Mental disorders may be reducible to sets of symptoms, connected through systems of causal relations. A clinical staging model predicts that in earlier stages of illness, symptom expression is both non-specific and diffuse. With illness progression, more specific syndromes emerge. This paper addressed the hypothesis that connection strength and connection variability between mental states differ in the hypothesized direction across different stages of psychopathology.t as a function of the three momentary states at t-1, and by examining moderation by SCL-severity.In a general population sample of female siblings (mostly twins), the Experience Sampling Method was used to collect repeated measures of three momentary mental states . Staging was operationalized across four levels of increasing severity of psychopathology, based on the total score of the Symptom Check List. Multilevel random regression was used to calculate inter- and intra-mental state connection strength and connection variability over time by modelling each momentary mental state at Mental states impacted dynamically on each other over time, in interaction with SCL-severity groups. Thus, SCL-90 severity groups were characterized by progressively greater inter- and intra-mental state connection strength, and greater inter- and intra-mental state connection variability.Diagnosis in psychiatry can be described as stages of growing dynamic causal impact of mental states over time. This system achieves a mode of psychiatric diagnosis that combines nomothetic (group-based classification across stages) and idiographic  components of psychopathology at the level of momentary mental states impacting on each other over time. Staging and profiling represent two important aspects of diagnosis in psychiatry, that recently have become more prominent with the work on the newest edition of the widely used classification manual for mental disorders, the Diagnostic and Statistical Manual for Mental disorders (DSM).There is no strong evidence that psychopathology comes as dichotomous "natural types", separated from mental health by ‘zones of rarity’ A major question in the construction of the DSM-V was whether a new risk syndrome for psychosis should be added The best example of a model that incorporates the concept of mental illness progressing along stages is the model of clinical staging Profiling refers to the tension between the representation of diagnostic categories as homogenous latent classes, used to cluster patients (nomothetic approach), and the widespread observation of heterogeneity between individuals in the same diagnostic class (idiographic approach) that may be important to predict treatment response and outcome. Part of the observed heterogeneity may flow from an incomplete model of psychopathology. For example, it has been proposed that psychopathology may be best conceptualized as a dynamic process of symptoms impacting on each other over time Describing clinical stages may be considered a nomothetic component of diagnosis, whereas the unique symptom profile of patients that move across these classes represents the idiographic part. Since in the earlier stages of illness, symptom expression is more diffuse, presenting as a ‘general distress’ syndrome, whereas with progression of illness, more specific syndromes present themselves In this paper, we examined the hypothesis that the way in which momentary mental states indexing positive affect, negative affect and paranoia impact on each other over time differs across different stages of severity of psychopathology, in that more severe stages of psychopathology are characterized by (i) stronger connections and (ii) more variable connections indicating more individual-specific associations between the mental states over time. The three mental states were chosen as they arguably constitute the core building blocks of an extensive range of symptoms across mental disorders . Psychopathology was assessed and classified across four levels of increasing severity in a general population sample. In order to examine the mutual impact of mental states over time, repeated measures of the three states, collected using the Experience Sampling Method, were used.We hypothesized that:Cross-time associations between mental states indexing positive affect, negative affect and paranoia become stronger across classes of (staged) severity (nomothetic aspect).Inter-individual differences in associations between mental states increase with increasing symptom severity, evidenced by an increasing random effect sizes (idiographic aspect).This study is part of a larger longitudinal research project investigating the heritability of gene-stress interactions in vulnerability to depression. Data come from 621 general population siblings, sampled from the East Flanders Prospective Twin Study register SCL-severity’) reflected increasing levels of symptom severity.The Symptom Checklist-90-R Data was collected using the Experience Sampling Method, a random time-sampling self-assessment technique that has been shown to be feasible, valid, and reliable Three ESM variables reflecting three mental states underlying symptoms across mental disorders The Structured Clinical Interview for DSM-IV Axis I disorders A Global Assessment of Functioning score was rated for each participant by an interviewer with a mental health-related profession. The GAF scale has a 100-point range indexing overall mental, social, and occupational functioning of adult individuals. The version with two separate scores was used: a symptom score and a handicap score. Higher scores indicate better functioning.Individuals subjectively rated their physical and mental health on a 5-point scale. These variables were recoded into a dichotomous variable, reflecting good  health versus bad  health.SCL-severity groups were compared in relation to the sum score of the depression, hallucination and delusion subscales of the SCID. Similarly, the four SCL-severity groups were compared in relation to (i) GAF-symptom and GAF-handicap scores and (ii) subjective ratings of both physical and mental health.All analyses were carried out using STATA 12. The validity of the assumption that the SCL-severity variable represented staged levels of psychopathology and need for care was first investigated. Thus, the four ESM data consist of multiple mental state observations per day, over multiple days, in each person. Analyses were controlled for clustering of data within persons, who, in turn, were clustered within families. As we had no hypothesis regarding genetic effects on transfer of momentary mental states, we did not differentiate between monozygotic and dizygotic twins.t was predicted by (i) negative affect, (ii) positive affect and (iii) paranoia, all at t-1. The same was done for positive affect at t and paranoia at t. Thus, all ESM mental state variables at t were predicted by all mental state variables at t-1. Each of these analyses was carried out separately in order to enable model convergence.To examine the dynamic impact of the mental states of positive affect, negative affect and paranoia on each other over time, time-lagged variables were used in multilevel random regression models: negative affect at t-1) and the four-level SCL-severity variable were fitted in the model predicting the mental state outcome variable (e.g. paranoia at t). Using the LINCOM command, regression coefficients (B) were calculated for each SCL-severity group separately. These regression coefficients represent the fixed effects that refer to patterns across groups (i.e. different stages).To examine whether the strength of the associations between mental states over time differed as a function of stages of symptom severity (staging), interactions between mental states .To examine whether more advanced stages of severity of psychopathology were associated with greater level of individual-specific patterns of mental states impacting on each other (profiling), random slopes of mental state predictors at Of the 621 subjects, 610 participated in the ESM study. Thirty-one participants were excluded because of too little (<30%) valid data points, leaving 579 individuals with data on paranoia and negative affect . Data on positive affect was available for 567 individuals. Subjects were aged between 18–61 years (mean age 27.7 (SD 7.9) years). The majority (64%) had a college/university degree, were in a relationship (76%) and employed (62%) or studying (36%) at baseline. Mean level of NA was 1.27 (SD 0.37), of PA 4.43 (SD 0.86), and of momentary paranoia 1.16 (SD 0.33).SCL-severity groups differed in mean levels of delusional ideation  = 353.3; p<0.001), hallucinatory experiences  = 145.0; p<0.001) and depression  = 1800.0; p<0.001). The SCL-severity groups similarly differed in GAF symptom score  = 1157.9; p<0.001), GAF handicap score  = 1185.0; p<0.001) and in level of physical (χ2(3) = 25000; p<0.001) and mental health (χ2(3) = 42000; p<0.001). Dose-response relations were apparent  negative affect at t-1 , (ii) positive affect at t-1  and (iii) paranoia at t-1  predicting negative affect at t (SCL-severity and (i) negative affect at t-1 , (ii) positive affect at t-1  and (iii) paranoia at t-1  predicting paranoia at t. No significant interactions were found between SCL-severity and (i) negative affect at t-1 , (ii) positive affect at t-1 , or (iii) paranoia  at t-1 predicting positive affect at t. The significant interactions are displayed in t-1 impacting on mental states at t across the four levels of the SCL-severity variable. Thus, mental states at t-1  predict mental states at t, suggesting transfer of momentary mental states. This transfer becomes increasingly stronger with increasing symptom severity. This transfer is seen within each mental state  and across mental states .Significant interactions were found between ect at t . SimilarSCL-severity and mental state at t-1 (i.e. in the models predicting negative affect and paranoia at t). Random slope effects were found to be increasing with increasing levels of SCL-severity. These patterns were most clear for negative affect and paranoia (t-1 predicting (i) negative affect at moment t or (ii) paranoia at moment t were very small. Again, a dose-response was apparent, in that random effects were smallest in the lowest SCL-severity group of SCL-severity and largest in the highest SCL-severity group. Thus, larger random effects in the higher SCL-severity groups reflect more individual effects, suggesting more profiling with increasing symptom severity.Random slope effects were examined for the above models with a significant interaction between paranoia ; random t-1  and paranoia at moment t-1  but not for positive affect at moment t-1 , predicting negative affect at t. Similarly, this increase of random effects over the SCL-severity groups was significant for negative affect at t-1  and paranoia at moment t-1  predicting paranoia at t. There was too little variation in the slope of positive affect at t-1 predicting paranoia at t to predict this based on the SCL-severity variable using linear regression.The linear regression analysis predicting the random effects with SCL-severity as independent variable showed that this increase of random effects over the SCL-severity groups (i.e. with increasing symptom severity) was significant for negative affect at Mental states indexing momentary positive affect, negative affect and paranoia impacted dynamically on each other over time, and dynamics changed with increasing stages of psychopathological severity in a general population sample of female twins. It was shown that more severe stages of psychopathology are characterized by (i) stronger and (ii) more variable and hence individual-specific inter- and intra-mental state connections over time.t-1 predicting mental states at t over the progressive severity stages. Second, the differences between individuals become progressively larger, as indicated by the increasing random slope effects over the progressive severity stages. The first pattern reflects the nomothetic process of staging  and the second refers to the idiographic concept of profiling .The results suggest that as individuals move through progressive stages of psychopathological severity as described in the clinical staging model One of the key notions of the clinical staging model is that mental distress and need for care are present long before possible assignment of a clinical diagnosis The symptom measures analysed in the current paper represent mental states indexing momentary positive affect, negative affect and paranoia in daily life. These mental states were measured in the general, mostly non-clinical population, and reflect subclinical, low-level expression of mental ill-health. The dynamics between these mental states may form the building blocks of observable symptoms of mental ill-health and are thus relevant in the context of early diagnosis since it allows for investigation the development of psychopathology arising from its earliest sub-symptomatic expressions.symptoms impacting on each other The rationale explored in this study could be extended to the hypothesis that dynamic patterns can also be observed in actual When investigating dynamics between mental states (micro-level) or symptoms (macro-level) in the context of development of need for care, the dynamic nature of associations should be taken into account. When moving across the spectrum of psychopathological severity, certain factors of risk or resilience may impact differently at different stages t-1 predicting both negative affect and paranoia at t, reflecting individual variation in these associations, were quite small. Thus, effects of positive affect do not differ much between individuals, and these small differences did not change much with increasing symptom severity. Thus, effects of positive affect on negative affect and paranoia are quite similar for all individuals, suggesting interventions that focus on (increasing) positive affect, e.g. mindfulness based interventions Random effects of positive affect at An important strength of this study is that it introduces an element of diagnostic novelty, aiming to investigate the development of psychopathology from an entirely new perspective: exploring the dynamics between mental states in individuals with increasing levels of psychopathology. As this is a first, exploratory step in this direction, replication of our findings in other samples is necessary.It is important to keep in mind that the current sample is a general population sample, in which the expected prevalence of significant psychopathology is around 15–20% Future research could extend the line of research explored in the current study with a focus on dynamic relationships between symptoms, comparing dynamics between mental states and/or symptoms across different stages and syndromes to explore and compare possible disorder-specific patterns. Ideally, samples should be used with differential clinical severity patterns, representing multiple clinical stages. Also, studies should ideally include a longitudinal dimension, following individuals over time, to investigate the transition from one stage to another. Furthermore, factors of risk and resilience that may impact on mental state and symptom dynamics, and on progression through successive clinical stages, plus their susceptibility to early interventions


Administration of tocilizumab, a humanized antihuman interleukin-6 receptor monoclonal antibody, promptly improved her clinical manifestations, and she has been in complete remission (DAS28 <2.6) without bone erosion and/or destruction. Positivity for both antibodies (anti-CCP and RF) can forecast the severity of JIA (radiographic bone destruction). In such cases the administration of biologic remissive therapy may be prudent early in the disease course.This report describes 3 year old girl with the unusual presentation of polyarticular juvenile idiopathic arthritis (JIA) with anti-cyclic citrullinated peptide (anti-CCP) antibodies and a positive rheumatoid factor (RF). She was initially treated with a nonsteroidal anti-inflammatory drug  followed by methotrexate (MTX, 10 mg/m Juvenile idiopathic arthritis (JIA), previously called “juvenile chronic arthritis” or “juvenile rheumatoid arthritis”, is the most common chronic autoimmune (auto-inflammatory) disease in childhood. The disease affects roughly 10 to 20 in 100,000 children [The anti-cyclic citrullinated peptide (anti-CCP) antibodies have been studied extensively in adult-onset RA and have proved to be highly specific for this disease 98%) . Recent 8% . ReceA Japanese girl, aged 3 years and 5 months, was referred to us for a 2-month history of bilateral knee, hand, and finger joint arthralgia with morning stiffness. She was born as a preterm infant at 28 weeks’ gestation by elective Caesarian section for fetal distress. Her birth weight was 872 g and she was under mechanical ventilation for 14 days. After that, her development was good and she remained healthy until 2 months before admission. Physical examination showed a well-appearing girl 93.2 cm tall and weighing 12.1 kg. Clinical examination revealed swelling and pain in bilateral knee joints, wrist joints, foot joints, hip joints and several metacarpophalangeal and proximal interphalangeal joints. She was unable to walk alone. Magnetic resonance imaging with T2 enhancement showed a synovial fluid collection without joint or bone destruction  and prednisolone (0.25 mg/kg/day) were added. During the next 6 weeks, acute-phase reactant levels did not decrease and DAS28 did not change (5.52) (Figure This is a report of the youngest child ever reported to develop both anti-CCP antibody positive and IgM-RF positive polyarticular JIA. Anti-CCP antibodies are now considered important markers for the diagnosis of RA in adults. In JIA, which is a very heterogenous groups of diseases compared to adult RA, the development of anti-CCP Abs is variable. High anti-CCP positivity is supposed to be related to highly RF-positive disease, and the RF-positive polyarticular type of JIA might be a pediatric equivalent of RA . JIA mimShe was born as a preterm infant. Interestingly, it is hypothesized that the pathogenesis of RA may be related to early life factors, such as birth weight and breastfeeding, which contribute to the development and shaping of the immune system . Recent in utero maturation, but did not appear to be associated with RA incidence in either cohort [Gestational age and prematurity may be related to infection susceptibility and to r cohort -16. Meanr cohort . The immIt is suggested that JIA with both RF and anti-CCP positive antibodies is a more aggressive and severe disease that leads to joint damage and disability . To prevThe importance of these antibodies in the evaluation of JIA and determination of possible treatment plans to prevent joint damage and disability was demonstrated. More studies are needed to resolve the precise roles of anti-CCP in JIA and to determine whether or not it works as a valuable marker for the selection of optimal treatments.This is a report of the youngest child known to develop anti-CCP antibody and RF double-positive polyarticular JIA who was successfully treated by tocilizumab. Early treatment of children with both RF and anti-CCP antibodies with a biologic may be optimal.Written informed consent was obtained from the patient and guardians for publication of this Case Report and any accompanying images.JIA: Juvenile idiopathic arthritis; CCP: Cyclic citrullinated peptide; RA: Rheumatoid arthritis.None of the authors have any conflict of interest to report.All authors worked in the ward of Hiroshima-City Hospital and conferred on the treatment and patient’s condition. The data was analyzed and interpreted mainly by KY and SS. All authors read and approved the final manuscript.


An aging population and better management of various heart diseases explain the exponential growth in incidence and prevalence of chronic heart failure, with poor prognosis and heavy health costs. Medical management is codified in international guidelines. The management of heart failure in over-80 year-old patients follows these guidelines, but no clinical trials have been able to confirm benefit. Moreover, registries show down-prescription of heart failure treatments in the elderly and over-80s.We present the design of the HF-80 ("Is there benefit in optimising heart failure treatment in over-80 year-old patients?") study, which is a prospective randomised open-label clinical trial with blinded end-points, designed to evaluate the effect of optimising management by adhering to guidelines in over-80 year-old heart failure patients. Patients over 80 years of age admitted with acute heart failure will be included. The primary endpoint is to assess quality of life at 6 months on the Minnesota questionnaire. The secondary endpoints are to assess the effect of optimised management on quality of life, mortality, readmission for acute heart failure, cardiac fibrosis and economic data at 12 months. 80 patients will be included, divided into 2 groups: group A, with usual heart failure management by general practitioners; and group B, with optimised management based on international guidelines.It is necessary to assess the benefit of guidelines in over-80 year-old heart failure patients because of the fragility of this population and the elevated risk of iatrogenic complications.NCT01437371.Clinical trials.gov number:  An aging population and improved management of various heart diseases involving ischemic aetiologies explain the growth in incidence and prevalence of chronic heart failure (HF) , with hiAngiotensin-converting enzyme inhibitors (ACEi) ,5 beta-bHeart failure management is now clearly codified for the general population, thanks to several studies and guidelines. Management of over-80 year-old HF patients, however, is simply extrapolated from their findings. No study has specifically assessed optimised HF treatment in the over-80s, where potential benefit could be counterbalanced by co-morbidity and iatrogenic complications. The HF-80 clinical trial was designed as a pilot study to investigate whether optimised management has an effect on quality of life (QOL) in over-80 year-old HF patients.The primary objective of this pilot study is to assess optimised HF management, according to the guidelines of the European Society of Cardiology (ESC) ,12, in tThe secondary objectives are to evaluate the effect of optimised management on:• Quality of life at 12 months• Mortality at 12 months• Readmission for acute HF at 12 months• Cardiovascular events at 12 months• Cardiac fibrosis, evaluated by collagen peptides.The primary assessment criterion is QOL at 6 months, assessed on the Minnesota Living with Heart Failure Questionnaire (LHFQ) .The secondary assessment criteria are QOL at 12 months, measured by both the SF 12  and LHFQThis pilot study will also help lay the groundwork for a French national multicentre study of the management of octogenarian HF patients to find what support is most appropriate.The HF-80 pilot study is a prospective randomised single-centre open-label clinical trial with blinded endpoints. Current lack of knowledge regarding management for this population requires a pilot study, to harvest data before starting a clinical trial to assess mortality. The study population is over-80 year-old patients recently admitted for acute HF. Inclusion and exclusion criteria are listed in Table Dementia will be assessed by the Mini mental state examination (MMSE): patients with scores under 24/30 will not be included. For the very elderly, a preliminary walking test will be performed, to exclude patients with reduced mobility, who are moreover very often subject to dementia.Included patients will be randomly allocated to either arm in a 1:1 ratio. The randomisation list is generated by minimisation  to maintOver-80 year-old patients will be recruited and randomised into 2 groups of 40 Figure :• Group A: "usual care" management by the patient's usual general practitioner (GP) and cardiologist;• Group B: "optimised" management strictly adhering to ESC guidelines ,12, perfPatients will be included in HF-80 at discharge from acute HF care. Before inclusion, trans-thoracic echocardiography will confirm that left ventricle ejection fraction is under 35% and that no exclusion criteria are present. During hospital care, patients of both groups will receive the same treatments, so far as possible using all HF therapeutics; different hospital treatment according to group would not be ethically acceptable. Mean hospital stay is about 10 days, which is too short to induce bias, as medical management optimisation applies only after discharge. Optimised management will be assessed with long-term prognosis.An identical assessment is to be performed at baseline and at 12 months for all patients (groups A and B) ;• Six-minutes walking test (6MWT);• Electrocardiogram (EKG);• Transthoracic echocardiography (TTE);• Blood test  , N-Termi• Renin, aldosterone and collagen peptides , and galectin 3;• Mini mental state examination (MMSE) .During primary hospital care for acute HF and at discharge, both groups will have the same management with initiation of the same treatments, following guidelines ,12.Group A subjects will be followed up by their usual GP and cardiologist without any day-hospital care . The GP and cardiologist will manage treatment optimisation as they are used to doing.Group B subjects will have the same management as group A but will also receive day-hospital care. The first 3 visits will be at 3 weekly intervals, except in case of unstable HF, and then every 6 weeks for 12 months, to optimise treatment.During each day-hospital visit in group B, certain data will be recorded to optimise HF management:• Clinical examination ;• Blood sample , by a single operator , at inclThe following measurements will be taken in each subject:2); RV volume; RV ejection fraction; TEI myocardial performance index; and tricuspid annular plane systolic excursion (TAPSE).2D/MM modes: Right ventricle (RV) diameter (mm); interventricular septum thickness at end diastole and end systole (mm); left ventricle (LV) posterior wall thickness at end diastole and end systole (mm); LV diameter at end diastole and end systole (mm); LV volumes at end diastole and end systole (ml); LV ejection fraction measured by the biplane Simpson method (%); LV mass index (g/m2); inferior vena cava diameter (mm); left and right atrium areas , peak A wave (cm/s), E/A ratio, E-wave deceleration time (m/s); pulmonary venous waveforms, including peak systolic (S) velocity, peak anterograde diastolic (D) velocity, and S/D ratio; VP, Color M-Mode flow propagation velocity; relaxation isovolumic time (m/s); cardiac output, tricuspid E wave; tricuspid regurgitation (none/mean/moderate/severe); systolic pulmonary arterial pressure; mitral regurgitation (none/mean/moderate/severe); and dp/dt for left and right ventricle.Doppler tissue imaging mode: lateral and septal E' wave and A wave at mitral annulus (cm/s), lateral and septal S wave at mitral annulus (cm/s); S' and E' wave at tricuspid annulus (cm/s).2D-Strain mode: Loops obtained by 2D on 3 cycles, with apical 4-cavities, 3-cavities, 2-cavities and parasternal short axis views, with frame rate > 60 frames/s.This will be performed for each patient at inclusion and at 12 months, and also at 6 months for group B . The tesThe usual blood tests made during acute HF hospitalisation will be performed by the hospital biochemistry laboratory: haemoglobin, K, Na, liver assessment, bilirubin, MDRD , NT-pro-It was decided to implement two QOL questionnaires . Termination for futility can thus be considered.With a 2-tailed significance threshold of 0.05, statistical power of 90% and allowing for 15% loss to follow-up, 80 patients will be needed to show a difference of 20 points (σ = 25) in quality of life (LHFQ) at 6 months between the 2 randomisation arms . MorcillThe number of patients included and the curve of the inclusions, the theoretical number of visits for the number of patients included, the number of visits actually made and the ratio will be presented for the 2 groups. The cumulative duration of follow-up and the "total follow-up/expected cumulative follow-up" ratio will be calculated.2 or Fisher-exact tests  and by Student's t tests or Mann-Whitney tests as appropriate (continuous variables). Multivariate analyses to control for confounding effects of variables will be performed.All analyses will be performed on an intention-to-treat basis. Clinically relevant baseline variables and primary and secondary endpoints will be compared between groups by ChiThe survival analysis will be conducted in univariate analysis by log-rank test to compare survival curves following Kaplan-Meier, and in multivariate analysis by the Cox proportional regression model.To measure the evolution of parameters over time points (visits), longitudinal data analysis will be conducted by ANOVA for repeated measures followed by Tukey-Kramer post-hoc test and by random effects models to measure within-subject correlation taking account of effects over time (random intercept and slope). The impact of covariates, such as randomisation group, will be explored to assess the impact of strategies on QOL score.Treatment compliance will be analysed initially in a descriptive step and, if necessary, included in multivariate analysis.A 2-tailed p value of 0.05 will be considered statistically significant . All analyses will be performed by STATAv11 .The aging of the population  is increUnfortunately, clinical trials on HF have recruited young patients. Clinical studies in cardiology, and particularly in HF, recruit young subjects at the expense of seniors who are underrepresented if not excluded -33. ThisA potential bias is present in this design. Patients in the "optimised" group will have more cardiology day-hospital visits; GPs will be in charge of their own management optimisation, as recommended in the ESC guidelines.Divergent data are present in the literature on elderly HF patients, and there is no consensus on managing over-80 year-old patients. The growing size of this population requires clinical trials to confirm that the HF management validated in younger subjects is also effective in those over 80 years of age.HF-80 study is in an activating recruiting phase since October 2011. Institute's committee on human research (CPP Sud Est VI) agreement was obtained in April 2011. Subjects will give their informed consent before being enrolled in the study. AFFSAPS agreement was obtained in May 2011. HF-80 will start enrolling patients in October 2011. Study completion date is estimated at December 2012. Clinical trials.gov number: NCT 01437371.HF: Heart Failure; QOL: Quality of life; LVHQ: Minnesota living with heart failure questionnaire; LV: Left ventricle; 6MWT: 6 minutes walking test; TTE: transthoracic echocardiography; ESC: European society of cardiology; ACEi: angiotensin conversing enzyme inhibitors; NYHA: New York Heart Association; GP: general practitioner.This clinical trial is funded by the support of Laboratoires Servier and Sorin group.The authors declare that they have no competing interests and no other source of fundings than those cited above.RE, FJ, SM, BP, and CV participated in the design of the study. RE and FJ participated in writing the manuscript. BP performed statistical section. VS participated in the biological part of the study. PM, JRL, BC helped to draft the manuscript, and participated in study design and coordination. All authors read and approved the final manuscript.


Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse cutaneous reactions to drugs. We describe the case of a 19 year old patient with SJS/TEN overlap syndrome, who developed severe interstitial pneumonia after she had received antiepileptic drugs. A cytomegalovirus infection was diagnosed by Real Time Polymerase Chain Reaction (RT-PCR) detection on Bronchoalveolar lavage. Based on observations on biological data, temporal relationship, and clinical features, it could be inferred that the reactivation of cytomegalovirus with viral replication can predispose a person to TEN-SJS. We discuss here, in the light of the current literature, the probable association between drug-induced SJS-TEN and fulminant reactivation of cytomegalovirus. Most cases of SJS-TEN are drug-induced. In patients with no drug use, TEN-SJS is induced by chemicals, Mycoplasma pneumonia, immunization, and viral infections.2,3Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are variants of acute, rapidly progressive mucocutaneous reactions. These reactions differ only in their body surface area (BSA) involvement: whereas SJS is the less severe condition insofar as skin sloughing is limited to less than 10% of the BSA, TEN involves sloughing of more than 30% of the BSA. The SJS/TEN overlap syndrome describes patients with the involvement of greater than 10%, but less than 30% of the BSA.We describe here a patient with the SJS/TEN overlap syndrome, who developed severe interstitial pneumonia caused by a cytomegalovirus in the wake of treatment with antiepileptic drugs. Miss. N, a 19 year old Moroccan woman, without a history of drug or food allergy, was prescribed Phenobarbital (100 mg/day) and Valproate (1000 mg/day) for epilepsy one month prior to her latest hospital admission due to erythroderma, fever (39.8°C), and dyspnea. On admission, the patient was conscious and reported chills, coughs, and rhinorrhea of two days’ duration. She had developed rash on her face six days after starting epilepsy treatment, with the condition progressing rapidly to her trunk, limbs, neck, and chest over the next four days. The facial rash subsequently evolved into pustules. On examination, there were multiple erosions over the mouth and vulva, and the conjunctiva was inflamed. Nikolsky’s sign was positive. The total extent of the erythematous rash was 55% of the BSA. Histological investigation of the injured skin revealed an aspect for drug eruption . Immunofluorescence markers showed negative staining. The diagnosis of SJS-TEN caused by antiepileptic drugs was established. 9 /µL. Chest X-ray demonstrated multifocal patch consolidations with ground-glass opacity in both lungs. No bacterial pathogen was isolated in the respiratory tract, urine, and blood. Viral serology (HIV and hepatitis B and C) was negative. Real Time Polymerase Chain Reaction (RT-PCR) (R-gène® Kits) of bronchoalveolar lavage (BAL) revealed that the cause of the respiratory symptom was cytomegalovirus (CMV); the finding was thereafter confirmed by cell culture on MRC-5 cells. Prior serology data showed that our patient had already sustained a primary CMV infection at 6 years old, which was in favour of the current reactivation. As was expected, RT-PCR in blood showed fulminant viremia with 459 copies/ml (threshold: 350). On the other hand, laboratory testing revealed anemia, eosinophilia, increased inflammatory markers, and white blood cell count of 10×10The antiepileptic drugs were withdrawn and anticoagulant therapy, parenteral analgesia, eye drops, and mouth antiseptic therapy were initiated. Intravenous Ganciclovir (10 mg/kg/day) was started. Oxygen therapy was initiated with parenteral nutrition and adequate hydration. Serial BAL assays were negative six days after the commencement of antiviral therapy, and the skin lesions began to heal without the need to introduce corticosteroids. The patient’s condition improved, and she was transferred to the general ward with a prescription of Ganciclovir for a further two weeks.4,5 Treatment with corticosteroids is recommended but not necessarily effective.5-7 Several drugs are at “high” risk of inducing TEN-SJS.1Mycoplasma pneumoniae and herpesvirus infections are well-documented causes. In some rare cases, however, the etiology remains unknown.8TEN and SJS are severe adverse cutaneous drug reactions.emporal relationship and clinical features strongly suggest CMV with viral replication, predisposing the patient to TEN-SJS. It is clear that without a thorough understanding of the underlying mechanisms involved, it is difficult to establish a direct causal link between CMV and drug hypersensitivity. However, a relationship between viral infections and the simultaneous or subsequent development of drug-induced rash has been observed in a number of clinical situations, while the full cascade of events leading from viral infections to the development of drug allergy in humans remains poorly understood. Ampicillin rash during infectious mononucleosis and an increased risk for developing drug-induced rash in AIDS are well-known examples of this relationship.3 The herpesvirus family is the most likely candidate to be able to greatly influence immune responses because herpesviruses can induce and maintain a potent memory T cell response due to their common properties of ubiquitous prevalence in human populations and the capacity to grow in lymphoid cells.8 Specific viral infections have been shown to increase CD95 (Fas) and/or Fas Ligand expression and increase sensitivity to Fas/Fas Ligand-dependent apoptosis.3The case presented here suggests a link between CMV replication and drug-induced TEN-SJS. Our patient developed TEN-SJS and in parallel, pneumonia caused by CMV reactivation, six days after the initiation of antiepileptic drugs. It is deserving of note that there are also cases in which the viral reactivation is accompanied by flu-like symptoms; therefore, it is possible that the six-day period before admission represents the duration of reactivation in our patient. T3 The hypothesis generated is whether or not TEN-SJS is linked to fulminant CMV infection and whether or not CMV can trigger an interaction between cytotoxic T-lymphocytes, natural killer cells, and keratinocytes. Further observational studies are warranted. Treatment strategies for TEN-SJS associated with CMV include treatment of the cause with Ganciclovir, avoidance of possible offending drugs associated with TEN-SJS, and avoidance of systemic steroids assuming that the underlying mechanism is most probably the interaction between CMV and some enzymes that detoxify, such as cytochrome P450. The offending drugs associated with TEN-SJS cause the deposition of the toxic and immunogenic metabolites of these drugs in the epidermis and lead to a series of immune reactions that culminate in TEN-SJS.The case presented herein illustrates that a possible CMV interstitial pneumonia (secondary to CMV reactivation) may predispose a patient to SJS-TEN. Implications for clinical practice include the notions that SJS-TEN is a potential adverse effect of some drugs and that patients at risk for the development of TEN-SJS may be identified by measuring CMV loads during the first few days after onset, even if CMV IgM and IgG levels are negative.


HIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries.Prospective, observational cohort study of adult inpatients with HIV-associated tuberculosis starting antiretroviral therapy in a dedicated tuberculosis hospital in Cape Town, South Africa. Causes of clinical deterioration and outcome were recorded in the first 12 weeks of antiretroviral therapy. Patients with rifampicin-resistant tuberculosis were excluded.3 (IQR 31–106) and HIV viral load 5.6 log copies/mL. All patients had significant comorbidity: 82% were bed-bound, 65% had disseminated tuberculosis and 27% had central nervous system tuberculosis. Seventy six patients (68%) developed 144 clinical events after starting antiretroviral therapy. TB-IRIS, hospital-acquired infections and significant drug toxicities occurred in 42%, 20.5% and 15% of patients respectively. A new opportunistic disease occurred in 15% of patients and a thromboembolic event in 8%. Mortality during the 12 week period was 10.6%.Between May 2009 and November 2010, 112 patients , with a median age of 32 years were enrolled. At baseline the median CD4 count was 55 cells/mmst three months following ART initiation.High rates of TB-IRIS, hospital-acquired infections and drug toxicities complicate the course of patients with HIV-associated tuberculosis starting antiretroviral therapy in hospital. Despite the high morbidity, mortality was relatively low. Careful clinical management and adequate resources are needed in hospitalised HIV-TB patients in the 1 HIV-TB patients with severe immunocompromise commonly have disseminated tuberculosis and significant comorbidity, and often require admission to longterm care facilities or dedicated tuberculosis hospitals. In Sub-Saharan Africa the majority of ART programs are outpatient-based requiring regular clinic attendance prior to starting ART. Few patients start ART in hospital, and studies that report the complications and outcomes among inpatients starting ART are limited. We aimed to describe the causes for clinical deterioration in hospitalised HIV-TB patients starting ART in order to inform resource allocation of diagnostic and therapeutic services required at tuberculosis hospitals in low- and middle-income countries.A prospective, observational cohort study of hospitalised patients with HIV-TB was conducted at Brooklyn Chest Hospital (BCH) from 29 April 2009 until 28 February 2011. BCH is a district level tuberculosis hospital serving the Cape Town metropole. Inpatients at BCH are either too ill for ambulatory care or have drug-resistant TB, and are transferred in from hospitals or TB clinics with a diagnosis of tuberculosis already made and TB treatment initiated. The adult inpatient population has been previously described; where more than two-thirds of patients in the drug-sensitive wards are HIV-co-infected, of whom 98% had significant comorbidities and 60% had a Karnofsky performance score of ≤30. 3 or WHO Stage 4 defining illness until 31 March 2010, following which guidelines changed to include all patients with HIV-TB and CD4 count ≤350 cells/mm3. Exclusion criteria included patients with known rifampicin-resistant tuberculosis and those unable to provide informed consent.Eligible patients were adults (≥18 years), hospitalised at BCH with confirmed HIV infection and a diagnosis of pulmonary (PTB) or extrapulmonary tuberculosis (EPTB), not on ART, who fulfilled national criteria for starting ART at the time of the study; CD4 count <200 cells/mmst April 2010, first-line ART comprised stavudine (d4T), lamivudine (3TC) and efavirenz as the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) in patients on concurrent TB therapy. In April 2010 new national guidelines were introduced with tenofovir (TdF) replacing d4T. Unless contraindicated, all patients received cotrimoxazole 960 mg daily as prophylaxis, and pyridoxine 25–50 mg daily during tuberculosis treatment as well as subcutaneous unfractionated heparin (5000 IU subcutaneously 12 hrly) for deep vein thrombosis prophylaxis if bedbound.First episodes of tuberculosis were treated as per national policy with standard fixed dose combination tablets composed of rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) for the 2-month intensive phase followed by RH for the 4-month continuation phase. For retreatment tuberculosis, RHZE was given for 3 months with 40-doses of streptomycin followed by RHE for 5 months. Prior to 1Follow-up was for 12 weeks after starting ART. Patients were assessed at 8 time-points: enrolment, ART initiation, then weekly for four weeks and again at week 8 and week 12 after ART initiation. At each scheduled visit, an infectious diseases specialist examined patients and targeted laboratory  and radiological investigations were performed if there was clinical deterioration. Baseline clinical and laboratory data was recorded: age, gender, CD4 T-lymphocyte count (CD4 count), HIV viral load, WHO stage, comorbid condition(s), weight and ambulatory status. Reasons for not being on ART at admission and prior ART exposure was established. Tuberculosis data included: prior tuberculosis episode(s), site of tuberculosis (EPTB/PTB), diagnostic method , and TB drug details . Unscheduled visits and additional investigations occurred in the event of clinical deterioration. Routine care was the responsibility of the ward doctor and nursing staff.We recorded the following outcome measures in the event of a clinical deterioration: new WHO stage 4 defining condition, drug-induced toxicity requiring a drug switch, hospital acquired infection, TB-IRIS, and significant other comorbidity necessitating investigation and treatment.Tuberculosis was diagnosed on the basis of smear or culture positivity. Where this was negative or unavailable, diagnosis was in line with WHO guidelines for diagnosis of smear negative or extrapulmonary tuberculosis in HIV-1 infected persons. The study was approved by the University of Cape Town’s Faculty of Health Sciences Research Ethics Committee (HREC No: 049/2009) and the Provincial Research Committee of the Department of Health, Western Cape. All participants signed written informed consent.Data were analysed using Stata version 12.0 . Measures were described with medians and interquartile ranges (IQR) or proportions. We used chi-square tests (replaced by exact tests for sparse data) to compare proportions, rank-sum tests to compare medians, and t-tests to compare mean values between groups. Kaplan-Meier methods were used to describe the survival of patients over time.A total of 130 participants were screened for enrollment , 112 of The median time from the start of anti-tuberculosis treatment to ART start was 36 days  and the majority (95%) received an efavirenz-based regimen, more commonly with tenofovir than stavudine . Twenty-Pneumocystis jirovecii pneumonia and Kaposi’s sarcoma) were the main reasons for deterioration  patients experienced a significant clinical deterioration after initiating ART. A total number of 144 events were recorded with a median of 2 events (range 1–5) per patient. Paradoxical TB-IRIS, HAI, drug toxicity (most commonly efavirenz-related neuropsychiatric toxicity) and unmasking of opportunistic diseases . Seven patients developed potentially life-threatening IRIS, 6 due to worsening tuberculous meningitis and one due cardiac tamponade requiring urgent pericardiocentesis. The only baseline variable that was significantly associated with the development of TB-IRIS on univariate analysis was CRP>10 mg/L . Corticosteroid use at the time of ART initiation was associated with a 40% reduction in TB–IRIS incidence, however this was not statistically significant (p = 0.06).Clostridium difficile diarrhoea and one patient developed chickenpox acquired following an exposure to another patient with herpes zoster. Thirteen isolates were identified in the 22 patients with bacterial sepsis, 9 of which were multi-drug resistant bacteria: 8 extended spectrum β-lactamase (ESBL)-producing enterobacteriaceae (7 from urine culture and 1 blood culture) and 1 methicillin-resistant Staphylococcus aureus (sputum culture).Twenty-three patients (20.5%) developed an HAI, the commonest being urinary tract sepsis in 9 patients. Seven patients had sepsis syndrome with a bloodstream infection, 3 pneumonia, 3 3 were not significantly associated with mortality. The cause of death was ascribed to sepsis in 11 patients and pulmonary embolism in one. None of the deaths were thought to be directly caused by paradoxical TB-IRIS.Twelve patients died during the 12-week follow-up period resulting in cumulative mortality of 10.6% . NeuroloOur study demonstrated that over two-thirds of hospitalised HIV-TB patients develop complications resulting in clinical deterioration after starting ART as inpatients. Over 40% experienced paradoxical TB-IRIS, with HAIs, drug toxicities, and opportunistic diseases being other frequent causes of deterioration. A novel finding is that HAIs were common (occurred in 20.5%), and 11 of the 12 deaths were attributed to sepsis. Reassuringly, despite the high incidence of clinical deterioration, 89% of participants were alive three months after ART initiation. Adequate clinical care and diagnostic and therapeutic resources are required to manage this HIV- as well as tuberculosis-associated morbidity.HIV infection, especially with a low CD4 count, is a risk factor for clinical deterioration and death on TB treatment. The high incidence of paradoxical TB-IRIS in our study (42%) corresponds with the higher estimates reported from previous cohort studies (8–43%) The large number of HAIs we diagnosed, and the associated mortality is alarming. Our findings suggest that once patients with advanced HIV and TB are established on appropriate TB treatment, ART and cotrimoxazole, then bacterial infections emerge as the most important cause of death. We suspect that colonization with multi-drug resistant bacteria occurred in the referring general hospital, as antibiotic selection pressure in TB hospitals is likely to be low. High rates of urinary catheterization during the acute admission at the referring hospital, is a likely contributing risk factor to the urinary tract infections. Depressed monocyte responses may be one of the reasons why HIV-infected patients with advanced immunosuppression are at high risk of bacterial infections. Our study has several limitations. The follow-up period was limited to the first 3 months of ART, so events occurring in the latter half of TB therapy were not ascertained. The generalizability of our findings is limited by the fact that all participants in the study were evaluated by a specialist physician trained in infectious diseases at study visits, which could in part explain our relatively low mortality. There was no control group to ascertain outcome of patients who did not receive input from an Infectious Diseases specialist. Another factor limiting generalizability of our outcomes is that BCH is relatively well-resourced with access to radiology and laboratory services. It is unlikely that such good outcomes can be achieved in less well-resourced facilities, which would be found in the majority of TB hospitals in low- to middle-income countries. However, specialist input and access to diagnostic facilities allowed us to ascertain the frequency and type of complications occurring in sick HIV-TB inpatients starting ART. Another limitation is that not all patients developing sepsis had appropriate cultures sent, as transportation of specimens to the off-site microbiology laboratory occurs only once a day during weekdays. In addition the causes of death were ascertained by the attending infectious diseases specialist and no post-mortem studies were performed on the patients. For the analysis of predictors of mortality the sample size was to too small to allow for meaningful comparison between groups.3 results in a reduction in death and AIDS.M. tuberculosis, including drug-resistant strains to the HIV-infected clinic population. Hence, integrating ART initiation into tuberculosis hospitals is vital to expedite ART initiation as well as to prevent TB transmission in ART clinics. With proper human resource allocation to tuberculosis hospitals such as BCH, ‘fast-track’ counselling can be employed to ensure patients are treatment ready. Patients in our study started ART a median of 36 days after TB treatment, much of the delay occurring because of the period it took for patients to be admitted to BCH after TB diagnosis.Our findings have important implications for service delivery and resource allocation at hospitals offering dedicated tuberculosis services. HIV-TB patients requiring long term admission are a vulnerable group with advanced immunosuppression, frequently have disseminated tuberculosis, and are at high risk of early mortality if ART is not initiated timeously. Three landmark trials have shown that ART initiated within 2–3 weeks after starting TB therapy in patients with HIV-associated tuberculosis and a CD4<50 cells/mmThe strength of our study is that it illustrates the clinical complexity of starting ART in hospitalized HIV-TB inpatients and the need for clinicians trained in the clinical management of these very ill patients. It argues strongly for proper training and resource allocation to manage this vulnerable group of patients.High rates of paradoxical TB-IRIS, HAIs, drug toxicities and new opportunistic infections occur in hospitalised HIV-TB inpatients with advanced immunosuppression initiating ART. Despite the high morbidity, relatively good short-term outcomes can be achieved with careful clinical management. There is a need for prospective studies in other settings, and for additional studies evaluating the effect of training and the provision of ART to HIV-TB inpatients.


The aim of this study is to present a new method for determining the root-derived extracellular acid phosphomonoesterase (EAPM) activity fraction within the total EAPM activity of soil. EAPM activity was determined for roots, organic and mineral soil. Samples were collected using paired PVC cylinders, inserted to a depth of 15 cm, within seven selected forest stands. Root-derived EAPM formed between 4 and18% of the total EAPM activity of soil from forests of differing maturity. A new approach, presented in this work, enables separation of root-derived EAPM activity from total soil EAPM. Separation of root-derived EAPM from soil provides a better understanding of its role in P-cycling in terrestrial ecosystems. The method presented in this work is a first step towards the separation of root- and microbe-derived EAPM in soils, which are thought to possess different kinetic properties and different sensitivity to environmental change. Extracellular acid phosphomonoesterase (EAPM)  plays an important role in the mineralization of soil organic phosphorus in a range of terrestrial ecosystems . Root-deversus soil microorganisms in the production of EAPM and thus their relative importance for P-cycling. EAPM from roots is known to possess different kinetic properties and sensitivity to other factors of environment compared to that derived from microorganisms [Different ecosystems are thought to have either plant- or microbe-derived EAPM prevailing in soil , 8. Neverganisms . Consequrganisms .Separation of plant root- and microbe-derived EAPM in soil is difficult. Hence, we have developed a new approach, focusing on the activity of root-derived EAPM as a part of the total EAPM activity of soil in different forest ecosystems.Fagus sylvatica L.) stands , young  and old  oak (Quercus robur L.) stands , and young , middle-aged , and old  spruce (Picea abies L.) stands . Soils within the studied stands were Dystric Luvisol (young beech and old oak), Haplic Cambisol (old beech and young oak), Dystric Cambisol (old spruce), Gleyic Cambisol (young spruce), and Leptic Cambisol (middle aged spruce) [In total, seven forest stands were selected for this study. These included young (19 years) and old (207 years) beech  were randomly inserted in every stand; cylinders within the same pair were always inserted side by side, to ensure similarity. After transportation to the laboratory in plastic bags, the litter layer in all cylinders was removed. One cylinder in each pair was used for separation of all the roots, which were washed in tap water and then in demineralized water. The soil from the second cylinder was separated into organic (F + H horizons) and mineral part to ensure consequent determination of EAPM activity of naturally developed soil layers without their artificial mixing together both parts were separately sieved through a 5 mm mesh, homogenised, and weighed.All roots from each of the cylinders were incubated, in succinate-borate buffer (pH 4.8) at 37°C for 30 min., with p-nitrophenyl phosphate (p-NPP) as a substrate . The sub2 of soil surface.EAPM was measured separately in organic and mineral soil. Fresh soil (1 g) was incubated, in 12 mL of succinate-borate buffer (pH 4.8) at 37°C for 1 h, with p-NPP as a substrate . EAPM acValues are given as means of five replicates with standard errors (SE). Significant differences were calculated using one-way ANOVA plus Fisher's LSD test.P < 0.05) higher in young oak, old oak, and young spruce than that in other forest stands (P < 0.05), the lowest total EAPM activity was found in the soil from the old beech forest stand. From the total EAPM activity of soil, up to 18% was derived from roots  and response to pollutants  and other compounds in soil [Origin of phosphomonoesterase was shown to affect its Michaelis-Menten characteristics ( in soil , 31. Als in soil  reportedIn conclusion, root-derived EAPM forms a lesser part of the total EAPM activity of soils in forest ecosystems. These findings can be generalized for acid forest soils where EAPM is of microbial and root origin. Alkaline soils with dominance of alkaline phosphomonoesterase of microbial origin are hypothesised to have especially plant root-derived EAPM activity; however, it still remains to be experimentally determined.


Previous studies of breast cancer have shown that patients whose tumors are detected by mammography screening have a more favorable survival. Little is known, however, about the long-term prognostic impact of screen detection. The purpose of the current study was to compare breast cancer-specific long-term survival of patients whose tumors were detected in mammography screening compared with those whose tumors were detected by other methods.N = 2,936). Detailed clinical, treatment and outcome data, as well as tissue samples, were collected. Women with in situ carcinoma, distant metastases at the time of primary diagnosis and women who were not treated surgically were excluded. The main analyses were performed after excluding patients with other malignancy or contralateral breast cancer, followed by sensitivity analyses with different exclusion criteria. Median follow-up time was 15.4 years. Univariate and multivariate analyses of breast cancer-specific survival were performed.Breast cancer patients diagnosed within five specified geographical areas in Finland in 1991 and 1992 were identified , 22% (n = 408) of cancers were screen-detected and 78%  were detected by other methods. Breast cancer-specific 15-year survival was 86% for patients with screen-detected cancer and 66% for patients diagnosed using other methods . Similar differences in survival were observed in women at screening age (50 to 69 years), as well as in clinically important subgroups, such as patients with small tumors (≤ 1 cm in diameter) and without nodal involvement (N0). Women with breast cancer diagnosed on the basis of screening mammography had a more favorable prognosis than those diagnosed outside screening programs, following adjustments according to patient age, tumor size, axillary lymph node status, histological grade and hormone receptor status. Significant differences in the risk of having future contralateral breast cancer according to method of detection were not observed.Of patients included in the main analyses (Breast cancer detected by mammography screening is an independent prognostic factor in breast cancer and is associated with a more favorable survival rate as well as in long-term follow-up. Breast cancers detected by screening mammography have more favorable prognostic characteristics than cancers detected by other methods -9. The tIn a recently published study of 2,592 Dutch breast cancer patients, screen detection was reported to be independently associated with better breast cancer-specific and overall survival after a median follow-up of 11 years . We obseMost breast cancer recurrences occur 2 to 3 years after diagnosis , but theMost of the data derived from previous studies in which long-term outcomes of breast cancer detected within screening programs were analyzed are from clinical trials that reported mortality . Only veThere has been disagreement on the observed mortality and survival differences between patients whose breast cancer was detected by mammography and those whose breast cancer was detected outside screening, owing to biases in the statistical analysis -33. In tScreen-detected cancers may be subject to selection bias in that true attendees may represent not the entire population, but rather a generally more health-conscious population. In addition, screening may lead to detection of indolent cancers that would never have caused symptomatic disease and therefore they are overdiagnosed.In the present study, our aim was to evaluate whether the survival advantage of patients with screen-detected cancers persists after long-term follow-up. For this purpose, we analyzed an unselected nationwide series of breast cancer patients, which was recently updated to include long-term follow-up data. In previous studies of screen detection and survival, various definitions of screen-detected breast cancer have been used. In some studies, for example, outcomes of invited women and noninvited women have been compared , or inteN = 5,551). Permission to use clinical data and formalin-fixed, paraffin-embedded tissues for research purposes was provided by the Ministry of Social Affairs and Health, Finland (permission 123/08/97). With reference to the large number of studied cases, the authorities granted permission to use tissue samples without individual patient consent.Five well-defined geographical areas comprising approximately 50% of the Finnish population were selected for the study. We identified 2,936 patients diagnosed with breast cancer in 1991 and 1992 from the files of the Finnish Cancer Registry, which constitutes 53% of all women diagnosed with breast cancer in Finland during that time period  had distant metastases at the time of diagnosis and were excluded. Patients who were not treated surgically  and patients with lobular or ductal carcinoma in situ  were excluded. Those with missing data on exclusion variables were excluded, except for missing metastasis status. All of the exclusion criteria mentioned above were used in subsequent analyses.Of the 2,936 patients, 14 were excluded because of zero follow-up time due to perioperative mortality or diagnosis at autopsy. In 46 patients (2%), incorrect diagnoses were recorded during data extraction and thus were also excluded. The remaining 2,883 patients formed the FinProg database, which has previously been published and made available as an online case-match prognostic tool n = 349, 12%). Furthermore, we excluded patients with recent, synchronous or later other cancers , except for cervical carcinoma in situ and basal cell carcinoma. We defined other cancer as recent if it had been diagnosed within 5 years before the index breast cancer. Thus all patients with other carcinoma diagnosed after 1 January 1985 were excluded. The total number of patients included in the main analyses was 1,934.In patients with contralateral breast cancer or other cancer, the true origin of potential distant metastases may be difficult to determine. For the main analyses, patients with previous, synchronous or later contralateral invasive breast carcinoma were excluded . We also excluded patients with other carcinoma only if it was recent (1985 and later) or synchronous . For the second sensitivity analyses, we included all patients with contralateral breast cancer or other cancer or both and used only the primary exclusion criteria mentioned above . In all analyses, one patient could have been excluded for several reasons. The consort diagrams of the study are given in Additional file For the first sensitivity analyses, we excluded patients with contralateral breast cancer only if it had been diagnosed before or at the same time as the index breast cancer n = 68, 6%. WA screening mammography program was launched in Finland in 1987. During 1991 and 1992, Finnish municipalities were obligated by legislation to organize mammography screening programs for women 50 to 59 years of age. A few of the municipalities, however, screened other age cohorts as well (women 40 to 49 years and/or older than 60). The information regarding the method of detection in the FinProg series was collected from hospital records and from the Mass Screening Registry, which is a department of the Finnish Cancer Registry. Consequently, in the FinProg database, patients diagnosed within the mammography screening program are patients who have been invited to have and also truly attended screening mammography.For cancers diagnosed on the basis of symptoms, as interval cancers between screening rounds or for any other reason outside the mammography screening program, we use the term "detected outside screening" or "non-screen-detected breast cancer." Screening round was not considered in this study.n = 32, 8%) than when diagnosed by other methods . Palpation as a method of measurement was used in 5 patients (1%) diagnosed by screening mammography compared to 51 patients (4%) diagnosed on the basis of other methods  breast cancers whose tumor measurements were done by the pathologist on the basis of tumor slides. Similar distributions of methods of measurement were seen in both screen-detected and non-screen-detected breast cancers, where 267 (65%) and 974 (66%) tumor measurements, respectively, were done by a pathologist and 86 (21%) and 301 (20%), respectively, were done by a surgeon. More tumors were screen-detected when measured by a radiologist  staining, evaluation of protein expression and lsewhere ,17,40,41lsewhere . For the2 test. Life tables were calculated according to the Kaplan-Meier method. BCSS was computed from the date of the diagnosis until death due to breast cancer. The logrank test was used to compare survival between subgroups. Multivariate survival analyses were performed using a Cox proportional hazards model by entering the following covariates: method of tumor detection , grade , ER and progesterone receptor (PR) status , histological type , and age at detection grouped to account for the nonlinear risk associated with age. The tumor size in centimeters and the number of metastatic axillary lymph nodes were entered into the multivariate model as continuous variables. Multivariate analysis of the risk of later contralateral breast cancer was performed using logistic regression by entering the same covariates into the model as were entered into the Cox proportional hazards model. A P-value of 0.05 was adopted as the limit for inclusion of a covariate. All P-values are two-sided. STATA version 10 statistical software  was used for the analyses.Frequency tables were analyzed using the χN = 1,884), 408 patients (22%) had screen-detected breast cancer and 1,476 (78%) had non-screen-detected breast cancer. Mammography screening is organized mainly for women 50 to 69 years of age. In the current series, 484 patients (26%) were ages 50 to 59 years and 365 (19%) were ages 60 to 69 years. Of these patients, 254 (52%) and 93 (25%) were patients with screen-detected cancer, respectively, and 230 (48%) and 272 (75%) had non-screen-detected cancer, respectively.In the main study series , compared to only 53% of non-screen-detected tumors.P < 0.001), which was also true among women 50 to 69 years of age . Among the screen-detected cancers, 66% of tumors were 20 mm or less and had no nodal involvement (T1N0), and only 36% of non-screen-detected cancers belonged to this category.Nodal involvement was less frequent in patients with screen-detected breast cancer than in non-screen-detected breast cancer  in non-screen-detected cancers. The proportion of lobular carcinomas (16%) was equal in both diagnostic groups. Screen-detected tumors were more often of a special histological type . Similar differences in histological profile were seen in the 50- to 69-year-old age cohort .The majority of screen-detected tumors were ductal carcinomas (70%). However, the proportion of ductal carcinomas was significantly higher . Correspondingly, screen-detected cancers were less often grade 2 or 3 tumors  than were non-screen-detected cancers  (P < 0.001). However, this association weakened with increasing tumor size .Tumors detected by mammography screening were more often of a lower grade of differentiation. There were 129 grade 1 breast cancers (32%) in the screen-detected group and 241 (16%) among tumors detected by other methods . In women at screening age (50 to 69 years), there were only 9% ER- tumors in screen-detected tumors compared to 19% in non-screen-detected tumors (P = 0.002). Similar differences were seen according to PR status (P < 0.001).Screen detection was associated with hormone receptor status (ER and PR), although in analyses consisting of all age groups, the association was weak , but the association was not statistically significant (P = 0.08).No statistically significant association between screen detection and P < 0.001). The use of adjuvant systemic therapy was not known in 5 patients (1%) with screen-detected cancers and in 40 patients (3%) with non-screen-detected cancers.Adjuvant systemic therapy was given less frequently to patients with screen-detected breast cancer than to women with non-screen-detected breast cancer  compared with non-screen-detected cancers. The distribution of clinicopathological features in women with breast cancer diagnosed by screening mammography and by other methods is shown in Table P < 0.0001, RR = 2.91, RR = risk ratio). The survival advantage was seen in tumor size categories 1 to 10 mm, 11 to 20 mm and 21 to 50 mm  . In patients with screen-detected node-negative breast cancer, 15-year BCSS was 91% compared to 77% in the non-screen-detected group (P < 0.0001 and RR = 3). Patients with screen-detected, node-positive breast cancer had a survival advantage compared to patients diagnosed by other methods .This study included 1,203 (62%) node-negative and 654 (34%) node-positive breast cancer patients. Among the node-negative breast cancer patients, breast cancer was screen-detected in 317 patients (78%) and non-screen-detected in 862 patients (58%) (P < 0.0001 and RR = 2.61). Similar differences in survival were observed in all other age cohorts  ages 50 to 69 years, of whom 347 (40%) were diagnosed by screening and 502 (58%) were diagnosed on the basis of other methods. There was a statistically significant difference in 15-year BCSS between the two subgroups  of 1.69 (95% CI = 1.06 to 2.70) between patients whose tumors were detected outside screening and those whose tumors were screen-detected. Tumor size, nodal status, tumor grade and es Table . The HR P = 0.74 and OR = 0.96). When patients 50 to 69 years of age were analyzed, the results were similar . After adjustments according to the same covariates as those used in the Cox multivariate survival analyses, the risk of having later contralateral breast cancer was slightly increased in patients with breast cancer detected outside screening compared to patients with screen-detected breast cancer (95% CI = 0.55 to 2.57 and OR = 1.18), but the difference was not statistically significant.Differences in the probability of having future contralateral breast cancer between screen-detected and non-screen-detected breast cancer patients during the 15-year follow-up time were assessed. For this analysis, we used the same exclusion criteria that we applied in the main analysis, with the exception of later contralateral breast cancers. Without any adjustments according to other variables, there were no significant differences if the primary breast cancer was diagnosed by screening mammography or by other methods  between patients with screen-detected and non-screen-detected cancers according to BCSS was somewhat lower, with a median follow-up of 15.4 years compared to the HR (2.1) after 9.5 years follow-up in our previous study . This fiin situ cancer [in situ cancers is higher in screen-detected than in non-screen-detected cancers. Only patients with invasive breast cancers were included in the current study. Whether the risk of contralateral breast cancer is altered according to the method of detection in women with primary in situ cancer remains to be investigated. According to this study, the follow-up for contralateral breast cancer should be similar in patients with screen-detected and non-screen-detected invasive breast cancers.The risk of contralateral breast cancer among breast cancer survivors is reportedly two- to sixfold the risk of breast cancer in the general population . The risu cancer . The proIn the current study, screen-detected cancer was defined according to true attendance at mammography screening. All other breast cancers, including those of patients who did not undergo mammography, were considered non-screen-detected. If we had included nonattendees in the screen-detected group, the survival estimates could be distorted, thus underestimating the survival advantage of screening. In a previous study, breast cancer mortality among the women invited to have mammographies was reduced by 22%, whereas the mortality reduction was 28% among true attendees .The use of adjuvant therapies was rather homogeneous during 1991 and 1992 in Finland. In this cohort, adjuvant therapy was given less frequently to patients with screen-detected tumors than to patients with breast cancer diagnosed by other methods. Thus the use of adjuvant therapies does not explain the survival advantage associated with screening in this study.Although there were significant differences in the proportion of many commonly used prognostic factors between screen-detected and non-screen-detected tumors, the frequency of lobular carcinoma was similar in both groups. Lobular carcinomas are often difficult to detect by mammography because they are radiologically elusive ,51. LobuAlthough we were able to adjust the HRs for the method of detection for an extensive series of known prognostic factors, survival differences remain to be explained. More detailed tumor profiling might aid in characterizing tumors and should be studied in future projects. The value of some commonly used prognostic factors is observed to diminish over prolonged follow-up times. In the present study, the screening benefit remained after long-term follow-up. According to this study, patients with screen-detected breast cancer may be overtreated if screening as a method of detection is not taken into account in risk estimation and therapy decision-making.The method of detection is an independent prognostic factor for long-term survival among breast cancer patients. According to this study, screening as a method of detection may be considered a favorable prognostic factor in risk estimation and therapy decision-making to avoid overtreatment of screen-detected breast cancers.in situ hybridization; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; PR: progesterone receptor.CISH: chromogenic The authors declare that they have no competing interests.in situ hybridization analysis. TL and JL performed the statistical analyses. All authors critically revised the manuscript and approved its final form.TL, HJ and JL designed the study and drafted the manuscript. HJ initiated the FinProg study and organized the collection of clinical data. JL, ML, TL, KH, LE, VK, TTH and JI collected the clinical data. JI organized the collection of tumor samples. TL collected the tissue for tissue microarrays. JI, HS and NL interpreted the results of the immunohistochemical and Consort diagrams for main analyses, the first sensitivity analyses and the second sensitivity analyses.Click here for fileN = 1,884)Table S1 Distribution of breast cancers in the FinProg data according to the method of measurement and the method of detection .Click here for file


Patients with acute myocardial infarction and newly detected abnormal glucose regulation have been shown to have a less favourable prognosis compared to patients with normal glucose regulation. The importance and timing of oral glucose tolerance testing (OGTT) in patients with acute myocardial infarction without known diabetes is uncertain. The aim of the present study was to evaluate the impact of abnormal glucose regulation classified by an OGTT in-hospital and at three-month follow-up on clinical outcome in patients with acute ST elevation myocardial infarction (STEMI) without known diabetes.Patients  with a primary percutanous coronary intervention (PCI) treated STEMI were followed for clinical events . The patients were classified by a standardised 75 g OGTT at two time points, first, at a median time of 16.5 hours after hospital admission, then at three-month follow-up. Based on the OGTT results, the patients were categorised according to the WHO criteria and the term abnormal glucose regulation was defined as the sum of impaired fasting glucose, impaired glucose tolerance and type 2-diabetes.The number of patients diagnosed with abnormal glucose regulation in-hospital and at three-month was 105 (47%) and 50 (25%), respectively. During the follow up time of (median) 33  months, 58 (25.9%) patients experienced a new clinical event. There were six deaths, 15 non-fatal re-infarction, 33 recurrent ischemia, and four strokes. Kaplan-Meier analysis of survival free of composite end-points showed similar results in patients with abnormal and normal glucose regulation, both when classified in-hospital (p = 0.4) and re-classified three months later (p = 0.3).Patients with a primary PCI treated STEMI, without previously known diabetes, appear to have an excellent long-term prognosis, independent of the glucometabolic state classified by an OGTT in-hospital or at three-month follow-up.http://www.clinicaltrials.gov, NCT00926133.The trial is registered at  Patients hospitalised with acute myocardial infarction (MI) have a reported incidence of known type 2 diabetes between 10 and 20% . In diabSeveral studies have reported that a substantial proportion of patients with acute MI, without known type 2 diabetes, have disturbed glucometabolic regulation ,7. In adWe have previously reported that patients with a primary PCI treated STEMI without known diabetes, have a high prevalence of undetected abnormal glucose regulation classified by an OGTT either in-hospital or three months later . HoweverAn additional rationale for an early OGTT in patients without known diabetes with a recent acute MI is to identify high-risk patients with poor prognosis. The aim of the present study was to investigate clinical outcome in patients with a primary PCI treated STEMI after exclusion of patients with known diabetes. Secondly, to evaluate whether abnormal glucose regulation classified by OGTT acutely in-hospital or in a stable condition at three-month follow-up was associated with poorer long-term prognosis after acute STEMI.Patients with an acute STEMI without known diabetes admitted to the coronary care unit, Oslo University Hospital, Ullevål, Oslo, Norway were prospectively enrolled from November 2005 to May 2007. The cohort is described in detail elsewhere . In brieBased on the result of the OGTT, the patients were glucometabolically classified according to the WHO guidelines from 2005 into one of the following categories   = OGTT (0 min) < 6.1 and OGTT (2 h) < 7.8<7.0 and OGTT (2 h) <7.8Impaired Fasting Glucose (IFG) = OGTT (0 min) ≥ 6.1 <7.0 and OGTT (2 h) ≥7.8 < 11.1Impaired Glucose Tolerance (IGT) = OGTT (0 min) Type 2 diabetes (T2DM) = OGTT (0 min) ≥7.0 and/or OGTT (2 h) ≥11.1.The term abnormal glucose regulation was defined as the sum of IFG, IGT and T2DM.This was an observational study. The results of analyses of blood glucose, either fasting or during OGTT were available for the treating physician at all time. Hyperglycaemia, if present, was treated at the physician's decision according to local, hospital practice. Patients were returned back to the referring hospital with a hospital record, which included information about the OGTT results. The responsible physician was asked to perform plasma glucose analyses repeatedly and start treatment if indicated. A diagnosis of diabetes was not based on the early OGTT performed during acute illness. The results of the OGTT and fasting glucose value were communicated to the general practitioners (GP) responsible for the patient. If an asymptomatic patient were diagnosed with type 2 diabetes at both occasions  the GP was contacted by phone and asked to confirm the diagnosis and initiate lifestyle changes and medical treatment according to national guidelines.STEMI was defined according to the universal definition of myocardial infarction as typical rise and fall of the cardiac biomarker troponin T with at least one value above the 99th percentile of the upper reference limit in patients presenting with symptoms of ischemia together with new ST elevation at the J-point in two contiguous leads with the cut-off points: 0.2 mV in men or 0.15 mV in women in leads V2-V3 and/or 0.1 mV in other leads or new left bundle-branch block . The medThe Regional ethics committee approved the study and all patients provided written and oral informed consent.rd generation TnT, Elecsys 2010, Roche, Mannheim, Germany). The lower detection limit of the assay is 0.01 ug/L with a recommended diagnostic threshold of 0.03 ug/L. The inter-assay coefficient of variation was 7%.After overnight fasting, blood samples for routine analysis including glucose and HbA1c were drawn and analysed by use of conventional methods. Serum cardiac specific Troponin T (TnT) was measured by electrochemiluminescence technology for quantitative measurement (3Insulin was measured by a competitive radioimmunoassay (RIA) kit  and C-peptide was determined by Immulite 2000 . Proinsulin was measured by an enzyme immunoassay (kit) from DRG instruments . The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as fasting serum insulin (in pmol/L) multiplied with fasting plasma glucose (in mmol/L) and divided by 135 .At three-month follow-up, clinical examination and a repeated OGTT were performed.99m-tetrofosmin . An Exeleris processing station  with 4D-MSPECT™ software (University of Michigan), was used for processing of all recordings and assessment LV volumes, LV ejection fraction (LVEF) and infarct size (proportion perfusion defect) expressed as percent of LV mass [In addition, left-ventricular (LV) function and infarct size were assessed at rest at follow-up. Perfusion imaging was performed according to ECG-gated SPECT after injection of  LV mass .In June 2009, at a median follow up time of 33 months, the patients were contacted and interviewed by telephone, regarding their health status, and any hospital admissions. Closing date was set to August 1st 2009. None of the patients were lost to long-term follow-up, but only 201 patients attended the three-month follow-up examination. In case of re-hospitalisation, hospital records were collected from the patients' community hospitals.The primary endpoint of the study was defined as the composite of the first event of non-fatal myocardial re-infarction, recurrent ischemia causing hospital admission, stroke, and all cause mortality. An end-point committee classified the end-points according to the hospital records, and death certificates were obtained from the Norwegian Death Certificate Registry.Continuous variables are presented as median and 25, 75 percentiles and categorical variables as proportions. Due to skewness in most of the measured variables, non-parametric statistics was used throughout. Differences among groups were analysed by Mann-Whitney test for continuous variables and the Chi square test for categorical data.Univariate and multivariate analyses of this dynamic cohort with censored data  were performed. Potential confounders that were associated with clinical outcome or abnormal glucose regulation with a p-value <0.2, were included in the model. The following risk factors were included in a stratification model; age, gender, treated hypertension at admission, previous myocardial infarction, smoking, body mass index, elevated triglycerides and cholesterol, TnTmax, and infarct size expressed as percent of ventricular mass. Adjustment for the potential confounders identified by the model was performed  and the A two-sided p value <0.05 was considered statistically significant. All analyses were performed using Epi-info software, 2005, version 3.3.2.In-hospital OGTT was successfully performed in all patients (n = 224) and categorised as described. As previously reported , the preThe OGTT was repeated in 201 patients three months after the acute STEMI. Twenty-three patients did not perform the repeated OGTT due to death (n = 1) or unwillingness (n = 22). The 22 patients who were unwilling to participate at three-month follow-up did, however, take part in the interview by telephone in June 2009. Five out of 22 patients reported a new clinical event during follow-up, one patient within the first three months, and four patients between three-month and (median time) 33 months follow-up. The number of patients with normal and abnormal glucose regulation classified in-hospital was 9 and 13, respectively, and two out of five with a new clinical event had abnormal glucose regulation. The prevalence of abnormal glucose regulation in the total population at three-month follow-up was reduced to 25% (n = 50), of whom 10 patients (20%)  were classified as having type 2 diabetes [Clinical characteristics of the study population according to the glucometabolic classification in-hospital and at three-month follow-up are shown in Table When comparing patients with and without new clinical events, there were no significant differences in clinical or biochemical characteristics (data not shown).Glucose lowering medication was not introduced in-hospital or during the three-month follow-up period in any of the patients.The median follow-up time for clinical events was 33 months . The long-term clinical outcome was excellent with low event-rate. Of the total population (n = 224), 58 (26%) patients experienced a new clinical event including 33 patients with recurrent ischemia. Six patients died, two of myocardial re-infarction, one of cancer, one of an infectious disease with multiorgan failure, and two died without known reason. Fifteen patients experienced a non-fatal re-infarction. Table The Kaplan-Meier curves for patients with normal (n = 119) or abnormal glucose regulation (n = 105) classified by an OGTT in-hospital are shown in Figure Long-term prognosis was also compared between groups of patients classified into normal (n = 151) and abnormal glucose regulation (n = 50) based on an OGTT performed in a stable condition at three-month follow-up. No significant difference in survival free of composite end-point was found between the groups  to evaluate early OGTT during an acute STEMI as a prognostic tool, in patients without previously known diabetes, and the first study who compared the prognostic value of an OGTT based classification in-hospital and after three months. The low event rate in the present study prevents firm conclusions about the prognostic value of OGTT screening in patients with acute STEMI. There was a non-significant trend towards increased hazard in patients with abnormal vs. normal glucose regulation and a real difference between groups may have been detected if the sample size was larger. However, our results are not in line with the similar sized GAMI study and may challenge the present guidelines, which emphasize the importance of early testing of all patients with acute MI, especially in the modern era of acute revascularization of STEMI patients.The excellent prognosis found in our study, regardless of the glucometabolic status, may partly be explained by the low proportion of patients classified with type 2 diabetes in-hospital and at three-month . Nevertheless, patients classified with abnormal compared to normal glucose regulation in-hospital and at three-month follow-up had significantly higher fasting values of HbA1c, circulating levels of insulin and proinsulin, and higher HOMA-IR score when measured both acutely and in a stable condition. These results correspond to another trial with acute MI patients showing that HbA1c and proinsulin were in the lowest range in patients with normal glucose regulation, intermediate in patients with impaired glucose tolerance, and highest in patients with type 2 diabetes . The preThe overall mortality rate in the present study was 2.7%. None died in-hospital and only one patient died during the first 30 days. Nine patients  experienced a new clinical event before the OGTT classification was performed at three-month follow-up. A low overall incidence of clinical events was found during the first three months of follow-up, suggesting that a early OGTT based classification of the glucometabolic status in order to identify high risk patients with worse prognosis is possibly of limited importance in low risk patients with a primary PCI treated STEMI.The low overall incidence of clinical events reported in our study may partly be explained by the inclusion criteria. Unstable patients with cardiogenic shock, renal failure, ongoing chest pain, nausea and persistent hyperglycaemia were excluded from the study, probably making a selection bias towards more glucometabolically normal patients with better prognosis.Furthermore, the patients included were relatively young and previous studies have shown a close relationship between newly diagnosed abnormal glucose regulation and age ,26-28. ASystematic use of recommended treatment (evidenced based medications and revascularisation) has been shown to have a favourable impact on one-year prognosis in patients with diabetes and coronary artery disease . PatientThe European guidelines on diabetes, pre-diabetes, and cardiovascular diseases recommend that patients with cardiovascular disease without known diabetes should be investigated with an OGTT , but wheThe present study has certain limitations such as a possible selection bias towards more glucometabolically normal patients due to the exclusion of patients who were hemodynamically unstable, had severe renal failure and persistent hyperglycaemia. Accordingly, patients included, were somewhat younger than expected from a general STEMI population, had relatively few comorbidities and mainly one-vessel disease. It is possible that different results would be obtained in older MI patients since high age has been shown to be associated with ischemia related hyperglycaemia and poor glycemic control .All aspects taken together may explain the overall low incidence of clinical events during the follow-up period, but may also reflect the advances in modern treatment of STEMI with primary PCI in all patients and optimal post-infarction treatment. The association between abnormal glucose regulation classified by an OGTT and clinical outcome should be further investigated in forthcoming studies including primary PCI treated STEMI patients, with a prolonged follow-up period, using major cardiovascular events as a primary end-point.Patients with a primary PCI treated STEMI, without previously known diabetes, appear to have an excellent long-term prognosis, independent of the glucometabolic state classified by an OGTT in-hospital or at three-month follow-up.The authors declare that they have no competing interests.ECK performed the statistical analysis and drafted the manuscript.MA made substantial contribution with statistical analysis. GØA contributed with the conception and design of the study. CM analysed the SPECT data. ECK, IS, MA, JE, AM, HA and GØA participated in the study design and interpretation and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6823/11/14/prepub