Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma.

MDM2-p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified "Delivery - Potency - Efficacy" relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2-p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine "active" unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2-p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood-brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly "poor" BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.

Evaluation of conditional cash transfers and mHealth audio messaging in reduction of risk factors for childhood malnutrition in internally displaced persons camps in Somalia: A 2 × 2 factorial cluster-randomised controlled trial.

BACKGROUND: Cash transfer programmes are increasingly used in humanitarian contexts to help address people's needs across multiple sectors. However, their impact on the key objectives of reducing malnutrition and excess mortality remains unclear. mHealth interventions show great promise in many areas of public health, but evidence for their impact on reducing the risk factors for malnutrition is uncertain. We therefore implemented a trial to determine the impacts of 2 interventions in a protracted humanitarian context, a cash transfer conditionality and mHealth audio messages. METHODS AND FINDINGS: A 2 × 2 factorial cluster-randomised trial was implemented in camps for internally displaced people (IDP) near Mogadishu, Somalia, starting in January 2019. The main study outcomes were assessed at midline and endline and included coverage of measles vaccination and the pentavalent immunisation series, timely vaccination, caregiver's health knowledge, and child diet diversity. Twenty-three clusters (camps) were randomised to receive or not receive conditional cash transfers (CCTs) and an mHealth intervention, and 1,430 households were followed up over 9 months. All camps received cash transfers made at emergency humanitarian level (US$70/household/month) for 3 months followed by a further 6 months at a safety net level (US$35). To be eligible to receive cash, households in camps receiving CCT were required to take their children <5 years age to attend a single health screening at a local clinic and were issued with a home-based child health record card. Participants in camps receiving the mHealth intervention were asked (but not required) to listen to a series of audio messages about health and nutrition that were broadcast to their mobile phone twice a week for 9 months. Participants and investigators were not blinded. Adherence to both interventions was monitored monthly and found to be high (>85%). We conducted intention-to-treat analysis. During the humanitarian intervention phase, the CCT improved coverage of measles vaccination (MCV1) from 39.2% to 77.5% (aOR 11.7, 95% CI [5.2, 26.1]; p < 0.001) and completion of the pentavalent series from 44.2% to 77.5% (aOR 8.9, 95% CI [2.6, 29.8]; p = < 0.001). By the end of the safety net phase, coverage remained elevated from baseline at 82.2% and 86.8%, respectively (aOR 28.2, 95% CI [13.9, 57.0]; p < 0.001 and aOR 33.8, 95% CI [11.0, 103.4]; p < 0.001). However, adherence to timely vaccination did not improve. There was no change in the incidence of mortality, acute malnutrition, diarrhoea, or measles infection over the 9 months of follow-up. Although there was no evidence that mHealth increased Mother's knowledge score (aOR 1.32, 95% CI [0.25, 7.11]; p = 0.746) household dietary diversity increased from a mean of 7.0 to 9.4 (aOR 3.75, 95% CI [2.04, 6.88]; p < 0.001). However, this was not reflected by a significant increase in child diet diversity score, which changed from 3.19 to 3.63 (aOR 2.1, 95% CI [1.0, 4.6]; p = 0.05). The intervention did not improve measles vaccination, pentavalent series completion, or timely vaccination, and there was no change in the incidence of acute malnutrition, diarrhoea, measles infection, exclusive breastfeeding, or child mortality. No significant interactions between the interventions were found. Study limitations included the limited time available to develop and test the mHealth audio messages and the necessity to conduct multiple statistical tests due to the complexity of the study design. CONCLUSIONS: A carefully designed conditionality can help achieve important public health benefits in humanitarian cash transfer programmes by substantially increasing the uptake of child vaccination services and, potentially, other life-saving interventions. While mHealth audio messages increased household diet diversity, they failed to achieve any reductions in child morbidity, malnutrition, or mortality. TRIAL REGISTRATION: ISRCTN ISRCTN24757827. Registered November 5, 2018.

Effects of a novel consensus bacterial 6-phytase variant on the apparent ileal digestibility of amino acids, total tract phosphorus retention, and tibia ash in young broilers.

The effect of a novel consensus bacterial 6-phytase variant (PhyG) on apparent ileal digestibility (AID) of amino acids (AA) and phosphorus (P) utilization in young broilers when added to diets with high phytate-P (PP) content without added inorganic phosphate (Pi) and deficient in digestible (dig) AA and metabolizable energy (ME) was investigated. A total of 256 Ross 308 male broilers were assigned to 4 treatments (8 birds/cage, 8 cages/treatment) in a completely randomized design. Treatments comprised a positive control (PC, 2,975 kcal/kg ME, 3.7 g/kg dig P, 2.83 g/kg PP, 8.4 g/kg Ca, 10.6 g/kg dig lysine), a negative control (NC) without added Pi (ME -68 kcal/kg, crude protein -10 g/kg, dig AA -0.1 to -0.4 g/kg, Ca -2.0 g/kg, dig P -2.2 g/kg, Na -0.4 g/kg vs. PC), and NC plus 500 or 1,000 FTU/kg of PhyG. Test diets were corn/soy/rapeseed-meal/rice-bran-based and fed from 5 to 15 d of age. Ileal digesta and tibias were collected on day 15. Excreta was collected during days 12 to 15 to determine P retention. The NC (vs. PC) reduced (P < 0.05) P retention (-10.4% units), tibia ash (-14.3% units), weight gain (-109 g), feed intake (-82 g) and increased FCR (from 1.199 to 1.504), confirming that the NC was extremely deficient in nutrients and energy. Phytase addition to the NC linearly (P < 0.001) improved performance, but did not fully recover it to the level of the PC due to the severe nutrients/energy reduction in NC. Phytase linearly increased P retention (P < 0.001), tibia ash (P < 0.001), AID of dry matter (P < 0.05), nitrogen (P < 0.01), gross energy (P < 0.05), and all 17 individual AA (P < 0.01). At 1,000 FTU/kg, phytase increased (P < 0.05) P retention vs. PC and NC (+14.5 and +24.9% units, respectively) and increased tibia ash vs. NC (+13.8% units), equivalent to PC. The NC decreased AID of Cys, Gly, Thr, and Met vs. PC (P < 0.05). At 1,000 FTU/kg, phytase increased AID of all 17 AA vs. NC (P < 0.01), equivalent to PC. At 1,000 FTU/kg, AID AA responses (above NC) ranged from +4.5% (Met) to +15.0% (Cys), being maximal for essential Thr (+10.4%) and Val (+8.2%) and non-essential Cys (+15.0%) and Gly (+10.4%). The results highlight the efficacy of PhyG at a dose level of 500 to 1,000 FTU/kg in young broilers for improving the ileal digestibility of nitrogen, AA, and energy alongside P retention and tibia ash. The performance data emphasize the need to consider digestible nutrient intake as a response variable in exogenous enzyme studies.

Microbial phytase is widely used in commercial broiler diets to improve digestion of phosphorus (P) and reduce its excretion into the environment. Phytase improves the digestion of phosphorus and other nutrients including amino acids (AA). This study evaluated the effect of a novel consensus bacterial 6-phytase variant (PhyG) added to a nutrient-reduced diet without any added inorganic P on the digestibility of nutrients including P and AA in the ileum of young broilers. Effects on P retention and bone mineralization were also assessed. Compared to an unsupplemented negative control diet, PhyG improved growth performance, P retention, bone mineralization (tibia ash), digestibility of dry matter, nitrogen, gross energy, and all 17 individual AA during 5 to 15 d post-hatch, in a dose-dependent manner (dose range 0 to 1,000 phytase units [FTU] per kilogram of feed). For some AA, the increases in digestibility with PhyG at 1,000 FTU/kg were substantial (cysteine: +15.0%, threonine:+10.4%), and for all AA were equivalent to the responses produced by a nutritionally adequate positive control (unsupplemented) diet. The results demonstrate the efficacy of PhyG to improve AA digestibility alongside growth performance, P retention, and bone mineralization in young broilers.

Responding to maternal, neonatal and child health equipment needs in Kenya: a model for an innovation ecosystem leveraging on collaborations and partnerships.

BACKGROUND: Up to 70% of medical devices in low-income and middle-income countries are partially or completely non-functional, impairing service provision and patient outcomes. In Sub-Saharan Africa, medical devices not designed for local conditions, lack of well-trained biomedical engineers and diverse donated equipment have led to poor maintenance and non-repair. The Maker Project's aim was to test the effectiveness of an innovative partnership ecosystem network, the 'Maker Hub', in reducing gaps in the supply of essential medical devices for maternal, newborn and child health. This paper describes the first phase of the project, the building of the Maker Hub. METHODS: Key activities in setting up the Maker Hub-a collaborative partnership between the University of Nairobi (UoN) and the Kenyatta National Hospital (KNH), catalysed by Concern Worldwide Kenya-are described using a product development partnership approach. Using a health systems approach, a needs assessment identified a medical equipment shortlist. Design thinking with a capacity building component was used by the UoN (innovators, public health specialists, engineers) working closely and with KNH nurses, physicians and biomedical engineers to develop the prototypes. RESULTS: To date, four medical device prototypes have been developed. Two have been evaluated by the National Bureau of Standards and one has undergone clinical testing. CONCLUSIONS: We have demonstrated an innovative partnership ecosystem that has developed medical devices that have undergone national standards evaluation and clinical testing, a first in Sub-Saharan Africa. Promoting a robust innovation ecosystem for medical equipment requires investment in building trust in the innovation ecosystem.

Anthropogenic environmental drivers of antimicrobial resistance in wildlife.

The isolation of antimicrobial resistant bacteria (ARB) from wildlife living adjacent to humans has led to the suggestion that such antimicrobial resistance (AMR) is anthropogenically driven by exposure to antimicrobials and ARB. However, ARB have also been detected in wildlife living in areas without interaction with humans. Here, we investigated patterns of resistance in Escherichia coli isolated from 408 wild bird and mammal faecal samples. AMR and multi-drug resistance (MDR) prevalence in wildlife samples differed significantly between a Sewage Treatment Plant (STP; wastes of antibiotic-treated humans) and a Farm site (antibiotic-treated livestock wastes) and Central site (no sources of wastes containing anthropogenic AMR or antimicrobials), but patterns of resistance also varied significantly over time and between mammals and birds. Over 30% of AMR isolates were resistant to colistin, a last-resort antibiotic, but resistance was not due to the mcr-1 gene. ESBL and AmpC activity were common in isolates from mammals. Wildlife were, therefore, harbouring resistance of clinical relevance. AMR E. coli, including MDR, were found in diverse wildlife species, and the patterns and prevalence of resistance were not consistently associated with site and therefore different exposure risks. We conclude that AMR in commensal bacteria of wildlife is not driven simply by anthropogenic factors, and, in practical terms, this may limit the utility of wildlife as sentinels of spatial variation in the transmission of environmental AMR.

Inaugural conference of the International Association of Immunization Managers (IAIM), Istanbul Turkey, 3-4 March 2015.

For more than 35 years, most national immunization programs have established managerial structures and processes for delivering vaccination services to their populations. These days, immunization managers are facing an increasing number of challenges due to the introduction of new vaccines, shifting demographic patterns, complex networks of service providers, and maintaining the gains achieved with previous vaccination efforts. To confront these challenges, better program performance will require better managerial practices, which incorporates new technologies. To that end, the International Association of Immunization Managers (IAIM) is the first global professional association launched to promote superior leadership and management skills among health professionals involved with vaccination efforts worldwide. From 3 to 4 March 2015, approximately 132 members from 70 countries representing six regions, gathered in Istanbul, Turkey for the inaugural conference of IAIM. In the two-day program, members selected thirteen peers to constitute the Governing Council. The 12 articles of the bylaws of the Association were also ratified. This conference was a forum for sharing managerial best practices through networking sessions, breakout sessions, and presentations. Members also learned about IAIM sponsored training opportunities to deepen their managerial competencies through peer-to-peer exchanges and scholarship training programs. We believe that the IAIM inaugural conference was an appropriate platform for equipping managers with tools and professional network of peers to support them in achieving national, regional and global immunization goals, including those of the Global Vaccine Action Plan of the World Health Organization.

Evoking and reducing mental contamination in female perpetrators of an imagined non-consensual kiss.

BACKGROUND AND OBJECTIVES: Mental contamination refers to feelings of internal dirtiness that can arise without physical contact with a contaminant. Previous research has demonstrated that contamination-related feelings and subsequent washing behaviours can be evoked by engaging in an imaginal task involving a non-consensual kiss. We sought to test the efficacy of neutralisation behaviours such as washing on experimentally induced mental contamination. METHODS: The current study used a female undergraduate sample (N = 80) to act as the perpetrator of an imagined non-consensual kiss of a 14-year old boy, to examine whether mental contamination would be evoked, and whether neutralisation would be effective. RESULTS: Mental contamination was successfully evoked in using the imaginal task. None of the neutralisation strategies (physical washing, mental washing, atonement) was more effective than a control group in reducing mental contamination. Groups using physical washing completed the experiment with higher levels of negative emotions than the control group, suggesting specific deleterious impact of this neutralisation behaviour. LIMITATIONS: The use of a non-clinical sample, as well as a uniform mental contamination method (rather than one specifically tailored to each participant) are limitations of the current study. CONCLUSIONS: Mental contamination is not reduced by a range of neutralisation strategies, and physical washing may have further negative effects such as increased negative emotion.