No abstract

Dear Editor, Dapsone has been recommended at a second-line therapy for immune thrombocytopenia (ITP) [1] although only one study reported its use immediately after failure of first-line therapy [2]. We therefore highlight our experience of treating a sequential series of adult patients with dapsone after failure of first-line therapy, finding a worse response rate (RR) than anticipated.During the 28-month study period (March 2009 to June 2011), we offered dapsone to all adult patients with primary ITP requiring second-line treatment (n=11), although therapeutic decisions were still individualised. Outcomes were audited retrospectively. Patients were identified systematically from an electronic patient record. ITP was diagnosed as per international consensus guidelines [1], and outcome criteria were defined as per international working group guidelines [3].All 11 patients received 75-100 mg oral dapsone daily (9 started at 100 mg, 2 at 50 mg, titrated up to 100 mg as tolerated), all received oral steroids first line and all had a normal haemoglobin prior to commencing dapsone. All were checked for G6PD deficiency except 2 northern European Caucasian women, and all tested were negative.Median time from diagnosis to commencing dapsone was 8 months (range 1-60 months). The median age at time of commencing dapsone was 32 (range 17-81 years). The median pre-treatment platelet count was 10 (range 3-61×10 9 /L). Eight patients were receiving prednisolone when dapsone was commenced, which was weaned in responding patients. The median duration of dapsone was 2 months (range 0.5-35 months) and a minimum of 2 months in those tolerating treatment. Eight patients had no response, two responded and one had a complete response. The overall RR was 3/11 (27 %) with a median time to response of 2 weeks (range 2-9 weeks). Of the two responding patients, one discontinued dapsone 1 week later due to a fall in haemoglobin and one lost their response after 12 weeks. The patient with complete response was maintaining her remission at 29 months. The overall RR at 6 months was therefore only 1/11 (9 %). Of the 10 patients discontinuing therapy, 6 stopped due to lack of efficacy and 4 due to side effects ( Table 1).Studies of dapsone for primary ITP have been recently reviewed [4]. The RR of 38-63 % [2, 5-9] is broadly comparable to rituximab, azathioprine or danazol [1]. It is cost-effective and well tolerated with only 0-10.6 % of patients discontinuing therapy due to side effects in most studies [2,[5][6][7]9]. Dapsone also largely avoids the risks of immunosuppression such as marrow suppression, infection and potential for secondary malignancy or progressive multifocal leukoencephalopathy.Although analysis was retrospective, all patients were identified electronically and all received dapsone, reducing selection bias. The 27 % RR and only 9 % at 6 months was worse than previous studies, despite the majority of these including patients relapsed or refractory to multiple lines of therapy. Our low RR was due to a combination of poor tolera...

Background:  In the progression of their disease, Alzheimer's disease (AD) patients have been observed to demonstrate various clinical features reminiscent of children. Based on behavioral, neurological and neuropathological findings, Reisberg et al. noted the relationships between development and dementia and proposed the ‘retrogenesis’ model. Methods:  The functional assessment staging procedure (FAST) was used for assessment of functional ability, and the Tanaka–Binet intelligence scale (TB scale) was used to assess intellectual ability in 24 patients with moderate to severe AD. Results:  Overall, there was a significant Spearman's correlation between the FAST stage and the basic age (BA) value (r = −0.85, P < 0.01). The BA by the TB scale was significantly different between FAST stages 5 and 6 to 7. The mean (standard error [SE]) BA values of FAST stages 5 and 6 were 4.2 (0.9) and 2.3 (0.7), respectively, the latter being significantly lower than the former (F = 10.2, P < 0.01 one‐way anova). The TB scale could not assess the BA of the FAST stage 7 patients because of floor effects. Conclusion:  Although further investigation using larger samples would be needed, the findings support the general concordance of intellectual and functional decline in AD with the converse developmental acquisition of the same capacities, as hypothesized in the retrogenesis model.

Background: We have described the clinical stages of the brain aging and Alzheimer's disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology "mild cognitive impairment" (MCI) for the first pre-dementia stage and "subjective cognitive decline" (SCD) for the pre-MCI stage. We now report the characteristics of a pre-SCD condition eventuating in likely AD. Objective: The aim of this study was to characterize a pre-SCD condition eventuating in AD. Method: Sixty healthy persons with "no cognitive decline" (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as "decliner," if SCD or worse, or "nondecliner" if NCD. Results: After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). Conclusion: This is ostensibly the first study to link psychometric cognitive decline to the subsequent SCD stage of eventual AD.

Cerebrovascular small vessel disease is now believed to be the major source of vascular burden of the brain. Cerebrovascular small vessel disease and Alzheimer's disease appear to represent pathophysiologic and clinical continua, rather than dichotomous entities. It appears that common etiopathologic mechanisms underlie the clinical presentation of both of these conditions. Therefore, the staging procedures that have been developed for the clinical continuum of age-associated memory impairment, mild cognitive impairment, and the progressive dementia of Alzheimer's disease appear to be applicable for the same continua in cerebrovascular small vessel disease. Although temporal and prognostic aspects have been studied for the Alzheimer's-related portions of this clinical staging continuum, they remain to be elucidated for cerebrovascular small vessel disease.

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One of the major efforts in Oil and Gas industry's digital transformation is the increased use of data in optimizing processes. This paper focuses on optimizing the process of section-milling during well abandonment by leveraging data gathered from past section-milling cycles. Several mathematical model-based techniques have been presented in recent years for improving the rate of penetration (ROP) in section-milling. However, only a few data-driven methodologies have been adopted in this field of interest, most likely due to unavailability of data. A trainingsubset of field data from section-milling operations is used for developing a range of machine learning models. Performance of these models is then evaluated using mean absolute percentage error (MAPE) against testing subset of data.