SHOP2: An HTN Planning System

The SHOP2 planning system received one of the awards for distinguished performance in the 2002 International Planning Competition. This paper describes the features of SHOP2 which enabled it to excel in the competition, especially those aspects of SHOP2 that deal with temporal and metric planning domains

Scoring system to facilitate diagnosis of Gaucher disease

Background: Gaucher disease (GD) manifests heterogeneously and other conditions are often misdiagnosed in its place, leading to diagnostic delays. The Gaucher Earlier Diagnosis Consensus (GED‐C) initiative proposed a point‐scoring system (PSS) based on the signs and covariables that are most indicative of GD to help clinicians identify which individuals to test for GD. Aims: To validate the PSS retrospectively in a test population including patients with GD and other conditions with overlapping manifestations. Methods: Four cohorts of adults with GD, liver disease (LD), haematological malignancy (HM) or immune thrombocytopenia were identified from hospital records. Clinical data were audited for GED‐C factors identified as potentially indicative of GD and aggregate scores calculated (sum of scores/number of factors) based on published PSS weightings. Threshold discriminatory PSS scores, sensitivity and specificity were determined by receiver‐operating characteristic (ROC) analysis. Results: Among 100 patients (GD, n = 25; non‐GD, n = 75), analyses based on 11 possible factors estimated group mean (standard deviation) PSS scores of: GD (n = 14), 1.08 (0.25); non‐GD (n = 38), 0.58 (0.31). Mean between‐group difference (95% confidence interval (CI)) was (−0.49 (−0.68, −0.31)) and area under the ROC analysis curve (95% CI) was 0.88 (0.78, 0.97). A threshold PSS score of 0.82 identified all 14 patients with GD in the analysis set (100% sensitivity) and 27 of 38 patients in the non‐GD group (71% specificity). Patients with LD and HM were most likely to have manifestations overlapping GD. Conclusions: Preliminary validation of the GED‐C PSS discriminated effectively between patients with GD and those with overlapping signs

Presenting signs and patient co-variables in Gaucher disease : outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative

© 2018 The Authors. Internal Medicine Journal by Wiley Publishing Asia Pty Ltd on behalf of Royal Australasian College of Physicians.Background: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. Aim: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify ‘at-risk’ patients who may benefit from diagnostic testing. Methods: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. Results: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. Conclusion: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.Peer reviewedFinal Published versio

Assessment of immunogenicity of romiplostim in clinical studies with ITP subjects

Romiplostim is an Fc-peptide fusion protein that activates intracellular transcriptional pathways via the thrombopoietin (TPO) receptor leading to increased platelet production. Romiplostim has been engineered to have no amino acid sequence homology to endogenous TPO. Recombinant protein therapeutics can be at a risk of development of an antibody response that can impact efficacy and safety. Hence, a strategy to detect potential antibody formation to the drug and to related endogenous molecules can be useful. The immunogenicity assessment strategy involved both the detection and characterization of binding and neutralizing antibodies. The method for detection was based on a surface plasmon resonance biosensor platform using the Biacore 3000. Samples that tested positive for binding antibodies in the Biacore immunoassay were then tested in a neutralization assay. Serum samples from 225 subjects with immune thrombocytopenic purpura (ITP) dosed with romiplostim and 45 ITP subjects dosed with placebo were tested for romiplostim and TPO antibodies. Prior to romiplostim treatment, 17 subjects (7%) tested romiplostim antibody positive and 12 subjects (5%) tested TPO antibody positive for pre-existing binding antibodies. After romiplostim exposure, 11% of the subjects exhibited binding antibodies against romiplostim and 5% of the subjects with ITP showed binding antibodies against TPO. The antibodies against romiplostim did not cross-react with TPO and vice versa. No cases of anti-TPO neutralizing antibodies were detected in romiplostim-treated subjects. The incidence of anti-romiplostim neutralizing antibodies to romiplostim was 0.4% (one subject); this subject tested negative at the time of follow-up 4 months later. No impact on platelet profiles were apparent in subjects that had antibodies to romiplostim to date. In summary, administration of romiplostim in ITP subjects resulted in the development of a binding antibody response against romiplostim and TPO ligand. One subject developed a neutralizing antibody response to romiplostim that impacted the platelet counts of this subject. No neutralizing antibodies to endogenous TPO were observed

Ras mutation cooperates with β-catenin activation to drive bladder tumourigenesis

Mutations in the Ras family of proteins (predominantly in H-Ras) occur in approximately 40% of urothelial cell carcinoma (UCC). However, relatively little is known about subsequent mutations/pathway alterations that allow tumour progression. Indeed, expressing mutant H-Ras within the mouse bladder does not lead to tumour formation, unless this is expressed at high levels. The Wnt signalling pathway is deregulated in approximately 25% of UCC, so we examined if this correlated with the activation of MAPK signalling in human UCC and found a significant correlation. To test the functional significance of this association we examined the impact of combining Ras mutation (H-RasQ61L or K-RasG12D) with an activating β-catenin mutation within the mouse bladder using Cre-LoxP technology. Although alone, neither Ras mutation nor β-catenin activation led to UCC (within 12 months), mice carrying both mutations rapidly developed UCC. Mechanistically this was associated with reduced levels of p21 with dependence on the MAPK signalling pathway. Moreover, tumours from these mice were sensitive to MEK inhibition. Importantly, in human UCC there was a negative correlation between levels of p-ERK and p21 suggesting that p21 accumulation may block tumour progression following Ras mutation. Taken together these data definitively show Ras pathway activation strongly cooperates with Wnt signalling to drive UCC in vivo

A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma

BACKGROUND Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria ofthe European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS Of 193 patients who could be evaluated, 92 percent had been treated with three or more ofthe major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immuno-fixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy

Fruit crops, 1986: a summary of research

Influence of treatments at planting on trellised apple tree performance / David C. Ferree -- Influence of growth regulators on branching of young apple trees / David C. Ferree and John C. Schmid -- Influence of growth regulators on scarf skin of Rome Beauty apples / David C. Ferree and John C. Schmid -- Influence of fungicides on scarf skin on Gallia Beauty / David C. Ferree and Michael A. Ellis -- Little relationship between root pruning and winter injury / James R. Schupp and David C. Ferree -- Performance of two apple cultivars on MS and M9 interstems on Antonovka / D. C. Ferree, R. M. McConnell, and J. C. Schmid -- Air sprayer jet deflection by travel or wind: as predicted by computer / R. D. Fox, R. D. Brazee, and D. L. Reichard -- Measuring atmospheric water vapor / R. D. Brazee and R. D. Fox -- A prototypic pollination unit made from expanded polystyrene / James E. Tew and Dewey M. Caron -- Effects of gibberellic acid (GA3) and daminozide (Alar) on growth and fruiting of Himrod grapes / G. A. Cahoon, M. L. Kaps, and S. P. Pathak -- Development of an action threshold for meadow spittlebug on strawberries / Mark A. Zajac and Franklin R. Hall -- Long-term yield of selected blackberry cultivars and selections in southern Ohio / Craig K. Chandler, Donald A. Chandler, and Greg L. Brenneman -- Electronic information transfer / R. C. Funt. -- A summary of research on synthetic pyrethroids and mites in the apple orchard ecosystem / Franklin R. Hall -- Controlling apple collar rot: effects of fungicides, soil amendments, and depth of planting / M. A. Ellis, D. C. Ferree, and L. V. Madden -- Validation of an electronic unit for predicting apple scab infection periods / M. A. Ellis, L. V. Madden, and L. L. Wilson -- Epidemiology and control of strawberry leather rot / G. G. Grove, M. A. Ellis, and L. V. Madden -- Research on cane diseases of thornless blackberry in Ohio / M. A. Ellis, G. A. Kuter, and L. L. Wilso