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 > 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

Spirituality as a Predictor of Well-Being, Mental Distress or Both:A Four-Week Follow-Up Study in a Sample of Dutch and Belgian Adults

In general, studies of spirituality show positive associations with measures of well-being, but less is known about the possible role of mental distress in this association. Following the two-continua model of mental health, the current quantitative four-week follow-up study examines how spirituality is associated with well-being and mental distress. Spirituality is measured using the Spirituality Attitude and Interest List questionnaire (SAIL), well-being by the Dutch Mental Health Continuum-Short Form (MHCSF-SF), and mental distress by the Symptom Questionnaire (SQ-48). At baseline, 874 adults from the Netherlands and Belgium completed the online questionnaire; four weeks later, 560 participants completed the follow-up questionnaire. Multiple regression analyses showed that spirituality at baseline, and in particular the subscale on ‘meaning in life,’ predicted higher well-being scores at follow-up after adjustment for baseline well-being scores. Spirituality also predicted changes in mental distress scores, in particular on the subscales of trust and transcendent experience. However, these associations were in opposite directions. Trust was associated with a small decrease in mental distress over time and transcendent experience was associated with a small increase in mental distress over time. The results confirm the importance of meaning in life, trust, and transcendent experience as elements of mental health

Re-integratie van zieke werknemers : feiten, verklaringen mogelijkheden

In juli 2006 publiceerde de Raad voor Werk en Inkomen de Re-integratiemarktanalyse 2006: 'de route naar resultaat'. In het rapport zijn een aantal witte vlekken in de kennis over de re-integratiemarkt benoemd, onder meer de re-integratie van "zieke werknemers wier terugkeer in de eigen functie problematisch is. Ten behoeve van verder onderzoek hiernaar heeft de Raad een aantal ontwikkelingen in de aanpak van re-integratie vertaald naar 6 thema's/vragen die in de onderhavige studie achtereenvolgens beantwoord worden. Het onderzoek geeft zicht op de mogelijkheden van partijen om re-integratie vorm te geven, op de aansluiting van vraag en aanbod in de re-integratiemarkt en op de knelpunten waar werkgevers en werknemers tegen aan lopen. De bevindingen maken duidelijk dat alle werkgevers, ongeacht omvang of sector, in staat zijn om samen met de zieke werknemer re-integratieactiviteiten te ontplooien, het zij in eigen beheer, het zij door het uit te besteden of samen te werken. Bijna tweederde van de langdurig zieken uit de onderzoekspopulatie heeft gedeeltelijk of volledig het werk hervat, het merendeel in de eigen functie. Het is aanzienlijk lastiger als de werknemer niet terug kan in de eigen functie, zelfs niet met bepaalde werkaanpassingen. Belemmerende factoren zitten dan veel meer in de complexiteit van het re-integratievraagstuk: bij onduidelijkheid over het herstel en de beschikbaarheid van passend werk, al dan niet gecombineerd met conflicten en/of disfunctioneren