Intensive Clinical Monitoring Research Articles

Factorial structure of the Comprehensive Assessment of At-Risk Mental States in help-seeking individuals: mapping the structure and the prediction of subsequent transition to psychosis

ObjectivesThe aim of the current study was 3-fold: 1) to examine the factorial structure of the Comprehensive Assessment of At-Risk Mental States (CAARMS) in help-seeking individuals undergoing an assessment on suspicion of psychosis risk; 2) to investigate the association of CAARMS factors with functioning; 3) and to test the association of any derived factors with the longitudinal outcome of transition to psychosis.MethodsThe study included 101 patients. First, a principal component analysis (PCA) was conducted using the Varimax rotation method. A minimum initial eigenvalues of greater than or equal to 1.0, analysis of Scree plots, percentage of variance explained by each component, reliability (Cronbach’s alpha) of factors above 0.7 and Parallel Analysis were the criteria used to determine the appropriate number of factors Second, Spearman correlations were run to analyze the relationship between CAARMS factors and sociodemographic and functional variables (i.e. age, schooling, Social and Occupational Functioning Assessment Scale-SOFAS- and Health of the Nation Outcome Scales-HoNOS- scores). Third, we performed a Logistic regression analysis to evaluate the association between baseline CAARMS factors and the risk of transition to psychosis at the 6-month follow-up.ResultsA total of 101 consecutive patiens were recruited. We found that: 1) a 6 factor model solution as the most appropriate, jointly accounting for 65% of the variance; 2) factors 1 (“negative-interpersonal”), 2 (“cognitive-disorganization”), 3 (“positive”), and 4 (“motor-physical changes”) were negatively correlated with SOFAS total score; factors 1, 2, and 3 showed positive correlations with HoNOS total score; factors 2 and 3 present similar patterns of correlations, factor 3 manifesting the strongest association with HoNOS symptoms, HONOS and SOFAS total score. Both factors 5 and 6 show significant associations with HoNOS behavioral impairment; 3) after 6 months 28 participants (30.1%) converted to psychosis. Factors 2 and 3 were positively associated with the risk of transition to psychosis; whereas, the factor 5 (“affective factor”) was negatively associated with the outcome variable.ConclusionsIt is thus crucial to recognize the type and severity of psychopathology in help-seeking individuals in order to intensive clinical monitoring of subclinical psychopathology risk profiles, and design specific care pathways.

#2778 The Charlson Index can be used prospectively to identify patients who will need a close follow up of surveillance for the vascular access

Abstract Background and Aims The primary screening methods for monitoring vascular access in haemodialysis involve measuring access blood flow and dialysis venous pressure. However, challenges are present in both aspects, potentially hindering the attainment of desired results. Research in this field is crucial to identify the optimal combination of intensive clinical monitoring and supplementary surveillance for effective outcomes. For this reason, we aim to describe the impact of comorbidities and patency of native arteriovenous fistulae (nAVF). Method Descriptive study of prevalent patients on haemodialysis, carried out by consulting electronic medical records over a period of 35 months. Demographic and vascular access-related variables were included. Primary and secondary patency was calculated for all accesses. Patients with upper limb AVF were classified according to distal and proximal access location; and the Charlson Index was used to categorise patients according to comorbidities. Kaplan Meyer survival curves were used to contrast the impact of comorbidities on the different patency. Results 52 patients, age 70.7 ± 1.57 years, 69.2% male, 42.3% diabetic, Charlson index with a median of 7 (6.5 - 7.73), 98.1% with a native fistula, the most frequent nAVF location in our population was humerocephalic (63.5%) and a predominance of the left upper extremity (65.4%). According to the location of the access, adjusted by the Charlson index, it is evident that in proximal accesses (humerocephalic and basilic humerus nAVF), with a Charlson Index less than or equal to 7, the time required to reach an event was statistically significantly longer (Log Rank Test (Mantel-Cox): primary patency p=0.057 and secondary patency p=0.069). This comparison was not significant in distal fistulas. Conclusion Using the Charlson comorbidity index information, we transformed it into an accessible and valuable tool for maintaining vascular access patency. Close follow-up in patients with proximal nAVF and high Charlson comorbidity index could be beneficial.

Management of respiratory failure in immune checkpoint inhibitors-induced overlap syndrome: a case series and review of the literature

BackgroundCheckpoint inhibitor-induced overlap syndrome ([OS] myocarditis, and myositis with or without myasthenia gravis) is rare but life-threatening.Cases presentationHere we present a case series of four cancer patients that developed OS. High troponinemia raised the concern for myocarditis in all the cases. However, the predominant clinical feature differed among the cases. Two patients showed marked myocarditis with a shorter hospital stay. The other two patients had a prolonged ICU stay due to severe neuromuscular involvement secondary to myositis and myasthenia gravis. Treatment was based on steroids, plasmapheresis, intravenous immunoglobulin, and immunosuppressive biological agents.ConclusionThe management of respiratory failure is challenging, particularly in those patients with predominant MG. Along with intensive clinical monitoring, bedside respiratory mechanics can guide the decision-making process of selecting a respiratory support method, the timing of elective intubation and extubation.

Preexisting Autoimmunity Is Associated With Increased Severity of Coronavirus Disease 2019: A Retrospective Cohort Study Using Data From the National COVID Cohort Collaborative (N3C).

Identifying individuals with a higher risk of developing severe coronavirus disease 2019 (COVID-19) outcomes will inform targeted and more intensive clinical monitoring and management. To date, there is mixed evidence regarding the impact of preexisting autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure on developing severe COVID-19 outcomes. A retrospective cohort of adults diagnosed with COVID-19 was created in the National COVID Cohort Collaborative enclave. Two outcomes, life-threatening disease and hospitalization, were evaluated by using logistic regression models with and without adjustment for demographics and comorbidities. Of the 2 453 799 adults diagnosed with COVID-19, 191 520 (7.81%) had a preexisting AID diagnosis and 278 095 (11.33%) had a preexisting IS exposure. Logistic regression models adjusted for demographics and comorbidities demonstrated that individuals with a preexisting AID (odds ratio [OR], 1.13; 95% confidence interval [CI]: 1.09-1.17; P < .001), IS exposure (OR, 1.27; 95% CI: 1.24-1.30; P < .001), or both (OR, 1.35; 95% CI: 1.29-1.40; P < .001) were more likely to have a life-threatening disease. These results were consistent when hospitalization was evaluated. A sensitivity analysis evaluating specific IS revealed that tumor necrosis factor inhibitors were protective against life-threatening disease (OR, 0.80; 95% CI: .66-.96; P = .017) and hospitalization (OR, 0.80; 95% CI: .73-.89; P < .001). Patients with preexisting AID, IS exposure, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19.

Smoking cessation Through Optimization of clinical care in Pregnancy: the STOP pragmatic randomized controlled trial

Smoking cessation improves pregnancy outcomes, yet there is uncertainty around the efficacy of models of antenatal intervention for smoking cessation in pregnancy. This study aimed to test the Smoking cessation Through Optimization of clinical care in Pregnancy (STOP) clinic as an antenatal care pathway for smoking cessation in pregnancy. The STOP intervention is a smoking cessation clinic staffed by a dedicated multidisciplinary team of obstetricians, midwives, and smoking cessation practitioners, who provide motivational and psychological support and intensive clinical monitoring of pregnancy. This was a pragmatic randomized controlled trial of the STOP clinic compared with routine antenatal care at a tertiary urban maternity hospital delivering >8000 infants per year. The primary outcome measured was continuous abstinence from smoking before 28+0 weeks' gestation, sustained throughout the duration of the pregnancy, and validated using biological measures. The secondary outcomes included maternal and fetal morbidity, delivery and neonatal outcomes, smoking outcomes, and qualitative measures. A total of 436 women were randomized, with 430 women included in the primary outcome analysis. Women attending the STOP antenatal clinic were more likely to quit smoking compared with those in routine care (odds ratio, 3.62; 95% confidence interval, 1.43-9.17). In addition, women who continued to smoke in the STOP clinic smoked fewer cigarettes daily at the time of delivery compared with controls: 5±4 in the STOP clinic and 7±5 in the control group (odds ratio, 0.28; 95% confidence interval, 0.13-0.59). However, this intervention did not alter postpartum relapse rates (4.3% intervention arm vs 1.5% control arm, not significant) at 4 to 6 months following delivery. The mean birthweight was similar in the intervention and control arms; however, quitters in both groups had infants with significantly higher birthweights compared with those of continued smokers. The STOP antenatal model of care leads to higher smoking cessation rates among pregnant smokers and lower daily cigarette consumption at time of delivery. Currently, there is no defined or dedicated antenatal pathway for pregnant smokers, despite the high-risk nature of their pregnancies. Our findings suggest that improved smoking cessation rates in pregnancy may be achieved using the holistic approach of the STOP model of care.

Clinical characteristics in immune thrombocytopenia patients after COVID-19 vaccination

ABSTRACT It is well documented that COVID-19 vaccines greatly reduce the severity and complications of SARS-CoV-2 infection. However, it has been reported that COVID-19 related vaccines may induce or exacerbate autoimmune hematological disorders, for example, a decrease in platelet numbers characteristic of immune thrombocytopenia (ITP). To investigate this, we retrospectively reported, for the first time, the clinical characteristics of 42 ITP patients after COVID-19 vaccination in southwest China. Of the 42 patients, 28 patients were historically diagnosed ITP, and their platelet counts (PC) decrease mainly occurred after the first-dose vaccinations. The average PC after vaccination was 39.5 × 109/L and recovered to an average of 80.6 × 109/L after treatment. Efficacy of treatment was 90%, and only 10% maintained low PC at the third month of treatment. More interestingly, of the 42 patients, 14 were newly diagnosed ITP following vaccination. Of these 14 patients, 6 patients (43%) were found PC deterioration after the first vaccine dose, and 7 patients (50%) after the second dose. Fortunately, the peripheral PC of all 14 patients recovered significantly after treatment, and the average PC was 139.4 × 109/L, including 8 CRs (complete response) and 6 PRs (partial response). Notably, 9 of the 14 cases were found to have abnormal immune indices when thrombocytopenia diagnosed. No severe organ hemorrhage was found in either subgroup. These results are reassuring the vaccine safety for ITP patients, in that the risks of aggravating thrombocytopenia by COVID-19 vaccination do exist, but it was transient and can be effectively controlled through intensive clinical monitoring and management.

Abstract 12524: Very Long-term Mortality After St Elevation Myocardial Infarction (stemi) Complicated By Cardiogenic Shock

Introduction: About 5-10% of myocardial infarctions develop severe form of presentation, with cardiogenic shock (CS). Despite evidence showing higher in-hospital and short-term mortality in patients with STEMI complicated by CS, long-term follow-up data is lacking. Hypothesis: The aim of this study was to assess very long-term prognosis of survived patients with STEMI complicated by CS. Methods: STEMI patients (n=1,444) were included (1998-2017) and followed for up to 17.6 years (median 5.4 [2.5-9.9] years). Long-term survival was assessed by Log-Rank test. Results: Compared to STEMI without CS, patients who presented CS (n=118) had no significant differences regarding age (62.0 ± 11.8 vs. 60.7 ± 12.7; p=0.31) and female sex (28.0% vs. 25.1%, p=0.51), but had lower left ventricle ejection fraction (38.8±13.0% vs. 49.7±13.1%, p&lt;0.001) and higher mean baseline creatinine levels (1.4±0.6mg/dL vs. 1.2±0.7mg/dL, p=0.002). Of note, CS patients presented higher in-hospital mortality (42.2%) compared to those without CS (OR=28.5; 18.1-44.7, p&lt;0.001). Long-term survival was lower in patients with CS (10.7±0.6 vs. 13.3±0.2 years, log rank =0.016). By multivariate analysis adjusted for baseline characteristics the main factors predicting mortality were age (HR=1.06; CI95% 1.05-1.07, p&lt;0.001), previous MI (HR=1.34;CI% 1.06-1.69, p=0.01), history of heart failure (HR=1.65; CI95% 1.15-2.37, p=0.007), stroke (HR=1.67; CI95% 1.12-2.47, p=0.01), diabetes (HR=1.41; CI95% 1.14-1.74, p=0.001) and the presence of CS (HR=3.65; CI95% 2.92-4.56, p&lt;0.001). Conclusions: In a very long-term follow-up after a STEMI, CS increased ~4-fold the mortality rates. After hospital discharge, CS remains an important independent risk factor for death in the follow-up. Our findings reinforce the importance of intensive clinical monitoring with optimal medical and non-pharmacological therapy for the remarkable risk factors in the very long-term post-STEMI complicated by CS.

Diabetic Macular Edema

Diabetic macular edema (DME) is a chronic retinal disease, which requires intensive clinical monitoring. Within the last ten years the intravitreal anti-VEGF (vascular endothelial growth factor) therapy has become the standard of care to improve and stabilize vision in patients with centre involving DME. Long-acting intravitreal corticosteroids can achieve similar visual results with fewer injection rates. Because of steroid-induced side effects (progression of cataract, glaucoma) these drugs are regarded as second-line medication. Since the introduction of anti-VEGF-medication the focal laser photocoagulation is no longer considered as first-line therapy for DME. However, a focal laser treatment can sometimes be a possible alternative in specific situations. In patients with proliferative diabetic retinopathy and DME, the intravitreal anti-VEGF therapy is approved for both conditions. In ischemic maculopathy the functional outcome is restricted. For the indication of anti-VEGF-treatment for DME with accompanying central ischemia not only visual acuity and optical coherence tomography parameters should be considered, the amount of ischemia seen on fluorescein angiography should also be taken into account. In tractional macular edema due to epiretinal membranes and vitreomacular adhesions a pars-plana vitrectomy with membrane peeling is indicated.

A Predictive Score for Early Mortality during Induction Therapy in Newly Diagnosed Transplant-Eligible Multiple Myeloma - an Analysis from Five GMMG and HOVON Multicenter Phase III Trials

A Predictive Score for Early Mortality during Induction Therapy in Newly Diagnosed Transplant-Eligible Multiple Myeloma - an Analysis from Five GMMG and HOVON Multicenter Phase III Trials

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

Predicting anti-Kell-mediated hemolytic disease of the fetus and newborn: diagnostic accuracy of laboratory management

There is controversy on critical cut-off values of laboratory testing to select pregnancies at increased risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. Without early detection and treatment, anti-Kell-mediated hemolytic disease of the fetus and newborn may result in progressive fetal anemia, fetal hydrops, asphyxia, and perinatal death. We aimed to determine the value of repeated anti-Kell titer determination and biological activity measurement using the antibody-dependent cellular cytotoxicity test determination in the management of pregnancies at risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. This was a retrospective cohort study of pregnancies with anti-Kell and a Kell-positive fetus, identified from January 1999 through April 2015. Laboratory test results and clinical outcome were collected from the Dutch nationwide screening program and the national reference center for fetal therapy in The Netherlands, the Leiden University Medical Center. Diagnostic accuracy was measured (receiver operating characteristic curves, sensitivity, specificity, positive and negative predictive values) for anti-Kell titers and antibody-dependent cellular cytotoxicity test. The relationship between the titer and antibody-dependent cellular cytotoxicity measurements and the 2 foregoing measurements were computed with a Pearson product-moment correlation coefficient. In a 16-year unselected cohort, representing screening results of 3.2 million pregnancies resulting in live births in The Netherlands, we identified 1026 Kell-immunized pregnancies. In all, 93 pregnant women had anti-Kell and a Kell-positive child, without other red cell alloantibodies. In all, 49 children (53%) needed intrauterine or postnatal transfusion therapy. The first anti-Kell titer showed already a high diagnostic accuracy with an area under the curve of 91%. The optimal cut-off point for the titer was 4 (sensitivity 100%; 95% confidence interval, 91-100), specificity 27% (95% confidence interval, 15-43), and positive predictive value 60% (49-71%). The antibody-dependent cellular cytotoxicity test was not informative to select high-risk pregnancies. Linear regression showed no significant change during pregnancy, when antibody titer and antibody-dependent cellular cytotoxicity test results were compared with every 2 foregoing measurements (P < .0001). Early determination of the anti-Kell titer is sufficient to select pregnancies at increased risk for hemolytic disease of the fetus and newborn with need for transfusion therapy. If the Kell status of the fetus is known to be positive, a titer of ≥4 can be used to target intensive clinical monitoring.

APL-2, a Complement C3 Inhibitor for the Potential Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH): Phase I Data from Two Completed Studies in Healthy Volunteers

BackgroundParoxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, potentially life-threatening disease characterized by complement-mediated hemolytic anemia. PNH arises from a somatic mutation resulting in impairment of an anchor protein responsible for the expression of numerous proteins at the cell surface of the red blood cells, including CD55 and CD59, two complement inhibitory proteins. The subsequent uncontrolled activation of the complement system leads to both intravascular hemolysis triggered by the membrane attack complex (MAC) and extravascular hemolysis, or cell opsonization, mediated by C3b accumulation at the cell surface. Eculizumab, an anti-C5 antibody, is available as a treatment for PNH, however some patients continue to be transfusion-dependent as a result of on-going activation of C3, upstream of C5. Due to the key position of C3 in the complement cascade, APL-2, a cyclic peptide inhibitor of C3, may prevent both intravascular and extravascular hemolysis and could therefore be potential treatment for PNH and beneficial for patients still requiring transfusions despite standard of care treatment.AimsThese initial phase I studies were designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of APL-2 administered by subcutaneous injection (SC) in healthy adult volunteers.MethodsBoth studies were conducted at a single center (Australia) and were double-blind, placebo-controlled designs. Subjects were monitored for up to 43 days following single dosing and 84 days following multiple dosing. Safety was assessed by intensive clinical monitoring. Serial blood sampling was performed for the determination of APL-2 concentrations in serum. Blood samples were also obtained to determine relevant markers of complement activity (C3, CH50 and AP50). Additional relevant PD markers (intact C3, iC3b, C3a, C4a and C5a) were measured in latter Cohorts. Prior to multiple dosing subjects received Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae Type B (Hib) vaccinations.ResultsIn total 51 subjects were enrolled into the two studies. Twenty-four subjects received APL-2 as a single dose (ranging from 45 to 1,440mg) and 7 subjects received placebo. Sixteen subjects received repeated daily doses of APL-2 for 28 consecutive days (ranging from 30 to 270 mg/day) and 4 subjects received placebo. There were no serious adverse events (SAE's), treatment emergent adverse events (TEAEs) leading to study drug discontinuation, or severe adverse events reported. There were no clinically relevant changes in vital signs, ECG findings or safety laboratory tests. Following single and multiple doses APL-2 exposure increased linearly with increasing dose up to the highest doses tested and APL-2 serum concentrations were close to steady-state after 28 days of daily dosing. A reduction in AP50 was seen following a single dose of 1440mg APL-2 and following multiple daily doses of 180 and 270 mg.ConclusionThe studies concluded that pharmacological doses of APL-2 were safe and well tolerated and that APL-2's PK/PD profile supports daily SC administration. In addition, daily APL-2 doses of 180mg and 270mg significantly reduced hemolytic activity as early as eight days after the start of dosing, and this inhibition was maintained through the dosing period. PK data from these studies has been used to develop a PK/PD model which has been used to aid dose selection in the subsequent studies in PNH patients. DisclosuresGrossi:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Bedwell:Apellis Pharmaceuticals Inc: Consultancy. Deschatelets:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Edis:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Francois:Revon Systems Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Liberate Medical Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apellis Pharmaceuticals Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Johnson:Apellis Pharmaceuticals Inc: Consultancy. Richardson:Apellis Pharmaceuticals Inc: Consultancy. Tan:Apellis Pharmaceuticals Inc: Consultancy. Vega:Apellis Pharmaceuticals Inc: Employment, Equity Ownership.

A efetividade das intervenções educativas em saúde bucal: revisão de literatura

Resumo Visando diminuir impactos negativos dos agravos bucais, intervenções educativas em saúde bucal têm sido propostas e avaliadas. Entretanto, a efetividade das iniciativas publicadas a partir de 2004 ainda não constituiu objeto de escrutínio acadêmico. Este trabalho objetivou revisar as intervenções educativas e estimar seu impacto sobre as condições de saúde bucal. Consultou-se a base de dados MEDLINE via PubMed, com termos livres e controlados, para identificar intervenções educativas publicadas no período de 2003 a 2013. Analisaram-se e sintetizaram-se qualitativamente os resultados dos estudos originais. Nos 37 estudos revisados, observou-se que as intervenções produziram resultados clínicos inconsistentes em curto prazo, incluindo a redução de placa bacteriana (melhor resultado [MR] -88,9%; pior resultado [PR] +29,7%), sangramento gengival (MR -77,8%; PR +72,2%) e menor incremento de cárie (MR -39,5%; PR +961,1%) e de cálculo dentário (+16,2%). Por sua vez, houve maior redução dos desfechos avaliados, quando os participantes receberam acompanhamento clínico intensivo, sugerindo que este é um aspecto importante das intervenções. De modo semelhante às revisões prévias da literatura, observou-se que as intervenções educativas para prevenção, controle ou redução de agravos bucais não apresentaram efeitos consistentes.

Reassessing long-term risk of suicide after a first episode of psychosis

BackgroundThe long-term risk of suicide after a first episode of psychosis is unknown, because previous studies have often been based on prevalence cohorts, have been biased to more severely ill, hospitalised patients, have extrapolated from a short follow-up time, and have made a distinction between schizophrenia and other psychoses. The aim of this study was to determine the epidemiology of suicide in a clinically representative, retrospective inception cohort of patients with a first episode of psychosis. MethodsAll 2723 patients who presented for the first time to secondary care services with psychosis in three defined geographical catchment areas in London (1965–2004, n=2056), Nottingham (1997–1999, n=203), and Dumfries and Galloway (1979–1998, n=464) were traced after a mean follow-up of 11·5 years. The main outcome measure was number of deaths by suicide and open verdicts according to International Classification of Diseases, editions 7–10. FindingsCase fatality from suicide was considerably lower than expected from previous studies: 1·9% (53/2723); proportionate mortality was 11·9% (53/444). Although the rate of suicide was highest in the first year after presentation, risk persisted late into follow-up, with median time to suicide being 5·6 years. Suicide occurred nearly 12 times more than expected from the general population of England and Wales (standardised mortality ratio 11·65, 95%CI 8·73–15·24), and 49 of the 53 suicides were excess deaths. Even a decade after first presentation, suicide risk remained almost four times higher than in the general population (3·92, 95%CI 2·22–6.89), a time when there may be less intense clinical monitoring of risk. InterpretationThe highest risk of suicide after a psychotic episode occurs soon after presentation, yet clinicians should still be vigilant in assessing risk a decade or more after first contact. The widely held view that 10–15% die from suicide is misleading because it refers to proportionate mortality rather than lifetime risk. Nonetheless, after a first espisode of psychosis, risk of suicide is substantially increased compared with that in the general population. FundingUK Medical Research Council.

Incidence, Clinical Spectrum, Risk Factors and Impact of HIV-Associated Immune Reconstitution Inflammatory Syndrome in South Africa

BackgroundImmune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART), but there are still limited data from resource-limited settings. Our objective was to characterize the incidence, clinical spectrum, risk factors and contribution to mortality of IRIS in two urban ART clinics in South Africa.Methods and Findings498 adults initiating ART in Durban, South Africa were followed prospectively for 24 weeks. IRIS diagnosis was based on consensus expert opinion, and classified by mode of presentation (paradoxical worsening of known opportunistic infection [OI] or unmasking of subclinical disease). 114 patients (22.9%) developed IRIS (36% paradoxical, 64% unmasking). Mucocutaneous conditions accounted for 68% of IRIS events, mainly folliculitis, warts, genital ulcers and herpes zoster. Tuberculosis (TB) accounted for 25% of IRIS events. 18/135 (13.3%) patients with major pre-ART OIs (e.g. TB, cryptococcosis) developed paradoxical IRIS related to the same OI. Risk factors for this type of IRIS were baseline viral load >5.5 vs. <4.5 log10 (adjusted hazard ratio 7.23; 95% confidence interval 1.35–38.76) and ≤30 vs. >30 days of OI treatment prior to ART (2.66; 1.16–6.09). Unmasking IRIS related to major OIs occurred in 25/498 patients (5.0%), and risk factors for this type of IRIS were baseline C-reactive protein ≥25 vs. <25 mg/L (2.77; 1.31–5.85), haemoglobin <10 vs. >12 g/dL (3.36; 1.32–8.52), ≥10% vs. <10% weight loss prior to ART (2.31; 1.05–5.11) and mediastinal lymphadenopathy on pre-ART chest x-ray (9.15; 4.10–20.42). IRIS accounted for 6/25 (24%) deaths, 13/65 (20%) hospitalizations and 10/35 (29%) ART interruptions or discontinuations.ConclusionIRIS occurred in almost one quarter of patients initiating ART, and accounted for one quarter of deaths in the first 6 months. Priority strategies to reduce IRIS-associated morbidity and mortality in ART programmes include earlier ART initiation before onset of advanced immunodeficiency, improved pre-ART screening for TB and cryptococcal infection, optimization of OI therapy prior to ART initiation, more intensive clinical monitoring in initial weeks of ART, and education of health care workers and patients about IRIS.

738P - Exposure-Response Relationship to Assess the Risk of Neutropenia in Patients with Hepatocellular Carcinoma (HCC) Treated with Tivantinib

Background: Tivantinib is a selective MET inhibitor that is extensively metabolized in the liver. In a randomized, placebo-controlled, phase 2 study in patients with advanced HCC, tivantinib monotherapy improved time to progression by 56%. However, in that study at the standard phase 2 dose of 360 mg twice daily (BID), tivantinib exposure was increased, and the absolute incidence of severe neutropenia increased approximately 6% compared to patients with solid tumors from previous studies. An exposure-response analysis was conducted to explore the relationship between neutropenia and tivantinib pharmacokinetics (PK). Methods: Tivantinib plasma concentration and incidence of grade ≥ 2 neutropenia were pooled from phase 1/1b and 2 studies. A population PK model (NONMEM v.7.1.0) was used to predict tivantinib exposure in HCC. The relationship between tivantinib exposure and neutropenia was evaluated by logistic regression analysis (S-plus v8.0). Results: Data were available from 289 cancer patients, including 73 patients with HCC and mild-to-moderate hepatic impairment. Cases of grade ≥ 3 (n = 28) and grade ≥ 2 (n = 40) neutropenia were included in the analysis. Based on the population PK analysis, tivantinib clearance was reduced approximately 67% in HCC patients, resulting in approximately 3 times higher exposure compared with other cancer patients. There was a significant (P < .001) relationship between tivantinib exposure and incidence of grade ≥ 2/3 neutropenia. By reducing the tivantinib starting dose from 360 to 240 mg BID, the incidence of grade ≥ 3 neutropenia is modeled to decrease from 28% to 16% in HCC patients. Further reduction in the risk of neutropenia (~6%) was achieved with intensive clinical monitoring and an aggressive dose-reduction schema. Conclusions: Based on the current analysis, the increased incidence of neutropenia in HCC patients compared to patients with other solid tumors resulted from increased tivantinib exposure due to hepatic impairment. Consistent with the model, the risk of neutropenia was successfully managed in HCC patients by implementing dose reduction and tighter clinical monitoring without compromising efficacy. • Patients with PK data from 4 studies were used to determine tivantinib exposure (Table 1) • Patients with safety data from 8 studies were used to evaluate the relationship between tivantinib exposure and incidence of neutropenia (Table 2) - A total of 289 patients, including 73 patients with HCC and mild-to-moderate hepatic impairment, were analyzed - There were 28 events of grade ≥ 3 neutropenia • Tivantinib steady state exposure was approximately 3 times higher in patients with HCC than in patients who had other cancers (Figure 1) - Tivantinib clearance was reduced by approximately 67% in patients with HCC • Among patients with mild to moderate hepatic impairment, Child-Pugh score also

Reassessing the Long-term Risk of Suicide After a First Episode of Psychosis

The long-term risk of suicide after a first episode of psychosis is unknown because previous studies often have been based on prevalence cohorts, been biased to more severely ill hospitalized patients, extrapolated from a short follow-up time, and have made a distinction between schizophrenia and other psychoses. To determine the epidemiology of suicide in a clinically representative cohort of patients experiencing their first episode of psychosis. Retrospective inception cohort. Geographic catchment areas in London, England (between January 1, 1965, and December 31, 2004; n = 2056); Nottingham, England (between September 1, 1997, and August 31, 1999; n = 203); and Dumfries and Galloway, Scotland (between January 1, 1979, and December 31, 1998; n = 464). All 2723 patients who presented for the first time to secondary care services with psychosis in the 3 defined catchment areas were traced after a mean follow-up period of 11.5 years. Deaths by suicide and open verdicts according to the International Classification of Diseases (seventh through tenth editions). The case fatality from suicide was considerably lower than expected from previous studies (1.9% [53/2723]); the proportionate mortality was 11.9% (53/444). Although the rate of suicide was highest in the first year after presentation, risk persisted late into follow-up, with a median time to suicide of 5.6 years. Suicide occurred approximately 12 times more than expected from the general population of England and Wales (standardized mortality ratio, 11.65; 95% confidence interval, 8.73-15.24), and 49 of the 53 suicides were excess deaths. Even a decade after first presentation-a time when there may be less intense clinical monitoring of risk-suicide risk remained almost 4 times higher than in the general population (standardized mortality ratio, 3.92; 95% confidence interval, 2.22-6.89). The highest risk of suicide after a psychotic episode occurs soon after presentation, yet physicians should still be vigilant in assessing risk a decade or longer after first contact. The widely held view that 10% to 15% die of suicide is misleading because it refers to proportionate mortality, not lifetime risk. Nevertheless, there is a substantial increase in risk of suicide compared with the general population.

Akuttherapie des Guillain-Barré-Syndroms und der myasthenen Krise

Das Guillain-Barré-Syndrom (GBS), eine akute Polyradikuloneuritis, und die Myasthenia gravis (MG), die wichtigste neuromuskuläre Übertragungsstörung, repräsentieren die beiden neuromuskulären Krankheiten, die aufgrund krisenhafter Zuspitzung am häufigsten einer Intensivüberwachung und -therapie bedürfen. Dies begründet sich u. a. mit einer im Vorfeld unvorhersehbaren Krankheitsdynamik. Beim GBS gilt es durch Plasmapherese oder Gabe von Immunglobulinen die Schwere der Ausfallerscheinungen bis zum Überschreiten des spontanen Krankheitsnadirs abzuschwächen und bei eintretender Ateminsuffizienz durch Beatmung bzw. bei vegetativer Instabilität die kritische Krankheitsphase intensivmedizinisch zu überbrücken. Die Therapie der myasthenen Krise umfasst die symptomatische Therapie mit Azetylcholinesterasehemmern, die Immunsuppression mit Glukokortikoiden und Plasmaaustauschverfahren. Alternativ können Immunglobuline gegeben werden. Im Gegensatz zum monophasischen GBS ist bei der MG eine Langzeitimmunsuppression erforderlich, die individuell angepasst werden muss. Durch die moderne Intensivmedizin konnte die Mortalität des GBS und der myasthenen Krise entscheidend gesenkt werden.

Dexamethasone in Induction Can Eliminate One Third of All Relapses in Childhood Acute Lymphoblastic Leukemia (ALL): Results of An International Randomized Trial in 3655 Patients (Trial AIEOP-BFM ALL 2000)

From 07/2000 to 06/2006, 4741 eligible pts with ALL (age range 1–17 years) were enrolled in the trial AIEOP-BFM ALL 2000 (registered at http://clinicaltrials.gov with identifiers NCT 00430118 (BFM) and NCT 00613457 (AIEOP)). 3655 patients from Germany, Italy, Austria, and Switzerland entered the randomized comparison of dexamethasone (DEX) at 10 mg/m2/d vs prednisone (PDN) at 60 mg/m2/d (both given daily from d8 to d29 of induction plus 9 days tapering after a 7d prednisone prophase). Induction therapy also comprised vincristine (1.5 mg/m2) and daunorubicine (30 mg/m2) both given on d8, 15, 22, 29, as well as L-asparaginase given at 5,000 IU/m2 x8 q3d from d12. I.T. methotrexate was given thrice (in CNS-2 and CNS-3 patients for 5 times) in induction. Post-induction therapy was derived from trial ALL-BFM 95 (A. Möricke et al, BLOOD 2008) but stratification and subsequent treatment intensity was based on early response as measured by prednisone response (on d8) and MRD quantification on d33 and d78. With a median follow-up of 4.4 years, 6-year event-free survival (6y-EFS) was 84.1% (SE 1%) and 79.1% (1%) for patients randomized to receive DEX or PDN, respectively (log-rank p=0.0083). The 6-year cumulative incidence (CI) of relapse was 11% (1%) and 18% (1%) for patients randomized to receive DEX or PDN, respectively (Gray p<0.001). The difference between the two groups was observed for isolated BM relapses (8% vs 12%), CNS-relapses (2% vs 4%) and other relapses (2% vs 3%). Higher toxicity was observed in patients treated with DEX: CI for death in induction was 2.0% for DEX and 0.9% for PDN (p=0.003). The latter value was similar to that of study ALL-BFM 95 (0.7%). CI for death in remission was similar being 2.0% and 1.6% for DEX and PDN groups. In each arm, only 0.2% did not achieve CR after intensive consolidation. Severe toxicities, mainly infections, were recorded for DEX treated patients more frequently. Three years into the trial, the DSMC and the TSC decided to halt the randomization for patients aged 10 years or older. CI for relapse/death in induction in this age group is now at 15%/4.5% for DEX, and 20%/2.4% for PDN (p=0.09/0.13). In patients less than 10 years of age, the CI for relapse/death in induction was 11%/1.4% if treated with DEX, and 18%/0.5% if treated with PDN (p<0.001/0.01). If specific biological subgroups were analyzed, a significantly lower CI of relapse for patients randomized to receive DEX was observed in T-ALL as well as TEL/AML1 positive and negative pcB-ALL patients. The reduction was most pronounced in T-ALL patients with good prednisone response after the prophase: CI for relapse in DEX treated patients (n=135) was only 6% (SE 2%) as compared to 20% (SE 4%) in PDN treated patients (n=138; p=0.003). Four patients died in the DEX arm, 3 in the PDN arm for toxicity. In TEL/AML1-positive patients with good prednisone response, the CI for relapse was 4% (SE 1%) in the DEX group and 13% (SE 2%) for PDN treated patients (p<0.001). This large difference became most evident only more than 2 years from diagnosis. The percentage of patients found negative for MRD at d33 was very similar between the randomized groups: It was 47.9% for patients treated with DEX, and 45% for patients treated with PDN. Interestingly, patients with pcB-ALL found MRD negative at d33 had significantly less subsequent relapses if treated with DEX in induction (p(Gray)=0.012). In conclusion, the use of DEX at the same dosage as applied in delayed intensification (10 mg/m2/d for 3 weeks) although associated with a greater risk of severe toxicity leads to a marked reduction of the risk of relapse, translating this into a significant benefit in terms of EFS. This was most evident in patients with in vivo sensitivity to the prednisone prephase, while the efficacy of DEX in poor responding patients was not convincing. In the future, more intensive clinical monitoring and early anti-infective interventions could render the advantage of using DEX even more evident. Moreover, other potentially toxic agents such as anthracyclines may be limited in induction for carefully selected subgroups of patients with the aim of limiting early or late toxicities.

Efficacy and safety of TDF/FTC-containing first-line HAART in clinical practice – 2-year data from the German Outpatient Cohort

Poster presentation: Purpose of the study First-line HAART with tenofovir DF (TDF) and FTC in pivotal trials has been associated with high efficacy and good tolerability. However, real-life clinical practice often differs from clinical trials due to co-morbidities, co-infections, and less intensive clinical monitoring. To evaluate efficacy and safety of first-line HAART in a day-to-day setting, this Gilead-sponsored non-interventional cohort was established. Methods Between July 2005 and August 2006, 533 HIV-1 infected antiretroviral-naive patients from 50 German centres enrolled in this non-interventional cohort. All patients were followed every 3 months for 3 years to monitor efficacy (viral load [VL], CD4), tolerability, renal safety, regimen changes and resistance profile. All patients received TDF+FTC as a single tablet (Truvada, TVD) in combination with either an NNRTI or PI/r as their first antiretroviral regimen. Summary of results As of June 2008, 2 years of therapy have been documented for 330/533 (62%) patients. At treatment initiation, 81% were male; median age was 39 years; clinical AIDS diagnosis was documented in 22%; 47% started therapy with CD4 <200 cells/mm3. TVD was combined with an NNRTI (43%) or a PI/r (57%). After 24 months, in an As-Treated (AT) analysis, 85% patients achieved a VL <50 copies/ml (VL <500 copies/ml: 97%), median CD4 count increased from 217 at baseline to 450 cells/mm3 (IQR: 325–608). Truvada showed a good safety profile; 76 adverse events (AEs) of any grade were reported in 66/533 patients (12%); six of these were judged serious. Fourteen (2.6%) patients discontinued TVD due to AEs. Renal abnormalities of any grade were reported in 10 patients (1.9%). Virological failure was documented in nine patients, of which eight were genotyped; M184V/I was detected in three, K65R in two patients. Conclusion During 2 years of follow-up, the overall safety of TVD was good; renal AEs of any grade were reported in 1.9% of patients. K65R was detected in two patients. First-line HAART with TVD plus an NNRTI or PI/r in clinical practice showed comparable efficacy to that observed in controlled clinical trials.