A randomized controlled trial of the effectiveness of a Computer-Assisted Cognitive Remediation (CACR) program in adolescents with psychosis or at high risk of psychosis: Short term and long term outcomes

The present study investigates the short- and long-term outcomes of a computer-assisted cognitive remediation (CACR) program in adolescents with psychosis or at high risk. 32 adolescents participated in a blinded 8-week randomized controlled trial of CACR treatment compared to computer games (CG). Clinical and neuropsychological evaluations were undertaken at baseline, at the end of the program and at 6-month. At the end of the program (n = 28), results indicated that visuospatial abilities (Repeatable Battery for the Assessment of Neuropsychological Status, RBANS; P = .005) improved signifi cantly more in the CACR group compared to the CG group. Furthermore, other cognitive functions (RBANS), psychotic symptoms (Positive and Negative Symptom Scale) and psychosocial functioning (Social and Occupational Functioning Assessment Scale) improved signifi cantly, but at similar rates, in the two groups. At long term (n = 22), cognitive abilities did not demonstrated any amelioration in the control group while, in the CACR group, signifi cant long-term improvements in inhibition (Stroop; P = .040) and reasoning (Block Design Test; P = .005) were observed. In addition, symptom severity (Clinical Global Improvement) decreased signifi cantly in the control group (P = .046) and marginally in the CACR group (P = .088). To sum up, CACR can be successfully administered in this population. CACR proved to be effective over and above CG for the most intensively trained cognitive ability. Finally, on the long-term, enhanced reasoning and inhibition abilities, which are necessary to execute higher-order goals or to adapt behavior to the ever-changing environment, were observed in adolescents benefi ting from a CACR.

Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). However, the treatment must be taken indefinitely and is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene), and is also bound to the alpha1-acid glycoprotein (AAG) in plasma. Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations were measured in 59 patients receiving Glivec® at diverse dosage regimens, using a validated chromatographic method developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one-compartment model with first-order absorption described the data appropriately, with an average apparent clearance of 12.4 l/h, a volume of distribution of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T and the AAG phenotype appears to modulate the disposition of imatinib. Large inter-individual variability (CV %) remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen. This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help in individualising the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Enhancement by diuretics of the antihypertensive action of long-term angiotensin converting enzyme blockade

Thirty-nine patients with various types of hypertension were treated by chronic blockage of the angiotensin converting enzyme, i.e. by twice daily administration of captopril, 50 to 200 mg p.o. The blood pressure reduction observed 1 hour following administration of the inhibitor was directly related to the baseline plasma renin activity (r=- 0.67, p < 0.001). Whenever blockade of the renin system alone did not lower blood pressure to normal levels additional sodium subtraction brought it under control. With the renin system neutralized, blood pressure becomes exquisitely sensitive to changes in sodium balance. Diuretics seem to preserve optimal natriuretic efficacy despite blood pressure reduction, probably because aldosterone levels are reduced and renal blood flow increases. Blockade of the renin system together with individually tailored salt subtraction provides an attractive new approach to long-term treatment of clinical hypertension.

Molecular epidemiology reveals long-term changes in HIV type 1 subtype B transmission in Switzerland.

BACKGROUND: Sequence data from resistance testing offer unique opportunities to characterize the structure of human immunodeficiency virus (HIV) infection epidemics. METHODS: We analyzed a representative set of HIV type 1 (HIV-1) subtype B pol sequences from 5700 patients enrolled in the Swiss HIV Cohort Study. We pooled these sequences with the same number of sequences from foreign epidemics, inferred a phylogeny, and identified Swiss transmission clusters as clades having a minimal size of 10 and containing >or=80% Swiss sequences. RESULTS: More than one-half of Swiss patients were included within 60 transmission clusters. Most transmission clusters were significantly dominated by specific transmission routes, which were used to identify the following patient groups: men having sex with men (MSM) (38 transmission clusters; average cluster size, 29 patients) or patients acquiring HIV through heterosexual contact (HETs) and injection drug users (IDUs) (12 transmission clusters; average cluster size, 144 patients). Interestingly, there were no transmission clusters dominated by sequences from HETs only. Although 44% of all HETs who were infected between 1983 and 1986 clustered with injection drug users, this percentage decreased to 18% for 2003-2006 (P<.001), indicating a diminishing role of injection drug users in transmission among HETs over time. CONCLUSIONS: Our analysis suggests (1) the absence of a self-sustaining epidemic of HIV-1 subtype B in HETs in Switzerland and (2) a temporally decreasing clustering of HIV infections in HETs and IDUs.

Anti-TNF therapy in acute sciatica reduces the long-term need for surgery: A three-year follow-up of a randomized double blind placebo controlled trial

Introduction: Two subcutaneous injections of adalimumab in severeacute sciatica have demonstrated a significant benefit on the numberof back surgeries in a short-term randomized controlled clinical trial[1]. This 3-year follow-up study aimed to determine whether theshort-term benefit was sustained over a longer period of time.Methods: Information on surgery was retrieved in 56/61 patients(93%). We used a Cox proportional hazard models to determinefactors predisposing to surgery.Results: Twenty-three (41%) patients had back surgery within 3 years,8/29 (28%) in the adalimumab group and 15/ 27 (56%) in the placebogroup, p = 0.038. Adalimumab injections reduced the need for backsurgery by 61% (Hazard Ratio (HR): 0.39 (95% CI: 0.17-0.92). In amultivariate model, treatment with a TNF-α antagonist remained thestrongest protective factor (HR 0.17, p = 0.002). Other significantpredictors of surgery were a good correlation between symptomsand MRI findings (HR = 11.6, p = 0.04), baseline intensity of leg pain(HR = 1.3, p = 0.06), intensity of back pain (HR = 1.4, p = 0.03)and duration of sickness leave (HR = 1.01 per day, p = 0.03).Conclusion: A short course of adalimumab in patients with severeacute sciatica significantly reduces the need for back surgery.

Pulmonary Sarcoid-like Granulomatosis after Multiple Vaccinations of a Long-term Surviving Patient with Metastatic Melanoma.

Autoimmune side effects are frequent in patients with cancer treated with immune checkpoint-targeting antibodies, but are rare with cancer vaccines. Here, we present a case report on a patient with metastatic melanoma who developed pulmonary sarcoid-like granulomatosis following repetitive vaccinations with peptides and CpG. Despite multiple metastases, including one lesion in the brain, the patient is alive and well more than 13 years after the diagnosis of metastatic disease. The strongly activated tumor-specific CD8(+) T cells showed robust long-term memory and effector functions. It is possible that long-term survival and adverse autoimmune events may become more common for vaccines inducing robust anticancer immune responses as were present in this patient. Cancer Immunol Res; 2(12); 1148-53. ©2014 AACR.

Long-term follow-up of follicular lymphoma (FL) patients receiving single agent rituximab at two different schedules in trial SAKK 35/98

Background: In FL, Rituximab as a single agent delivered in the standard schedule (4 times weekly) may induce a response rate of 50−70% with an event-free survival (EFS) of 1−3 years according to patients' characteristics. Prolonged Rituximab exposure seems to improve EFS at least in responding patients and to increase the rate of longterm responders. Here we report long-term results of a clinical trial comparing single agent Rituximab delivered in the standard schedule versus prolonged exposure, with focus on the proportion of long-term responders and their characteristics. Material and Methods: Between 1998 and 2002, chemotherapy na¨ıve (n = 64) or pre-treated (n = 138) FL patients received Rituximab in the standard schedule. Those responding or with stable disease were randomized to no further treatment (observation, n = 78) or 4 additional doses of Rituximab given at 2-month intervals (prolonged exposure, n = 73). EFS was calculated from the first dose of standard schedule until progression, relapse, second tumor or death. Results: At a median follow up of 9.4 years and with all living patients having been followed for at least 5 years, the median EFS is 13 months for the observation and 24 months for the prolonged exposure arm (p = 0.0007). In the observation arm 13% had no event at 5-years and only 4% at 8 years, while in the prolonged exposure arm it was 27% at 5 years and remained 21% at 8 years. The only significant prognostic factor for EFS in a multivariate Cox regression was the prolonged Rituximab schedule (hazard ratio 0.58, CI 0.39−0.86, p = 0.007), whereas being chemotherapy na¨ıve, presenting with stage long-term toxicity from treatment was observed. There were 22 cases of second malignancy: 12 on observation, 10 on prolonged exposure. 5 patients developed myelodysplastic syndrome; all received previous chemotherapy treatment. Conclusions: Our results confirm that the prolonged exposure to Rituximab significantly improves EFS as compared to the standard schedule. This benefit continues for many years after the end of therapy and the prolonged exposure seems to be the sole factor which may be considered of prognostic value. Patients treated with prolonged schedule (8 doses of Rituximab) may have approximately 25% and 20% chances to be in remission at 5 and 8 years respectively and to avoid subsequent chemotherapy treatment.

Reproductive allocation strategies: a long-term study on proximate factors and temporal adjustments in a viviparous lizard.

Optimisation of reproductive investment is crucial for Darwinian fitness, and detailed long-term studies are especially suited to unravel reproductive allocation strategies. Allocation strategies depend on the timing of resource acquisition, the timing of resource allocation, and trade-offs between different life-history traits. A distinction can be made between capital breeders that fuel reproduction with stored resources and income breeders that use recently acquired resources. In capital breeders, but not in income breeders, energy allocation may be decoupled from energy acquisition. Here, we tested the influence of extrinsic (weather conditions) and intrinsic (female characteristics) factors during energy storage, vitellogenesis and early gestation on reproductive investment, including litter mass, litter size, offspring mass and the litter size and offspring mass trade-off. We used data from a long-term study of the viviparous lizard, Lacerta (Zootoca) vivipara. In terms of extrinsic factors, rainfall during vitellogenesis was positively correlated with litter size and mass, but temperature did not affect reproductive investment. With respect to intrinsic factors, litter size and mass were positively correlated with current body size and postpartum body condition of the previous year, but negatively with parturition date of the previous year. Offspring mass was negatively correlated with litter size, and the strength of this trade-off decreased with the degree of individual variation in resource acquisition, which confirms theoretical predictions. The combined effects of past intrinsic factors and current weather conditions suggest that common lizards combine both recently acquired and stored resources to fuel reproduction. The effect of past energy store points out a trade-off between current and future reproduction.

Immediate and long-term results of valve replacement for native and prosthetic valve endocarditis.

BACKGROUND: The objective of the present study was to compare current results of prosthetic valve replacement following acute infective native valve endocarditis (NVE) with that of prosthetic valve endocarditis (PVE). Prosthetic valve replacement is often necessary for acute infective endocarditis. Although valve repair and homografts have been associated with excellent outcome, homograft availability and the importance of valvular destruction often dictate prosthetic valve replacement in patients with acute bacterial endocarditis. METHODS: A retrospective analysis of the experience with prosthetic valve replacement following acute NVE and PVE between 1988 and 1998 was performed at the Montreal Heart Institute. RESULTS: Seventy-seven patients (57 men and 20 women, mean age 48 +/- 16 years) with acute infective endocarditis underwent valve replacement. Fifty patients had NVE and 27 had PVE. Four patients (8%) with NVE died within 30 days of operation and there were no hospital deaths in patients with PVE. Survival at 1, 5, and 7 years averaged 80% +/- 6%, 76% +/- 6%, and 76% +/- 6% for NVE and 70% +/- 9%, 59% +/- 10%, and 55% +/- 10% for PVE, respectively (p = 0.15). Reoperation-free survival at 1, 5, and 7 years averaged 80% +/- 6%, 76% +/- 6%, and 76% +/- 6% for NVE and 45% +/- 10%, 40% +/- 10%, and 36% +/- 9% for PVE (p = 0.003). Five-year survival for NVE averaged 75% +/- 9% following aortic valve replacement and 79% +/- 9% following mitral valve replacement. Five-year survival for PVE averaged 66% +/- 12% following aortic valve replacement and 43% +/- 19% following mitral valve replacement (p = 0.75). Nine patients underwent reoperation during follow-up: indications were prosthesis infection in 4 patients (3 mitral, 1 aortic), dehiscence of mitral prosthesis in 3, and dehiscence of aortic prosthesis in 2. CONCLUSIONS: Prosthetic valve replacement for NVE resulted in good long-term patient survival with a minimal risk of reoperation compared with patients who underwent valve replacement for PVE. In patients with PVE, those who needed reoperation had recurrent endocarditis or noninfectious periprosthetic dehiscence.

Reoperative Roux-En-Y Gastric Bypass Provides Similar Long-Term Results as Primary Surgery

Background: The increasing prevalence of obesity worldwide is associated with a massive increase in the number of yearly performed bariatric procedures, many of them purely restrictive. Consequently, a growing number of surgical revisions are necessary, and conversion to Roux-en-Y gastric bypass (RYGBP) is a common option. So far, few series including mostly patients reoperated using open surgery,and limited follow-up, have been reported.Patients and methods: Retrospective analysis of prospectively collected data of all patients undergoing revisional RYGBP in our two departments.Results: Between June 1999 and February 2011, 186 patients were submitted to revisional RYGBP, 161 women and 25 men with a mean age of 43 years. Their mean initial BMI was 45,3 kg/m2, their mean nadir BMI between the index operation and revision was 34, and their mean pre-revision BMI was 38,5. The initial procedure was gastric banding in 134 (72 %) patients, VBG in 48 (25,8 %), RYGBP in 5 (2,7 %), and others in 3. The main indications for revision were complications from the primary procedure with or without weight regain. A laparoscopic approach was usedin 137 (73,7 %) cases. Overall early morbidity was 18,8 %, and major morbidity was 3,2 %. Comparing patients in the first, second and last third of our experience, the percentage of patients operated using a laparoscopic approach increased from 53,2 % to 71 % and finally 96,7 %, and overall morbidity decreased from 27,4 % to 24,2 % and then 4,8 %. There were more wound infections after laparotomy (22,4 versus 2,9 %, p<0,001). There was no mortality. The mean BMI remained between 30 and 32 up to nine years after revision. Up to this limit, a BMI of <35 was maintained in between 75 and 83 % of the patients.Conclusions: Revisional RYGBP proves to be an effective and safe procedure. It can be performed by laparoscopy in most cases, especially as experience increases., It is associated with an acceptable morbidity, though higher than with primary RYGBP. Long-term results are equivalent to those of primary RYGBP, and can be considered as very satisfactory considering the fact that, on average, patients requiring redo surgery represent a sub-selection of difficult bariatric patients.

In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression.

Via a transcription factor, Foxp3, immunoregulatory CD4(+)CD25(+) T cells (T reg cells) play an important role in suppressing the function of other T cells. Adoptively transferring high numbers of T reg cells can reduce the intensity of the immune response, thereby providing an attractive prospect for inducing tolerance. Extending our previous findings, we describe an in vivo approach for inducing rapid expansion of T reg cells by injecting mice with interleukin (IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb). Injection of these IL-2-IL-2 mAb complexes for a short period of 3 d induces a marked (>10-fold) increase in T reg cell numbers in many organs, including the liver and gut as well as the spleen and lymph nodes, and a modest increase in the thymus. The expanded T reg cells survive for 1-2 wk and are highly activated and display superior suppressive function. Pretreating with the IL-2-IL-2 mAb complexes renders the mice resistant to induction of experimental autoimmune encephalomyelitis; combined with rapamycin, the complexes can also be used to treat ongoing disease. In addition, pretreating mice with the complexes induces tolerance to fully major histocompatibility complex-incompatible pancreatic islets in the absence of immunosuppression. Tolerance is robust and the majority of grafts are accepted indefinitely. The approach described for T reg cell expansion has clinical potential for treating autoimmune disease and promoting organ transplantation.