Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of a metabolic syndrome. To date, liver biopsy has been the gold standard used to differentiate between simple steatosis and steatohepatitis/fibrosis. Our aim was to compare the relevance of serum non-invasive parameters and scoring systems in the staging of liver fibrosis and non-alcoholic steatohepatitis (NASH) in patients with NAFLD.A total of 112 consecutive patients diagnosed with NAFLD were included. A liver biopsy was performed on 56 patients. The Kleiner score was used for the staging and grading of the histology. Non-invasive parameters for fibrosis ; and inflammation (M30 and M65 cytokeratin-18 fragments) were measured and calculated. The same analyses were performed in 56 patients diagnosed with NAFLD, who were not indicated for liver biopsy. Based on the liver histology, NASH was diagnosed in 38 patients; simple steatosis in 18 patients. A cut-off value of 750 U/L of serum M65 discriminated patients with and without NASH with a 80% sensitivity and 82% specificity (95% CI:57–95). Fibrosis stage F0–F2 was present in 39 patients; F3–F4 in 17 patients. Serum concentrations of hyaluronic acid were higher in patients with advanced fibrosis (p<0.01); a cut-off value of 25 µg/l discriminated patients with F3–F4 with a 90% sensitivity and 84% specificity from those with F0–F2 (95% CI:59–99). When applying the non-invasive criteria to those patients without a liver biopsy, NASH could only be diagnosed in 16%; however, advanced fibrosis could be diagnosed in 35% of them.In patients with NAFLD, non-invasive serum parameters with a high accuracy can differentiate those patients with NASH and/or advanced fibrosis from those with simple steatosis. A substantial portion of those patients not indicated for liver biopsy might have undiagnosed advanced fibrosis. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of a metabolic syndrome, a disease affecting a substantial portion of modern populations Whereas simple liver steatosis is regarded as a benign condition, NASH can be a progressive liver disease leading to fibrosis and ultimately to cirrhosis. A liver biopsy has long been the only method for NASH diagnosis and for the staging of liver fibrosis. However, there are several drawbacks associated with this procedure. A liver biopsy is an invasive diagnostic method which is distressing to patients. Although it is generally safe, there is some unavoidable risk of major complications (1−3% of patients) or even fatal ones (0.01% of patients) Several non-invasive tools and methods have been developed to predict NASH, or to quantify liver fibrosis without having to resort to a liver biopsy. They are either based on an assessment of single substances, or on the calculation of specific scores. Only a minority of these have been externally validated on large numbers of patients. From the large spectrum of biomarkers tested, cytokeratin-18 fragments have shown the most consistent results for differentiating NASH from steatosis BMI, AST to ALT Ratio, Diabetes mellitus) Original European Liver Fibrosis) Enhanced Liver Fibrosis) panels In addition to the necessity to differentiate NASH from simple steatosis, another necessary goal is the non-invasive assessment of liver fibrosis. For the individual patient, the stage of fibrosis is probably the most important prognostic factor. Moreover, early recognition of cirrhosis enables regular screening for the development of portal hypertension and hepatocellular carcinoma. Many serum tests and scores have been developed, with some of them only available commercially. There are simple tests based on routinely available biochemical markers such as: AST/ALT ratio The aim of our prospective study was to compare the relevance of serum hyaluronic acid levels and other non-invasive scoring systems  A total of 112 patients with NAFLD were included in the prospective study. The patient population was recruited from all consecutive patients referred to the 4th Department of Internal Medicine of the General University Hospital in Prague between 2010 and 2013, and in whom a diagnosis of NAFLD had been confirmed. The clinical and laboratory data were either collected from the time of liver biopsy or from the time of confirmation of NAFLD in those patients not indicated for liver biopsy. As inclusion in the study did not involve any especially invasive examination (only blood sampling coupled with the regular blood check), after careful explanation, no patients declined inclusion. The indication for liver biopsy depends solely on the clinical situation and the patient's decision, and was not the determinant factor for inclusion in the study (see paragraph “Liver biopsy”).The diagnosis of NAFLD was based on liver histology in 56 patients with an available liver biopsy, and on clinical and laboratory parameters in the remainder of the patients. These clinical and laboratory parameters included: 1) elevated levels of ALT, AST, GGT; the presence of steatosis, fibrosis, or cirrhosis on abdominal ultrasound, and 2) a clinical situation compatible with NAFLD (i.e. the presence of metabolic syndrome or certain components of this syndrome), and exclusion of another etiologies of liver disease 9/L) × 100 9/L) × ALT (IU/l); the NAFLD fibrosis score 9/L) −0.66 × albumin (g/dl); and the BARD score  as the sum of the following three values: BMI>28 = 1 point, AST/ALT >0.8 = 2 points, diabetes = 1 point The scoring systems examined for the presence of liver fibrosis were calculated on the basis of following formulae: APRI was calculated as AST  was measured by immunonephelometry (Behring Nephelometer II), and inflammatory cytokines  by Luminex technology . Adiponectin, leptin, and insulin were measured by the ELISA technique . Serum HA was measured using a method of latex agglutination . M30 and M65 levels were measured by commercially available ELISA tests . Blood for laboratory examination was collected on the same day as the biopsy was performed.For sample size determination, we used an estimation based on the AUROC evaluation for single parameters. To reject the null hypothesis, AUC = 0.50 on the 0.05 significance level with the test power at 80%, the sample size is n = 16 in each group.The results are presented as the mean values with the standard deviation. Either a two-sample t-test or the Mann-Whitney rank test for non-Gaussian distributed variables were used to estimate the intergroup differences. The correlations between different parameters were evaluated by Pearson resp. Spearman correlation coefficient and linear regression. The Chi-square test, resp. Yates's corrected chi-square test was used for frequency table analyses. All tests were two-sided with p<0.05, considered statistically significant. Receiver operating characteristic curve analysis was used to assess the utility of different non-invasive parameters in the discrimination between those patients with/without significant fibrosis or with/without steatohepatitis. The statistical analyses were performed using BMDP Statistical Software (Release 8.1.) and MedCalc software.NAFLD was diagnosed in 112 patients −79 males and 33 females. Both gender groups exhibited no differences in both the anthropometric, biochemical parameters, and/or the fibrosis stage (data not shown). The male patients had significantly lower ages compared to the females .The clinical and laboratory parameters of all patients with NAFLD as well as the controls are given in Histological signs of NASH were present in 38 patients, with simple steatosis in the remaining 18 patients. Clinical and laboratory data of these two subgroups are presented in The entire group was subdivided into the histological stage of fibrosis see . FibrosiTo discriminate between significant liver fibrosis (F3+F4) and mild to moderate or no fibrosis (F0–F2), the sensitivity and specificity were calculated for the different parameters. The most significant parameter for this discrimination was serum HA concentration  There are two aspects in the evaluation of steatosis/steatohepatitis in patients with NASH. Although the steatosis could be diagnosed by imaging techniques such as ultrasound, its sensitivity is not high enough Another important finding in this study was that a single biochemical parameter (HA serum concentration) was able to discriminate between NAFLD patients with or without significant liver fibrosis. HA cut-off values of 20−30 µg/g were similar to the results of other authors Similar results regarding fibrosis detection were recorded with the OELF and ELF scores. However, it remains questionable if specific and costly laboratory examinations used for OELF and ELF (PIINP and TIMP-1) can be transferred into routine daily medical practice. The other scores that were calculated in our study correlated closely to the stage of fibrosis; however, the discrimination values did not reach a satisfactory accuracy, having had low sensitivity and specificity (data not shown). Surprisingly, this was also the case with the NAFLD fibrosis score, which is endorsed by current AASLD guidelines There are also novel approaches to build-relevant panels for non-invasive fibrosis assessment; for instance, the use of non-linear machine learning techniques Another interesting observation concerns the high percentage of possible advanced fibrosis in patients not indicated for liver biopsy. In our study, liver biopsies confirmed NASH in 38 patients . Based on a M65 threshold value of 750 U/l, NASH was probably present in 65% of patients . To the contrary, in patients not indicated for liver biopsy  NASH would be diagnosed in only 16% (!!) of patients. Significant fibrosis was described from biopsies in 17 patients . When using the simple non-invasive test  significant fibrosis would be considered in 29% of patients . In patients not indicated for liver biopsy, the same percentage as in the biopsy group (35%) fulfilled the criteria for significant fibrosis. This data could indicate that the basic clinical and laboratory parameters used in routine practice, when considering the indication to liver biopsy, could select for patients having steatohepatitis; however, a remarkable proportion of those patients with liver fibrosis might elude a proper diagnosis. Our observation documents the fact that diagnosis of significant fibrosis, when based on routine liver function tests and standard ultrasonography, is not appropriate.One of the limitations of our study appears to be the fact that not all patients had a liver biopsy performed. Nevertheless, the group of patients without a liver biopsy, which had the same battery of biochemical and clinical examination as those patients with a biopsy available, is interesting for many reasons. First, worldwide, hepatologists face this problem in their daily practice. This is due to the lack of strict criteria existing for an indication for a liver biopsy, as well as not all patients indicated for liver biopsy being willing to undergo such an invasive procedure. Selection of our patients was not based on randomization, but rather depended on the clinical situation. As the application of non-invasive criteria for NAFLD/NASH/fibrosis diagnosis to these patients showed, the selection directed most of the patients with NASH toward a liver biopsy. Among patients without a biopsy, only 15% patients presented with a M65 value corresponding to NASH. By contrast, when considering the non-invasive diagnosis of fibrosis, an even higher percentage of patients without biopsy (compared to those with biopsy) had values corresponding to significant fibrosis . This emphasizes the need to follow and accurately examine those patients with suspected NAFLD but not indicated for a liver biopsy. Paradoxically, the fact that biopsy was not performed in all of our patients and that the selection of this group was affected by factors common in routine clinical practice is one of the most interesting findings in our study!In conclusion, our study supports the use of non-invasive parameters such as HA, OELF and ELF scores, or cytokeratin-18 fragments in diagnosing of NASH/fibrosis in those patients with NAFLD. It should be emphasized that a high percentage of patients not undergoing a liver biopsy (for a variety of reasons) might have significant fibrosis.Table S1Clinical and laboratory data in patients with different stages of liver fibrosis.(DOC)Click here for additional data file.


Increased mortality rates in patients sustaining hip and vertebral fractures are well documented; however in distal radius fracture patients the results are conflicting. The aim of this study was to examine short- and long-term mortality in distal radius fracture patient in comparison with the background population. Patients aged ≥50 years with distal radius fracture living in Southern Norway who suffered a fracture in the two year period 2004 and 2005 were included in the study. The mortality risk of the standard Norwegian population was used to calculate the standardized mortality ratio (SMR). The number of distal radius fractures was 883 (166 men and 717 women). Mean age was 69 years (men 65 years and women 70 years). After one year the overall mortality rate was 3.4% (men 5.4% and women 2.9%) and after five years 4.6% (men 4.0% and women 4.8%). The SMR for men and women compared to the Norwegian population for the first year was 1.6 : 0.6, 2.7) and 0.9 , respectively, and after five years 1.7  and 2.0 . Stratified on age groups (50–70 and >70 years) an increased SMR was only seen in female patients aged >70 years five years after the fracture . In conclusion, increased SMR was found in female patients aged >70 years five years after the distal radius fracture, but not in men or in women younger than 70 years. Distal radius fracture is one of the most common osteoporotic fractures in middle-aged and older men and women Increased mortality rates in patients sustaining hip and vertebral fractures are well documented Thus, the aim of this study was to evaluate the short- and long-term mortality after distal radius fracture in males and females in Southern Norway, and to compare it with the background Norwegian population.The study was approved by the Regional Committee for Medical Research Ethics for Southern and Eastern Norway.th Revision (ICD-10) in the two year recruitment period. For all individuals diagnosed with a distal radius fracture, data on sex, birth, and place of residency were collected. Further, we examined the patients' medical- and X-ray records to confirm the distal radius fracture diagnosis. As previously described, a high- or a low-energy fracture was determined based on information when reviewing the medical records Annual incidence data on distal radius fracture from Southern Norway in individuals aged 50 years and older has previously been reported for the two year period 2004 and 2005 st, 2009 and 2010.The follow-up time for the distal radius fracture patients was from the month when the fracture occurred to death, or to the censoring dates of January 1Distal radius fracture mortality rates were calculated for the first and the fifth year, for all, separately for each gender, and for the age groups 50–70 and >70 years. The 70 years cutoff was chosen as it was close to the mean age of our patients. To calculate the standardized mortality ratio (SMR), the mortality risk of the standard Norwegian population was used As previously reported Data on mortality rates and SMR are given in Data on mortality rates and SMR by sex and age groups are presented in The results did not substantially change when only low-energy distal radius fractures where included in the analyses as shown in In this study compared to the general population increased SMR after five years follow-up was only found in female distal radius fracture patients aged >70 years and was not found in men or in women younger than 70 years. One year follow-up did not show any significant elevated mortality rates either for men or for women with distal radius fracture.Our one year follow-up mortality data are in accordance with Endres et al. Most of the studies investigating mortality in distal radius fracture patients have not detected any differences compared to the general population The conflicting findings may be explained by different study design, unlike definition of distal radius fracture and thus inclusion of patients, as well as differences in frailty or comorbidities, and thus the risk of fall. Unfortunately, we did not have any information on frailty, previous falls, comorbidities and other risk factors associated with mortality, or causes of death. Therefore, our study does not identify whether or not distal radius fracture is an independent risk factor in middle-aged and older women five years after the fracture. Rozental et al. Our study has limitations. The numbers of distal radius fractures may have been underestimated due to the retrospective study design as the diagnosis system may not have identified all distal radius fracture patients due to wrong ICD-10 coding. Nonetheless, a retrospective study design may be superior to a prospective one. We have previously in a hip fracture study shown that more patients were identified retrospectively using the ICD-10 diagnosis code system compared to when patients were identified prospectively Previous data have showed a high prevalence of low bone mineral density In conclusion, increased SMR was found in female patients aged >70 years five years after the distal radius fracture, but not in men or in women younger than 70 years. Distal radius fracture in older women may thus be a clinical marker of poor future outcome and health.


CYP2D6 genotype have been developed. The CYP2D6 Screening Among Elderly (CYSCE) trial is designed to address the potential health and economic value of genotyping for CYP2D6 in optimizing dose-finding of nortriptyline and venlafaxine.Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotyping determined in peripheral blood obtained by finger-prick, patients will be grouped into poor, intermediate, extensive, or ultrarapid metabolizers. Patients with deviant genotype  will be randomly allocated to an intervention group in which the genotype and dosing advice is communicated to the treating physician, or to a control group in which patients receive care as usual. Additionally, an external reference group of patients with the extensive metabolizer genotype is included. Primary outcome in all groups is time needed to obtain an adequate blood level of the antidepressant drug. Secondary outcomes include adverse drug reactions measured by a shortened Antidepressant Side-Effects Checklist (ASEC), and cost-effectiveness of the screening.In a pragmatic randomized controlled trial, patients diagnosed with a major depressive disorder according to the DSM-IV and aged 60 years or older will be recruited from psychiatric centers across the Netherlands. After Results of this trial will guide policy-making with regard to pharmacogenetic screening prior to treatment with nortriptyline or venlafaxine among older patients with depression.NCT01778907; registration date: 22 January 2013.ClinicalTrials.gov: The online version of this article (doi:10.1186/s13063-015-0561-0) contains supplementary material, which is available to authorized users. Depressive disorder is a chronic disease with a considerable impact on mental and physical health as well as quality of life . The 1-mMDD can be treated with antidepressants, which are classified into different groups: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressant (TCAs) and others , mirtazapine, monoamine oxidase inhibitors). Although overall efficacy estimates are virtually similar between these drug groups, adverse drug profiles differ . WorldwiCYP2D6 based on genetic material, it is not dependent on the actual antidepressant intake (patient compliance) or collection time of the sample, like TDM samples are.Venlafaxine and nortriptyline are both metabolized by the polymorphic cytochrome P450 (CYP2D6) iso-enzyme . Its polFor nortriptyline and venlafaxine genotyped-based dose adjustment guidelines have been formulated ,12,13. ICYP2D6 on the time needed to obtain adequate blood levels of nortriptyline or venlafaxine. Since older persons are more vulnerable for adverse drug reactions, beneficial effects of genotype adjusted dosing are expected to be more apparent in this population. Therefore, the trial is conducted among older depressed patients starting with nortriptyline or venlafaxine. The cost-effectiveness of this screening will be assessed to support decision-making on the potential implementation of screening for CYP2D6 genotype in daily clinical practice. The trial is designed to allow reporting according to the CONSORT guidelines [Despite the large number of studies that assessed the relationship between pharmacogenetics and pharmacokinetics of antidepressants, implementation of pharmacogenetic knowledge into clinical practice is still scarce. The hypothesized clinical improvements facilitated by genotype-based dose adjustments in addition to current TDM, like improved efficacy and prevention of adverse drug reactions, are still a matter of controversy and discussion ,17. Theridelines .The study is a multicenter randomized controlled trial across multiple old age psychiatry and geriatric mental health care institutions in the Netherlands. Patients will be recruited by their treating physician or a specialized trial nurse. The study consists of two parts and for both parts separate written informed consent will be obtained. The first part is a basic genotype screening study in which each eligible patient (see description in Participants below) starting with nortriptyline or venlafaxine will be asked permission for genotyping. Patients with a PM, IM and UM genotype will be selected for participation in the second  part of the study. After giving the second informed consent, the trial entails a follow-up period of 6 weeks or longer in order to monitor the blood levels and adverse reactions of either nortriptyline or venlafaxine. A random selection of patients with an EM genotype will be allocated to an additional reference group Figure . RecruitDiagnostic and Statistical Manual of Mental Disorders, fourth edition text revision (DSM-IV TR) [Patients 60 years or older and diagnosed with a major depression according to the M-IV TR) , criteriM-IV TR) .CYP2D6 gene. Presence of an allele that completely lacks enzyme activity  paired with another allele completely lacking enzyme activity results in a PM phenotype prediction and in an IM phenotype prediction if paired with an allele with decreased enzyme activity . Presence of only one allele lacking enzyme activity, or two alleles with decreased enzyme activity also results in an IM phenotype prediction. Duplications of the CYP2D6 gene results in an UM phenotype prediction unless it is combined with any allele with reduced or lacking enzyme activity. Duplications combined with any allele with reduced or lacking enzyme activity results in exclusion of the patient from follow-up because no adequate dosing advice can be given for these genotypes. After inclusion, genotype information will be available for randomization within 6 to 9 days.In the first part of the study, a DBS sample for genotyping will be taken at the time of prescription of nortriptyline or venlafaxine by means of a finger-prick . The samBaseline assessment will include a severity of depression score measured by the Montgomery-Asberg Depression Rating Scale and measurement of symptoms which are followed-up as adverse events during the further trial . In addiCYP2D6 are expected to be found in approximately 30% of the population [After the genotype is determined, patients with a PM, IM, or UM genotype are selected and randomly allocated by computer to the ‘deviating genotype-intervention arm’ (DG-I) or ‘deviating genotype-control arm’ (DG-C) for participation in the main study Figure . An addipulation . TherefoThe DG-I arm includes patients with a PM, IM, or UM genotype. The specific genotype accompanied by dosing advice is directly communicated to the treating physician. This should preferably take place 14 days after inclusion. The dosing advice is based on the genotype and drug only, meaning some standard advice depending on these two variables is given by an automatically generated message  , qualityBased on clinical experience in the research setting it is expected that on average it takes 4 weeks for patients with a deviating genotype to reach adequate serum drug levels. It is hypothesized that time to reach adequate levels will be reduced by 50% (2 weeks) if we provide the screening information to the physician within 6 to 9 days. To obtain 90% power to detect a 50% reduction from 4 to 2 weeks (SD 3 weeks) with a type-1 error of 2.5% to account for multiple testing , a minimum of 48 patients per arm is needed. To account for loss to follow-up we intend to include at least 75 patients per arm.Reporting and analysis of the data from this trial will be in accordance with the CONSORT 2010 guidelines .t-tests or non-parametric alternatives for continuous variables and Chi-square tests for categorical variables.Baseline characteristics will be presented using descriptive statistics including means or medians for continuous variables and percentages for categorical variables. Analytical statistics to estimate difference between the group of patients who were lost to follow-up versus patients who completed the trial as well as between the different study arms will be determined by t-test or a non-parametric alternative if not normally distributed. Analysis of variance (ANOVA) or Kruskal-Wallis test will be applied to test for potential differences between the trial groups and the external reference group.The primary analysis will assess the mean time needed to obtain adequate drug levels. The first time drug blood levels are within the therapeutic range and dose is not increased or decreased in the following 3 weeks is the moment that is considered as the time needed to obtain adequate drug levels. Mean differences in time to reach adequate drug levels between trial groups will be estimated using the Secondary analysis will focus on statistical differences in median number and severity scores of side-effects of the drug. Since the side-effect profile is different for nortriptyline and venlafaxine, these analyses will be drug-specific.Effects and costs will be determined from a societal perspective including both indirect and direct costs. Data on health care associated resource use will be collected and effects on productivity and quality of life (EQ5D) will be investigated. To determine the incremental cost-effectiveness ratio for intervention versus control strategy from a societal perspective, guideline unit costs will be linked to these resource use data. Incremental cost-effectiveness will be calculated using state-of-the-art methods including uncertainty analysis , scenario analysis, (probabilistic) sensitivity analysis and presentation in cost-effectiveness acceptability curves.CYP2D6 polymorphism genotyping among older depressed patients starting with nortriptyline or venlafaxine in clinical practice adds value to regular care. Results of this trial will generate evidence as to whether routinely-based genotype testing can reduce the time needed for dose-finding at the start of treatment and as a result reduce adverse drug reactions.To the best of our knowledge, this is the first pragmatic randomized controlled trial designed to test whether A possible limitation of this study is that the genotype information is given to the physician after treatment with the antidepressant has already been started for several days. For the purpose of this trial, it would be ideal to give the genotype information before treatment has started. However, in clinical practice due to the urgency of the disease, time between initiating a therapy with nortriptyline or venlafaxine and actual start is limited. Waiting for the genotype information before starting pharmacotherapy could delay pharmacotherapy and is, therefore, unwanted. Nevertheless, an effect of genotype is still expected, because at start of treatment a low dose is generally prescribed. When the treating physician has to evaluate therapy and to decide if the dosage should be increased, the genotype information will be available .Another limitation of this study is the study domain represented by a heterogeneous group of severely depressed patients, since the disease shows much variation in symptomatology, severity and co-existing psychiatric diseases like anxiety disorders and physical diseases, especially in secondary care . HoweverFurthermore, the drug concentration-effect relationship for venlafaxine is still a subject of debate . This isStrengths of this study are the random allocation of subjects to receive genetic information that avoids incomparability of groups, strict protocolled design with regular measurements, and a large number of patients to detect statistically significant differences. We also included an external control arm (NG-C) including patients with the EM genotype. This ensures physicians do not know the genotype of control patients or that it deviates from EM.CYP2D6 screening may be underestimated in this trial, since the genotype is a lifelong characteristic and is, therefore, affecting the metabolism of many other drugs than the drugs studied in this trial. We only look at a short drug-specific time effect in this study; however, it is not unlikely that patients might benefit from their genotype information during further pharmacotherapy.The overall impact of The recruitment of patients started in spring 2013 and is expected to continue until spring 2016.


Indirect comparison (IC) and direct comparison (DC) of four inhaled corticosteroid (CS) treatments for asthma were conducted, and the factors that may influence the results of IC were investigated. Among those factors, we focused on the effect of common comparator selection in the treatment of asthma, where little control group bias or placebo effect is expected.IC and DC were conducted using the change from baseline in forced expiratory volume in 1 s (FEV1(L)) as an outcome parameter. Differences between inhaled CS were evaluated to compare the results of IC and DC. As a common comparator for IC, placebo (PLB) or mometasone (MOM) was selected. Whether the results of IC are affected by the selection of a common comparator and whether the results of IC and DC are consistent were examined.23 articles were identified by a literature search. Our results showed that ICs yielded results similar to DCs in the change from baseline of FEV1(L). No statistically significant difference was observed in inconsistency analysis between ICs and DCs. It was clinically and statistically confirmed that ICs with PLB and those with MOM did not differ in terms of the results of FEV1(L) analysis in this dataset.This study demonstrated that ICs among inhaled CS can deliver results consistent with those of DCs when using the change from baseline in FEV1(L) as an outcome parameter in asthma patients. It was also shown that using an active comparator has similar results if there is no effect of control group bias. It should be emphasized that the investigation of control group bias is a key factor in conducting relevant ICs so that an appropriate common comparator can be selected. Indirect comparison (IC) analysis has recently been recognized as an alternative method for investigating the efficacy and safety of target interventions when head-to-head comparison data are not available. The number of studies reporting the results of ICs and network meta-analysis is increasing. ICs areIn response to the above, recently the International Society for Pharmacoeconomics and Outcomes Research—Academy of Managed Care Pharmacy—National Pharmaceutical Council (ISPOR-AMCP-NPC) Good Practice Task Force has proposed using a consensus-based 26-item questionnaire to help decision makers assess the relevance and credibility of ICs of treatment options and network meta-analysis to help inform healthcare decision making[We previously reported an IC study of antipsychotics to investigate factors that may influence the results. ControlWe also pointed that a well-defined endpoint should be used for IC analysis to obtain consistent results. At the same time, little control group bias and placebo effect is expected for inhaled corticosteroid (CS) studies in asthma because objective assessments such as spirometry measurement are commonly used for assessing the efficacy of inhaled CS, while subjective assessments are generally used for evaluating psychiatric diseases such as schizophrenia, depression, and anxiety disorders. In this paper, we not only report IC and DC results but also investigate factors that may influence the outcomes of IC to highlight points for consideration to ensure that it yields credible results. As one such factor, we focused on the effect of common comparator selection using inhaled CS studies for the treatment of asthma as an example.A literature search was conducted in PubMed and Embase, using the key words “fluticasone,” “budesonide,” “beclomethasone,” “mometasone,” “forced expiratory volume,” and “asthma.” Those four interventions were selected because inhaled CS is recommended as the first intervention for mild-to-moderate asthma patients in the Global Initiative for Asthma guidelines that areThe search was limited to “randomized controlled trial” and conducted in December 2013. All literature published in English from January 1990 through December 2013 was searched. After screening the search results, reports using similar doses and treatment periods ranging from 4 to 26 weeks were selected. If inhaler devices were different, for example, aerosol and dry-powder inhalers, it was first determined whether the conversion dosages were clinically equal. If they were equal, the data were included. Crossover studies were excluded from the analysis because the carry-over treatment effect may cause misleading results. The quality of the reports was evaluated based on the Jadad score[The primary efficacy endpoint for this analysis was the change from baseline in forced expiratory volume in 1 s (FEV1(L)) as assessed using spirometry.As a common comparator for ICs, PLB or mometasone (MOM) was selected. We first investigated whether the results of ICs were affected by the selection of a common comparator and then examined the results of ICs with PLB and DCs.2 values in meta-analysis suggested the existence of heterogeneity. In conducting IC for each analysis, we followed Bucher et al.’s method[1, D2 is the mean difference in the change from baseline in FEV1(L) obtained by meta-analysis between drug 1 or drug 2 and the common comparator; SE1, SE2 is the standard error of the mean difference in the change from baseline in FEV1(L) obtained by meta-analysis between drug 1 or drug 2 and the common comparator; DIC is the mean difference in the change from baseline in FEV1(L) between drug 1 and drug 2 obtained by IC; and SEIC is the standard error of the mean difference in the change from baseline in FEV1(L) between drug 1 and drug 2 obtained by IC.As described previously, for con’s method using meDC and DIC in a simple z-test[Dinconsis = DDC—DIC  and its 95% confidence interval (95% CI) using DC is the mean difference obtained by DC and DIC is that obtained by IC; and SEDC, SEIC is the standard error of the mean difference in the change from baseline in FEV1(L) obtained by DC and IC, respectively. Inconsistency between ICs with MOM and PLB can be calculated using the same method. The 95% CI can be calculated asThe results were used to investigate statistical inconsistencies between IC and DC results or among ICs using different common comparators. The assumption of consistency can be evaluated by comparing Dle z-test. We esti23 studies were identified by the literature search that fulfilled the selection criteria , Fig. 1.Safety endpoint analysis was not conducted in this study since no critical event has been reported with inhaled CS for acute-phase treatment, and limited safety information was available in this dataset.First, DCs between four inhaled CS and PLB or MOM were conducted. Subsequently, those DC data were applied for ICs between FP and BUD, FP and BDP, and BUD and BDP using PLB or MOM as a common comparator. The results of these analysis are shown in All head-to-head study data were used for direct analysis, allowing three DCs to be conducted . SubsequThe results of inconsistency analysis are shown in The mean change in FEV1(L) of the inhaled CS groups in all studies are shown in Inhaled CS were first launched in the 1960s and are now widely used for the treatment of asthma, recommended for both a control-based first-line treatment for mild asthma and as subsequent therapy in combination with a beta-2 agonist or leukotriene-receptor antagonist. We compared the efficacy of FP, BUD, BDP, and MOM in asthma patients using the DC and IC methods and attempted to determine the factors that may influence the DC and IC results. The effects of common comparator selection for ICs were also examined in this dataset as an example where little control group bias and placebo effect were expected. FEV1(L) change was selected as the efficacy endpoint. A previous report stated tThe 23 studies included in this meta-analysis involved patients with similar demographic characteristics, such as age, duration of disease, and baseline FEV1(L) values, which may have affected the results of DC and IC. In addition, this dataset contained only five head-to-head comparisons, although 28 reports in the literature involved comparisons with PLB. The reason for this is assumed to be sponsors’ or investigators’ intent to confirm the efficacy of a treatment intervention compared with PLB rather than to show noninferiority over an active comparator. PLB-controlled studies are easier to conduct from the viewpoints of number of patients required, approval by regulatory authorities, or investigation of the comparative safety profile of an intervention. Active-comparator studies usually require more patients when a noninferiority/superiority confirmation study is designed.No statistically significant difference was observed in inconsistency analysis between IC and DC. Clinically and statistically, ICs with PLB and MOM showed no difference in the results of FEV1(L) analysis in this dataset where no control group bias was observed. The absolute difference in FEV1(L) in point estimates ranged 0 to 0.14. A difference of 0.23 L in FEV1(L) has minimal clinical meaning in PLB-controlled trials.Inconsistent results were observed in DC and IC between BUD vs MOM. DC showed a statistically significant difference in favor of MOM, whereas IC did not. We included Corren et al.’s study for thisRegarding the selection of a common comparator, Salanti et al. addressed different PLB effects in ICs using four topical fluoride treatments and two control interventions (and no treatment) in preventing dental caries in children. They foIn pharmaceutical development, a PLB arm is frequently used to investigate the efficacy and safety of drugs, especially in dose-finding and early phase studies. However, it is less common in confirmatory phase 3 studies, especially when a difference in efficacy is apparent between PLB and active comparators. As described in detail previously, ICs canThis report highlights the importance of common comparator selection. If the effects of both control group bias and number of DCs are limited, researchers are encouraged to use IC in a head-to-head approach because it can be expected to yield results similar to DC with fewer difficulties. One of limitations of the present study is that the number of studies using DCs and ICs is limited. Therefore further investigations and examples are necessary to clarify the importance of common comparator selection. Secondary it should be noted that selecting homogeneous population could be controversial for generalizability of the result. It can allow a good control of confounder and result as we have shown, on the other hand it might hinder generalizability of the result in more various settings. This point needs to be considered as well.This study demonstrated that IC between inhaled CS can deliver results consistent with those of DC when using the change from baseline in FEV1(L) in asthma patients. It was also shown that using active comparators has similar results when control group bias is limited. It should be emphasized that determining the degree of control group bias is a key factor in conducting relevant, appropriate IC and selecting appropriate common comparators.S1 Fig(DOCX)Click here for additional data file.S1 PRISMA Checklist(DOC)Click here for additional data file.


Osteogenesis imperfecta (OI) can be a severe disorder that can be diagnosed before birth. Transplantation of mesenchymal stem cells (MSC) has the potential to improve the bone structure, growth, and fracture healing. In this review, we give an introduction to OI and MSC, and the basis for pre- and postnatal transplantation in OI. We also summarize the two patients with OI who have received pre- and postnatal transplantation of MSC. The findings suggest that prenatal transplantation of allogeneic MSC in OI is safe. The cell therapy is of likely clinical benefit with improved linear growth, mobility, and reduced fracture incidence. Unfortunately, the effect is transient. For this reason, postnatal booster infusions using same-donor MSC have been performed with clinical benefit, and without any adverse events. So far there is limited experience in this specific field and proper studies are required to accurately conclude on clinical benefits of MSC transplantation to treat OI. Osteogenesis imperfecta (OI), or brittle bone disease, is a group of genetic disorders caused mainly by defects in collagen synthesis . The majCurrently, the goal of clinical management is to optimize the patient’s gross motor abilities and to achieve a level of independence during childhood life. This is largely accomplished empirically through physical rehabilitation and life-long orthopedic interventions in correcting bony deformities of the long bones and vertebra . PharmacDue to the lack of effectiveness in current modalities of treatment, which does not address the underlying molecular defect, alternative approaches are currently being explored. Some of these experimental treatments include allogeneic cell transplantation . The genin vivo self-renewal properties  the relatively smaller cell doses required due to the size of the fetus, (ii) the shunting of the intravenously delivered cells to the arterial circulation through the patent foramen ovale in fetal life rather than being trapped in the lungs in postnatal life, and (iii) possibly the lower risks of immune rejection in the developing immune system of the recipient .oim mouse, a naturally occurring recessive mouse model approximating human type III OI, with progressive deformities and skeletal fractures  and allowed to litter naturally in this xenogeneic transplantation model in a fully immune-competent recipient  of donor osteoblast engraftment in the bone , 2001. Tlocities . Thus, ilocities . Not witlocities . Moreovelocities .Promising results of tissue repair in animal studies have led to numerous clinical studies using MSC to treat severe disorders and several reports indicate a role for MSC therapy in the treatment of OI both pre- and postnatally. As described above, 6/kg HLA-unmatched hfMSC at gestational week 31. At 4 months of age, bisphosphonate treatment was initiated due to presence of vertebral compression fractures. Until 8 years of age, she was doing acceptably well with little more than one fracture and one compression fracture per year . Remarkably she continued growing and followed her own height and weight growth curve at -5 SD until the age of 6, when it had deteriorated to -6.5 SD at the age of 8 years. Due to the increased fracture rate and declined growth, the patient was transplanted with 2.8 × 106/kg same-donor cells at the age of 8 years. The subsequent 2 years after the re-transplantation the patient did not suffer from any new fractures and the linear growth and mobility improved . Donor osteoblastic cells were detected in the bone, but not in any other tissues, at 9 months and 9 years of age. The level of engraftment was varying, between 0.003 and 16.6%. Only one other patient is currently known to have an identical COL1A2 mutation and presented with a very severe phenotype of OI. This patient did not receive MSC therapy and succumbed at 5 months of age despite postnatal bisphosphonate therapy.The first case presented at gestational week 15 and was later diagnosed as OI type III, which postnatally was confirmed with genetic analysis . No donor cells were detected in umbilical cord blood, umbilical cord, and placenta. There have been no opportunities to obtain bone samples for analysis in this case. Bisphosphonate therapy was initiated from 1 month of age due to poor mineralization. The patient followed her own growth curve until 12 months of age (just below the 3rd centile), where longitudinal length plateaued. A postnatal infusion of 10 × 106/kg MSC from the same donor was performed at 19 months of age, resulting in resumption of her growth trajectory and she continued to grow just below the 3rd centile. She started to walk shortly after the transplantation.The second case was a baby with OI type IV who presented with short long bones (<5th centile) and multiple fresh and healing fractures at 26 weeks of gestation . The babSimilarly as described in the study by Horwitz and colleagues, the above described pre- and postnatal transplantations report a transient clinical effect after hfMSC infusion , and sev6 to 30 × 106/kg at prenatal transplantation and from 2.8 × 106 to 10 × 106/kg at postnatal transplantation. All doses were well tolerated, however, it is unclear from this data on two patients or from data on adult MSC transplantation for other disorders if a high cell dose is more efficacious. This remains to be investigated.The cell dose is a critical parameter in cell transplantation since it may relate to efficacy but a high cell dose may cause toxicity. In the reported hfMSC transplantations, the cell dose varied from 5 × 10The two cases described here suggest the safety and feasibility of prenatal transplantation using HLA-mismatched hfMSC. Furthermore, it suggests a potential benefit to children with OI. However, the benefit from a single transplant before birth was transient and subsequent boosters with same-donor cells were performed with good effect. This is in line with the results from the study on postnatal MSC therapy in OI by To accurately evaluate if pre- and postnatal MSC therapy in OI is an effective treatment, coordinated studies and joint efforts are necessary. Development of common programs, registries and guidelines , as well as coherence between investigators within the field is of significant importance. Considering the complexity of the disease and procedure, we see this as the only realistic way to proceed if we are to accurately evaluate the potential of MSC therapy in OI.The summarized cases demonstrate that prenatal transplantation of allogeneic hfMSC and postnatal boosters using same-donor cells in OI is safe. The MSC infusions appear to give clinical benefit, although transiently. However, so far we have limited experience and further studies are required.Jerry K. Y. Chan and Cecilia Götherström drafted, wrote, and revised the manuscript. Both authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The laboratory and field tests demonstrate the feasibility of coupling the sensor with the UAVs. However, further work must be done in the areas of sensor selection and calibration as well as flight planning.Blasting is an integral part of large-scale open cut mining that often occurs in close proximity to population centers and often results in the emission of particulate material and gases potentially hazardous to health. Current air quality monitoring methods rely on limited numbers of fixed sampling locations to validate a complex fluid environment and collect sufficient data to confirm model effectiveness. This paper describes the development of a methodology to address the need of a more precise approach that is capable of characterizing blasting plumes in near-real time. The integration of the system required the modification and integration of an opto-electrical dust sensor, SHARP GP2Y10, into a small fixed-wing and multi-rotor copter, resulting in the collection of data streamed during flight. The paper also describes the calibration of the optical sensor with an industry grade dust-monitoring device, Dusttrak 8520, demonstrating a high correlation between them, with correlation coefficients (R Coal exports from Queensland from March 2013 to March 2014 totaled more than $24.5b [2), nitrogen, nitrogen oxides (NOx) and sulfur oxides (SOx) are the primary residues produced by blasting events at mining sites. In an ideal situation, the exothermic reaction produces CO2, water vapor and molecular nitrogen (N2); however, due to environmental and technical factors, other noxious gases are often produced in a range of concentrations [Blasting in particular includes effects such as airblast, ground vibration, flyrock, toxic gases and particulate matter ,3. Partitrations .In this paper, we propose the use of small unmanned aerial vehicles (UAV) carrying air quality sensors to allow precise characterization of blasting plumes in near-real time. This approach may lead to actionable data for harm avoidance or minimization. Most pollution dispersion models use predefined estimates of pollution sources and atmospheric conditions; near-real time information from within the plume has been practically impossible to collect. Flight instrument data transmitted as telemetry from the UAV provides high resolution instantaneous micrometeorological data that can assist interpretation of concentrations detected by on-board air quality sensors. In addition, this information including location, micrometeorological data and air quality, can be delivered in real time to analytical software. The data stream may therefore be used to feed flight path-planning algorithms or atmospheric dispersion models in near-real time.In order to assess this approach, fixed-wing and multi-rotor UAVs were used. These UAVs were developed at The University of Queensland for ecological investigations. The platforms were capable of autonomous predetermined flight path planning or semi-autonomous direction. These platforms have weight restrictions and require sensors with high temporal sampling resolution -based optical sensors due to the combination of essential characteristics including rapid response, light weight and ease of data digitization. To date, two dust sensors have been tested with the UAV (SHARP GP2Y10 and Samyoung DSM501A) .Development or modification of micro UAV platforms that can be safely operated near active mine blasts.3 PM10).Identification of sensors with necessary sampling rates (<1 s), weight (<500 g), data output format and sufficient sensitivity (1 mg/mSystem endurance sufficient to capture plume evolution and dynamics (>20 min).Integration and formatting of data streams necessary for mathematical predictive models via live telemetry.Characterizing blasting plumes and predicting dispersion using this approach requires integration of a number of factors:This project aims to develop tools that inform, cross calibrate and validate plume models for particulate and gaseous pollutants associated with blasting activities.This paper is organized as follows: et al. developed a multi-platform system using ground-based dust samplers in combination with balloon-carried samplers near open pit mines. The data collected informed multiple regression and neural network models how to monitor and predict the drifting of blast plumes [Blast-associated dust is a significant potential hazard, and novel monitoring methods are continuously explored. Roy t plumes ,8. As sat plumes .2 and PM10 emissions of coal mining in the Hunter Valley, Australia have been examined using gravimetric and LIDAR methods. LIDAR provided long-path laser-integrated concentration signal with very low limit of detection, but required a fixed location [et al. used a different approach by implementing NDIR (non-dispersion infrared) and mini-DOAS  for prediction of NOx and other pollutant gases. This method also required a fixed-location ground-based sensing apparatus. Modelling in AFTOX (Air Force toxics model) resulted in overestimation of plume concentrations at a distance [Furthermore, fugitive NOdistance .Richardson (2013) assessed particulate fractions using a scintillation probe dust sensor  and a real-time laser photometer (Dusttrak) in Hunter Valley and Central Queensland (Goonyella Riverside) and confirmed that PM2.5 is a small fraction of the overall suspended blast-associated particles, while PM10 is dominant .The method and type of sensors used to measure contaminant gas or dust emissions will vary according to the type of emission, concentration range of concern, and required response time. Sensors are commonly based on ultrasound, optical, and electrochemical sensing elements ,13,14. TA complex criteria matrix must be considered when selecting an airborne sensor to monitor blast plumes. Factors include dimensions (weight and size); tolerance of vibration and movement given mounting on a UAV platform (up to 15 m/s); concentration range of sensor as well as the accuracy and limitations of the sensor .Optical LED particulate sensors are potentially suitable devices that could be used to explore the proposed system. LED sensors have the advantages of low power consumption, high durability, compact size, and easy handling and have been tested as a reliable source light for DOAS . They al2, CH4 and water vapor [2 and NH3 [4 [et al. [2 using a NDIR gas analyzer which had a response time of 20 s. A spectrum-specific video camera has been developed to visualize SO2 emissions from volcanoes by Brown et al. [et al. integrated a multi-rotor-sensing platform that monitors air pollutants in real time and provides 3D visualization [6H6, NO2, O3, SO2, NOX and PM10, as well as thermal IR images to detect sewage discharges along the coastline of Italy [Researchers are identifying advantages of UAVs to undertake investigations in difficult terrain/landscape areas, where health and safety risks exist, or where there is a lack of resources (human and/or economic). Gas sensing with small-micro UAVs using electrochemical and optical sensors is still not well established due to rapid development of sensors and UAVs. Sensing of COer vapor , NO2 and and NH3 , ethanold NH3 [4 ,31, have [et al. , used a n et al. . Lega etlization . Severalof Italy ,35. Fixeof Italy . Target Rapid sensor response time is important in mobile sensing platforms that move relative to both air and ground.Limited power requires flight efficiency and sensors with low power consumption.Sensors that require extended duration equilibration times (~20 s) require sampling chambers, and delayed response times result in difficult or impossible flight performance required to return to the estimated plume location.Multi-rotor platforms operate via GPS, and thus approximate a ground-based sampler independent of the fluid it is sampling. Fixed-wing platforms move through a defined volume of air in a given time regardless of ground location.Moving platforms require flow control for sample chambers to ensure calibrated values can be reported.etc.), each of which have limitations to their performance [The use of mathematical models is an essential element when monitoring air quality and atmospheric contamination. Defining appropriate models given the type of data collected is important. There are several approaches commonly used for air  and DSM501A (Samyoung) for PM10. The SHARP and Samyoung sensors tested were connected through an Arduino microcontroller to integrate sensor-telemetry data streams. The sensor and associated electronics are low weight and constrained size to allow simple installation in other multi-rotor or fixed-wing platforms. The dust-sensing module was placed on the top side of the quadrotor platform to minimize high velocity air flow that is fundamental to similar quadcopters ,44. FiguThe system is constructed around an Arduino MEGA 2560, powered by a 7.4 V lithium polymer battery, data telemetry is via XBee Pro S1 (2.4 GHz) radio transmitter while a GP-635T provides a timestamp for serial port data. Sensors include a SEN51035P temperature and humidity sensor and GP2Y10 SHARP dust sensor . All datBoth a fixed-wing and a multi-rotor UAV were selected to develop the sensing system. These aerial vehicles operate in fundamentally different ways with fixed-wing UAVs traversing a set volume of air in a given time while the hovering ability of rotary-winged UAVs allow collection of data at specific locations in space and time; however, they experience wind.The suitability of three fixed-wing platforms was considered for integration with the optical and/or electrochemical sensors. All UAVs are constructed of expanded polypropylene (EPP) and composite materials that have been demonstrated as safe and robust platforms in the mining industry environment. Specifications for the models considered during this investigation are provided in All UAVs listed in The Teklite was selected as the best platform for the type of test to be conducted due to its portability, ease of integration of sensors, successful flight testing, light weight and low (<100 ft) target flight altitude. The UAV is controlled using a ground control station. The flight plan is preloaded from the ground station that displays the flight parameters of the UAV, flight route and atmospheric pollution readings in real time. The flight plan can also be modified manually using a handheld radio transmitter and/or by altering the parameters through the ground station.etc.) are used to pre-plan the UAV flight path to follow and characterize the blasting plume. If required, a flight path can be modified and uploaded into the ground station based on post-blasting observations. The UAV is restricted to fly more than 35 m above ground level as a safety factor to avoid collision with trees or infrastructure.The UAV can be flown from as far as 1.5 km from the ground control station. Weather conditions  of 0.5 and was therefore deemed an unsuitable option for the integration of the dust-monitoring module and UAVs.A gas chamber see  based onet al.  was consTests for PM10 and PM2.5 where undertaken for the SHARP dust sensor. An initial data collection test was used to correlate the raw values obtained from the sensor, which is the voltage modified by the light absorption of the receiver, with the values registered by the Dusttrak see . A lineaThe original algorithm of M. Chardon and Trefois  developeA third test was done using two SHARP sensors and the Dusttrak . An offsSensor variability due to temperature changes ,30, was The air intake and discharge were modified to produce a continuous flow inside the SHARP sensor chamber see . Air samSeveral flights were made to test the feasibility of integrating the SHARP sensor with the Teklite platform. The first test was conducted on 6 June 2014 in order to evaluate the integration of the system. The test used a fire in an open area as an airborne particulate source. The UAV was programmed to fly around the fire for approximately 30 min. Data collected from the UAV and the air quality sensor are shown in High frequency noise consistent with electrical switching of motors and servos was filtered by installing a 50 V (0.1 µF) capacitor to the power source.3/h). Talcum powder was used due to its safe handling and availability. Talcum powder is composed of 0.2–0.3 mass fraction with a particle diameter no greater than 10 µm [A second field test was conducted on 13 October 2014 using “talcum powder” lifted into the atmosphere using a petrol-powered leaf blower (STIHL BG 56 Blower—max of 730 man 10 µm ,49.3 to 66 mg/m3, describing the shape of the plume when dispersed by the wind.In order to determine PM10 concentrations measured during the flight, the data was processed using the particle correlation  obtainedTests 1 and 2 demonstrated the functionality and feasible integration of the system; however, the need for systematic characterization of a particulate plume of known composition and size remained. This is required to demonstrate the ability to calculate particulate emission rates, as most parameters can be independently measured using a constant powder emission, constant emission rate, known atmospheric conditions and particle size distribution of the source.To achieve a systematic plume characterization, it was necessary that the UAV reproduced a fixed experimental flight pattern to aid spatial calculations and also exclude biased measurements that could easily be made when flying manually into the visible plume produced by the powder ejected. A flight path consisting of concentric circles at different heights and radius was planned for Test 3. The flight path ensures the UAV covers the designated area around the source. This ensures that the sensor intersects the plume and tests the ability of the data to describe the behavior of the plume in the air space surrounding it.Test 3 was undertaken on 3 March 2015. The setup for the field experiment was based on Test 2, incorporating modifications to satisfy UAV flight and rigorous plume modelling requirements. The fixed-wing and multi-rotor UAVs were able to fly following the patterns programmed for the tests. The talcum powder plume was generated using a petrol-powered fan connected to a 5.5 m long and 0.05 m diameter PVC stack. The powder was loaded into the airstream through an intersection custom made for the powder containers at an approximate rate of 300 g/min .For Test 3, the SHARP sensors where recalibrated due to the different characteristics including color and particle diameter that smoke and talcum powder have. The calibration procedure previously used for smoke particles was repeated for the talcum powder. A correlation equation was calculated using a polynomial fit by processing the data obtained with the Dusttrak 8520 and with the SHARP sensor . Integra3 to 19 mg/m3 and their distribution described the path followed by the powder plume to the west, downwind from the source (PM10 concentration values ranged from 0.5 mg/me source a,b. Mid-Future tests will also include measurements of background levels during flight monitoring periods to determine their influence in the UAV readings.3 without an observable pattern (For safety reasons and the complexity involved in flying two UAVs simultaneously, the quadcopter and the fixed-wing UAVs were not flown simultaneously. The fixed-wing UAV was flown after the quadcopter and recorded maximum concentrations of 2.0 mg/m pattern c. WeatheThe sensor systems developed to date are technically capable of delivering data comparable to industrial quality dust-monitoring devices but require individual calibration equations for each sensor used to characterize dust plumes. The use of talcum powder is primarily a detection exercise at this stage as most particulate matter in this product has a diameter greater than 10 μm. System testing at PM2.5 will require a chemical source such as a smoke generator.3; more precise readings of smaller concentrations will require the use of a different optical sensors and reference calibration with more precise equipment. Cross-contamination sources will require to be controlled in further experiments, and background levels will need to be measured to determine their content percentage in the final concentrations. These measurements will allow the programming of different flight patterns which could be focused in the intersection of the plume and will provide additional flight time.The tests described in this paper only measured concentrations with a precision of 1 mg/mCurrent experimental work indicates that integration of air quality sensor and autopilot data is feasible and will characterize airborne particulates in time and space.Further work will be focused on the analysis of near-real time data to feed atmospheric modeling software and for flight path-planning algorithms.


There is little published research about differences in doctor-patient communication of different specialties. Accordingly, we compared doctor-patient communication skills in two different specialties, general surgery (GS) and general practice (GP).Twenty residents from the Bahrain Defence Force Hospital  participated in 200 patient first visit consultations. The consultations were video-recorded and analysed by four trained observers using the MAAS Global scale.2 = 0.84 for raters was high, 2) GP residents spent more time (12 minutes) than GS residents (7 minutes), in the visits, 3) There were several differences on the MAAS Global items between GP and GS residents , and 4) The present participants performed well compared to normative samples as well as to criterion-referenced cut-off scores. The general level of communication skills in both specialties, however, was ‘unsatisfactory’ and ‘doubtful’, as it is for normative samples.1) Internal consistency reliability of the MAAS Global (> 0.91) and EpExcellent doctor-patient communication is essential but does not appear to receive the amount of attention that it deserves in practice settings. There are some differences between specialties as well as unsatisfactory communication skills for both specialties, since residents from both programs spent less time than recommended on each consultation. Our findings emphasize the need to improve the communication skills of physicians and surgeons in general. Communication skills are essential to the effective practice of medicine as they may lead to improved patient outcomes and fewer complaints from patients regarding medical practice.5Clear communication is essential for diagnostic accuracy, health outcomes, patient satisfaction,10Researchers are still exploring both what makes communication effective and the underlying mechanisms by which patients’ and providers’ outcomes are affected.Some believe that general practitioners use a predominant patient-centred style and general surgeons tend to use a doctor-centred approach.A total of twenty residents, ten from general practice (GP) and ten from general surgery (GS) from year 1, 2, and 3 of their residency program, were chosen at random and invited to participate in the study. The age of residents ranged from 25–33 years old with a mean age of 28 years. In general surgery there were 6 (60%) male doctors and 4 (40%) female doctors, whereas in general practice, there were 8 (80%) female doctors and 2 (20%) male doctors. The residents had completed a communication skills course during their medical education. None had attended extra courses in communication skills.A total of 240 first visit patients to general surgery clinics and general practice clinics were selected and invited to participate. Patients’ age ranged from 15 to 90 years. There were 124 (62%) female patients and 76 (38%) male patients. Patient consent for the video-recording was obtained. The complexity of patients in clinical settings can range from easy to difficult. However the very easy cases and very difficult, complicated cases, which required specialist consultation, were not selected for the study. Cases of average difficulty were chosen. The level of difficulty was approved by two specialists in the relevant specialty.This comparative study used a quantitative analysis of checklist scores to compare doctor-patient consultations in general surgery and general practice. The study was conducted in the outpatient departments of the two specialties, general surgery and general practice, in the Bahrain Defence Force Hospital (BDFH). Patients come mainly from the military population and their relatives, and some from the civilian population.All residents in both specialties received a written or verbal invitation, explaining the aim of the research, and they agreed to the video-recording of twelve first visit patient consultations. There was no drop-out of doctors from the study. Each resident was evaluated with twelve first visit patients. The first two patients in the evaluation were not used in the study as they were practice sessions to allow the doctors to become comfortable with the videotaping.Twelve first visit patients were selected for residents to do an entire patient consultation in 15–20 minutes. A selection of ten patients is considered to be sufficient to allow comparisons of mean scores at the group level.The MAAS Global instrument for rating doctor communication skills was used. This instrument consists of a checklist and a 30-page scoring manual, listing criteria for each item.The focus of the first thirteen items was on the communication skills, while the last 4 items related to the medical content. Since we limited our study to first-time patient visits, we excluded item number two which relates to follow up consultations. Several studies have provided evidence for the validity of the MAAS Global for assessing communication skills.16Each rater reviewed 50 video-recorded consultations and gave a score for each consultation. The raters received standardized training, carried out by one trainer. The communication was evaluated by 4 trained observers who rated the videotapes using the MAAS Global checklist. The inter-observer reliability coefficient for each group of ratings was high (> 0.90).The study was approved by the Ethics Committee of Bahrain Defence Force Hospital. Each doctor consented to take part and be video-recorded in the study. Consent for recording was also obtained from patients.2) were conducted to determine the generalizability of various facets, including inter-rater reliability. A p value of < 0.05 was considered the critical value for significance.Descriptive statistics were computed on the data, between specialty differences were explored with one-way multivariate analysis of variance (MANOVA) of the scale items  and was followed-up with post-hoc one-way ANOVAs. The internal consistency reliability was computed with Cronbach’s α and overall generalizability analyses  produced α= 0.92 and the subscale α range from 0.65 to 0.87. A fully-crossed single-facet (4 raters × 10 consultations) generalizability analysis resulted in an Epp < 0.001) and subsequent post-hoc ANOVAs showed that there were several differences on single items and on one subscale. A close inspection of p < 0.05) and diagnosis  but GP residents outperformed GS residents on information giving . The means and SD values are quite typical of studies of this sort.16The between general surgery and general practice analyses were conducted with MANOVA  and are summarized in p < 0.05; this contains the 2 items where GS outperformed GP).The communication skills of residents in both specialties are low as they ranged from 2 (unsatisfactory) to 3 (doubtful) in most of the communication items. The overall mean for the MAAS Global was 2.65 (unsatisfactory - doubtful) and as shown in In one recent study, Reinders and colleagues192 for raters was high, 2) The patient encounters were brief, but GP residents spent more time than GS residents, 3) There were several differences on the MAAS Global items in performance between GP and GS residents, and 4) The present participants performed well compared to normative samples as well as to criterion-referenced cut-off scores.The results are 1) Internal consistency reliability of the MAAS Global and Ep2 analyses and found high consistency across raters indicating that our data has high reliability Reinders et al.2 > 0.70. We exceeded this minimum with 4 raters for each of 10 consultations.The α reliability of the MAAS Global was high (> 0.90) in the present study as has been found in previous research.The present study is the first one to investigate the differences and similarities in doctor-patient communication skills in these two specialties, general surgery and general practice. Our findings indicate that doctor-patient communication differs between the specialties in history taking, information giving, and diagnosis as well as medical aspects. Moreover, the actual time spent with patients differed between specialties (GP > GS). As well, GP residents did better than GS residents in information giving, but the reverse was true for history taking, diagnosis and medical aspects as medical content. These differences probably reflect the differences in practice specialties, with GS more focused on the surgical aspects of the consultation whereas the GP residents may focus more on information sharing or giving. These differences are small (effect sizes ≈ 0.30), however, and there are no differences between the specialties on 13 of the 16 items or on the total scale score of the MAAS Global. Accordingly, GS and GP residents appear to be quite similar in their communication skills at least for first time patient encounters, although GP residents tend to spend more time with patients than GS residents.We found that the general level of communication skills in both specialties received unsatisfactory or doubtful ratings on the MAAS Global. This finding is in concordance with several other studies of GP doctor-patient communications. Indeed, our GS and GP residents compared favourably with these normative samples on the MAAS Global. Based on the criterion-referenced cut-off scores, the present participants performed comparatively, with the majority passing the minimum standard. Nonetheless, both the GS and GP residents in the present study as well as the GPs in the normative studies require improvements in communication skills. This is likely true of many other physicians worldwide. Fortunately, there is evidence that structured individual communication improvement activities based on performance assessment are effective in improving communication skills in physicians. In a randomised controlled trial,Some communication skills such as information-giving and understanding the patient’s viewpoint are general competences that should be used by all physicians. These include giving greater importance to subjective aspects of the illness, chronic conditions, prevention, and screeningThe present research was conducted in a military hospital in Bahrain, with military doctors, thus restricting the generalizability of the findings. Accordingly, further research in other settings and cultures should be conducted. Notwithstanding these limitations, the present results are in concordance with other work, particularly that conducted in the Netherlands.Excellent doctor-patient communication is essential in healthcare and does not appear to receive the amount of attention that it deserves in practice settings. We found that there are some differences between specialties as well as unsatisfactory communication skills for both specialties. Both GP and GS residents also spent less time than recommended on each consultation. Our findings emphasize the need to improve the communication skills of physicians and surgeons in general.


Objective. The objective of this study was to describe the recent clinical characteristics of labor using 3 systems of Japanese midwife-led primary delivery care, as follows: (1) those intending to give birth at home managed by midwives who do not belong to our hospital, (2) those planning to give birth in our hospital managed by the same midwives, and (3) those planning to give birth managed by midwives who belong to our hospital. Methods. A retrospective cohort study was performed. Results. There were no significant differences in the obstetric or neonatal outcomes among the 3 groups. The rate of transfers during labor with the system involving midwives belonging to our hospital was higher than those with the other 2 systems. In addition, the timing of transfers in the system with the midwives belonging to our hospital was earlier than with the other 2 systems. Among the 3 groups, there were no significant differences in the rate of the main 2 indications for transfers: fetal heart rate abnormality and failure to progress. Conclusion. There were no significant differences in perinatal outcomes among the 3 systems; however, there were some differences in the status of transfers to obstetric shared care. Midwife-led primary delivery care for “low-risk” pregnant women during labor has been reported to have various advantages, such as increased odds of high maternal satisfaction and a decrease of unnecessary medical interventions –8. AlthoIn our institute, one of the main Tokyo city perinatal centers, there are 3 Japanese systems of midwife-led delivery care, as follows: (1) those intending to give birth at home managed by midwives who do not belong to our hospital, (2) those planning to give birth on “futons”  in Japanese tatami mat delivery rooms in our hospital managed by the same midwives who do not belong to our hospital, and (3) those planning to give birth in Japanese tatami mat delivery rooms managed by midwives who belong to our hospital. The objective of this study was to describe trends in transfers and perinatal outcomes among labors using these 3 Japanese systems of midwife-led primary delivery care.The protocol for this analysis was approved by the Ethics Committee of the Japanese Red Cross Katsushika Maternity Hospital. In addition, informed consent for analysis from a retrospective database was obtained from each subject during their hospital visit.In our hospital, pregnant women who are initially considered “low-risk” at 34–36 weeks of gestation can choose freely between the 3 systems of midwife-led care and obstetric shared care. In the midwife-led care units, midwives can practice autonomously and are fully accountable for their own practice, unsupervised by obstetricians.Factors used to exclude women from the “low-risk” group comprise the following –12: (1) A retrospective study was performed to examine trends in transfers and perinatal outcomes among labors that started using the 3 systems of midwife-led primary delivery care. In this study, neonatal asphyxia was defined as an Apgar score < 7 at 1 minute. t-test was used for continuous variables and the χ2 test for categorical variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated. Differences with p < 0.05 were considered significant.Student'sBetween 2009 and 2012, a total of 678 low-risk women were placed in the 3 forms of midwife-led primary delivery care at the onset of labor pains and/or rupture of membranes at 37–41 weeks of gestation. Of these, 123 (18%) intended to give birth at home, 88 (13%) planned to give birth in the Japanese tatami mat rooms in our hospital managed by midwives who do not belong to our hospital, and 467 (59%) planned to give birth managed by the midwives belonging to our hospital.p < 0.01; 38% in planned hospital birth: OR 2.51, 95% CI 1.7–3.8, p < 0.01). In addition, the timing of transfers in the system run by the midwives belonging to our hospital (before the second stage of labor: 52%) was earlier than those in the other 2 systems . However, if classified into nulliparous and parous women, there were no significant differences in the rate of transfers among the 3 groups, as shown in Our obstetric care system involves the division of women in labor into low- and high-risk groups –12. The This may be the first report concerning the differences in the timing of transfers from midwife-led care to obstetric shared care among the 3 systems of midwife-led primary delivery care in Japan. In this study, there was no evidence that the primary midwife-led care is unsafe for “low-risk” pregnant women in any of these 3 midwife-led delivery care systems. The current results support some of our previous observations –12. HoweThe major limitations of this study were the small sample size and lack of long-term follow-up of mothers and children to consider the potential of the findings based on our own context. There were no cases of fetal/neonatal death under the midwife-led delivery care. The most evaluated outcome under midwife-led delivery was the satisfaction of pregnant women with the development of mother-child relationships after delivery. In addition, there might be some bias related to the backgrounds in the selection of the systems because this was not a randomized trial study. Therefore, a further large prospective study with long-term follow-up may be needed.There are various systems of midwife-led primary delivery care in Japan. There were no significant differences in perinatal outcomes among the 3 systems; however, there were some differences in the status of the transfers to the obstetric shared care. Careful selection of the system may be needed.


To determine if open-angle glaucoma (OAG)-associated single nucleotide polymorphisms (SNPs) are associated with incident glaucoma and if such genetic information is useful in OAG risk prediction.Case-control from within a population-based longitudinal study.study population: Individuals aged over 49 years of age living in the Blue Mountains region west of Sydney and enrolled in the Blue Mountains Eye Study. observation: Cases for this sub-study (n = 67) developed incident OAG between baseline and 10-year visits, in either eye, while controls (n = 1919) had no evidence for OAG at any visit. All participants had an ocular examination and DNA genotyped for reported OAG risk SNPs. main outcome measure: Incident OAG.CDKN2B-AS1 and SIX1/SIX6) were both significantly associated with incident OAG in the Blue Mountains Eye Study cohort . The TMCO1 locus was nominally associated (P = .012), while the CAV1/CAV2 and 8q22 loci were not associated. Multivariate logistic regression and neural network analysis both indicated that the genetic risk factors contributed positively to the predictive models incorporating traditional risk factors.Two loci also known to be associated with cup-to-disc ratio as well as OAG (9p21 near This study shows that previously reported genetic variations related to OAG and cup-to-disc ratio are associated with the onset of OAG and thus may become useful in risk prediction algorithms designed to target early treatment to those most at risk of developing glaucoma. Open-angle glaucoma (OAG) is one of the most common causes of blindness worldwide and the number of affected individuals is expected to increase as the population ages.Current guidelines for the Screening, Prognosis, Diagnosis, Management, and Prevention of GlaucomaTMCO1 on chromosome 1q24,CDKN2B-AS1,SIX1/SIX6TMCO1) have been identified in an advanced OAG cohort, suggesting they could be important in disease progression leading to the observed enrichment in advanced disease. Both regions are also associated with less severe OAG cases, indicating they may also be important to the vulnerability to OAG and its initiation.Several common genetic variants increasing the risk of OAG have recently been identified through genome-wide association studies GWAS; . Three sThere have been no previous reports seeking to examine genetic risk associated with the onset of OAG. To fill in this gap of knowledge, we have undertaken an analysis in an older Australian cohort from the Blue Mountains Eye Study (BMES), to determine whether genetic analysis could inform on the likelihood of an individual's being diagnosed with glaucoma in the future. The BMES is a well-known longitudinal population-based study of ophthalmic health and disease that includes baseline and 5-year and 10-year follow-up data. This population is considered to be stable, homogeneous, and representative of the Australian population, but older compared to the average for the state of New South Wales, where it was recruited.The Blue Mountains Eye Study was approved by the Human Research Ethics Committee of the University of Sydney for investigation of the epidemiology and genetics of ocular disease. The BMES has been described previously.P values at each locus were chosen for this analysis. In the case of the 9p21 locus reported independently in 2 papers,Single nucleotide polymorphisms (SNPs) were selected for analysis if they had been previously reported to be associated with OAG  at genome-wide significance in white populations. The reported SNPs with the smallest P value of .007, assuming a population disease prevalence of 5.67%.Power calculations were conducted with the Genetic Power Calculator.P < .007 under a Bonferroni correction, to account for the 7 SNPs tested. One associated SNP from each significant or nominally significant locus and the clinical variables were included in a logistic regression model using IBM SPSS Statistics V20. SNPs were coded to the number of OAG risk alleles carried by each participant at each SNP . Collinearity between variables in the model were assessed by calculating the tolerance and the variance inflation factor (VIF). No collinearity was detected (no VIF >2).Differences in the demographics of the available cohort were assessed using IBM SPSS Statistics V20. Association analysis was conducted under a univariate allelic model and also using logistic regression under an additive model adjusted for baseline measurements of age, sex, mean IOP of both eyes, mean cup-to-disc ratio of both eyes, mean disc diameter of both eyes, and systolic and diastolic blood pressure using Plink.The rank importance of each model component was also assessed using a large population of neural networks . A neural network can be thought of as a small machine capable of learning. It is trained by exposure to a dataset comprising inputs  and outputs (the winning horse). After each round of training, the link strengths within the network are changed, and further training is undertaken until its predictive performance on a previously unseen “validation” dataset no longer improves. The resulting network's performance is then measured using a final, also unseen “test” dataset. In this study, each neural network drew its inputs from unique subset of 7 SNPs and 7 clinical variables . To cover all possible permutations of these 14 inputs, 16 383 neural networks were required.Each neural network was trained and tested with a cohort comprising glaucoma patients (n = 67) and an equal number of randomly selected controls: 70% of the cohort was used to train the network, 15% to validate its performance during training, and the remaining 15% were unseen during training and were used to test the final performance of each network. Each neural network was trained and tested 20 times. In separate analyses, controls were either age matched to within 2 years of incident cases or not age matched. An error score was calculated to describe the performance of each neural network: the error score was the proportion of cases incorrectly classified (as glaucoma or as not glaucoma) by the network. Ranking of the importance of input variables  was achieved by ranking their influence on neural network error score. If the presence of a particular SNP or clinical variable  reduced the error score, that SNP or variable can be considered to make a positive contribution to the performance of the network .P < .001) and had a higher proportion of female subjects (P = .009). IOP and VCDR at the baseline visit were also significantly different between those who later developed OAG and those who did not  at the 9p21 locus as well as rs10483727 (P = .004) at the SIX1/SIX6 locus. Additional SNPs at 9p21 and also at TMCO1 were nominally significant but did not survive after correction for multiple comparisons. The SNPs at the 8q22 and CAV1/CAV2 loci did not show association with incident glaucoma. Adjustment for covariates under an additive genetic model showed association at the same SNPs, although only SIX1/SIX6 remained significant after correction for testing 7 SNPs (P ≤ .007)  .Table 3ATMCO1, 9p21, and SIX1/SIX6) were included in a single regression model, all variables except blood pressure contributed significantly to the model ,TMCO1),TMCO1 has been associated with intraocular pressure,SIX1/SIX6 are associated with cup-to-disc ratioSIX1/SIX6, 9p21, and nominally at TMCO1 with incident OAG. Thus, loci associated with advanced glaucoma and relevant biometric traits are also associated with the initial onset of OAG (incidence). Those SNPs discovered in previous cohorts with typical (nonadvanced) OAG are not found to be associated with OAG incidence in our cohort, although power to detect weaker associations or those at rarer SNPs is limited. The association of sex with incident OAG in the cohort has been previously reported,19The selected loci have been discovered through genome-wide association studies for OAG  patient recruitment, although significant effects were still observed in this study, suggesting that the SNPs may be more important in predicting disease onset than progression, or that the true effect size is larger than previously reported. However, larger prospective cohorts will be needed to properly assess the 8q22 and TMCO1. This SNP has a lower allele frequency than others in the study (11% in controls) and the finding did not reach significance here in the context of multiple testing, owing to the lower power of this study (∼36%) to detect an effect at the minor allele frequency of 11%. We have previously reported an association of this locus with prevalent OAG in the BMES cohort with odds ratio (OR) = 1.57, P = .022.P = .013) despite the smaller sample size. We thus conclude that TMCO1 is also confirmed to be associated with incident OAG.A nominal association was observed at The current study shows that OAG loci that are associated with OAG-relevant ocular parameters (cup-to-disc ratio and intraocular pressure) are specifically associated with OAG incidence independently of other known risk factors. This suggests that these loci are responsible at least in part for the initiation of OAG, consistent with their role in determination of these risk factor traits, which are themselves predictive for OAG development. We show also that the loci specifically associated with advanced glaucoma may also be important in initiation of OAG, and thus could be important in risk stratification among glaucoma suspect and early glaucoma patients.The multivariate logistic regression model indicates that mean vertical cup-to-disc ratio at baseline is by far the most significant predictor of incident glaucoma in this cohort, while in the context of other parameters blood pressure contributes almost nothing to this model. Although vertical cup-to-disc ratio is a well-recognized parameter in the prediction of OAG risk, the accuracy of prediction based solely on this parameter is poor owing to disc appearance in preclinical and early glaucomatous damage overlapping with the normal range of this trait. Predictive accuracy for the individual patient should be improved by the inclusion of other variables, including genetics. With the genetics tools available at this time, discriminatory power above and beyond that achievable with clinical risk factors is minimal; however, ongoing research uncovering the genetic basis of OAG is likely to lead to better risk prediction models.TMCO1 SNP, rs4656461, becoming the highest-ranked genetic variable. This is consistent with a previously reported finding of the association of this SNP with age of onset of OAG.Neural networks allow an alternative approach to estimating the usefulness of clinical and genetic variables in predicting incident glaucoma. Input variables that are predictive of incident glaucoma naturally benefit the performance of the network. However, we see that those variables of trivial or no predictive value negatively affect the performance of the network: their inclusion necessarily makes the network structure more complex, which will lead to increased noise in the network. Neural networks are therefore helpful in distinguishing those patient characteristics that might help the clinician to predict glaucoma incidence and those that will merely overload him or her with unhelpful information. This approach could easily be expanded to larger datasets where specific combinations of variables that are particularly beneficial might become apparent. The matching of age (an important OAG risk factor) between cases and controls in the neural network analysis resulted in the Each of the associated SNPs in the logistic regression model also contributed positively in the neural network. Thus, the combination of IOP, disc parameters, and genotype at-risk SNPs could improve the accuracy of OAG risk prediction, which in turn will inform early treatment decisions for those most likely to develop this blinding disease.