Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

Factors Associated with Work Participation and Work Functioning in Depressed Workers: A Systematic Review

Background Depression is associated with negative work outcomes such as reduced work participation (WP) (e.g., sick leave duration, work status) and work functioning (WF) (e.g., loss of productivity, work limitations). For the development of evidence-based interventions to improve these work outcomes, factors predicting WP and WF have to be identified. Methods This paper presents a systematic literature review of studies identifying factors associated with WP and WF of currently depressed workers. Results A total of 30 studies were found that addressed factors associated with WP (N = 19) or WF (N = 11). For both outcomes, studies reported most often on the relationship with disorder-related factors, whereas personal factors and work-related factors were less frequently addressed. For WP, the following relationships were supported: strong evidence was found for the association between a long duration of the depressive episode and work disability. Moderate evidence was found for the associations between more severe types of depressive disorder, presence of co-morbid mental or physical disorders, older age, a history of previous sick leave, and work disability. For WF, severe depressive symptoms were associated with work limitations, and clinical improvement was related to work productivity (moderate evidence). Due to the cross-sectional nature of about half of the studies, only few true prospective associations could be identified. Conclusion Our study identifies gaps in knowledge regarding factors predictive of WP and WF in depressed workers and can be used for the design of future research and evidence-based interventions. We recommend undertaking more longitudinal studies to identify modifiable factors predictive of WP and WF, especially work-related and personal factors

Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.

Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a \u3e 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

Different work capacity impairments in patients with different work-anxieties

Purpose: Persons with work-anxieties are especially endangered for work-impairment and sick-leave. Work-impairment is not directly due to symptoms but due to illness-related capacity impairments. Work capacity impairments can be described on different dimensions (e.g. social interaction, decision making and judgment, endurance, mobility). Understanding the type of work capacity impairment is important for reintegration interventions This is the first study to investigate work capacity impairment in risk-patients with different work-anxieties. Methods: Two hundred forty four patients in inpatient rehabilitation suffering from work-anxieties were investigated concerning degree of work capacity impairment. Capacity impairment was described on 13 capacity dimensions according to the internationally evaluated observer-rating Mini-ICF-APP (impairment grades 0-4, grade 2 and higher indicating clinically relevant observable impairment). A physician´s rating on global work ability prognosis was obtained, and sick-leave duration during six months after assessment. Patients with different work-anxieties were compared concerning capacity impairments. Results: Patients with different work-anxieties were impaired in different capacity dimensions: work-related social anxiety went along with clinically relevant impairment in capacity of assertiveness (M=2.40), anxiety of insufficiency went along with impaired capacity of endurance (M=2.20), work-related generalized worrying was accompanied by impairment in the capacity for decision making (M=1.82). Specific capacity impairment dimensions were related with sick-leave duration, while a global work ability prognosis was not. Conclusions: The capacity approach is useful to describe work-impairment more precisely and beyond symptoms. On this basis reintegration-focusing interventions such as capacity training (e.g. social interaction training) or work adjustment (e.g. reducing exposure with interactional work tasks) can be initiated

Arbeidsmarktonderzoek woningcorporaties 2016

Arbeidsmarktonderzoek: corporaties signaleren personele mismatch. Door meer en complexer werk ontstaat een toenemende mismatch tussen vraag naar en aanbod van arbeid bij corporaties. Werkgevers en werknemers nemen het signaal serieus. Dat blijkt uit het Arbeidsmarktonderzoek Woningcorporaties 2016, verricht in opdracht van FLOW. Werkgevers hebben meer moeite kwalitatief goed personeel te vinden en zijn wat minder tevreden over inzetbaarheid, opleidingsniveau, kwalificaties en werkervaring. Het onderzoek laat echter ook zien dat werknemers vaker extra scholing volgen en zeggen daar in hun werk profijt van te hebben. Zij lijken daarmee hun verantwoordelijkheid te voelen en die ook te nemen, aldus de onderzoekers. Het stimuleren van dergelijke initiatieven en het hierin begeleiden van medewerkers, komt de ontwikkeling van werknemers ten goede en beperkt daarmee de mogelijke mismatch