Safety and Efficacy of Dihydroartemisinin-Piperaquine in Falciparum Malaria: A Prospective Multi-Centre Individual Patient Data Analysis

BACKGROUND: The fixed dose antimalarial combination of dihydroartemisinin-piperaquine (DP) is a promising new artemisinin-based combination therapy (ACT). We present an individual patient data analysis of efficacy and tolerability in acute uncomplicated falciparum malaria, from seven published randomized clinical trials conducted in Africa and South East Asia using a predefined in-vivo protocol. Comparator drugs were mefloquine-artesunate (MAS3) in Thailand, Myanmar, Laos and Cambodia; artemether-lumefantrine in Uganda; and amodiaquine+sulfadoxine-pyrimethamine and artesunate+amodiaquine in Rwanda. METHODS AND FINDINGS: In total 3,547 patients were enrolled: 1,814 patients (32% children under five years) received DP and 1,733 received a comparator antimalarial at 12 different sites and were followed for 28-63 days. There was no significant heterogeneity between trials. DP was well tolerated with 1.7% early vomiting. There were less adverse events with DP in children and adults compared to MAS3 except for diarrhea; ORs (95%CI) 2.74 (2.13 to 3.51) and 3.11 (2.31 to 4.18), respectively. DP treatment resulted in a rapid clearance of fever and parasitaemia. The PCR genotype corrected efficacy at Day 28 of DP assessed by survival analysis was 98.7% (95%CI 97.6-99.8). DP was superior to the comparator drugs in protecting against both P.falciparum recurrence and recrudescence (P = 0.001, weighted by site). There was no difference between DP and MAS3 in treating P. vivax co-infections and in suppressing the first relapse (median interval to P. vivax recurrence: 6 weeks). Children under 5 y were at higher risk of recurrence for both infections. The proportion of patients developing gametocytaemia (P = 0.002, weighted by site) and the subsequent gametocyte carriage rates were higher with DP (11/1000 person gametocyte week, PGW) than MAS3 (6/1000 PGW, P = 0.001, weighted by site). CONCLUSIONS: DP proved a safe, well tolerated, and highly effective treatment of P.falciparum malaria in Asia and Africa, but the effect on gametocyte carriage was inferior to that of MAS3

Some code smells have a significant but small effect on faults

We investigate the relationship between faults and five of Fowler et al.'s least-studied smells in code: Data Clumps, Switch Statements, Speculative Generality, Message Chains, and Middle Man. We developed a tool to detect these five smells in three open-source systems: Eclipse, ArgoUML, and Apache Commons. We collected fault data from the change and fault repositories of each system. We built Negative Binomial regression models to analyse the relationships between smells and faults and report the McFadden effect size of those relationships. Our results suggest that Switch Statements had no effect on faults in any of the three systems; Message Chains increased faults in two systems; Message Chains which occurred in larger files reduced faults; Data Clumps reduced faults in Apache and Eclipse but increased faults in ArgoUML; Middle Man reduced faults only in ArgoUML, and Speculative Generality reduced faults only in Eclipse. File size alone affects faults in some systems but not in all systems. Where smells did significantly affect faults, the size of that effect was small (always under 10 percent). Our findings suggest that some smells do indicate fault-prone code in some circumstances but that the effect that these smells have on faults is small. Our findings also show that smells have different effects on different systems. We conclude that arbitrary refactoring is unlikely to significantly reduce fault-proneness and in some cases may increase fault-proneness.Peer reviewe

An Information Foraging Theory Perspective on Tools for Debugging, Refactoring, and Reuse Tasks

Theories of human behavior are an important but largely untapped resource for software engineering research. They facilitate understanding of human developers\u27 needs and activities, and thus can serve as a valuable resource to researchers designing software engineering tools. Furthermore, theories abstract beyond specific methods and tools to fundamental principles that can be applied to new situations. Toward filling this gap, we investigate the applicability and utility of Information Foraging Theory (IFT) for understanding information-intensive software engineering tasks, drawing upon literature in three areas: debugging, refactoring, and reuse. In particular, we focus on software engineering tools that aim to support information-intensive activities, that is, activities in which developers spend time seeking information. Regarding applicability, we consider whether and how the mathematical equations within IFT can be used to explain why certain existing tools have proven empirically successful at helping software engineers. Regarding utility, we applied an IFT perspective to identify recurring design patterns in these successful tools, and consider what opportunities for future research are revealed by our IFT perspective. © 2013 ACM

Locally recurrent rectal cancer::oncological outcomes of neoadjuvant chemoradiotherapy with or without induction chemotherapy

Achieving a clear surgical resection margin (R0 resection) is one of the most important prognostic factors determining survival after surgical resection of locally recurrent rectal cancer (LRRC)1. In radiotherapy-naive patients, the most common approach to facilitating an R0 resection is to administer long-course neoadjuvant chemoradiotherapy2. However, many patients with LRRC have undergone chemoradiotherapy previously for the primary tumour. The role of reirradiation in LRRC in these patients is still debated, as well as the addition of induction chemotherapy (ICT)3,4. In previously irradiated patients, there is no consensus on whether downstaging by reirradiation in combination with ICT results in better oncological outcomes than upfront surgery. No convincing evidence exists proving the superiority of either approach5.In this study, outcomes of two Dutch referral centres were compared, both considering long-course chemoradiotherapy and chemoreirradiation as standard treatment for LRRC. One centre routinely treated patients with additional ICT, whereas the other did not. The aim was to evaluate long-term oncological outcomes in patients with LRRC, comparing the results from these two centres

Building a collaborative model of sacroiliac joint dysfunction and pelvic girdle pain to understand the diverse perspectives of experts

Background: Pelvic girdle pain (PGP) and sacroiliac joint (SIJ) dysfunction/pain are considered frequent contributors to low back pain (LBP). Like other persistent pain conditions, PGP is increasingly recognized as a multifactorial problem involving biological, psychological, and social factors. Perspectives differ between experts and a diversity of treatments (with variable degrees of evidence) have been utilized. Objective: To develop a collaborative model of PGP that represents the collective view of a group of experts. Specific goals were to analyze structure and composition of conceptual models contributed by participants, to aggregate them into a metamodel, to analyze the metamodel's composition, and to consider predicted efficacy of treatments. Design: To develop a collaborative model of PGP, models were generated by invited individuals to represent their understanding of PGP using fuzzy cognitive mapping (FCM). FCMs involved proposal of components related to causes, outcomes, and treatments for pain, disability, and quality of life, and their connections. Components were classified into thematic categories. Weighting of connections was summed for components to judge their relative importance. FCMs were aggregated into a metamodel for analysis of the collective opinion it represented and to evaluate expected efficacy of treatments. Results: From 21 potential contributors, 14 (67%) agreed to participate (representing six disciplines and seven countries). Participants' models included a mean (SD) of 22 (5) components each. FCMs were refined to combine similar terms, leaving 89 components in 10 categories. Biomechanical factors were the most important in individual FCMs. The collective opinion from the metamodel predicted greatest efficacy for injection, exercise therapy, and surgery for pain relief. Conclusions: The collaborative model of PGP showed a bias toward biomechanical factors. Most efficacious treatments predicted by the model have modest to no evidence from clinical trials, suggesting a mismatch between opinion and evidence. The model enables integration and communication of the collection of opinions on PGP