interactions was 23%. When compared to the opinion of the clinical pharmacologist and drug-drug interaction compedia, the sensitivity of the drug interaction database to correctly identify clinically relevant adverse drug interactions was 81% (95%CI 77%-85%) and the specificity was 88% (95%CI 86-89%). The positive predictive value was poor (67%, 95%CI 62%-71%) but the negative predictive value was excellent (94%, 95%CI 92%-95%). Discussion: The database was an efficient tool for rapidly checking for potentially harmful drug interaction, but also flagged up several clinically non-significant interactions. When used appropriately, this drug interaction database could help physicians decrease prescription error, by ruling out the risk of clinically relevant adverse drug interactions for newly prescribed drugs, and thereby increase patient safety.
Methods: Data was collected using a questionnaire survey in schools, colleges and universities in the Tayside area of Scotland, UK in February 2010. Results: A total of 1006 individuals completed the survey [501 (49.8%) males and 505 (50.2%) females], of whom 349 classified their educational institute as a school and 657 as a college/university. Among them 205 (20.3%) reported previous use of mephedrone; 23.4% reported using only using mephedrone on one occasion previously, although 4.4% reported daily use. A total of 56% of those who had used mephedrone, reported at least one unwanted effect associated with its use. A total of 17.6% of users reported 'addiction or dependence' symptoms associated with their mephedrone use. A total of 48.8% of users sourced mephedrone from street level dealers, 10.7% from the Internet. Conclusions: We have shown in this study that the use of mephedrone among school and college/university students is common and that users found it easy to obtain. There was a high prevalence of unwanted effects associated with its use. Further work is needed to determine the impact of the recent changes in the UK legislation relating to mephedrone and other related cathinones and whether this has been effective in reducing the prevalence of mephedrone use.
Macrophage migration inhibitory factor (MIF) was the original cytokine, described almost 50 years ago and has since been revealed to be an important player in pro-inflammatory diseases. Recent work using MIF mouse models has revealed new roles for MIF. In this review, we present an increasing body of evidence implicating the key pro-inflammatory cytokine MIF in specific biological activities related directly to cancer growth or contributing towards a microenvironment favouring cancer progression.
Results: In the first year of service, 43 aHUS patients received eculizumab, 15 children and 28 adults. Twenty-three were new patients and 20 prevalent. Fifteen of the 23 new patients required dialysis before eculizumab was started, 8 of these recovered renal function. Twelve of the 20 prevalent patients who received eculizumab were transplant patients, 8 with prophylactic use and 4 for recurrent disease; the outcome in all was good. Eculizumab was withdrawn in 14 patients, 5 were patients who had not recovered renal function. In 3 of the 14 patients, it was necessary to reintroduce eculizumab because of recurrent disease (2 extra-renal and 1 renal). There were 2 deaths in the 43 patients, and neither was associated with use of eculizumab. There were no episodes of meningococcal disease. Conclusions: The establishment of this national service has enabled aHUS patients in England to receive eculizumab when they need it for as long as they need it.
Lynch syndrome (LS) is the most common of all inherited cancer syndromes, associated with substantially elevated risks for colonic and extracolonic malignancies, earlier onset and high rates of multiple primary cancers. At the genetic level, it is caused by a defective mismatch repair (MMR) system due to presence of germline defects in at least one of the MMR genes-MLH1, MSH2, MSH6, PMS2 or EPCAM. An impaired MMR function during replication introduces infidelity in DNA sequence and leads to ubiquitous mutations at simple repetitive sequences (microsatellites), causing microsatellite instability (MSI). Although previously, clinicopathological criteria such as Amsterdam I/II and Revised Bethesda Guidelines were commonly used to identify suspected LS mutation carriers, there has been a recent push towards universally testing, especially in case of colorectal cancers (CRCs), through immunohistochemistry for expression of MMR proteins or through molecular tests (polymerase chain reaction, PCR) for MSI, in order to identify LS mutation carriers and subject them to genetic testing to ascertain the specific gene implicated. In this review, we have discussed the latest diagnostic strategies and the current screening and treatment guidelines for colonic and extracolonic cancers in clinically affected and at-risk individuals for LS.
Objective: To report on the clinical presentations, laboratory abnormalities, treatment and outcomes in 54 patients with neurosarcoidosis (NS). Background: Sarcoidosis is an inflammatory granulomatous disease affecting multiple organ systems. Neurosarcoidosis (CNS involvement) is seen in approximately 25% of patients with systemic sarcoidosis, although it is subclinical in most of these cases. Because of its rarity, exposure of neurologists to the clinical spectrum of NS is limited to case reports or short case series. Patients and Methods: A database of 3900 patients treated at the Vanderbilt Multiple Sclerosis Clinic between 1995 and 2008 was searched for 'neurosarcoidosis', 'neurosarcoid', 'sarcoidosis' and 'sarcoid'. Of the 162 patient records that were retrieved, 54 patients were found to meet the criteria for definite, probable or possible neurosarcoidosis and were reviewed, including their clinical presentation, Cerebrospinal fluid (CSF) findings, Magnetic resonance imaging (MRIs), biopsy results, treatment, and where available, outcomes 4 months to 20 years after onset of the presenting illness. Results: Clinical presentations and imaging findings in NS were varied. Cranial nerve abnormalities were the most common clinical presentation and involvement of the optic nerve in particular was associated with a poor prognosis for visual recovery. Isolated involvement of lower cranial nerves had a more favorable outcome. T2 hyperintense parenchymal lesions were the most common imaging finding followed by meningeal enhancement. Long-term treatment consisted of prednisone and/or other immunomodulators (azathioprine, methotrexate or mycophenolate mofetil). Conclusions: Unlike systemic sarcoidosis, there is difficulty in making tissue diagnosis when involvement of CNS is suspected. MRI and CSF studies are sensitive in the detection of CNS inflammation but lack specificity, making the ascertainment of neurosarcoidosis a clinical challenge. In addition the low prevalence of the disease makes clinical trials difficult and therapeutic decisions are likely to be made from careful reporting from case studies.
The object of this article is to review the past decade of research on teenage suicide, with a particular emphasis on epidemiologic trends by age, gender and indigenous ethnicity. As such, a review of research literature from 2003 to 2014 was conducted via a comprehensive search of relevant psychological and medical databases. Wide gaps in our knowledge base exist concerning the true extent of teenage suicide due to lack of data, particularly in developing countries, resulting in a Western bias. The gender paradox of elevated suicidality in females with higher completed suicide rates in males is observed in teenage populations worldwide, with the notable exceptions of China and India. Native and indigenous ethnic minority teens are at significantly increased risk of suicide in comparison to general population peers. Often those with the highest need for mental health care (such as the suicidal adolescent) have least access to therapeutic support. Globally, suicide in teenagers remains a major public health concern. Further focused research concerning completed suicides of youth below the age of 18 is required across countries and cultures to understand more about risk as children progress through adolescence. Gender and ethnic variations in suicidality are embedded within cultural, historical, psychological, relational and socio-economic domains. Worldwide, the absence of child/adolescent-specific mental health policies may delay the development of care and suicide prevention. Overall, it is vital that clinicians adopt a holistic approach that incorporates an awareness of age and gender influences, and that cultural competency informs tailored and evaluated intervention programmes.
Background: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. Methods: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. Results: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 +/- 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. Conclusion: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.
Background: Histological diagnosis by surgical lung biopsy for interstitial lung disease (ILD) is currently limited. Transbronchial cryobiopsy via flexible bronchoscope may this for more patients. The relative costs, diagnostic yields and safety of this approach and more traditional approaches have not been determined. Objectives: To perform a systematic review and meta-analysis of transbronchial cryobiopsy, forceps transbronchial biopsy and video assisted (VATS) surgical lung biopsy assessing their relative diagnostic yields and safety. To perform a cost analysis to demonstrate any savings through change to the newer technique. Methods: We performed a systematic review of the literature using MEDLINE and EMBASE for all original articles on the diagnostic yield and safety of transbronchial cryobiopsy, forceps transbronchial biopsy and VATS-biopsy in ILD up to February 2016. Data were extracted on yield and complication rates, in addition to study characteristics. Theoretical cost analysis was performed from local institution financial data, 2015-16 reimbursement tariffs and results of the systematic review. Results: A meta-analysis of 11 investigations for transbronchial cryobiopsy, 11 for forceps transbronchial biopsy and 24 for VATS-biopsy revealed diagnostic yields of 84.4% (75.9-91.4%), 64.3% (52.6-75.1%) and 91.1% (84.9-95.7%), respectively. Pneumothorax occurred in 10% (5.4-16.1%) of transbronchial cryobiopsy procedures, moderate bleeding in 20.99% (5.6-42.8%), with three deaths reported. Surgical mortality was 2.3% (1.3-3.6%). Cost analysis demonstrated potential savings of 210 pound per patient in the first year and 647 pound in subsequent years. Conclusions: Transbronchial cryobiopsy represents a potentially cost-saving approach to improve histological diagnosis in ILD, however is accompanied by a significant risk of moderate bleeding.
Background: Scleroderma renal crisis (SRC) is an important complication of systemic sclerosis, causing acute renal failure, and usually hypertension. Aims: To review the clinical and pathological features of SRC, and correlate them with renal outcomes and mortality. Design: Retrospective case series. Methods: We identified 110 cases of SRC managed at a single centre between 1990 and 2005. Results: SRC occurred in 5% of scleroderma cases under follow-up. Cases were predominantly female (81%), with diffuse cutaneous disease (78%). RNA polymerase antibodies were found in 59% of cases tested. Almost all (108/110) received treatment with ACE inhibitors (ACEIs). Dialysis was not required in 36%, was required temporarily (for up to 3 years) in 23%, was required permanently in 41%. Patients not on dialysis showed improvement in estimated glomerular filtration rate after SRC (mean change +23 ml/min over 3 years). Poor renal outcome was associated with lower blood pressure at presentation, and with higher age in those requiring dialysis. Steroid use, microangiopathic haemolytic anaemia, and antibody profile were not related to renal outcome. In the 58 renal biopsies available for clinical correlation, acute changes of mucoid intimal thickening in arteries and fibrinoid necrosis in arterioles were associated with a poorer renal outcome. Mortality was high (59% survival at 5 years), and was higher in men. Discussion: Despite the efficacy of ACEIs in managing SRC, the poor long-term outcome warrants evaluation for additional treatments for this devastating complication of systemic sclerosis.
Liver fibrosis is the generic response to chronic injury of varying aetiologies. A number of common mechanisms link this response to the pathogenesis of fibrosis in other organs. While long thought to be relentlessly progressive, there is now excellent evidence in both human liver disease and animal models that hepatic fibrosis is potentially reversible. The liver therefore provides an excellent bidirectional model for the study of fibrogenesis and fibrosis resolution. In this article, we will review the evidence for the reversibility of liver fibrosis. We will highlight some of the mechanisms responsible for fibrogenesis and fibrosis regression, focussing on the role of hepatic myofibroblast activation and apoptosis, the importance of matrix metalloproteinases and their tissue inhibitors and the central involvement of hepatic macrophages in orchestrating this process. Finally, we will briefly discuss what renders liver fibrosis irreversible and how this accumulating knowledge base could lead to badly needed anti-fibrotic therapies in the future.
Background: There has been significant media interest in the use of novel psychoactive substances ( also known as 'legal highs') and reports in the medical literature of toxicity associated with their use. However, most surveys of recreational drug use focus on classical drugs such as cocaine and ecstasy, and there is limited information on how commonly emerging novel psychoactive substances are used. Aim: To collect data on use prevalence patterns of a wider range of novel psychoactive substances in South London gay nightclubs. Design: Questionnaire survey. Methods: Individuals attending gay-friendly nightclubs in South East London (July 2011) were asked about life-time use, last month use and/or use on the night of the survey/planned use later that night of novel psychoactive substances, cocaine and MDMA/ecstasy. Results: A total of 313 individuals were surveyed over 4 nights; 206 (65.8%) had previously used a 'legal high'. Mephedrone had the highest prevalence of last month use (53.2%) and use on the night of the survey (41.0%). This was greater than both cocaine (44.6% and 16.7%, respectively) and MDMA/ecstasy (26.9% and 5.8%). There was limited on the night use of the non-mephedrone 'legal highs': methoxetamine (1.6%) and 1-benzylpiperazine (0.6%), Spice/K2 (0.6%) and pipradrols (0.6%). Conclusions: Although a significant proportion of individuals report previous use of novel psychoactive substances, it seems that only mephedrone has become an established part of the recreational drug scene. It is important that there is a considered approach to determining the utilization of drug prevention/education and enforcement budgets to ensure that this is appropriately targeted to drugs that are used recreationally.
Background: Gout and serum uric acid are associated with mortality but their simultaneous contributions have not been fully evaluated in the general population. Purpose: To explore the independent and conjoint relationships of gout and uric acid with mortality in the US population. Methods: Mortality risks of gout and serum uric acid were determined for 15 773 participants, aged 20 years or older, in the Third National Health and Nutrition Examination Survey by linking baseline information collected during 1988-1994 with mortality data up to 2006. Multivariable Cox proportional hazards regression determined adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each exposure and all analyses were conducted in 2011 and 2012. Results: Compared with subjects without a history of gout, the multivariable HR for subjects with gout were 1.42 (CI 1.12-1.82) for total and 1.58 (CI 1.13-2.19) for cardiovascular mortality. Adjusted HRs per 59.5 mu mol/l (1 mg/dl) increase in uric acid were 1.16 (CI 1.10-1.22) for total and cardiovascular mortality and this pattern was consistent across disease categories. In the conjoint analysis, the adjusted HRs for mortality in the highest two uric acid quartiles were 1.64 (CI 1.08-2.51) and 1.77 (CI 1.23-2.55), respectively, for subjects with gout, and were 1.09 (CI 0.87-1.37) and 1.37 (CI (1.11-1.70), respectively, for subjects without gout, compared with those without gout in the lowest quartile. A similar pattern emerged for cardiovascular mortality. Conclusions: Gout and serum uric acid independently associate with total and cardiovascular mortality. These risks increase with rising uric acid concentrations.