Psychotic disorders are a group of severe mental disorders that cause considerable disability to sufferers and a high level of burden to families. In many low- and middle-income countries (LMIC), traditional and faith healers are the main providers of care to affected persons. Even though frequently canvassed as desirable for improved care delivery, collaboration between these complementary alternative health providers (CAPs) and conventional health providers has yet to be rigorously tested for feasibility and effectiveness on patient outcomes.COSIMPO is a single-blind, cluster randomized controlled trial (RCT) being conducted in Nigeria and Ghana to compare the effectiveness of a collaborative shared care (CSC) intervention program implemented by CAPs and primary health care providers (PHCPs) with care as usual (CAU) at improving the outcome of patients with psychosis. The study is designed to test the hypotheses that patients receiving CSC will have a better clinical outcome and experience fewer harmful treatment practices from the CAPs than patients receiving CAU at 6 months after study entry. An estimated sample of 296 participants will be recruited from across 51 clusters, with a cluster consisting of a primary care clinic and its neighboring CAP facilities. CSC is a manualized intervention package consisting of regular and scheduled visits of PHCPs to CAP facilities to assist with the management of trial participants. Assistance includes the administration of antipsychotic medications, management of comorbid physical condition, assisting the CAP to avoid harmful treatment practices, and engaging with CAPs, caregivers and participants in planning discharge and rehabilitation. The primary outcome, assessed at 6 months following trial entry, is improvement on the Positive and Negative Symptom Scale (PANSS). Secondary outcomes, assessed at 3 and 6 months, consist of levels of disability, experience of harmful treatment practices and of victimization, and levels of perceived stigma and of caregivers’ burden.Information about whether collaboration between orthodox and complementary health providers is feasible and can lead to improved outcome for patients is important to formulating policies designed to formally engage the services of traditional and faith healers within the public health system.NCT02895269. Registered on 30 July 2016National Institutes of Health Clinical Trial registry, ID: The online version of this article (doi:10.1186/s13063-017-2187-x) contains supplementary material, which is available to authorized users. Psychotic disorders are a group of severe mental disorders that cause considerable disability to sufferers and significant burden to families and caregivers. The Global Burden of Disease project estimates that, in 2010, schizophrenia was responsible for 1.1% of all Disability-adjusted Life Years due to non-communicable diseases and 2.4% of Years Lived with Disability –5, only Diagnostic and Statistic Manual of Mental Disorders, version IV (DSM-IV) disorders, with about 30% of these being cases of psychosis  for binary outcomes and (2) as mean differences and standardized mean differences (SMDs), with 95% confidence intervals for continuous outcomes. Missing data on the outcomes will be estimated using multiple imputations in Stata. Secondary analyses will include repeated measures analyses of data collected at 3 and 6 months, which make efficient use of all available data. No interim analysis of outcomes is planned.An economic evaluation is included in COSIMPO. For this purpose, we will use the Service Utilization Questionnaire (SUQ), adapted for the purpose, to systematically collect resource-use data, including any inpatient care, consultations with health providers, use of drugs and laboratory tests, as well as payment in kind (such as chickens and goats) and the offering of sacrifices and rituals For this exercise, we will use previously computed estimates of unit costs for resource inputs related to the use of public facilities, including primary health care. We expect an increase in the use of conventional services by the patients in the intervention arm. On the other hand, patients in the control arm may engage in more financially burdensome visits to providers who offer less effective care. Since psychosis and associated disability outcomes for the collaborative care intervention are expected to improve significantly, the intervention will “dominate” usual care . Such a hypothesis negates the need for a power calculation. If, however, costs turn out to be higher in the intervention group, bootstrapped incremental cost-effectiveness ratios for PANSS and WHO-DAS disability scores level will be derived. A publication policy has been designed and approved by the investigators to guide authorship of publications. Other than dissemination through academic channels , dissemination workshops are planned for CAPs and PHCPs at the study sites at the end of trial and analysis of results.Our data-sharing procedure will be guided by the following principles: (1) the need to ensure that the datasets are first used to address the primary aims of the project (which will be done within 2 years of data collection); (2) every effort will be made to offer unrestricted access thereafter, with the only proviso being the continued protection of the anonymity of participants; and (3) due acknowledgment is given by subsequent users to the original source of the data of the funding. These conditions are in line with the NIMH data-management and data-sharing policy. We will work to ensure that the data, whenever it becomes available to the public, is in the form that can be understood and used by the research community.There is a large treatment gap for people with psychosis and other mental disorders that is far more evident in LMIC where there is a dearth of mental health professionals , 39. BriOther than inadequate numbers of specialists to meet the need of persons in need of mental health service, there is also the factor of cultural belief that determines where patients with psychotic disorders and their caregivers seek care . BecauseCOSIMPO is designed as a test of the feasibility of task-shifting for the care of persons with psychosis not only to primary care providers, through training in the delivery of evidence-based care for such persons, but also through collaborative shared care for psychosis delivered by these providers and complementary health providers. The study is designed to provide empirical evidence for the effectiveness of this approach in responding to the treatment gap for severe mental disorders. The promise of the trial is not only in regard to providing such evidence, but in also determining to what extent a collaborative shared care between traditional and faith healers, on the one hand, and primary health care workers, on the other hand, can lead to a reduction in the use of potentially harmful treatment practices by the former. Addressing the concern about the use of such practices in the treatment of severe mental disorders will be an important contribution to the discussion about the feasibility of integrating these healers into the mainstream mental health services in LMIC.The design of COSIMPO takes account of several important features that, from our formative studies, are crucial in engendering trust and mutual respect. The entry point to treatment for patients will be from the traditional healers or faith healers . The CAPs take responsibility for the patient and commence treatment. The contract to care for the patient therefore lies with the CAP. The discretion about when to seek clinical support from or refer to the PHCP also lies with the CAP. The PHCP in turn provides the necessary support and assistance needed. In providing clinical support to the CAP, the PHCP may engage with the CAP, the patient, and caregivers of the patient. Beyond specific referrals and consultations, the PHCP will maintain regular weekly scheduled personal contacts with the CAPs as part of the collaboration, using such contacts to reinforce information on best clinical practice, provide information on patient rehabilitation, and attend to other clinical issues that the CAPs may bring to the attention of the PHCP.The results of our formative work with CAPs showed that their treatment modalities can be broadly grouped into (1) harmful, (2) innocuous and (3) possibly helpful. Harmful practices include shackling, beating/physical assaults, scarification, imposed long periods of fasting (starvation) and isolation. PHCPs will discourage these practices and offer to assist in managing patients who are being exposed to such practices, possibly as a result of the severity or challenging nature of their illness. During on-going engagement with the CAPs, PHCPs will always be mindful of the need for sensitivity, respect and avoiding undermining the authority of the CAPs. Innocuous practices are not harmful to the patients and very often reflect deep cultural and religious beliefs shared by both patients/relatives and CAPs. Examples include the use of sacrifices and rituals. PHCPs will be trained and encouraged to remain open-minded about the use of innocuous practices and to leave deeply held belief systems undisturbed provided that they do not have the potential to result in harm. Possibly helpful practices within the CAM system include the use of herbs, animal products and minerals. For the purpose of potential referral/consultations to the PHCP, it is important that PHCPs are aware of the content and side effects of herbs, so as to be able to manage them if the need arises. For this reason, CAPs who use herbs will be encouraged to provide the names of the herbs. Research team will seek to obtain the active ingredients of such herbs from the literature. PHCPs will be provided with this information as well as ways to respond to any adverse events in the patients who are administered such herbs and take appropriate action.Cluster randomized controlled trials have peculiar challenges. One of such challenges is that of possible contamination. This was minimized in this study by stratifying eligible and consenting clusters by LGA before allocation to the CSC or the CAU arm using a computer-generated random number sequence, thus avoiding contiguous clusters being in the same arm. Furthermore, the availability of collaboration in the CSC arm was not publicized to other CAPs. The stratification of the clusters also took account of size, thus limiting the potential limitation of differential recruitment into the arms of the study. We have continued to monitor the recruitment of participants into the arms. Subsample selection bias has been avoided in this study by recruiting all eligible and consenting participants from randomized clusters, thus maintaining the power of the study.The protocol version number is 14.0 submitted on the 7th December, 2016. Enrollment into the study commenced on 1st September, 2016 and projected to end June 30, 2017.


S. haematobium [SH]) and intestinal/hepatic (S. mansoni and other species) complaints and chronic morbidity [Schistosomiasis is a trematode infection that is still spreading through Africa ,2,3. It orbidity . Currentorbidity . These porbidity ; lack oforbidity . Health orbidity . Second,orbidity ,9,10.This expansion of urogenital schistosomiasis may lead to a lack of recognition of the symptoms of the disease in countries with a high inflow of migrants and where schistosomiasis is only rarely encountered . In noneWe reviewed the clinical history, laboratory findings, and imaging findings in a series of eight male patients (migrants from West Africa) who were consecutively encountered in our practice from July 2015 to January 2016. Patients were first seen by an ED physician and then referred to different wards or services according to their symptoms. The decision based on the clinical workup of each patient was taken by different ED physicians according to their clinical judgment and the availability of services, rather than shared protocols. The present review process was aimed at understanding how the different specialists approached each case, how the diagnosis was surmised, how the diagnosis was finally confirmed, and whether improvements in the system could be introduced. All patients were accompanied to the ED by a representative of the non-governmental organization (NGO) that had them in their charge.All eight patients presented with hematuria. The ED physicians decided to refer five of them to the radiologist, one to the urologist, and three to the infectious disease specialist . In one Seven patients had bladder abnormalities that were considered compatible with chronic SH infection  Table 2Table 2. All eight patients with macroscopic hematuria underwent cystoscopic examination, as a first approach in one case and to exclude the presence of a tumor in the others. Cystoscopic findings were compatible with intermediate and late manifestations of SH infection .Although SH infection may lead to squamous cell carcinoma of the bladder, this was not detected in this small series, which is in line with the reported low incidence of this complication  . SH infeNo bladder biopsy was performed in three cases that met the composite clinical and diagnostic criteria for SH infection . In simiThus, our experience with the series described suggests that, in developed areas, young migrants from SH-endemic countries may predominantly have hematuria and may present to—or rather, may be accompanied by NGO representatives to—the ED; further, other differential diagnoses may primarily be considered, should anamnestic parameters (age and country of origin) not be adequately considered. Within this framework, there was an excess use of resources , both because SH infection was not considered in the first place and, more importantly, because a diagnostic workup commonly used for young European patients presenting with hematuria was employed.The number of international migrants worldwide has continued to grow rapidly over the past 15 years. Over the last year, this number has increased sharply, and the current migration patterns are likely to persist in the near future –18. In vBulinus truncatus, has been found [The recently described Corsica outbreak of SH infection in 2013 and the subsequent transmission occurring in 2015 after a bathing ban had been lifted –20 provien found . This spen found . These oAbandoning the present shortsighted or passive attitude in European countries regarding SH infection in migrant populations and the associated potential risks for both migrant and local populations may be difficult owing to the current limited awareness. The present case series highlights the fact that this disease is not considered a diagnostic possibility in European EDs, and this may lead to a misuse of health resources. Awareness could induce renewed efforts towards a more cost-effective approach.Useful measures to constructively address this issue include educational, epidemiological, and clinical interventions. First, educational efforts have to target emergency and primary care physicians. Population changes need to be considered with increased awareness of SH infection symptoms and upgrading of diagnostic workup protocols to include not only symptoms but also disease prevalence in the country of origin. Increased involvement of infectious/tropical disease specialists, as well as widespread use of urine testing as a first diagnostic approach, will improve both the care of these populations and cost effectiveness. Second, a registry of emergency referrals to the ED of young adults from endemic countries would provide a real measure of the problem of SH infection in Europe. Distribution of urine tests to NGO facilities and testing of migrants on arrival would increase the accuracy of the estimation of the real prevalence of SH infection in this population. Further, a systematic survey of areas with the presence of suitable intermediate snail hosts could dismiss or confirm the risk for the transition to a local SH transmission cycle. In addition, geolocalization of SH infection cases in migrant populations may allow for assessment of the coexistence of SH-infected persons in areas where the intermediate snail host is known to be distributed, thus allowing for the estimation of the risk for local SH endemic transmission.Finally, the introduction of MDA upon arrival in Europe in specific target populations may represent an innovative and cost-effective solution to decrease the long-term clinical complications of urogenital schistosomiasis and to reduce urinary egg elimination, thus helping to avoid a future persistence of SH infection in Europe. Identification of the optimal target population and reaching the identified target population should not be an issue among arriving migrants, thus allowing for campaign efficacy with high coverage rates –20.In conclusion, SH infection is potentially set to become a stable presence in Europe, with a high likelihood of new prevalent cases associated with migration and the risk of a rising incidence, should establishment of endemicity occur in freshwater areas where intermediate snail hosts are already present. To improve the current efficiency of care, more attention should be paid to identification procedures and clinical protocols.


It has been hypothesised that the perception of adverse events in placebo-controlled antidepressant clinical trials may induce patients to conclude that they have been randomized to the active arm of the trial, leading to the breaking of blind. This may enhance the expectancies for improvement and the therapeutic response. The main objective of this study is to test the hypothesis that the efficacy of antidepressants in panic disorder is mediated by the perception of adverse events. The present analysis is based on a systematic review of published and unpublished randomised trials comparing antidepressants with placebo for panic disorder. The Baron and Kenny approach was applied to investigate the mediational role of adverse events in the relationship between antidepressants treatment and efficacy. Fourteen placebo-controlled antidepressants trials were included in the analysis. We found that: (a) antidepressants treatment was significantly associated with better treatment response ; (b) antidepressants treatment was not associated with adverse events ; (c) adverse events were negatively associated with treatment response . Finally, after adjustment for adverse events, the relationship between antidepressants treatment and treatment response remained statistically significant . These findings do not support the hypothesis that the perception of adverse events in placebo-controlled antidepressant clinical trials may lead to the breaking of blind and to an artificial inflation of the efficacy measures. Based on these results, we argue that the moderate therapeutic effect of antidepressants in individuals with panic disorder is not an artefact, therefore reflecting a genuine effect that doctors can expect to replicate under real-world conditions. In randomised studies allocating patients to antidepressants or placebo it is possible that differences in efficacy may, at least in part, be explained by the emergence of adverse events. In the treatment of major depression the evidence is controversial. A meta-analysis of studies comparing fluoxetine with placebo reported a strong correlation between adverse events and efficacy, and authors supposed that the rating scores for patients allocated to antidepressants might have been amplified when study participants became aware of being allocated to active treatment by experiencing adverse events . A more A similar hypothesis may be formulated for antidepressants in the treatment of panic disorder, as patients with panic disorder may be particularly prone to adverse events and these, in turn, may have an impact on efficacy measures. The hypothesis is the following. During the informed consent procedure, patients with panic disorder are told that they may receive placebo and are also informed of the side effects to be expected from the real drug. Hence, when they experience side effects, they are likely to conclude that they have been randomized to the active arm of the trial. In fact, most patients and doctors in clinical trials are successfully able to guess whether the patient has been randomized to drug or placebo . Since If drug-placebo differences are due to the breaking of blind, then they ought to be associated with the perception of adverse events. The purpose of the study reported here is to test the hypothesis that the effects of antidepressants are correlated with the perception of adverse events and to assess what remains of the drug effect when side effects are controlled statistically. We were able to test this hypothesis performing a mediational analysis.The present study is based on an ongoing Cochrane systematic review and meta-analysis of published and unpublished randomised trials comparing antidepressants versus placebo for panic disorder . We refeWe included randomized double-blind comparisons of antidepressants as monotherapy versus placebo in the treatment of panic disorder. For trials that had a crossover design, only results from the first randomized period were considered.Participants were in- and out-patients aged 18 years or older of both sexes, with a primary diagnosis of panic disorder with or without agoraphobia, diagnosed according to the criteria described in the Diagnostic and Statistical Manual of Mental Disorders (DSM) , or accoTwo reviewers (IB and AB) independently extracted data from the included studies, and any disagreement was discussed with a third member of the review team (CB).For the purposes of the analysis reported here, the following two outcomes were extracted: (a) efficacy, measured as number of patients responding to treatment as defined by the original investigators; (b) adverse events, measured as proportion of patients complaining with any adverse events.Additionally, the following information was collected using an electronic spreadsheet: year of publication, type of antidepressant, sample size, inclusion of elderly participants, setting of intervention, diagnostic criteria, baseline number of panic attacks per week (as a proxy of illness severity), dose and probability of receiving placebo, rated according to Papakostas and colleagues . Mean dometareg command in STATA, which performs standard random-effects meta-regression using aggregate-level data. Analyses were adjusted for the following variables: sample size, year of publication, type of antidepressant (SSRI versus any other), antidepressant dose (PDD/DDD), probability of receiving placebo (high versus low), outpatients , elderly patients , severity at baseline   .As second analytical step, the Baron and Kenny mediational model was applied to investigate whether adverse events mediated the relationship between antidepressant treatment and efficacy ,14. ThesA graphical representation of the model applied to antidepressant trials is presented in In model 1 we tested the relationship between antidepressant treatment and treatment response. In model 2 we tested the relationship between antidepressant treatment and adverse events. In model 3 we tested the relationship between adverse events and treatment response. In model 4 we tested the effect of antidepressant treatment and adverse effects on treatment response. Statistical significance was set at p < 0.05. Mediation was assessed by changes in statistical significance and in the magnitude of correlation coefficients (ß coefficient) between the pathways 1 and 4. To adjust for possible confounding, the four regression analyses included the following variables: sample size, year of publication, probability of receiving placebo, baseline severity, outpatients, elderly patients. A nonparametric bootstrap method of statistical accuracy was used in the four models of linear regression analyses, assuming that the observed distribution of the present sample was a good estimate of the true population distribution . All calOf the original 41 randomised controlled trials included in the Cochrane review, 11 were excluded because they did not report data on treatment response, and other 16 were excluded because they did not report the number of subjects experiencing adverse effects, leaving 14 studies for the present analysis . The stuOverall, 18 comparisons and 38 treatment arms were considered. The following compounds were investigated in the included studies: imipramine (one study), paroxetine (5 studies), sertraline (3 studies), fluoxetine (one study), fluvoxamine (2 studies), citalopram (one study), escitalopram (one study) and venlafaxine (4 studies). The main characteristics of included studies are shown in Multivariable meta-regression analysis showed that, after adjustment for potential confounding variables, the RR for efficacy was not associated with the frequency of antidepressant  and placebo  adverse events .Model 2 tested the relationship between antidepressants treatment and adverse events. In this model, antidepressants treatment was not significantly associated with higher rates of subjects with adverse events .Model 3 tested the relationship between adverse events and treatment response. In this model, adverse events were inversely associated with treatment response .Finally, model 4 tested the combined effect of antidepressants treatment and adverse effects on treatment response. When adverse events were added to model 1, the relationship between antidepressants treatment and treatment response was still statistically significant , although the effect was slightly attenuated, as can be inferred from the magnitude of the coefficient.To our knowledge, this is the first study that formally investigated the potential role of adverse events as mediators of treatment effect in antidepressant clinical trials conducted in individuals with panic disorder. We did not find evidence that the effects of antidepressants are mediated by the perception of adverse events.Our results do not confirm the findings of Greenberg and colleagues , who sugStrengths of this study include the following. Data were extracted from an ongoing Cochrane systematic review, which employed a comprehensive search without language restrictions, and included unpublished studies. Standard Cochrane methodology was applied throughout the steps of study selection, data handling and analysis . AlthougHowever, a number of limitations should be acknowledged. First, it was impossible to investigate the breaking of blind directly, as the majority of the included clinical trials did not assess this aspect. A second limitation is that only 14 trials out of the 41 potentially relevant studies reported data on the number of participants experiencing adverse events. This is a major issue not only because the analysis might have been more powerful statistically, but also because it is difficult to speculate on whether lack of reporting happened by chance or rather it may reflect some kind of reporting bias. Another limitation is that the meta-regression analysis may suffer from low statistical power. Finally, study quality was not used as a confounding variable as the Cochrane risk of bias tool is considered a qualitative and not quantitative tool .The finding that the drug-placebo differences are not due to the breaking of blind, as there was no relationship with the perception of adverse events, is of paramount relevance clinically and methodologically. Clinically, it implies that the moderate therapeutic effect of antidepressants in individuals with panic disorder is not an artefact, therefore reflecting a genuine effect that doctors can expect to replicate under real-world conditions. Methodologically, it implies that double-blind placebo-controlled antidepressant trials are not biased by the differential emerging of adverse effects in those allocated to the active and control condition, at least in patients with panic disorders.In terms of implications for research, we argue that strategies to check blindness in future clinical trials should always be employed. This could be achieved by using tools like the one developed by Even and colleagues, who devised a short seven-point checklist to evaluate the degree to which supposedly blind trials are protected from blindness penetration . We alsoA different and more radical strategy to overcome this issue would be to avoid placebo-controlled antidepressant trials and require active-control trials in the evaluation of newer antidepressants. In comparative head-to-head trials it is expected that adverse events similarly occur in both treatment arms, with a substantially lower risk of breaking the blind. This seems reasonable in panic disorder, as effective drugs treatments are available in this condition to be used as reference standards ,34,35. RIn summary, this analysis does not support the hypothesis that the perception of adverse events in placebo-controlled antidepressant clinical trials may induce patients to conclude that they have been randomized to the active arm of the trial, leading to the breaking of blind and to an artificial inflation of the efficacy measures.S1 Table(XLS)Click here for additional data file.S2 Table(XLS)Click here for additional data file.


Aphasia has a large impact on the quality of life and adds significantly to the costs of stroke care. Early recognition of aphasia in stroke patients is important for prognostication and well-timed treatment planning. We aimed to identify available screening tests for differentiating between aphasic and non-aphasic stroke patients, and to evaluate test accuracy, reliability, and feasibility. We searched PubMed, EMbase, Web of Science, and PsycINFO for published studies on screening tests aimed at assessing aphasia in stroke patients. The reference lists of the selected articles were scanned, and several experts were contacted to detect additional references. Of each screening test, we estimated the sensitivity, specificity, likelihood ratio of a positive test, likelihood ratio of a negative test, and diagnostic odds ratio (DOR), and rated the degree of bias of the validation method. We included ten studies evaluating eight screening tests. There was a large variation across studies regarding sample size, patient characteristics, and reference tests used for validation. Many papers failed to report on the consecutiveness of patient inclusion, time between aphasia onset and administration of the screening test, and blinding. Of the three studies that were rated as having an intermediate or low risk of bias, the DOR was highest for the Language Screening Test and ScreeLing. Several screening tools for aphasia in stroke are available, but many tests have not been verified properly. Methodologically sound validation studies of aphasia screening tests are needed to determine their usefulness in clinical practice. For people aged 65 years or more, the worldwide prevalence of stroke ranges from 46 to 73 per 1000 persons , a condiAltogether, it is pivotal that the presence and severity of aphasia are adequately evaluated in patients who suffered a stroke. A large number of diagnostic instruments are available to examine the type and degree of aphasia. As many of these diagnostic test batteries are fairly demanding and time-consuming, they may be too cumbersome for stroke patients in the acute phase. Given that the aphasia characteristics are generally instable shortly after stroke and can change rapidly, extensive testing may be a waste of time and resources. In addition, a speech and language therapist (SLT) is not always sufficiently available in the first days after stroke to obtain a detailed linguistic profile. Hence, a short and simple screening test, easy to administer by various disciplines, is essential for referring patients for additional assessment and adequate language therapy. Furthermore, advice regarding communication may be better personalized using results from screening tests.The aim of this review was to identify available screening tests for differentiating between aphasic and non-aphasic patients after stroke, and to evaluate the accuracy, reliability, and feasibility of those tests.We searched PubMed, EMbase, Web of Science, and PsycINFO for published studies on screening tests aimed at assessing the presence and/or severity of aphasia in patients who suffered an ischemic or hemorrhagic stroke. The following search string was used for NLM Pubmed-Medline and was adapted for the other databases: AND (infarct*[tw] OR ischem*[tw] OR ischaem*[tw] OR hemorrh*[tw] OR haemorrh*[tw] OR hematom*[tw] OR haematom*[tw] OR thrombos*[tw] OR thrombot*[tw] OR thromboembol*[tw] OR thrombol*[tw] OR apoplex*[tw] OR emboli*[tw] OR bleed*[tw]))) AND  AND (test[tw] OR tests[tw] OR testing*[tw] OR screen*[tw] OR tool*[tw] OR instrument*[tw] OR assessment*[tw]) AND . We applied no search limits. The reference lists of the selected articles were checked, and experts in the field of aphasia research were contacted to detect additional published studies. The initial search was carried out in March 2012 and updated in May 2015 with search in Pubmed.Eligible for inclusion were full-text articles, written in Dutch, English, French, German or Spanish, on cohort or cross-sectional studies of stroke patients who underwent a screening test to detect aphasia. A screening test was defined as a diagnostic test designed to assess the presence and/or severity of aphasia, requiring a short turnaround time that is at most 15 min. Studies evaluating patients with aphasia due to other causes than stroke or with an unspecified etiology were not included. We also excluded studies in which test scores of aphasic stroke patients were compared with those from healthy controls instead of stroke patients without aphasia, as we specifically aimed to evaluate screening tests suitable for use in clinical practice.Articles had to report the results of the screening test for aphasia as well as those from a reference test or gold standard. Data should be described in such a way that the sensitivity and specificity of the screening test could be calculated. If sensitivity and specificity were given without reporting the original data, the authors of the paper were contacted. In the case, authors were not able to provide the requested data; the study was excluded from this review.First, titles and abstracts of the retrieved studies were checked, and obviously, irrelevant articles were excluded. If a decision could not be made based on the information in the title and abstract, then the full-text article was checked for the above-mentioned in- and exclusion criteria.From the selected studies, we recorded the clinical characteristics of the patient sample . The following features of the validation method were collected: consecutiveness of patient inclusion, the type of reference test that was used, and blinding of the test assessors. All estimates of test accuracy reported in the studies had to be based on the exact numbers of patients and were recalculated to check for errors and non-verification (that is whether only patients who could be assessed with the reference as well as with the screening test were included and reported which indicates selection bias). We collected the following data on the screening tests: the language in which the validation study was conducted, subtests, score range, time needed for administration, and type of patients for which the test was initially developed, and reported suitability for bedside use.We expressed the results of the validation studies of each screening test in 2 × 2 tables and estimated the sensitivity, specificity, likelihood ratio of a positive test (LR+), and the likelihood ratio of a negative test (LR−). Sensitivity was estimated by the number of aphasic patients who were correctly classified with the screening test divided by the total number of patients with aphasia. Specificity was estimated by the number of patients without aphasia who were correctly classified divided by the total number of patients without aphasia. LR+ was estimated by the sensitivity divided by 1-specificity. LR− was estimated by dividing 1-sensitivity by the specificity . The diaWe evaluated the methodological quality of the selected studies by scoring three items: consecutiveness of patient inclusion, representativeness of the patient sample, and blinding. Consecutive patient inclusion is essential to eliminate selection bias and to ensure that the full range of aphasia types and severities is represented in the patient sample. Furthermore, the patient sample should be representative for the general stroke population, since this is the population in which the screening test will be used. Blinding is of importance to minimize expectation bias. The assessor of the screening test should not be aware of the results of the reference test, and vice versa .The score assigned for the representativeness of the patient sample in the validation study  was based on the size of the cohort, available data on stroke type, and mean age and sex of the patient sample. Consecutiveness was scored as either ‘0’ (no consecutive inclusion or consecutiveness not reported) or ‘2’ (consecutive inclusion of patients). The degree of blinding was rated as ‘0’ (when assessment was not blinded or blinding was not reported on), ‘1’ , or ‘2’ (in the case of blinding for both the reference and the screening test).Finally, we assigned a score for the risk of bias based on the three above-mentioned items. A total score of ≤2 was classified as high risk of bias, a total score of 3 or 4 as intermediate risk of bias, and a total score of ≥5 as low risk of bias.The electronic search resulted in 1004 records. We identified 13 additional articles after hand-searching the reference lists and another 4 by asking experts in the field. After screening all titles and abstracts, 956 records were excluded  –15, LangTable One study lacked blinding , in one Table In Table Given the impact of aphasia on the quality of life, rehabilitation after stroke, and the costs of stroke care , it is oIn this systematic review, we evaluated ten studies reporting on the validation of eight screening tests for aphasia after stroke, with emphasis on the methodological quality of the validation study. Nearly, all included screening tools usually reflect the approach taken in the traditional aphasia test batteries that assess language modalities, such as spontaneous speech, auditory and written comprehension, reading and writing in addition to naming and repetition, except the ScreeLing and the SVF. The ScreeLing comprises tasks directly aimed at the basic linguistic components . The SVF addresses semantic verbal fluency only. Although it is not always explicitly mentioned in the test descriptions, all tests are suitable to be administered at bedside, a requirement for the use in the acute stage.Several issues have to be taken into account when appraising studies that claim to validate a screening test against a reference test . ClearlyFor many of the screening tools, the cut-off value below or above which the test result is considered abnormal  was derived from studies performed in stroke patients with aphasia and healthy control subjects, while cut-off values based on a general stroke population are preferred. Finally, the assessor of the screening test should be blind for the result of the reference test and the other way around. Many of the evaluated studies did not report whether or not blinding was secured, making it difficult to estimate the risk of expectation bias. Altogether, most of the validation studies had serious methodological limitations, thus hampering firm conclusions about utility of the aphasia screening tools for clinical practice.Of the four studies with an intermediate or low risk of bias, the LAST  and ScreBesides the screening tools evaluated in this review, there are several well-known screening tests for aphasia that are widely used in clinical practice. For the Acute Aphasia Screening Protocol , the AacIn conclusion, several screening tools for aphasia in stroke are available, but many tests have not been verified in a proper way. Future studies should focus on a better validation of the available aphasia screening tests in large stroke populations. The design should include a reliable reference diagnosis, a consecutive inclusion of stroke patients to make them representative of a general stroke population, a secured blinding of the assessments, details on the numbers of aphasics and non-aphasics correctly classified, and a good description of the subtests of the screening test, to eliminate the risk of bias as much as possible.


In the era of classical analysis when major and minor constituents of materials such as rocks and ores were determined by gravimetric and titrimetric methods, a measure of the quality of an analysis was the closeness to which the summation of constituents approached 100%. Trace constituents were considered to be those known to be present but in amounts so small that they made no appreciable contribution to the summation. An early authority was Hillebrand , in his The modern definition of “trace” is more flexible, as illustrated by a quotation from a 1965 book, “Trace Analysis” edited by George Morrision : “The coFor trace analysis to emerge as a specialty in its own right, two conditions had to be met: specific needs and applicable methods. Qualitative methods in general emerged much earlier than quantitative ones. Quite a few qualitative tests and even a few quantitative methods of great sensitivity existed before the turn of the century, but they remained largely unused as interesting curiosities until a need arose. The decade of the 1940s represented a watershed in creating a variety of new demands for analytical methods of exceptional sensitivity and difficulty. World War II had quite a stimulating effect with respect to new needs, but it also stifled free publication for several years, with the result that shortly after the end of the war in 1945, there was a release of enormous amounts of previously classified material for publication. Methods and instrumentation developed to solve specific problems now became available for wider application.It is now convenient to consider five periods in history—(1) antiquity to the beginning of modern chemistry late in the 18th century, (2) late 18th century through the 19th century, (3) the period from 1900 to 1939, (4) the decade of the 1940s, and (5) the period from 1950 to the present.Probably the earliest example of trace analysis is fire assay or cupellation, to which several references are made in the Old Testament.Szabadvary  states tThe phlogiston era, from the late 17th to the late 18th century, was essentially barren from the viewpoint of trace analysis. An exception is the work of Marggraf (1709–82), who used the Prussian Blue test for iron, a flame test to distinguish between sodium and potassium salts, and the microscope as an analytical instrument. Another important chemist of this era was Torbern Bergman (1733–84), who wrote the first analytical textbook (1780) and originated analytical chemistry as a distinct branch of chemistry .Modern chemistry began to flourish with the abandonment of the phlogiston theory, but for a long time trace analysis remained of interest for only a few constituents of special value or special effects, such as imparting color, taste, or odor to drinking water.Colorimetry developed relatively early in the primitive form of visual comparison of the intensity of color of an unknown in a cylindrical tube with that of a series of standards of known concentration. Some early examples are the estimation of iron or nickel in a cobalt ore , copper via the ammonia complex , iron via the thiocyanate complex , titanium via hydrogen peroxide (1870), hydrogen sulfide via methylene blue (1883), and silica via molybdosilicic acid (1898) [An outstanding development of the 19th century was atomic emission spectroscopy, introduced by Bunsen and Kirchhoff in 1860 [However, apart from Bunsen’s laboratory, the method did not see general use for several decades, even for qualitative purposes. Slavin  has tracElectroanalytical chemistry can be traced back to 1833, when Faraday discovered the laws of quantitative electrolysis. Electrogravimetry, which could in some cases be applied to trace analysis, dates back to 1864. Real advances, however, were not to come about until the emergence of solution physical chemistry around the turn of the century.O’Haver  has tracA closely related method is phosphorescence, which is characterized by a time delay in the emission. This phenomenon has been recognized since 1568, when Cellini described a luminescent diamond . A greatThe whole nature of analytical chemistry underwent a profound change when the principles of physical chemistry began to be applied systematically to the understanding of analytical procedures. A highlight was in 1894, when Wilhelm Ostwald, one of the leading physical chemists of the day, published a book entitled “Die Wissenschaftlichen Grundlagen der Analytische Chemie.” Ostwald showed how ionic equilibria could be applied to acid-base and precipitation reactions, how precipitates undergo recrystallization upon standing , etc.Oddly enough, he did not mention the Nernst Equation, which had been published in 1889  while NeSorensen’s development of the concept of the pH in 1909 led to a direct application of the Nernst equation to trace analysis . The devPotentiometric titrations also originated with Nernst. A great many analytical applications were made by pioneers such as Erich Müller and I. M. Kolthoff during the 1920s, but the emphasis was on accurate and selective titrations rather than on trace analysis.Collections of the Czechoslovak Chemical Communications, Many trace analytical applications were described for inorganic, organic, and biological systems. Although Kolthoff and his students had been involved in polarographic research since 1935, no publications emerged from his school until 1939 [The discovery of polarography in 1922  by Heyro−10%, depending on the locality. The accepted average value is 4×10−10% or 4 μg/L.The most sensitive trace analytical method cited by Sandell, op. cit. is the isolation of a bead of gold from two liters of sea water followed by its microscopical measurement. This method, described by Fritz Haber in 1927 , was useSome of the early colorimetric methods have already been mentioned. With the development of the photoelectric colorimeter and the spectrophotometer and the increasing demand for trace methods during the 1930s and 40s, and with the increasing knowledge about solution equilibria involving coordination compounds, a great many sensitive trace methods emerged. Especially noteworthy is the dithizone method, based on selective extraction of trace metals as dithizone complexes to enhance both the selectivity and sensitivity of the methods. Sandell  gave a pFluorescence methods were stimulated by the introduction of a photoelectric fluorometer by Jette and West in 1928 . Cohen, candoluminescence by Nichols in 1928. Its use in qualitative analysis dates back to Donau in 1913, but its use as a quantitative trace method is primarily due to Townshend and Belcher, beginning in 1972 [A special form of luminescence is observed when certain metal oxides containing trace quantities of activating elements are placed at the outer edge of a hydrogen diffusion flame. This phenomenon was observed as early as 1842 by Balmain and termed  in 1972 . It has Although catalyzed reactions have been long recognized and used as the basis of sensitive qualitative tests, the first quantitative use of reaction rates in trace analysis appears to be the work of Sandell and Kolthoff  in 1934,Industrial and Engineering Chemistry and of its Analytical Edition. He soon brought in L. T. Hallett as an associate editor, and they began to lay plans for a separate analytical journal. Ralph H. Müller began a column on Instrumentation in 1946, a new format had been adopted by 1947, and in 1948 the new name of Analytical Chemistry became fully operational.The decade of the 1940s represents a special time in the history of trace analysis because the outbreak of World War II in September 1939 suddenly cut off a great deal of international communication. Even domestic communication was impeded because of the secrecy of several wartime research programs. These research programs introduced an urgent need for trace analytical methods of a wide variety. In the years immediately following the end of the war in 1945, a great surge of publication occurred. Fortunately, the ACS had foreseen the revolutionary changes occurring in analytical chemistry, and had prepared for the flood of publications. In 1943, Walter J. Murphy became editor of Upon the outbreak of World War II, the delivery of the Nejedly Polarograph was cut off, and the E. H. Sargent company was granted the right to market U.S.-made instruments under the same name. The first U.S.-made photographic-recording instruments of 1940 were later replaced by pen-and-ink instruments introduced by Sargent and by Leeds and Northrup. For some 25 years, polarography had dominated electroanalytical chemistry, but beginning in the 1940s other microelectrode techniques began to supplant and replace classical polarography.The long time interval between the first discovery of the principles of steady state voltammetry and of amperometric titrations and their modern usage has already been noted. There are other interesting gaps of this sort. Coulometry could be said to date back to Faraday, but it did not emerge as a modern analytical technique until 1938, when Szebelledy and Somogyi  introducOf the wartime programs, the best known is the nuclear energy program, which put severe demands upon trace analysis capabilities. Not only were materials such as graphite needed in unheard-of purity levels, but methods were needed for elements that did not even exist in nature, and for elements in matrices of exceptional complexity, such as fission products. Methods were needed for accurate isotope ratios, and for extremely small amounts of elements of unknown chemistry, the transuranium elements.Less generally recognized are the other classified programs of the era. The antimalarial program required analytical methods for new drugs in blood plasma at concentration levels that kept decreasing as the drugs improved. Here extraction and fluorescence methods sensitive to ppb levels were devised. Another wartime effort was the synthetic rubber program which involved emulsion polymerization for the first time in the U.S., and which brought demands for trace analysis methods not only in the emulsion system but for the raw materials and products. In the area of chemical warfare, trace methods were needed for known chemical agents as well as for new ones being developed.These wartime demands spawned a reexamination of many existing trace methods, the adaptation of old methods to new problems, and the creation of entirely new approaches, Instrumentation often had to be improved to meet new demands, but electronics was still in the era of vacuum tubes and the digital computer had not yet been developed, so much remained to be done in the postwar period. Let us examine a few of the wartime advances.In 1939, mass spectrometry was still in a relatively primitive state as far as trace analysis is concerned . The earIon exchange had been recognized since 1850, but few analytical applications had been made by 1939. The first synthetic ion exchangers appeared in the mid-30s, but the real impetus for analytical separations came during the nuclear program when rapid rare earth separations became necessary. These developments, both at Oak Ridge under G. E. Boyd and at Iowa State under F. H. Spedding, were published in 1947 ,29 and lInfrared spectrometry, in 1939, was still largely a specialized structural tool although a few analyses of major and minor constituents had been reported. A key publication by Norman Wright of Dow in 1941 showed the possibility of organic analysis by IR . The warIn a similar way, UV spectroscopy was stimulated to emerge as an everyday analytical method through the introduction of the Beckman DU instrument in 1941 . PublicaAtomic emission spectroscopy, as mentioned above, remained largely a qualitative method until the introduction of methods for comparison of line intensities on photographic plates were worked out in the 1920s and 30s. These methods included the log sector and step sector rotating disks and the microphotometer. The atomic emission method remained relatively cumbersome and inexact until the direct reading spectrometer became a reality in the late 1940s. For this to happen, the photomultiplier tube and associated electronics had to be developed. Many later developments have involved multichannel capabilities and computerized data processing.Electroanalytical methods likewise found many trace applications stimulated by wartime needs. For example, amperometric titration methods found application for monitoring mercaptan levels in emulsion polymerization systems, and in coulometric titrations of trace arsenic at micromolar concentration levels. Linear sweep and cyclic voltammetry were studied independently in several countries although publication did not emerge until after the war. Several electroanalytical methods were hampered by instrumental limitations which were gradually overcome in postwar years by improvements in oscilloscopes, development of solid state electronics, and the microcomputer.The invention of the transistor in 1947 proved to be critical in revolutionizing instrumental approaches to trace analysis. Not only were solid state electronic devices more reliable, stable, sensitive, and less expensive than their vacuum tube counterparts but they consumed far less power and were capable of miniaturization. The microcomputer became so much cheaper and smaller that it became practical to incorporate data processing elements into individual instruments. The laser and fiber optic techniques have permitted miniaturization of a variety of optical methods. The recent history of many trace methods has involved the use of long known principles of physics and rendering them practical for analytical applications through modern instrumentation.Electroanalytical chemistry since 1950 has moved in several directions, including (a) ion selective electrodes, (b) other electrochemical sensors, and (c) combinations of electrochemical and optical techniques. These will be considered in turn.a. Ion selective electrodes in their modern forms are relatively recent developments, beginning in the 1960s. As early as 1923, Horovitz  showed tA few solid state membrane electrodes were described by Trümpler  in 1921,2 diffusion membrane to the glass electrode. This has stimulated several other sensors for gases which affect the pH of water, as well as composite electrodes consisting of a primary detector electrode coupled with some sort of specific generating system. The nature of the generating system has been varied widely. The earliest seems to be the enzyme-substrate system urease-urea, sensed by Guilbault and Montalvo [The idea of using a glass electrode for the sensing of gases originated in 1958 with Severinghaus  who coupMontalvo  in 1970 Montalvo  has beenA different principle used for membrane sensors was introduced in 1956 when L. C. Clark  used a db. Electrolytic techniques shifted away from classical polarography to other microelectrode techniques. Several reasons for this shift of emphasis can be traced in retrospect: (a) While diffusion theory to the dropping electrode was understood relatively early  , many phClassical polarography played a key historic role in leading to the development of various microelectrode methods. A good example is chronopotentiometry, or measurement of transition times during electrolysis at constant current under diffusion control. The theory of transition times dates back to Sand (1901)  who veric. Combinations of optical and electrochemical techniques such as electrochemiluminescence, and combinations of electrochemical sensors with separation techniques such as HPLC, are finding applications, especially in bioanalytical chemistry. The concept of fiber optic sensors goes back to 1976 , when thCuriously enough, the atomic absorption method did not emerge until 1955. The hollow cathode tube of Walsh was largely responsible for its spectacular rise thereafter. Another factor, however, was that the need for trace analytical data increased greatly during the 1950s and 1960s. For example, environmental chemistry stimulated interest in measuring pollutants, and increasing awareness of the effects of trace constituents in materials such as alloys and solid state electronics materials provided an enormous stimulus.The technique of atomic fluorescence spectroscopy was suggested by Alkemade in 1962 and introduced analytically by Winefordner, who remarked in 1976 “The method has not become popular despite significant advantages over atomic absorption in some cases. The reasons are not very clear. Lack of commercial instrumentation may be part of the explanation, but more likely it is the overwhelming popularity of atomic absorption methods. Atomic fluorescence has not yet made it into the club” [Chemiluminescence has been known since the 19th century but only in recent years has it seen extensive use in trace analysis because of a lack of selectivity. By controlling the reaction conditions and by improved instrumentation it is now possible to determine many substances including trace metals, oxidizing and reducing gases, and biochemicals by direct or indirect methods involving chemiluminescence. The measurements are usually transient in character so they require advanced instrumentation for their full exploitation. No doubt this is the reason for the slow development of this method. Another factor is the need for careful consideration of the chemical reactions involved.The use of catalyzed reactions, and of kinetic methods in general was delayed until the development of instrumentation made possible the convenient measurement of reaction rates, even though the theoretical basis of such methods was well understood. For example, glucose oxidase has been used as a specific catalyst since 1957  for the A different type of application of enzymes arose with the use of immobilized enzymes at an electrode surface. The first use of such an immobilized enzyme appears to be that of Clark and Lyons  in 1962,During the 1960s the development of the microcomputer made it possible to automate the measurement of the initial reaction rate by using the small change in voltage output of a transducer to register a small change in concentration. The transducer could be based on various principles, such as measurement of potential, current, or absorbance. Although some notable examples of trace analysis by non-catalytic methods have been described, the vast majority of kinetic trace methods are based on catalytic reactions.Nuclear methods have existed in principle since the discovery of radioactivity at the turn of the century. Tracer techniques using naturally occurring isotopes date back at least to 1919, when Paneth used thorium B, a naturally occurring isotope of lead as a tracer to study the reactions of lead. With the discovery of artificial radioactivity in 1934, tracer techniques became more general. By the late 1930s Kolthoff was using radioactive bromine, prepared by using a radon-beryllium neutron source to study the aging of silver bromide . ActivatBiochemical Journal was not available during the war in many countries, and in any case, this journal was not one that most analytical chemists would consult. Soon after the publication of several papers in the early 1950s, commercial development followed. In the U.S., apparently the first GC was built at Monsanto by Ralph Munch in 1953 and described at a Gordon Conference in 1954. It used a thermal conductivity detector. By 1955 commercial equipment was available. Many of the early applications were for major and minor constituents in mixtures and for analysis of small samples, but later, trace methods became important, especially after the introduction of more sensitive detectors such as the flame ionization detector in 1958. About the same time, the open tubular column or capillary column GC, and GC-MS were developed, both of which greatly expanded trace applications. Commercial GC-MS did not become available until around 1970, because of the need for small dedicated computers to handle the voluminous amount of data.The gas chromatographic method had been mentioned in a 1941 publication  but it lThe introduction of ion chromatography by Small et al.  in 1975 Liquid chromatography underwent a revolution starting in 1967 with the introduction of the Waters ALC 100 high pressure liquid chromatography system. The letters HPLC were first used to designate high pressure liquid chromatography and later high performance liquid chromatography. Coupling of LC with MS began in 1973–74 with the publication of results from the laboratories of E. C. Horning, F. W. McLafferty, and R. P. W. Scott. However, early efforts were fraught with difficulties due to the need for removing the solvent, and even today improvements are being actively pursued.Mass spectrometry has continued to develop in several forms as an important trace analytical method. Spark source MS dates back in principle to Dempster in 1934 but modern instrumentation and quantitation did not come about until the 1950s. Time of flight MS originated with A. E. Cameron in 1948 and was commercialized by Bendix in 1955. Secondary ion MS, using an ion beam to sputter material from a solid surface, emerged in the 1960s and is important both in the imaging and ion probe configurations. Tandem mass spectrometry (MS/MS) was first introduced as a structural tool in the mid-1960s but it did not become important as a trace analytical method until the triple quadrupole system of the late 1970s. The quadrupole MS dates back to Paul and Rather in 1955, and became commercially available during the 1960s. The triple QMS system, developed by Yost and Enke in 1978 and commercially available since 1981, is becoming increasingly important in trace analysis, especially for complex organic mixtures. Still another variant is ICR MS, or ion cyclotron resonance mass spectrometry, which originated in principle as the Omegatron at NBS in 1950, and which became commercially available from Varian in 1967. The Fourier transform version, introduced in 1974, has improved its applicability to analytical problems, but it is still not primarily a trace analytical instrument.X-ray emission is another trace analytical method that was slow to develop. The principles were known at the time of Moseley (1913), who discovered the concept of atomic numbers, but analytical applications were slow to emerge. Birks, who with Friedman introduced the modern version of the x-ray fluorescence in 1948, has traced the slow development of the method over the intervening 35-year period . In 1914The electron microprobe, also based on x-ray emission, was patented in 1947 by Hillier of RCA in 1947 but he did not pursue the method and Guinier and Castaing reported on their conversion of the electron microscope to a microprobe in 1949. An independent development by Borovskii in the U.S.S.R. occurred about the same time. The microprobe was of special significance because it permitted the direct observation of spatial distribution of constituents that on the basis of average composition would be trace constituents but would sometimes have pronounced effects because of segregation in regions of higher concentration such as grain boundaries. A closely related technique allowing for finer spatial resolution at the expense of selectivity and sensitivity is the use of energy-dispersive x-ray analysis of surfaces with the scanning electron microscope, developed during the 1960s.Another important x-ray technique is x-ray photoelectron spectroscopy (XPS or ESCA), developed in the late 1960s by Siegbahn. Analytical applications were greatly stimulated by the publication of a monograph in 1967 and by the introduction of commercial instrumentation in 1970. More recently, the trend has been to incorporate ESCA measurements with other ultrahigh vacuum spectroscopy techniques involving a number of different excitations  and various types of signal . Although these are primarily surface techniques where the local concentration is not necessarily at the trace level, the extreme sensitivity of the techniques suggests their inclusion in any discussion of trace analysis. Ion etching of the surface permits probing of composition into the third dimension.From these historical examples it is clear that long delays often occurred between the discovery of a trace method and its practical application. Several reasons for these delays can be found in retrospect. Sometimes, as in the case of amperometric titrations and voltammetry, the theory was ill-understood at the time of the original discovery. In other cases, e.g., gas chromatography, the seminal publication did not reach the proper readership for a long time. In still other cases, as in chronopotentiometry, the basic theory was well known but the measurements could not be put to practice because of the lack of instrumentation. Another factor was that certain types of measurements required special materials for their exploitation, as in the case of thermometric measurements which were facilitated by the development of the thermistor. Finally a need must exist before widespread use of a method will occur. Oftentimes more than one of these factors came into play, as in the case of atomic emission spectroscopy.If we look at trace analytical methods as a group, we find a parallelism during the past 50 years regardless of the early history. In the first place there was not a great emphasis on quantitative applications of trace methods until the need arose, so many fundamental findings tended to lie stagnant until about 1940. Secondly, instrumentation was relatively primitive until the 1930s when electronics began to play a significant role. Electronic instrumentation was to undergo two major leaps ahead, first the change from vacuum tube to solid state electronics, and second with the emergence of the microcomputer, which became small enough and inexpensive enough to become an integral part of the measurement system. The availability of commercial instrumentation has also been an important factor in the use of a particular approach.Type of sample. Solid samples may be analyzed directly by some methods but require dissolution for others. The dissolution process may be so time consuming as to rule against the use of some methods. Similarly, gaseous samples and liquid samples may be directly analyzed by some methods but require conversion in others.Homogeneity of samples. Some methods inherently examine extremely small samples, and therefore are more susceptible to sampling errors if the average composition is sought. Conversely, if distribution is to be studied, a method of sufficient spatial resolution is required.Cost of equipment. Some methods require enormous capital investments, which may or may not be justified by the nature of the problem.Cost of personnel. Some methods are easily converted to a routine procedure that gives reliable results in the hands of a technician trained specifically for that procedure, while other methods inherently involve adjustments depending on the sample and therefore need personnel of greater training. This factor is important, for example in the relatively great usage of spectroscopic methods for trace metal determination as compared with electrochemical methods, which involve much lower investments in capital equipment.Type of information needed. If just elemental composition is required, it is better to use a method insensitive to the chemical state of the elements. By the same token, such a method will not give information as to the chemical state, if that information is required. Neutron activation analysis is a good example of a method insensitive to chemical state, while electrochemical methods do respond to chemical state, and therefore provide information of this type.Speed. Some problems require rapid response, and therefore require a method of appropriate speed. Continuous analysis of a flowing stream represents a problem requiring a rapid response time.Dynamic range. Some methods will respond to samples ranging widely in composition, while others need a prior adjustment by dilution or concentration to bring samples into their dynamic range.Selectivity. Some methods are subject to numerous interferences unless provision is made for prior separations. Nevertheless, if the interferences are known to be absent, such a method may find uses in special situations.Number of samples to be analyzed. The analysis of a single sample may lead to a different choice of method than the analysis of a series of samples. Furthermore, the chosen method may be different in different laboratories depending on the available equipment and personnel.It may also be relevant to consider the reasons for the popularity of certain trace methods in relation to others. Among the factors that determine which method is to be used for a given problem (given that the sensitivity is adequate) are the following:It has been my purpose to discuss the origins of a variety of trace analytical methods and to examine the reasons for the sometimes halting nature of their development into modern form. It would also be proper to consider recent trends, which are a useful guide to future expectations, and to make a critical comparison of the various trace analytical methods. However, there are to be two talks on the present day status of trace analysis, so these topics are better left for my colleagues.


Recently, cases of medical disputes and even acts of violence toward physicians by patients in China have been escalating. It remains unknown whether competition improves the patient-physician relationship.This paper analyzes the relationship between hospital competition and the probability of medical disputes occurrence according to the theory of social control. Data from all hospitals in the Sichuan province of China from 2011 to 2014 were included in the study. The fixed radius approach with GIS information was employed to define hospital market, and the differences in competition over time and across regions were utilized. Our analysis is based on the fixed effect estimation, which accounts for the time-invariant unobserved heterogeneity among hospitals.We found an inversed U-shaped relationship between HHI and the likelihood of medical disputes. As beneath either situation of monopoly or full competition, the burst of physician-patient dispute was downward into a valley, but it rises and then falls again with the increase of HHI, it reached the peak at the typical semi-market hospital competition structure.Our results highlight the probability of change in disputes occurrence with the transition of hospital competition and its psychological explanation, providing implications for China’s future health reform. The ecology of Chinese medical practice has been characterized by a skyrocketing number of medical disputes and even outright violence toward physicians , 2. In 2The high occurrence of physician-patient disputes can reflect the current physician-patient relationship, echoing the state of chaos that exists in the healthcare market in China. An important goal for the new round of China’s health reform policies is to improve the efficiency of the delivery of healthcare throughout China, and shift the strategy to market competition. Chinese government has emphasized the role of market mechanisms in the new round of health reform. The private capital is encouraged to investing in the health care sector for the current health policy, driving the China’s health care market towards higher intensive of “competition” in the recent years . However“Antitrust finds itself some twenty years later an unwelcome guest at the wedding as state and federal legislators prepare to embrace competition in their overhaul of the health care system”. When hospitals wish to win out in cruel competition, they have to try their best to improve their quality of service in order to avoid both patients dissatisfaction and medical disputes. However, caution is urged as many have argued that hospital competition may result in a medical arms race, leading to higher prices for patients and unnecessary service utilization due to possible supplier-induced demands , which represents the most serious physician-patient dispute.This result implied the process of medical dispute variates according to the revolution of hospital market structure. From most monopoly  to the breakup of monopoly, the likelihood of medical dispute is increasing. The probability of medical dispute reached the peak value as a HHI of 0.937. However, after that, with increasing marketization, the probability of medical dispute continues to decrease smoothly.p > .05). The difference between hospital scale and medical dispute can be captured by the number of beds. A large number of beds can further dilute the probability of dispute. In China, it can also be explained by the resource concentration in big hospitals. They possessed doctors with better medical skills, more advanced equipment, and a lower probability of medical dispute. However, if the hospital scale was controlled, the likelihood of medical dispute increased significantly with the total number of visits . When the admissions to the hospital increased 100,000 annually, the probability of medical dispute incremented by 3%.We did not find any evidence that the features of a hospital are associated with increased likelihood of medical dispute. Although there is a negative index for hospital rank, which indicates that a lower probability of medical dispute occurring in higher rank hospitals , this was not statistically significant (p < 0.01), higher urbanization (p < 0.01), and less developed economy (p < 0.1).The regional characteristics statistically affect the likelihood of dispute. The hospital has a lower probability of medical dispute if located in regions with denser population  of UK received 111 notifications of disputes across all health professions  in 2013/14; this is higher than the 80 disputes reported in 2012/13 . SimilarMuch of the literature around medical disputes, mostly from the 1990s, has focused on patients’ views and experiences –56. MoreDespite the outright physician-patient disputes and even violence against doctors in recent years , three CCompetitive markets are the best way yet found for efficiently organizing the production of goods and services”, our study supported this, by showing that the occurrence of medical disputes was higher with lower levels of health care market competition.As mentioned by World Development Report  “CompetiSecond, it verified the power of monopoly as a sense of authority by providing social control in the face of potential uncertainty. Thus, when patients are suffering the uncertainty of the disease , and staPerceptions of chaos can arise during times of economic uncertainty , 65. MonDuring China’s dramatic change of macro-social environment, there are many uncertain and demanding parts of the social change process . The psyThis could also be verified in other nations. The UK was known as a single-payer health care , while tInvisible Hand of Adam Smith [As a single-payer healthcare system, the National Health Service (NHS) in the UK is closely associated with the Keynesian welfare settlement of the 1940s . While tam Smith , the UK am Smith , 75. Theam Smith , 77. ForThe current research has advantages on measurement of the market competition and monopoly compared with empirical studies on Chinese medical market competitions. This is the first study to employ the fixed radius approach to define the hospital market in China. Instead of defining the hospital market according to the administrative divisions, as previous research did , 28, 78,China’s rapid economic growth has resulted in it becoming one of the most industrialized countries in a very short time span. The experience of industrialization and modernization provided us with a perception of a world of continuous change that is striding forward . ChineseMany countries all over the world are in the midst of adjusting the structure of their health care markets. The role of government control and free market competition are two important ideologies. The key to health care market construction is adjusting measures to local conditions. Methods include giving enough authority to the government public welfare work, or giving the full play of market competition after setting up the market order. No matter which method is chosen, the possibility of medical disputes can be decreased by guaranteeing people’s feelings of control. However, a mixture or semi-market competition appeared to be linked with higher levels of medical disputes and should be avoided.Understanding more about the reform of the economy and health system processes will allow us to interpret much about the role of governments, culture, and other agencies in the market transition from monopoly to competition - a transition characterized by an uncertain environment that impacts everyone in the health care market. The social problems brought by rapid economic development and social transformation are generally universal for any country or region, which makes the case of China a valuable example to be referenced.Nevertheless, we recognize that this study has a number of limitations. First, the empirical strategy used in this study cannot fully resolve the endogeneity problem in hospital competition, particularly the endogeneity arising from the simultaneity between disputes likelihood and hospital market structure, as well as the time-variant unobserved factors, e.g., local governance, which affected both of the dispute and competition. Second, a dummy variable indicating the probability of medical dispute occurrence is used, and the number of dispute occurrences are not included in this study due to the limitation of administrative data availability. Considering our binary measurement of medical dispute could not reveal changes of patients’ right-protection awareness over time, we have added “Year” as a dummy variable in our regression to detect more truly results by controlling its effect. Third, the radius calculation is only applied to the unstable health market. Although it’s a popular method to measure regional competition in many references , it’s


This edited volume, containing 11 chapters, is based on papers presented at a conference on “Housing Market Challenges in Europe and the United States—Any solutions available?”, held in September 2008 and organised by the Oesterreichische National Bank . In total, 16 authors from seven countries were involved in this project.The first chapter serves as the introduction, which is actually little more than a brief statement on the origin of the papers, noting that they were revised in 2010 to account for more recent developments. After this very short statement, the contents of the book and the main conclusions of the 11 chapters are presented. Unfortunately, this introduction offers neither a general theoretical framework nor any reflections by the editors.In the second chapter, “Housing markets in Europe and in the USA: what are the relevant issues today?”, Peter Mooslechner and Karin Wagner identify some key aspects of the economic relevance of housing markets and analyse these in the context of the credit crunch at the beginning of 2010. The key aspects include the relationship of housing markets to their national but also their international macro-economic surroundings, some fiscal and regulatory issues, and the possibility for central banks to react proactively to asset price movement. On the basis of their analysis the authors conclude that there is no definite answer yet to the question of how central banks should best deal with asset prices. Of course, this is a somewhat disappointing outcome. The good news is that a lot of important work remains to be done by housing market researchers and policy advisors.The third chapter, on the “Subprime mortgage market and current financial crisis”, by Philip Arestis and Elias Karakitos, sheds light on financial liberalisation and innovations like the subprime mortgage market, which helped create the climate for the financial crisis of August 2007. The authors also discuss recent economic policies to deal with the current financial crisis. Their most important piece of advice is that governments should regulate their financial engineering much more rigorously to prevent too much risk-taking. It was not the financial instruments, like subprime mortgages, themselves but the fraud surrounding them which caused the current economic problems. So, in the view of the authors, it was financial engineering that allowed the US housing bubble to form. A striking standpoint, in the light of the current government cuts in Europe, is their plea for public spending as the most effective way of getting out of the current financial and economic troubles.In chapter four, Elisabeth Springler and Karin Wagner turn their attention to homeownership in an attempt to identify the “Determinants of homeownership rates: housing finance and the role of the state”. More precisely, they advance a time series model of mortgage debt and the cost of financing an owner-occupied home and apply it to the European and US economies. This model confirms the importance of housing costs for the development of homeownership rates. The results also underscore the importance of the role of the state and highlight the immediate effects that housing policies can have.Chapter five, by Dieter Gstach, elaborates on the rental market. It contains an interesting review of the literature on the macro-economic role of housing, emphasising its contribution to an understanding of rental housing. The chapter also presents some relevant statistics based on the EU SILC data. Gstach brings a largely neglected option to the fore: that the rental sector could provide an important feedback route for changing housing market conditions.Chapter six, on “Housing markets, business cycles and economic policies”, by Christophe André and Nathalie Girouard, brings us back to the main theme of this book: the relationship between housing markets and the general economy. The advice offered by these authors has already been articulated by Arestis and Karakitsos in chapter three: restoring conditions for a sustainable development of housing markets will imply reinforcing the supervision and regulation of the financial system, in particular, by controlling the level of leverage, avoiding pro-cyclical provisioning and capital standards. Some other important requirements, in the view of the authors, are risk management and transparency as well as ensuring appropriate underwriting standards. To solve the current problems in our housing markets, André and Girouard are in favour of supporting overall demand through targeted fiscal subsides and are also in favour of restoring the normal functioning of financial markets through the provision of state guarantees.In chapter seven, we turn back to the rental markets. Montserrat Pareja-Eastaway and Maria Teresa Sánchez-Martines inquire into the development of the Spanish rental sector: “European rental markets: regulation or liberalization? The Spanish case”. They start with an overview of the diverse housing contexts and trends in Europe that have developed over the past few decades. They then describe the main features of their theoretical analysis of the role of the tenure system in providing proper housing. The ensuing Spanish case amounts to a historical overview of failed policy approaches for the rented sector. In their conclusion the authors recommend that the government show positive discrimination towards the rented sector in order to avoid a lack of confidence among tenants and landlords, such as that prevailing in most European countries in the past.In chapter eight, Guido Wolswijk addresses the fiscal aspects of housing in Europe. By describing the fiscal policy instruments applied in discrete housing markets, his contribution stresses that huge differences still exist between the housing systems in Europe. And because of the differences in the tax treatment of housing in the euro area, there is no single prescription for all countries.In chapter nine, “Towards a new housing system in transitional countries: the case of Hungary”, József Hegedüs considers the dissolution of the East European housing regimes. He argues that countries in transition followed the same trends because they were facing the same housing market challenges after the transition. Since then, differences between the institutional solutions in housing finance and housing welfare schemes have become more and more pronounced. He also notes that the economic crisis had a big impact on the housing markets in the transitional countries, leading to declining house prices, increasing mortgage arrears, and difficult access to mortgages.The last three chapters are more instrumental in nature and stray a little from the central theme of the book. In chapter ten, house prices and other housing market data are described from a user perspective by Antony Murphy. Then, in chapter 11, Martin Eiglsperger presents the residential property price indices for the euro area and the EU member states, as compiled by the ECB in co-operation with the EU national central banks. Finally, in chapter 12, Pirmin Fessler, Peter Mooslechner, Martin Schürz and Karin Wagner consider micro-economic data in “Housing and financial wealth in Austria: what can survey data tell us for the analysis of financial stability issues?”.The overarching objective of this book—namely, to develop more insight in the housing market challenges in Europe and the US under the current economic and financial crisis—is in my opinion well addressed. The chapters form a collection of interesting and highly relevant papers. Recent statistics and developments are combined with excellent, mostly econometric, analyses and empirical work, while highly relevant policy conclusions are drawn. Some of the chapters also contain elaborate literature reviews, which could make this volume useful as a textbook. Unfortunately, the editors do not offer much in the way of a general introduction and have omitted a concluding chapter. Given that the individual papers are well connected to the theme—most of them address the background of the housing crisis and discuss relevant policy solutions—this would not have been a difficult task for the editors to fulfil.