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In this consensus paper, the Belgian Bone Club aims to provide a state of the art on the epidemiology, diagnosis, and management of osteoporosis in frail individuals, including patients with anorexia nervosa, patients on dialysis, cancer patients, persons with sarcopenia, and the oldest old. All these conditions may indeed induce bone loss that is superimposed on physiological bone loss and often remains under-recognized and under-treated. This is of particular concern because of the major burden of osteoporotic fractures in terms of morbidity, mortality, and economic cost. Therefore, there is an urgent need to appreciate bone loss associated with these conditions, as this may improve diagnosis and management of bone loss and fracture risk in clinical practice., SCOPUS: re.j, info:eu-repo/semantics/published

Pain is common in intensive care units (ICUs)[1]. Regular pain assessment can improve patient satisfaction and clinical outcomes. It is commonly performed by nurses [2], yet physician-led assessment can improve analgesic management. Using pain documentation as a surrogate for assessment, a review showed physiological parameters i.e. cardiovascular assessment, were more frequently documented by doctors than pain in critically ill patients [3].

Objective Bladder cancer (BC) has the highest lifetime treatment costs per patient of all cancers. The high recurrence rate and ongoing invasive monitoring requirement are the key contributors to the economic and human toll of this disease. The purpose of this paper was to utilize the recent literature to identify opportunities for improving the benefits and costs of BC care. Methods A PubMed search was performed of recent publications concerning (BC) cost-effectiveness. We reviewed studies, reviews, opinion papers and cost-effectiveness analyses, focusing primarily on non-muscle-invasive bladder cancer (Ta/T1; NMIBC). Results New diagnostic tools such as urine markers may assist in more cost-effectively detecting BC at an earlier stage, however, these markers cannot replace the cystoscopy, which is the current standard of care. A photodynamic diagnostic tool (PDD) using hexylaminolevulinate (Hexvix®) enhances tumor visibility and improves transurethral resection of bladder cancer (TURB) results, potentially reducing recurrence rates and lowering treatment costs. While the importance of BC research has been acknowledged, research investment has been continuously reduced during the last 5 years. Conclusions The economic burden of BC is well-characterized in the literature. This study suggests that new technologies (i.e., urine-based tests, PDD) and therapeutic regimes (intravesical chemotherapy, adjuvant immunotherapy) have significant potential to improve the diagnosis, treatment and on-going monitoring of BC patients, with potential improvements in clinical outcomes and concurrent cost-savings. A renewed interest and investment in BC research are required to ensure future advancements.

The first biosimilar monoclonal antibody (infliximab, CT-P13) was registered by the European Medicines Agency in 2013 for the treatment of several inflammatory conditions including rheumatoid arthritis (RA). Biosimilar infliximab is first being marketed in the Central and Eastern European countries. This paper presents the estimated budget impact of the introduction of biosimilar infliximab in RA over a 3-year time period in six selected countries, namely Bulgaria, the Czech Republic, Hungary, Poland, Romania and Slovakia. A prevalence-based model was constructed for budget impact analysis. Two scenarios were compared to the reference scenario (RSc) where no biosimilar infliximab is available: biosimilar scenario 1 (BSc1), where interchanging the originator infliximab with biosimilar infliximab is disallowed, and only patients who start new biological therapy are allowed to use biosimilar infliximab; as well as biosimilar scenario 2 (BSc2), where interchanging the originator infliximab with biosimilar infliximab is allowed, and 80 % of patients treated with originator infliximab are interchanged to biosimilar infliximab. Compared to the RSc, the net savings are estimated to be €15.3 or €20.8 M in BSc1 and BSc2, respectively, over the 3 years. If budget savings were spent on reimbursement of additional biosimilar infliximab treatment, approximately 1,200 or 1,800 more patients could be treated in the six countries within 3 years in the two biosimilar scenarios, respectively. The actual saving is most sensitive to the assumption of the acquisition cost of the biosimilar drug and to the initial number of patients treated with biological therapy. The study focused on one indication (RA) and demonstrated that the introduction of biosimilar infliximab can lead to substantial budget savings in health care budgets. Further savings are expected for other indications where biosimilar medicines are implemented.

Whether to use a medication during pregnancy can be a concern for both women and health care providers. It has been estimated that up to 10% of congenital anomalies may be caused by environmental exposures–that is, exposures to medications, alcohol, or other exogenous factors that have adverse effects on the developing embryo or fetus [1]. Avoiding all potentially adverse exposures can prevent these adverse effects. However, it is not always possible to avoid taking medications during pregnancy. Women who are pregnant continue to experience short-term and long-term health conditions that must be managed. Discontinuing treatment of a serious condition when a woman becomes pregnant can have profound, long-term implications both for her health and that of her baby. In a retrospective study from eight health maintenance organizations, researchers estimated that approximately 59% of pregnant women were prescribed a medication other than a vitamin or mineral supplement at some time during pregnancy [2]. Use of over-the-counter medications during pregnancy may be even higher, and many women take a dietary or herbal supplement other than multivitamins or folic acid while pregnant [3, 4]. Preconception care provides the opportunity to optimize a woman’s use of medications in preparation for pregnancy. Such care includes identifying patterns of medication use before pregnancy occurs; adjusting those patterns to avoid the use of nonessential medications; minimizing exposure to medications known to be harmful to the embryo or fetus; and adjusting the dose, route of administration, and timing of essential treatments to optimize maternal health at each stage of pregnancy while safeguarding the embryo, fetus, and infant. In this paper, we summarize the basic principles of teratology and the current state of knowledge about the effects of medication use during pregnancy; outline basic components of preconception care that can help minimize the risk of birth defects; and provide examples of approaches to planning for the safe and effective use of medications during pregnancy through preconception care.

Purpose Data from an ongoing European pharmacoepidemiological study (MONITOR-CKD5) were used to examine congruence between physician-reported risk-based individualisation of target haemoglobin (Hb) and the actual Hb targets set by these physicians for their patients, as well as actual Hb levels in their patients. Methods Physician investigators participating in the study completed a questionnaire about their anaemia practice patterns and attitudes post-TREAT at the start of the study (T1) and in summer 2013 (T2). These data were compared with the Hb targets identified at baseline for actual patients (n = 1197) enrolled in the study. Risk groups included presence/absence of hypertension, diabetes, cardiovascular complications, history of stroke, history of cancer, and age/activity level (elderly/inactive or young/active). Results At each time point, more than three quarters of physicians responded that results from the TREAT study, in patients not on dialysis, have influenced their use of erythropoiesis-stimulating agents in patients on haemodialysis. At T1, there was a clear difference in physician-reported (theoretical) target Hb levels for patients across the different risk groups, but there was no difference in patients’ actual Hb levels across the risk groups. A similar disparity was noted at T2. Conclusions Physicians’ theoretical attitudes to anaemia management in patients on haemodialysis appear to have been influenced by the results of the TREAT study, which involved patients not on dialysis. Physicians claim to use risk-based target Hb levels to guide renal anaemia care. However, there is discrepancy between these declared risk-based target Hb levels and actual target Hb levels for patients with variable risk factors.

Aim To provide an estimate of the annual cost of atrial fibrillation (AF) in Sweden. Methods Prevalence-based cost analysis of AF in Sweden for 2007. Direct medical (hospitalizations, hospital outpatient care, primary health care, non-pharmacological interventions, pharmaceuticals, and anticoagulation monitoring) and non-medical (transportation associated with health care visits) costs of AF, direct costs of AF complications (stroke and heart failure), and indirect costs (production loss), were included. Data were based on Swedish registries, reports and databases, published literature, and an expert panel. Results There were 100,557 individuals with AF as primary or secondary diagnosis that were either hospitalized or treated in hospital outpatient care in 2007. The total cost of AF was estimated at €708 million. The major cost driver was the direct cost of complications (54%), followed by hospitalization due to AF including AF as secondary diagnosis (18%), and production loss (12%). Conclusion This is a comprehensive, nation-based cost analysis of AF where relevant data were derived from national registries covering the entire Swedish population. The results showed that the annual cost of AF was high in comparison with other diseases, but likely to be underestimated as a conservative approach was applied in the analysis.

Pre-exposure prophylaxis (PrEP) for HIV prevention is a promising experimental approach currently being tested globally. A number of PrEP trials are evaluating the safety and effectiveness of PrEP in men who have sex with men (MSM) and other populations at risk for HIV, and results will be available from this first generation of efficacy trials over the next few years. Here we review the rationale for orally-administered antiretrovirals for prevention, and outline issues the first generation trials will address as well as questions that may be addressed in future studies. We also describe the rationale for combination prevention approaches that may combine PrEP with other prevention modalities as part of a larger prevention package.

Current adherence assessments typically detect missed doses long after they occur. Real-time, wireless monitoring strategies for antiretroviral therapy may provide novel opportunities to proactively prevent virologic rebound and treatment failure. Wisepill, a wireless pill container that transmits a cellular signal when opened, was pilot tested in ten Ugandan individuals for 6 months. Adherence levels measured by Wisepill, unannounced pill counts, and self-report were compared with each other, prior standard electronic monitoring, and HIV RNA. Wisepill data was initially limited by battery life and signal transmission interruptions. Following device improvements, continuous data was achieved with median (interquartile range) adherence levels of 93% (87–97%) by Wisepill, 100% (99–100%) by unannounced pill count, 100% (100–100%) by self-report, and 92% (79–98%) by prior standard electronic monitoring. Four individuals developed transient, low-level viremia. After overcoming technical challenges, real-time adherence monitoring is feasible for resource-limited settings and may detect suboptimal adherence prior to viral rebound.

Background The diagnosis of myocarditis continues to be a challenging task in clinical practice. The purpose of our study was to investigate cardiovascular magnetic resonance imaging in the diagnostic workup of ambulatory patients with the suspicion of early myocarditis after respiratory or gastrointestinal tract viral infection. The need for accurate diagnosis of early myocarditis arises from the low diagnostic accuracy of routine clinical tests. Methods We examined 67 consecutive patients with symptoms of weakness, palpitations, and fatigue after respiratory or gastrointestinal tract infection. We compared these patients to 31 controls. ECG-triggered, T2-weighted, fast-spin-echo triple inversion recovery sequences and delayed enhancement imaging were obtained in all patients, as well as functional parameters of left ventricular function and dimensions. In addition, in 25 patients and 10 controls, ECG-triggered, T1-weighted, multi-slice spin-echo images were obtained in axial orientation. Results We found a significant difference between patients with suspected myocarditis and controls in T2-global myocardial signal intensity. In addition, the ratio of global myocardial signal intensity/muscle signal intensity was 2.3 ± 0.4 in patients and 1.8 ± 0.3 in controls, which was highly significant (p

Background In contrast to surveys in cardiologist settings, presentation and management of atrial fibrillation (AF) in primary care patients is less well studied. Methods and results The prospective ATRIUM (OutpatientRegistry Upon Morbidity of Atrial Fibrillation) collected data from patients with AF seen by 730 physicians representing a random sample of all primary care physicians in Germany. ATRIUM enrolled 3,667 patients (mean age, 72 ± 9 years; 58% male, mean CHADS2 score 2.2 ± 1.3), 994 (27.1%) with paroxysmal, 944 (25.7%) with persistent or long-standing persistent and 1,525 (41.6%) with permanent AF (no AF type was specified in 204 patients). Mean duration since initial diagnosis of AF was 61 ± 66 months (median 42, interquartile range 14–88). Reported symptoms included palpitations (43%), shortness of breath (49%), fatigue (49%), dizziness (37%) and angina (20%). Most common concomitant conditions were hypertension (84%), heart failure (43%), coronary artery disease (345%), diabetes (35%) and chronic kidney disease (20%). Prior myocardial infarction was present in 11% of patients, prior stroke in 10% and prior transient ischemic attack in 10%. Antithrombotic medication was used by 93% of the patients (oral anticoagulants, 83%). Rate control therapy was reported in 75% and rhythm control therapy in 33%, often added to rate control. Drugs for rhythm and rate control included ß-blockers (75%), calcium antagonists (15%), digitalis (29%), sodium channel blockers of type IA (quinidine, 1.0%) or IC (flecainide or propafenone, 5%), and potassium channel blockers including amiodarone (11%). In the year prior to enrollment, 46% of the patients had been cardioverted (23% by drugs, 22% electrically), catheter ablation had been performed in 5%, and 10% received a pacemaker or defibrillator. A high proportion (44%) of the patients were hospitalized in the year prior to enrollment. Conclusions Patients with AF managed in primary care often receive guideline-conforming therapy including antithrombotic therapy, rate control and rhythm control (numbers given above). Despite this apparent adherence, almost half of the patients were hospitalized in the year prior to enrollment, suggesting that the therapies applied do not stabilize patients sufficiently to keep them out of hospital.

Purpose To calculate the burden of lung cancer illness due to radon for all thirty-six health units in Ontario and determine the number of radon-attributable lung cancer deaths that could be prevented. Methods We calculated the population attributable risk percent, excess life-time risk ratio, life-years lost, the number of lung cancer deaths due to radon, and the number of deaths that could be prevented if all homes above various cut-points were effectively reduced to background levels. Results It is estimated that 13.6 % (95 % CI 11.0, 16.7) of lung cancer deaths in Ontario are attributable to radon, corresponding to 847 (95 % CI 686, 1,039) lung cancer deaths each year, approximately 84 % of these in ever-smokers. If all homes above 200 Bq/m3, the current Canadian guideline, were remediated to background levels, it is estimated that 91 lung cancer deaths could be prevented each year, 233 if remediation was performed at 100 Bq/m3. There was important variation across health units. Conclusions Radon is an important contributor to lung cancer deaths in Ontario. A large portion of radon-attributable lung cancer deaths are from exposures below the current Canadian guideline, suggesting interventions that install effective radon-preventive measures into buildings at build may be a good alternative population prevention strategy to testing and remediation. For some health units, testing and remediation may also prevent a portion of radon-related lung cancer deaths. Regional attributable risk estimates can help with local public health resource allocation and decision making.

Background Chronic kidney disease is almost always accompanied by anaemia. Erythropoietin-stimulating agents (ESA) can increase haemoglobin concentration and thus reduce the frequency of anaemia-related complications including the cardiovascular events. Aim The aim of the study was to collect prospective data on 12-month standard ESA therapy used in haemodialyzed patients in selected CEE countries as well as on cardiovascular complications, iron status and anaemia treatment. Patients and methods Fifty centres in 3 countries participated in the study. A group of 398 haemodialysed stable patients (M-231, F-167) aged 19–90 years (57.5 ± 14.7) on standard ESA therapy for chronic renal anaemia were recruited. Twelve-month prospective data on iron parameters, ESA therapy and cardiovascular events were collected. The use of iron, folic acid and blood transfusions were also assessed. Patient were divided into three groups according to ESA therapy start: group A—patients who received ESA after start of haemodialysis, group B—patients who received ESA within 3 months from the day of first haemodialysis and group C—patients who had received ESA more than 3 months before haemodialysis. Chi2 test for qualitative data and Kruskall–Wallis test for quantitative data with p

Objectives To assess the cost effectiveness of palivizumab for prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants in Spain, incorporating country-specific observational hospitalisation data. Methods An existing decision tree model, designed using data from a large international clinical trial of palivizumab versus no prophylaxis, was updated to include Spanish observational hospitalisation data. The analysis was performed for preterm children born at or before 32 weeks gestational age, who are at high risk of developing severe RSV disease requiring hospitalisation. Data sources included published literature, official price/tariff lists and national population statistics. The primary perspective of the study was that of the Spanish National Health Service in 2006. Results The base-case analysis included the direct medical costs associated with palivizumab prophylaxis and hospital care for RSV infections. Use of palivizumab produces an undiscounted incremental cost-effectiveness ratio (ICER) of €6,142 per quality-adjusted life-year (QALY), and a discounted ICER of €12,814/QALY. Conclusion Palivizumab provides a cost-effective method of prophylaxis against severe RSV disease requiring hospitalisation among preterm infants in Spain.

Purpose Clostridium difficile infection (CDI) represents a significant economic healthcare burden, especially the cost of recurrent disease. Fidaxomicin produced significantly lower recurrence rates and higher sustained cure rates in clinical trials. We evaluated the cost-effectiveness and budget impact of fidaxomicin compared with vancomycin in Germany in the first-line treatment of patient subgroups with CDI at increased risk of recurrence. Methods A semi-Markov model was used to compare the cost-effectiveness and budget impact of fidaxomicin vs. vancomycin from a payer perspective in Germany. The model cycle length was 10 days. The time horizon was 1 year. Model inputs were probability of clinical cure, 30-day probability of recurrence, and 30-day attributable mortality based on evidence from two randomized controlled trials comparing fidaxomicin and vancomycin in patients with CDI. Cost-effectiveness outcomes were cost per quality-adjusted life year gained, cost per bed-day saved, and cost per recurrence avoided. Results Despite higher drug acquisition costs, fidaxomicin was dominant in the cancer subgroup (less costly and more effective) and cost-effective in the other subgroups, with incremental cost-effectiveness ratios vs. vancomycin ranging from €26,900 to €44,500. Hospitalization costs of the first-line treatment of CDI with fidaxomicin vs. vancomycin were lower in every patient subgroup, resulting in budget impacts ranging from −€1325 (in patients ≥65 years) to −€2438 (in cancer patients). Reductions in the cost of treating recurrence with fidaxomicin ranged from −€574.32 per patient in those receiving concomitant antibiotics to −€1500.68 per patient in renally impaired patients. Conclusions In patient subgroups with CDI at increased recurrence risk, fidaxomicin was cost-effective vs. vancomycin, and less costly and more effective in patients with cancer. Electronic supplementary material The online version of this article (doi:10.1007/s15010-016-0894-y) contains supplementary material, which is available to authorized users.

Established in 2008, the National Cardiovascular Homograft Bank (NCHB) has been instrumental in creating an available supply of cardiovascular tissues for implantation in Singapore. This article introduces its collaboration with Singapore General Hospital Skin Bank Unit. The procedure of homograft recovery, processing, cryopreservation and quality assurance are presented. Since its establishment, the NCHB has followed the guidelines set by the Ministry of Health Singapore and the American Association of Tissue Banks. A total of 57 homografts had been recovered and 40 homografts were determined to be suitable for clinical use. The most significant reasons for non-clinical use are positive microbiological culture or unsuitable graft condition. Crucial findings prompted reviews and implementation of new procedures to improve the safety of homograft recipients. These include (1) a change in antibiotic decontamination regime from penicillin and streptomycin to amikacin and vancomycin after a review and (2) mandating histopathogical examination since the discovery of cardiac sarcoidosis in a previously undiagnosed donor. Further, the NCHB also routinely performs dengue virus screening, for donors suspected of dengue infection. Cultural factors which affect the donation rate are also briefly explored. By 2010, 31 homografts had been implanted into recipients with congenital or acquired heart valve conditions. More than half of these recipients were children. Post-operative outcomes had been encouraging, with no report of adverse events attributed to implanted homografts.

Although monotherapy with angiostatic drugs is still far from effective, there is abundant evidence that angiostatic therapy can improve the efficacy of conventional treatments like radiotherapy. This has instigated numerous efforts to optimize and clinically implement the combination of angiostatic drugs with radiation treatment. The results from past and present clinical trials that explored this combination therapy indeed show encouraging results. However, current findings also show that the combination has variable efficacy and is associated with increased toxicity. This indicates that combining radiotherapy with angiostatic drugs not only holds opportunities but also provides several challenges. In the current review, we provide an update of the most recent insights from clinical trials that evaluated the combination of angiostatic drugs with radiation treatment. In addition, we discuss the outstanding questions for future studies in order to improve the clinical benefit of combining angiostatic therapy with radiation therapy.

This paper identifies best practice recommendations for managing diabetes and sight-threatening diabetic eye disease. The authors provide an update for ophthalmologists and allied healthcare professionals on key aspects of diabetes management, supported by a review of the pertinent literature, and recommend practice principles for optimal patient management in treating visual impairment due to diabetic eye disease. In people with diabetes, early optimal glycaemic control reduces the long-term risk of both microvascular and macrovascular complications. The authors propose more can and should be done to maximise metabolic control, promote appropriate behavioural modifications and encourage timely treatment intensification when indicated to ameliorate diabetes-related complications. All people with diabetes should be screened for sight-threatening diabetic retinopathy promptly and regularly. It is shown that attitudes towards treatment adherence in diabetic macular oedema appear to mirror patients' views and health behaviours towards the management of their own diabetes. Awareness of diabetic macular oedema remains low among people with diabetes, who need access to education early in their disease about how to manage their diabetes to delay progression and possibly avoid eye-related complications. Ophthalmologists and allied healthcare professionals play a vital role in multidisciplinary diabetes management and establishment of dedicated diabetic macular oedema clinics is proposed. A broader understanding of the role of the diabetes specialist nurse may strengthen the case for comprehensive integrated care in ophthalmic practice. The recommendations are based on round table presentations and discussions held in London, UK, September 2016.

Aims/hypothesis The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. Methods In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. Results There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p

For over 10 years cardiac stem cell therapy has received a considerable amount of attraction, potential, and research money. Autologous bone marrow stem cell therapy has been reported to be safe and to substantially increase cardiac function [1–4]. However, this beneficial effect is not invariably the case as shown in 2011 by the Dutch HEBE trial directed by the Interuniversity Cardiology Institute of the Netherlands together with the Netherlands Heart Foundation (ICIN/NHS) [5–7]. More importantly, the present cardiac bone marrow stem cell research trials have differed in the effect sizes they reported, for reasons that are not fully understood. A recent meta-analysis published in the British Medical Journal (BMJ) on 28 April 2014, the so-called DAMASCENE study [8], did show that many of the most promising results in the field are illusive and that the potential benefits of stem cells to treat heart disease are probably far more modest than has been presumed until now. By pooling all available results from trials of bone marrow stem cells in patients with ischaemic heart disease or congestive heart failure, a Cochrane review found slight evidence to suggest a benefit for stem-cell therapy in those populations. In pooled results from smaller randomised trials it was shown that bone marrow stem cell treatment was associated with reduced mortality (RR 0.28, 95 % CI 0.14–0.53) and less hospitalisations for heart failure (RR 0.26, 95 % CI 0.07–0.94) at follow-up exceeding 1 year. However, the quality of the evidence was considered low, and no significant differences were seen in those outcomes with shorter follow-up. Additionally, it was commented that ‘this research raises disturbing questions about ethics and research conduct and misconduct in a high-flying field’ [9]. What did the BMJ study address in depth? Nowbar from the group of Francis (Imperial College, London, UK) investigated whether discrepancies in trials of use of bone marrow stem cells in patients with heart disease account for the variations in reported effect size in improvement of left ventricular function [8]. To that purpose, the authors selected randomised controlled trials that evaluated the effect of autologous bone marrow stem cells for heart disease on mean left ventricular ejection fraction (LVEF). The trials were examined for discrepancies and categorised into the following three types: 1) discrepancies in the design-for example, conflicting statements as to whether the study was randomised; 2) discrepancies in methods and baseline characteristics-for example, sample or subgroup sizes that could not be an integer number of patients; 3) discrepancies in results-for example, conflicts between tables and figures or impossible values. In total, over 600 discrepancies in 133 reports from 49 trials were found. One of the most important findings was a remarkable association between the number of discrepancies and the reported change in LVEF with bone marrow stem cell therapy, i.e. between the number of errors and the treatment effect. The five studies with no discrepancies showed no improvement in LVEF (−0.4 %), whereas the five studies with the largest number of discrepancies (>30) showed a significant improvement in LVEF (+7.7 %). The authors had no straightforward explanation for the observed discrepancies. One possibility is that investigators might feel pressure for results to match expectations. One signal of a misguided desire to please is the phenomenon of directed editing of rounded percentages to force them to add up to 100 %. In reality, correctly rounded percentages often do not add up to 100 % when there are many categories. Secondly, exciting new treatments might be reported before full checking. One signal of this, in the neighbouring speciality of cardiomyocyte-derived stem cell therapy, is the insertion of the word ‘randomised’ into the title of the journal publication that was not present in the manuscript. There were seven controls in total, but after subtraction of the four who were not randomised and one who was randomised to stem cells but refused treatment, the number of randomised controls was only two. Thirdly, bone marrow stem cell therapy might be less effective when it is carried out in a rigidly standardised way. Institutions with less attention to detail might incorporate an unnoticed contaminant that enhances the effect of treatment, producing reports with more discrepancies. The final possibility is that in the reports with the fewest discrepancies, the LVEF effect might also have been measured with least error. If so, the true effect of bone marrow stem cells on ejection fraction is zero. What lessons can be learned from this meta-analysis. The authors strongly suggest that the following useful information can be drawn for the design of future trials of bone marrow stem cells: 1) prior registration on a public clinical trial registry should become universal and will be helpful in distinguishing unambiguously between trials that were multiply published or merely identical by coincidence; 2) reports should include a spreadsheet of all the data used for construction of the tables, so that incorrect values could be more easily identified (disclosing the individual patient data could help to correct more errors); 3) it is important for studies, when solely relying on changes in LVEF as an endpoint, to be properly designed to resist error and to have adequate sample size to ‘beat’ the effects of biological variability. LVEF is a changeable variable, which in some modalities is easily manipulated innocently by clinicians who have prior beliefs on what a realistic value should be for a particular patient. Sample size planning can sometimes be erroneously omitted when clinicians are enthusiastic to demonstrate the effectiveness of a treatment seen as exciting. These astonishing findings call into question the validity of cardiac stem cell therapy; is it as beneficial as has been proclaimed? Recently two important papers from the stem cell expert group led by Piero Anversa (Boston, USA), one published in Circulation in 2012 [10] and one in the Lancet in 2011 [11], have been discredited as a result of an ongoing investigation at Harvard Medical School and Brigham and Women’s Hospital in Boston. As a result of this investigation, the Circulation paper was recently (22 April 2014) retracted by the American Heart Association because ‘the data are sufficiently compromised that a retraction is warranted’ [10]. The Lancet, which published the SCIPIO study in 2011 (also from the Boston group) [11, 12], issued a formal Expression of Concern in March of this year. Francis and colleagues had already issued a warning about this in 2013 [13], when they expressed devastating critiques of multiple papers from the German research group directed by Strauer [14], and the C-CURE study published in the Journal of the American College of Cardiology (JACC) [15]. To summarise, the current meta-analysis in BMJ clearly shows that any reports of trials of bone marrow stem cell therapy contain factual discrepancies. Avoiding discrepancies is difficult but is important because discrepancy count is related to effect size. Trials with over 30 discrepancies report a large effect size, whereas trials with fewer discrepancies have found progressively smaller effect sizes, culminating in discrepancy-free trials reporting an effect size of zero. The mechanism is still unknown but should be explored in the design of future bone marrow stem cell trials. Consequently, there is an obvious need for large-scale, adequately powered studies with well-defined participant cohorts and long-term follow-up to confirm (or refute) the beneficial effects of bone marrow stem cells in terms of improved cardiac function, less hospitalisations and reduced mortality.

© 2017 The Author(s). Background: Despite the expansion of conventional medical treatments for headache, many sufferers of common recurrent headache disorders seek help outside of medical settings. The aim of this paper is to evaluate research studies on the prevalence of patient use of manual therapies for the treatment of headache and the key factors associated with this patient population. Methods: This critical review of the peer-reviewed literature identified 35 papers reporting findings from new empirical research regarding the prevalence, profiles, motivations, communication and self-reported effectiveness of manual therapy use amongst those with headache disorders. Results: While available data was limited and studies had considerable methodological limitations, the use of manual therapy appears to be the most common non-medical treatment utilized for the management of common recurrent headaches. The most common reason for choosing this type of treatment was seeking pain relief. While a high percentage of these patients likely continue with concurrent medical care, around half may not be disclosing the use of this treatment to their medical doctor. Conclusions: There is a need for more rigorous public health and health services research in order to assess the role, safety, utilization and financial costs associated with manual therapy treatment for headache. Primary healthcare providers should be mindful of the use of this highly popular approach to headache management in order to help facilitate safe, effective and coordinated care.

Background Magnesium plays a key role in maintaining internal homeostasis through actions in the musculoskeletal, nervous, endocrine and cellular messenger systems. Renal excretion is the major route of magnesium elimination from the body. A positive magnesium balance would be expected in renal failure. However, a compensatory decrease in tubular reabsorption is expected to operate to maintain adequate urinary magnesium excretion even when glomerular filtration rate is very low. Patients with end-stage renal disease and those on dialysis have impaired regulatory mechanisms, predisposing them to disturbances in magnesium levels. The effects of high or low magnesium can have deleterious health outcomes, which impact on the co-morbidities and outcomes of chronic renal disease. This systematic review aims to determine the prevalence and clinical outcomes of magnesium disorders in end-stage renal disease. Methods/Design We will undertake a comprehensive search of various databases, MEDLINE, PubMED, EMBASE, Cochrane Library, Cochrane Collaboration, CIHNAL (Ebsco), Web of Science and Google Scholar, for observational studies and clinical trials on magnesium disorders in end-stage renal disease using key terms to identify papers for inclusion. Paper selection and data extraction (where appropriate) will be performed in duplicate on socio-demographic characteristics of participants, diagnosis of end-stage renal disease, magnesium levels, prevalence and clinical outcomes. An assessment of quality will be performed using a modified Newcastle-Ottawa Scale (NOS), including identification of any bias, which may influence findings. Data will be pooled together according to whether the studies were on pre-dialysis, hemodialysis or peritoneal dialysis participants. References from individual papers will also be screened as appropriate. Paper organisation and data extraction and analysis will take place using Microsoft Excel® and Stata version 13®. Discussion This systematic review will represent a significant effort at pooling together information on prevalence and outcomes of magnesium disturbances amongst end-stage renal disease patients, which may guide further research and management of the disorders. Systematic review registration PROSPERO: CRD42014014354 Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0063-x) contains supplementary material, which is available to authorized users.

According to national and international guidelines, achieving and maintaining asthma control is a major goal of disease management. In closely controlled clinical trials, good asthma control can be achieved , with the medical treatments currently available, in the majority of patients , but large population-based studies suggest that a significant proportion of patients in real-life setting experience suboptimal levels of asthma control and report lifestyle limitations with a considerable burden on quality of life. Poor treatment adherence and persistence, failure to use inhalers correctly, heterogeneity of asthma phenotypes and associated co-morbidities are the main contributing factors to poor disease control. Now, it is widely accepted that peripheral airway dysfunction , already present in patients with mild asthma, is a key contributor of worse control. The aim of this paper is to investigate the association between small-airways dysfunction and asthma symptoms/control. We therefore performed a PubMed search using keywords : small airways; asthma (limits applied: Humans, English language) and selected papers with a study population of asthmatic patients, reporting measurement of small-airways parameters and clinical symptoms/control.

Background Inflammatory bowel disease is an idiopathic chronic disease that affects around 28 million people worldwide. Symptoms are distressing and have a detrimental effect on patients’ quality of life. A possible link between exacerbation of symptoms and psychological factors has been suspected but not established. Previous reviews concerned with this link had conceptual and methodological limitations. In this paper we set out a protocol that lays the foundations for a systematic review that will address these shortcomings. The aim of this review is to provide researchers and clinicians with clarity on the role of psychological factors in inflammatory bowel disease symptom exacerbation. Method/design We will identify all original, published, peer reviewed studies relevant to the topic and published in English from inception to November 2012. The databases MEDLINE, EMBASE, CINAHL and PsychINFO will be systematically searched. The search terms will include: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, psychological stress, mental stress, life stress, family stress, hassles, social stress, coping, mood disorders, anxiety and depression in sequential combinations. Studies will be screened according to predetermined inclusion and exclusion criteria by two reviewers. We will include clinical prospective cohort studies of all human participants aged 18 years or over with a diagnosis of inflammatory bowel disease. All eligible papers will be independently and critically appraised using the Critical Appraisal Skills Programme (CASP) tool by two reviewers. Two reviewers will independently extract and synthesise data from the studies using a predefined data extraction sheet. Disagreements will be resolved by discussion between reviewers and a third party will be consulted if agreement is not reached. Synthesised data will be analysed using Bradford Hill criterion for causality. If data permits, meta-analysis will be performed. Discussion This study will provide the most comprehensive review and synthesis of current evidence around the link between psychological factors and symptom exacerbation in inflammatory bowel disease. Results will inform clinicians in appropriate intervention development for this patient group that would reduce symptom exacerbation and therefore improve patients’ quality of life.

Background Continuous positive airway pressure (CPAP) is typically recommended as first line therapy for obstructive sleep apnea, but the adherence rate of CPAP is problematic. This study’s objective was to systematically review the literature relating to CPAP as first line therapy for OSA and compare it to surgical literature on the same topic. Methods A systematic review was conducted according to PRISMA guidelines, examining Medline-Ovid, Embase, and Pubmed databases. The primary search objective was to identify all papers reporting the results of (1) randomized clinical trials (RCT) of CPAP for the treatment of adults with OSA; and (2) both randomized and non-randomized clinical trials and case series on the surgical treatment of OSA in adults. A PhD-level biostatistician first screened papers, and then those that met study criteria were retrieved and analyzed using standardized forms for each author. The primary outcomes were adherence rates of CPAP. Results A total of 82 controlled clinical trials for CPAP and 69 controlled and non-controlled surgery trials were identified for analysis. Variation in CPAP use within reported RCT trials were identified, and the majority of patients in the studies would eventually be considered non-adherent to CPAP. Conclusions When considering the numerous patient-related factors that come into play when CPAP is prescribed, the concept of CPAP as gold-standard therapy for OSA should be reconsidered. In many cases surgery can provide a better overall outcome. This study’s results suggest that certain patients with OSA may be managed more effectively with surgery than CPAP, without confounding issues of treatment adherence. Electronic supplementary material The online version of this article (doi:10.1186/s40463-016-0136-4) contains supplementary material, which is available to authorized users.

Acute respiratory distress syndrome (ARDS) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension (PH). Multiple factors may contribute to the development of PH in this setting. In this review, we report the results of a systematic search of the available peer-reviewed literature for papers that measured indices of pulmonary haemodynamics in patients with ARDS and reported on mortality in the period 1977 to 2010. There were marked differences between studies, with some reporting strong associations between elevated pulmonary arterial pressure or elevated pulmonary vascular resistance and mortality, whereas others found no such association. In order to discuss the potential reasons for these discrepancies, we review the physiological concepts underlying the measurement of pulmonary haemodynamics and highlight key differences between the concepts of resistance in the pulmonary and systemic circulations. We consider the factors that influence pulmonary arterial pressure, both in normal lungs and in the presence of ARDS, including the important effects of mechanical ventilation. Pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient (TPG) depend not alone on the intrinsic properties of the pulmonary vascular bed but are also strongly influenced by cardiac output, airway pressures and lung volumes. The great variability in management strategies within and between studies means that no unified analysis of these papers was possible. Uniquely, Bull et al. (Am J Respir Crit Care Med 182:1123–1128, 2010) have recently reported that elevated pulmonary vascular resistance (PVR) and TPG were independently associated with increased mortality in ARDS, in a large trial with protocol-defined management strategies and using lung-protective ventilation. We then considered the existing literature to determine whether the relationship between PVR/TPG and outcome might be causal. Although we could identify potential mechanisms for such a link, the existing evidence does not allow firm conclusions to be drawn. Nonetheless, abnormally elevated PVR/TPG may provide a useful index of disease severity and progression. Further studies are required to understand the role and importance of pulmonary vascular dysfunction in ARDS in the era of lung-protective ventilation.