A comparison of the activity, lysosomal stability, and efficacy of legumain-cleavable and cathepsin cleavable ADC linkers.

1. Over the past two decades antibody-drug conjugates (ADCs) have emerged as a highly effective drug delivery technology. ADCs utilize a monoclonal antibody, a chemical linker, and a therapeutic payload to selectively deliver highly potent pharmaceutical agents to specific cell types.2. Challenges such as premature linker cleavage and clearance due to linker hydrophobicity have adversely impacted the stability and safety of ADCs. While there are various solutions to these challenges, our team has focused on replacement of hydrophobic ValCit linkers (cleaved by CatB) with Asn-containing linkers that are cleaved by lysosomal legumain.3. Legumain is abundantly present in lysosomes and is known to play a role in tumor microenvironment dynamics. Herein, we directly compare the lysosomal cleavage, cytotoxicity, plasma stability, and efficacy of a traditional cathepsin cleavable ADC to a matched Asn-containing legumain-cleavable ADC.4. We demonstrate that Asn-containing linker sequences are specifically cleaved by lysosomal legumain and that Asn-linked MMAE ADCs are broadly active against a variety of tumors, even those with low legumain expression. Finally, we show that AsnAsn-linked ADCs exhibit comparable or improved efficacy to traditional ValCit-linked ADCs. Our study paves the way for replacement of the traditional ValCit linker technology with more hydrophilic Asn-containing peptide linker sequences.

Assessing Engagement of Adolescents and Young Adults (AYA) in HIV Research: A Multi-method Analysis of a Crowdsourcing Open Call and Typology of AYA Engagement in Sub-Saharan Africa.

Engagement of adolescents and young adults (AYA) in HIV research is increasing in many settings. We organized a crowdsourcing open call to solicit examples of how AYA have been engaged in HIV research in Africa and to develop an engagement typology. We formed a steering committee, promoted the open call, organized judging and recognized finalists. We used a multi-methods approach to identify emerging themes and measure engagement. We received 95 entries from individuals in 15 countries; 74 met the eligibility criteria. More than three-quarters of entries were from AYA (55/74, 74%). Four themes characterized AYA engagement: (1) AYA were co-creators in the HIV research process. (2) AYA were involved in community-level capacity building. (3) AYA were co-leaders in minor risk research. (4) AYA used digital methods to enhance engagement. Our open call identified diverse methods of AYA engagement, which can enhance strategies used to reach AYA in African HIV studies.

Physical restraint in older people: a statement from the Early Career Network of the International Psychogeriatric Association.

The International Psychogeriatric Association (IPA) has expressed significant concerns over the use of physical restraints in older people across diverse aged care settings. Following an extensive analysis of the available literature, the IPA's Early Career Network (ECN) has formulated a collection of evidence-based recommendations aimed at guiding the use of physical restraints within various care contexts and demographic groups. Physical restraints not only infringe upon human rights but also raise significant safety concerns that adversely impact the physical, psychological, social, and functional well-being of older adults. Furthermore, their effectiveness in geriatric settings remains inadequate. Given these considerations, the IPA and its ECN firmly assert that the use of physical restraints should only be considered as a final recourse in the care of older people.

Population Abundance and Density Estimates of Poorly Documented Near-Threatened Calabar Angwantibo (Arctocebus calabarensis) in Oban Hills Region.

Population abundance and density estimates play important roles in biodiversity conservation assessment and can lead to prioritization of conservation efforts, strategies, and management. The Calabar angwantibo (Arctocebus calabarensis) is a poorly studied, Near-Threatened nocturnal, arboreal mammal species occurring only in the lowland moist tropical rainforest blocks of southeastern Nigeria and southwestern Cameroon. Like other arboreal nocturnal mammals, there are gaps in knowledge of the distribution and abundance of this species, which may be facing population declines due to habitat loss and hunting. In this study, we investigated the abundance and density of A. calabarensis in the Oban Hills Region of Nigeria. We conducted systematic distance sampling survey along 32 transects in different habitats in a 1227 km of survey efforts. A total of 41 sightings of A. calabarensis were detected, resulting in an abundance of 7345 individuals (95% CI = 1.51-4.37) with an estimated density of 2.57 animals/km2. The estimated population abundance is 6515 individuals in closed-canopy forests and 830 individuals in secondary forests, with encounter rates of 0.52 individual/km2 and 0.60 individuals/km2 in the closed canopy and secondary forest habitats. The global estimates encounter rate of A. calabarensis across the habitat types is 0.33 individuals/km2 and population abundance of 4456 individuals. Our findings indicate that the A. calabarensis populations can adapt to low changes in forest habitat modifications resulting from increasing and widespread forest disturbance by human-dominated activity, which is giving way to forest clearance for agriculture cultivation and infrastructural development. Our findings help to fill a knowledge gap regarding this species and may help establish a baseline for future management, population monitoring, and conservation of the cryptic population of A. calabarensis in Cross-Sanaga Forests.

Crowdsourcing to support training for public health: A scoping review.

Crowdsourcing is an interactive process that has a group of individuals attempt to solve all or part of a problem and then share solutions with the public. Crowdsourcing is increasingly used to enhance training through developing learning materials and promoting mentorship. This scoping review aims to assess the literature on crowdsourcing for training in public health. We searched five medical and public health research databases using terms related to crowdsourcing and training. For this review, the concept of crowdsourcing included open calls, designathons, and other activities. We used a PRISMA checklist for scoping reviews. Each full-text was assessed by two independent reviewers. We identified 4,071 citations, and 74 studies were included in the scoping review. This included one study in a low-income country, 15 studies in middle-income countries, 35 studies in high-income countries, and 11 studies conducted in multiple countries of varying income levels (the country income level for 12 studies could not be ascertained). Nine studies used open calls, 35 used a hackathon, designathon or other "a-thon" event, and 30 used other crowdsourcing methods, such as citizen science programs and online creation platforms. In terms of crowdsourcing purpose, studies used crowdsourcing to educate participants (20 studies), develop learning materials (17 studies), enhance mentorship (13 studies) and identify trainees (9 studies). Fifteen studies used crowdsourcing for more than one training purpose. Thirty-four studies were done in-person, 31 were conducted virtually and nine used both meeting options for their crowdsourcing events. Seventeen studies generated open access materials. Our review found that crowdsourcing has been increasingly used to support public health training. This participatory approach can be a useful tool for training in a variety of settings and populations. Future research should investigate the impact of crowdsourcing on training outcomes.

Tracking adaptation strategies of an HIV prevention intervention among youth in Nigeria: a theoretically informed case study analysis of the 4 Youth by Youth Project.

BACKGROUND: Although many behavioral interventions are adapted, little is known about the reasons for adaptations and the process and outcomes influencing adaptations. To address this gap, we explored the adaptations made to promote HIV prevention services, including HIV self-testing (HIVST), among Nigerian youth. METHODS: The main objective of this qualitative case study design was to document the adaptations made over time using the Framework for Reporting Adaptations and Modifications - Expanded (FRAME). Between 2018 and 2020, we organized four participatory activities as part of the 4 Youth by Youth project to increase the uptake of HIVST services in Nigeria-an open call, a designathon, a capacity-building bootcamp and a pilot feasibility trial. We also began the process of implementing a final intervention using a pragmatic randomized control trial (RCT). The open call solicited creative strategies to promote HIVST among Nigerian youth and then had experts evaluate them. The designathon brought together youth teams to further develop their HIVST service strategies into implementation protocols. Teams determined to be exceptional were invited to a four-week capacity-building bootcamp. The five teams that emerged from the bootcamp were supported to pilot their HIVST service strategies over a 6-month period. The adapted intervention is currently being evaluated in a pragmatic RCT. We transcribed meeting reports and conducted document reviews of study protocols and training manuals. RESULTS: Sixteen adaptations were identified and categorized into three domains: (1) modifications to the content of the intervention (i.e. photo verification system and/or Unstructured Supplementary Service Data (USSD) system to verify HIVST); (2) modifications to the delivery the intervention (i.e. implement participatory learning community sessions to provide supportive supervision and technical support); (3) modifications to the evaluation processes (i.e. economic evaluation to estimate the cost of implementing intervention on a larger scale). Frequent reasons for adaptation included increasing intervention reach, modifying interventions to enhance their appropriateness and fit with the recipient, and increasing the intervention's feasibility and acceptability. Most adaptations were planned and reactive, and the need for modifications was determined by the youths, 4YBY program staff, and advisory group. CONCLUSIONS: Findings suggest that the nature of adaptations made throughout the implementation process reflects the necessity of evaluating services in context while adjusting to specific challenges as they are identified. Further research is needed to understand the effect of these adaptations on the overall intervention effect as well as the quality of youth engagement.