Trial of SAGE-217 in Patients with Major Depressive Disorder

BACKGROUND: Altered neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (+/-SE) change in the HAM-D score from baseline to day 15 was -17.4+/-1.3 points in the SAGE-217 group and -10.3+/-1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P \u3c 0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.)

A Review on the Application of Isotopic Techniques to Trace Groundwater Pollution Sources within Developing Countries

Owing to a lack of efficient solid waste management (SWM) systems, groundwater in most developing countries is found to be contaminated and tends to pose significant environmental health risks. This review paper proffers guidelines on the application of isotopic techniques to trace groundwater pollution sources from data spanning from 2010 to 2020 within developing countries. Earlier groundwater studies in those countries were mainly focused on using hydrochemical and geophysical techniques. The limitation of these techniques is that they can only monitor the concentration of pollutants in the water bodies and possible leachate infiltration but cannot determine the specific sources of the pollution. Stable isotopes of δ18O, δ2H and δ13C can confirm leachate migration to water bodies due to methanogenesis. The high tritium in landfill leachates is useful to identify leachate percolation in groundwater. The δ15N technique has been used to distinguish between synthetic and organic nitrogen sources but its application is limited to differentiating between atmospheric vs. inorganic nitrogen sources. The use of a dual isotope of δ15N–NO3− and δ18O–NO3− is beneficial in terms of identifying various sources of nitrogen such as atmospheric and inorganic fertilizers but is yet to be used to differentiate between nitrogen pollution sources from dumpsites, sewage and animal manure. The coupling of the 11B isotope with δ15N–NO3− and δ18O–NO3− and other hydrochemical parameters has proven to be effective in distinguishing between nitrate fertilizer, animal manure, seawater contamination and sewage. Therefore, in areas affected by agricultural activities, landfill leachates, domestic or sewage effluent and seawater intrusion, it is incumbent to couple hydrochemical (Cl−, NO3−, B, DO) and isotope techniques (δ18O, 2H, δ13C, δ18O–NO3−, δ15N–NO3−, δ11B and 3H) to effectively determine pollution sources of groundwater in developing countries. The foregoing review will provide guidelines for studies that may aim to critically distinguish between seawater intrusion, dumpsites, sewage and septic leachates

A Review on the Application of Isotopic Techniques to Trace Groundwater Pollution Sources within Developing Countries

Owing to a lack of efficient solid waste management (SWM) systems, groundwater in most developing countries is found to be contaminated and tends to pose significant environmental health risks. This review paper proffers guidelines on the application of isotopic techniques to trace groundwater pollution sources from data spanning from 2010 to 2020 within developing countries. Earlier groundwater studies in those countries were mainly focused on using hydrochemical and geophysical techniques. The limitation of these techniques is that they can only monitor the concentration of pollutants in the water bodies and possible leachate infiltration but cannot determine the specific sources of the pollution. Stable isotopes of δ18O, δ2H and δ13C can confirm leachate migration to water bodies due to methanogenesis. The high tritium in landfill leachates is useful to identify leachate percolation in groundwater. The δ15N technique has been used to distinguish between synthetic and organic nitrogen sources but its application is limited to differentiating between atmospheric vs. inorganic nitrogen sources. The use of a dual isotope of δ15N–NO3− and δ18O–NO3− is beneficial in terms of identifying various sources of nitrogen such as atmospheric and inorganic fertilizers but is yet to be used to differentiate between nitrogen pollution sources from dumpsites, sewage and animal manure. The coupling of the 11B isotope with δ15N–NO3− and δ18O–NO3− and other hydrochemical parameters has proven to be effective in distinguishing between nitrate fertilizer, animal manure, seawater contamination and sewage. Therefore, in areas affected by agricultural activities, landfill leachates, domestic or sewage effluent and seawater intrusion, it is incumbent to couple hydrochemical (Cl−, NO3−, B, DO) and isotope techniques (δ18O, 2H, δ13C, δ18O–NO3−, δ15N–NO3−, δ11B and 3H) to effectively determine pollution sources of groundwater in developing countries. The foregoing review will provide guidelines for studies that may aim to critically distinguish between seawater intrusion, dumpsites, sewage and septic leachates

Seasonal assessment of heavy metal contamination of groundwater in two major dumpsites in Sierra Leone

AbstractConsumption of water contaminated with heavy metals has serious health consequences and these include hypertension, kidney disease, cancer, anaemia, brain damage, etc. However, groundwater pollution with heavy metals may occur naturally or anthropogenically as a result of water-rock interaction, dumpsite leachate, agricultural activities, or sewage percolation. Therefore, the apportionment of the specific sources of heavy metals to groundwater is vital to prevent and control its pollution to groundwater. The present work assessed thirty-four (34) groundwater samples from the vicinity of the Granvillebrook and Kingtom dumpsites, Freetown, Sierra Leone. The objective of the research was achieved by integrating geospatial, indexical, and multivariate statistical methods. The results showed that heavy metals such as Cu, Cr, Fe, and Mn exceeded the permissible levels in the majority of the groundwaters. As and Pb were below the detection level of the instrument in all the groundwaters analyzed. Seasonal variations revealed that the concentration of heavy metals is relatively higher in the dry season due to the effect of dilution. The heavy metal evaluation index and degree of contamination analyses respectively showed that 16.7 and 41.6% of the groundwaters in the Granvillebrook dumpsite are highly polluted by heavy metals. All the groundwater samples in the Kingtom dumpsites except well KW17 are unaffected by heavy metals. The principal component analysis showed that fuel combustion, brake abrasion, and discharge of municipal and industrial waste from the dumpsites are some of the anthropogenic sources that impact groundwater pollution in the study areas. The findings of this research revealed the urgent need to develop strategies to control and mitigate the occurrences of heavy metals and thus serve as a base for future research in the study areas

Public health-relevant consequences of the COVID-19 pandemic on malaria in sub-Saharan Africa: a scoping review.

Heuschen A-K, Lu G, Razum O, et al. Public health-relevant consequences of the COVID-19 pandemic on malaria in sub-Saharan Africa: a scoping review. Malaria journal. 2021;20(1): 339.BACKGROUND: The COVID-19 pandemic has resulted in unprecedented challenges to health systems worldwide, including the control of non-COVID-19 diseases. Malaria cases and deaths may increase due to the direct and indirect effects of the pandemic in malaria-endemic countries, particularly in sub-Saharan Africa (SSA). This scoping review aims to summarize information on public health-relevant effects of the COVID-19 pandemic on the malaria situation in SSA.; METHODS: Review of publications and manuscripts on preprint servers, in peer-reviewed journals and in grey literature documents from 1 December, 2019 to 9 June, 2021. A structured search was conducted on different databases using predefined eligibility criteria for the selection of articles.; RESULTS: A total of 51 papers have been included in the analysis. Modelling papers have predicted a significant increase in malaria cases and malaria deaths in SSA due to the effects of the COVID-19 pandemic. Many papers provided potential explanations for expected COVID-19 effects on the malaria burden; these ranged from relevant diagnostical and clinical aspects to reduced access to health care services, impaired availability of curative and preventive commodities and medications, and effects on malaria prevention campaigns. Compared to previous years, fewer country reports provided data on the actual number of malaria cases and deaths in 2020, with mixed results. While highly endemic countries reported evidence of decreased malaria cases in health facilities, low endemic countries reported overall higher numbers of malaria cases and deaths in 2020.; CONCLUSIONS: The findings from this review provide evidence for a significant but diverse impact of the COVID-19 pandemic on malaria in SSA. There is the need to further investigate the public health consequences of the COVID-19 pandemic on the malaria burden. Protocol registered on Open Science Framework: https://doi.org/10.17605/OSF.IO/STQ9D. © 2021. The Author(s)

Dalzanemdor (SAGE‐718), a novel, investigational N‐methyl‐D‐aspartate receptor positive allosteric modulator: Safety, tolerability, and clinical pharmacology in randomized dose‐finding studies in healthy participants and an open‐label study in participants with Huntington's disease

Abstract N‐methyl‐D‐aspartate receptor (NMDAR)‐positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE‐718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first‐in‐human, phase I, double‐blind, dose‐finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single‐ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple‐ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open‐label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once‐daily dosing. Following single and multiple doses in healthy participants, median terminal half‐life was 8–118 h, and the median time to reach maximum plasma concentration was 4–7 h. Exposures were dose‐proportional after single dose (6–46 ng/mL) and more than dose‐proportional after multiple doses (6–41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction

Development of a set of community-informed Ebola messages for Sierra Leone

The West African Ebola epidemic of 2013-2016 was by far the largest outbreak of the disease on record. Sierra Leone suffered nearly half of the 28,646 reported cases. This paper presents a set of culturally contextualized Ebola messages that are based on the findings of qualitative interviews and focus group discussions conducted in 'hotspot' areas of rural Bombali District and urban Freetown in Sierra Leone, between January and March 2015. An iterative approach was taken in the message development process, whereby (i) data from formative research was subjected to thematic analysis to identify areas of community concern about Ebola and the national response; (ii) draft messages to address these concerns were produced; (iii) the messages were field tested; (iv) the messages were refined; and (v) a final set of messages on 14 topics was disseminated to relevant national and international stakeholders. Each message included details of its rationale, audience, dissemination channels, messengers, and associated operational issues that need to be taken into account. While developing the 14 messages, a set of recommendations emerged that could be adopted in future public health emergencies. These included the importance of embedding systematic, iterative qualitative research fully into the message development process; communication of the subsequent messages through a two-way dialogue with communities, using trusted messengers, and not only through a one-way, top-down communication process; provision of good, parallel operational services; and engagement with senior policy makers and managers as well as people in key operational positions to ensure national ownership of the messages, and to maximize the chance of their being utilised. The methodological approach that we used to develop our messages along with our suggested recommendations constitute a set of tools that could be incorporated into international and national public health emergency preparedness and response plans