Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma

_Background_ This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). _Methods_ In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-dailyAMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and dedifferentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. _Results_ AMG 232 had acceptable safety up to up to 240 mg

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Factors influencing adults to drop out of intensive lifestyle interventions for weight loss

Reducing ≥5% of body weight can decrease the risk of developing chronic diseases in adults with excess weight. Although Intensive Lifestyle Interventions (ILIs) that include cognitive-behavioral techniques to improve physical activity and eating habits are the best approach for losing weight, the failure to retain participants is a barrier to their successful implementation. We aimed to investigate the factors influencing adults to drop out of ILIs for weight loss at six months. We conducted retrospective multiple logistic regression analysis of 268 participants with excess weight (body mass index ≥ 25 kg/m2) from a multicenter study (n = 237, in-person ILI in five clinics, delivered by nutrition interns), and a randomized controlled trial (n = 31, one online ILI, delivered by a master's degree student). The same research team conducted both studies in Northern Mexico, using the same intervention components, and identical instruments and techniques to collect the data. We found that older participants (≥50 years) were less likely to drop out of the ILI for weight loss compared to participants <35 years old (OR = 0.34, 95% CI = 0.16-0.70). For each unit increase in the bodily pain scale of the SF-36 (less perceived pain), the risk of dropping out decreased by 2% (OR = 0.98, 95% CI = 0.97, 0.996), while a change in the interventionist during the 6-month intervention more than doubled the risk of dropping out (OR 2.25, 95% CI = 1.23-4.14). Retention in ILIs may be improved by ensuring that the same interventionist remains during the six-month intervention. In addition, ILIs may need further tailoring for younger ages and for participants with higher perceived pain. © The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.; Weight loss is hard. The best way to do it is to enroll in an intervention that includes frequent sessions with a health coach who uses cognitive-behavioral techniques to help participants improve their eating and physical activity habits. Retaining participants in these types of intervention is a challenge for health practitioners and researchers. Our objective was to identify the factors that increase the participants’ risk of dropping out of the intervention. We analyzed the data of 268 Mexican adults who participated in studies that evaluated intensive lifestyle interventions for weight loss. We found that participants who are younger, experience more pain, and whose health coaches are replaced before the intervention is completed have a higher risk of dropping out of the intervention. By accounting for these factors when designing the intervention, we could increase the chances that participants stay in the intervention until the end. This way they are more likely to be successful in losing weight.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Health promotion to prevent obesity

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