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To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound MMV1557817 is a selective, nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. MMV1557817 can kill sexual-stage P. falciparum , is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials. MMV1557817 -resistant P. falciparum exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these results confirm MMV1557817 as a lead compound for further drug development and highlights the potential of dual inhibition of M1 and M17 as an effective multi-species drug-targeting strategy.IMPORTANCEEach year, malaria infects approximately 240 million people and causes over 600,000 deaths, mostly in children under 5 years of age. For the past decade, artemisinin-based combination therapies have been recommended by the World Health Organization as the standard malaria treatment worldwide. Their widespread use has led to the development of artemisinin resistance in the form of delayed parasite clearance, alongside the rise of partner drug resistance. There is an urgent need to develop and deploy new antimalarial agents with novel targets and mechanisms of action. Here, we report a new and potent antimalarial compound, known as MMV1557817 , and show that it targets multiple stages of the malaria parasite lifecycle, is active in a preliminary mouse malaria model, and has a novel mechanism of action. Excitingly, resistance to MMV15578117 appears to be self-limiting, suggesting that development of the compound may provide a new class of antimalarial., Competing Interests: The authors declare no conflict of interest.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of Plasmodium M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant Plasmodium falciparum ( Pf A-M1) and Plasmodium vivax ( Pv A-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets Pf A-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on Pf A-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of Pf A-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.

Online apparel shopping is popular amongst women and offers salient visual information for making body image and self-worth judgements. Apparel segments which emphasize the value of women's bodies are particularly effective for eliciting low body image and self-worth. Across two studies, we investigated the association between self-reported and experimental online activewear exposure on women's self-worth, body image, appearance attitudes, mood and gaze behavior. In Study 1, participants (N = 399) completed a survey collecting their online apparel shopping habits, body appreciation, self-esteem, appearance comparison tendencies and self-objectification attitudes. Activewear was the second-most popular apparel segment amongst women (after casualwear) and weekly activewear browse time was positively correlated with appearance comparison tendencies, desires to be muscular/athletic and body shame. In Study 2, participants (N = 126) were randomly allocated to browse an activewear, casualwear or homewares website and completed pre and post measures of mood, body image, implicit self-esteem and body gaze behavior. In the activewear condition, there was a significant reduction in positive body image and implicit self-esteem scores. There were no experimental effects for body gaze behavior. These findings illustrate that apparel choices have value for understanding the aetiology of maladaptive body image attitudes and low self-esteem in women., Competing Interests: Declaration of Competing Interest The authors declare that this research was conducted in the absence of any conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To identify the incidence and mechanisms of concussion in elite Field Hockey in different age groups and also the postconcussion symptoms and recovery times., Methods: Data was collected retrospectively, for both training and matches, over a 12-month period from national level Field Hockey players across under-16, under-18, under-21, Development and Senior players. Mechanism of injury (including player role and field position), postconcussive symptoms and recovery times were recorded following a semistructured interview with each player. Additional information on training hours, matches and squad size were also recorded in order to calculate the incidence per 1000 match hours., Results: Of the 28 recorded cases, only 11 could be included in the study. Women had the highest incidence of concussion, with the majority being in the under-21 age group. Overall incidence varied from 3/1000 match hours in training to 0.02/1000 match hours in matches, with an overall incidence of 0-0.02/1000 match hours across all age groups. The most common mechanism of injury was collision with another player, followed by impact from a stick or ball Midfield and attacking forwards sustained the highest incidence of concussion. None of the concussed athletes wore protective headgear (there were no cases of concussion in goal keepers) and all occurred in open play rather than a penalty corner (when protective headgear is often worn). Postconcussion headaches and difficulty concentrating were the most commonly reported postconcussion symptoms. Average recovery time and return-to-play was 2-4 weeks., Conclusions: Due to the low numbers, only limited conclusions can be made, but it would appear that the risk of concussion in elite Field Hockey is low. As age and skill increases, the risk decreases. Postconcussion symptoms and average return-to-play times are similar to other sports. From this study, no conclusions can be made as to the role of protective headgear to reduce the risk of concussion., Competing Interests: Competing interests: None declared.

Methysergide is a serotonin antagonist and is used as a long-term prophylactic treatment for migraine. Although many patients experience adequate control of migraine episodes, methysergide has been reported to cause retroperitoneal and pleuropulmonary fibrosis. Cardiovascular side effects mainly in the form of valvular fibrosis have been less recognized. We report 2 cases of methysergide-related mitral valve fibrosis.

The New Doctor highlights aspects of educational supervision for preregistration house officers that may serve as a lesson for improving the educational experience of all doctors in training. On the basis of research carried out in mid-Trent, this article highlights some of the issues relating to the training of educational supervisors and how these need to be put into context if further advances in education and training are to take place.

Most flexible trainees believe that their full-time colleagues perceive flexible training as flawed in some way. However, most consultants and full-time trainees actually view flexible trainees and their posts in a positive light.