Novel Cocrystals of Vonoprazan: Machine Learning-Assisted Discovery.

Vonoprazan (VPZ) is the first-in-class potassium-competitive acid blocker (P-CAB), and has many advantages over proton pump inhibitors (PPIs). It is administered as a fumarate salt for the treatment of acid-related diseases, including reflux esophagitis, gastric ulcer, and duodenal ulcer, and for eradication of Helicobacter pylori. To discover novel cocrystals of VPZ, we adopted an artificial neural network (ANN)-based machine learning model as a virtual screening tool that can guide selection of the most promising coformers for VPZ cocrystals. Experimental screening by liquid-assisted grinding (LAG) confirmed that 8 of 19 coformers selected by the ANN model were likely to create new solid forms with VPZ. Structurally similar benzenediols and benzenetriols, i.e., catechol (CAT), resorcinol (RES), hydroquinone (HYQ), and pyrogallol (GAL), were used as coformers to obtain phase pure cocrystals with VPZ by reaction crystallization. We successfully prepared and characterized three novel cocrystals: VPZ-RES, VPZ-CAT, and VPZ-GAL. VPZ-RES had the highest solubility among the novel cocrystals studied here, and was even more soluble than the commercially available fumarate salt of VPZ in solution at pH 6.8. In addition, novel VPZ cocrystals had superior stability in aqueous media than VPZ fumarates, demonstrating their potential for improved pharmaceutical performance.

Promoting health, preserving culture: adapting RARE in the Maasai context of Northern Tanzania.

HIV/AIDS prevention strategies often neglect traditions and cultural practices relevant to the spread of HIV. The role of women in the HIV/AIDS context has typically been relegated to high-risk female groups such as sex workers, or those engaged in transactional sex for survival. Consequently, these perceptions are born out in the escalation of HIV/AIDS among communities, and female populations in particular where prevention frameworks remain culturally intolerant. We have attempted to address these issues by using an adapted Rapid Assessment Response and Evaluation (RARE) model to examine the impact of HIV/AIDS in the Maasai community of Ngorongoro. Our adapted RARE model used community engagement venues such as stockholder workshops, key informant interviews, and focus groups. Direct observations and geomapping were also done. Throughout our analysis, a gender and a pastoralist-centered approach provided methodological guidance, and served as value added contributions to out adaptation. Based in the unique context of a rural pastoralist community, we made recommendations appropriate to the cultural setting and the RARE considerations.

Descriptive study of the occupational outcome of bipolar patients.

INTRODUCTION: The purpose of this study was to describe the occupational outcome of bipolar patients 3 years after being hospitalized in a psychiatry department, and the determinants of this outcome. METHODS: One hundred and one bipolar patients consecutively hospitalized between 1st January 2002 and 31st December 2003, were recruited. Their occupations and medical items were assessed at baseline from the medical records and reassessed 3 years later, using a questionnaire on their work and treatment, and a quality of life scale. Occupational outcome was compared by univariate and multivariate analyses. RESULTS: Of the 101 patients initially recruited, 36 were excluded and 34 were lost to follow-up. Among the 31 bipolar patients included in the study, 58.1% were working in 2003 and 54.8% were working in 2006. The presence of a personality disorder was significantly associated with a poorer occupational outcome and a lower rate of "return to work". CONCLUSION: More than half of a population of hospitalized bipolar patients was employed. The presence of a personality disorder appeared to be a pejorative factor for "return to work", although other studies are needed to define the factors that determine the occupational outcome of bipolar patients.

Kinematic variables and water transport control the formation and location of arc volcanoes.

The processes that give rise to arc magmas at convergent plate margins have long been a subject of scientific research and debate. A consensus has developed that the mantle wedge overlying the subducting slab and fluids and/or melts from the subducting slab itself are involved in the melting process. However, the role of kinematic variables such as slab dip and convergence rate in the formation of arc magmas is still unclear. The depth to the top of the subducting slab beneath volcanic arcs, usually approximately 110 +/- 20 km, was previously thought to be constant among arcs. Recent studies revealed that the depth of intermediate-depth earthquakes underneath volcanic arcs, presumably marking the slab-wedge interface, varies systematically between approximately 60 and 173 km and correlates with slab dip and convergence rate. Water-rich magmas (over 4-6 wt% H(2)O) are found in subduction zones with very different subduction parameters, including those with a shallow-dipping slab (north Japan), or steeply dipping slab (Marianas). Here we propose a simple model to address how kinematic parameters of plate subduction relate to the location of mantle melting at subduction zones. We demonstrate that the location of arc volcanoes is controlled by a combination of conditions: melting in the wedge is induced at the overlap of regions in the wedge that are hotter than the melting curve (solidus) of vapour-saturated peridotite and regions where hydrous minerals both in the wedge and in the subducting slab break down. These two limits for melt generation, when combined with the kinematic parameters of slab dip and convergence rate, provide independent constraints on the thermal structure of the wedge and accurately predict the location of mantle wedge melting and the position of arc volcanoes.