br Changes to the Trial Protocol

Changes to the Trial Protocol after Initiation of the Study
Discussion A clinical trial on P. vivax treatment that was conducted after the initiation of the current study indicated that PQ efficacy in clearing P. vivax hypnozoites is influenced by genetic polymorphisms affecting PQ metabolism by cytochrome P450 2D6 (CYP2D6) (Bennett et al., 2013). The relevance of CYP2D6 variants for gametocyte clearance remains to be established; we did not perform genotyping for CYP2D6 which requires larger sample volumes (Dicko et al., 2016) and therefore cannot determine its impact on gametocyte clearance or malaria transmission after PQ. In our study population, PQ was well tolerated with no statistically significant or clinically relevant hemolysis. Treatment-associated hemolysis has been previously observed following a single dose PQ at 0.75mg/kg (Eziefula et al., 2014a; Shekalaghe et al., 2010) and 0.4mg/kg (Eziefula et al., 2014a) and has been associated with G6PD deficiency. In our trial, cdc42 changes were observed in all trial arms with the greatest difference from baseline, −7.5g/dl observed on day 7 in a female in the DHAP arm. However, she recovered completely without clinical symptoms due to anemia. This pattern of marked drop in hemoglobin followed by full recovery is commonly observed also in patients with acute uncomplicated falciparum malaria (Ekvall et al., 2001) and the current study does not show a marked effect of PQ on hemoglobin concentrations post-treatment. It is important to acknowledge that this trial was not designed to look at safety and included only G6PD normal individuals with relatively high hemoglobin concentrations (≥8g/dl). If PQ is considered for inclusion in malaria control programs, safety studies are needed with PQ at doses within the therapeutic range in G6PD deficient individuals. In conclusion, we report that a single course of PQ when given together with DHAP rapidly and significantly reduces gametocytemia. We observed very low levels of post-treatment infectivity to mosquitoes, which did not allow a robust comparison between treatment arms. The low level of infection raises questions about the added value of PQ in preventing transmission to mosquitoes 7days post- treatment. Future studies should address the safety of PQ in G6PD-deficient individuals.
Declaration of Interest
Contributors
Role of the Funding Source
Acknowledgments
Introduction Skin losses as results of a number of common diseases and injuries affect over 11 million people worldwide annually (Clark et al., 2007; Peck, 2011). Repairing massive skin deficiencies remains as a major clinical challenge, due to lack of suitable cutaneous tissue. Mechanical stretch is a stimulus that can initiate both in vivo and in vitro cell proliferation and regeneration (Mihic et al., 2014; Li et al., 2013). The clinical application of mechanical stretch, skin expansion, is a reliable reconstructive method for complex wounds. Constant mechanical stretch induced by inflating silicone expander stimulates in vivo skin regeneration (Handschel et al., 2013) that creates additional well-vascularized cutaneous tissue that is well-matched to the color, texture and contour of surrounding skin (Weng et al., 2010; Xie et al., 2013). Often times in large area of tissue reconstruction, more skin is needed for reconstruction than tissue expansion can provide, because skin does not have the growth capacity to be expanded beyond two to three times its original area. Overexpansion results in thin, poorly vascularized tissue, which leads to skin necrosis and reconstructive failure (Huang et al., 2011; Elshahat, 2011). Bone marrow stem cell therapies have showed promise in promoting tissue regeneration, as applications have been reported in wound healing, critical limb ischemia, bone growth and cardiac tissue remodelling (Backly and Cancedda, 2010; Liu et al., 2012). We proposed the hypothesis that the transplantation of stem cells could possibly promote mechanical stretch induced skin regeneration and mitigate traditional limitations of skin expansion. Our recent preclinical findings supported this hypothesis (Yang et al., 2011). Additionally, combining mechanical stretch and stem cell transplantation for skin regeneration may wider the clinical implications for other types of in vivo tissue regeneration.