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Abstract Background Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of the racialization process in incident dementia. Methods In the US Health and Retirement Study (n = 6,908), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic white) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates). Results The 6-year cumulative incidence of dementia is 12%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels ( ≥ 75th percentile or 4.73μg/mL) are associated with 1.26 (95%CI: 0.98, 1.62) times greater risk of incident dementia than low CRP (

Abstract Traditional approaches to coastal defence often struggle to reduce the risks of accelerated climate change. Incorporating nature-based components into coastal defences may enhance adaptation to climate change with added benefits, but we need to compare their performance against conventional hard measures. We conduct a meta-analysis that compares the performances of hard, hybrid, soft and natural measures for coastal defence across different functions of risk reduction, climate change mitigation, and cost-effectiveness. Hybrid and soft measures offer higher risk reduction and climate change mitigation benefits than unvegetated natural systems, while performing on par with natural measures. Soft and hybrid measures are more cost-effective than hard measures, while hybrid measures provide the highest hazard reduction among all measures. All coastal defence measures have a positive economic return over a 20-year period. Mindful of risk context, our results provide strong an evidence-base for integrating and upscaling nature-based components into coastal defences in lower risk areas.

Soil nutrient availability and their spatial distributions are strongly related to land use and landscape morphology. This study aims to address the knowledge gap regarding the interaction between these factors and the underlying mechanisms. We selected five land uses (grassland with Artemisia gmelinii, woodland with Robinia pseudoacacia, shrubland with Caragana korshinskii and Hippophae rhamnoides, and apple orchard with Malus pumila) and nine slope positions across hillslopes in the Loess Plateau, China, to investigate their combined effects on the contents and stocks of soil organic carbon (SOC), total nitrogen (TN) and total phosphorus (TP). Parametric and non-parametric statistical tests were conducted to determine the significant differences in the means or the medians of the soil nutrient variables. Results showed that the SOC and TN contents of shrubland with Caragana korshinskii were statistically significantly greater than those of the grassland (p

Abstract Climate‐smart agriculture (CSA) serves as a credible mechanism to simultaneously address food security, climate change, and agricultural productivity. Despite the widespread adoption of CSA approaches across West Africa, many countries have still not been able to resolve the problems of food insecurity and rural poverty. This systematic review evaluates published evidence on the types of CSA practices, the determinants and benefits of adoption, and the barriers confronting the adoption of CSA practices across West Africa, following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement checklist. Articles published in English from January 2010 to March 2023 investigating the benefits of and barriers to the adoption of CSA practices in West Africa were retrieved from ScienceDirect, Web of Science, and Scopus databases. The methodological quality of studies was assessed using Joanna Briggs Institute critical appraisal tools for use in systematic reviews. The themes emerging from the articles were extracted, and a summary was provided to illustrate each theme. After applying the eligibility criteria, 12 articles were included in the final review. The studies reviewed revealed that farmers used more knowledge‐, water‐, carbon‐, and nitrogen‐smart practices, compared to weather‐ and energy‐smart practices. Across the reviewed papers, factors such as the education level of farmers, age, gender, household size, membership of a social group, agricultural extension services, and access to credit/financial resources influenced CSA adoption. The reviewed studies identified that farmers who used CSA practices reported benefits such as improved soil fertility, higher yield, improved household income, climate resilience (such as overcoming the effects of drought and extreme temperatures), and food security. Some farmers adopted CSA practices to reduce the effect of droughts and high temperatures on their crops, and thus increase their resilience to climate variability and change. However, farmers’ adoption is confronted with challenges related to the technicality of some CSA practices, high cost of labor for CSA implementation, lack of credit and government support, limited access to weather and climate information, limited information about CSA options, high illiteracy level of smallholder farmers, and incompatibility of some practices with farmers’ crop of interest. Our findings show that most CSA practices in the studies we reviewed are not well targeted to meet farmers’ crop of interest, and that governments should provide more practical training to enhance farmers’ understanding of CSA practices, especially those related to weather‐ and energy‐smart initiatives. There should also be more robust financial and institutional support to improve the adoption and usage of CSA practices at all levels. Additionally, socio‐cultural factors such as values, customs, and beliefs should be properly integrated into CSA plans as they influence the adoption of CSA practices.

Abstract The need to recognise plural values and integrate these into policy design has long been of interest in nature conservation. However, we also need to understand whether and how different values are prioritised among diverse stakeholders. This is particularly important when indigenous and traditional cultures play a role in how land is managed and protected. Working in the sacred forests of Nigeria, we applied the principles of biocultural conservation and sociocultural valuation to understand the values that underpin people's relationship with nature and with other users of nature. We operationalised this by employing participatory workshop methods to identify multiple values of sacred forests, and conjoint analysis to elicit local people's value priorities and preferences for conserving sacred forests. We identified multiple values attributed to sacred forests, but the strongest preferences were for improved provision of medicinal values. However, preference heterogeneity analysis showed that sacred forests are valued differently among clusters of people with distinct sociodemographic profiles. Our findings also showed that the current management strategy for the conservation of sacred forests is inadequate to galvanise shared and collective responsibility from diverse stakeholders. Using a value‐based approach, more robust management strategies that will yield high utility to the public were determined and recommended for implementation. Policy implications. Overall, our study demonstrates that sacred forests are valued in multiple ways above and beyond their role in a cultural belief system. New strategies are therefore needed to effectively manage and conserve them. We recommend a plural approach to the conservation of sacred forests that will incorporate multiple values. This can be achieved by integrating biocultural conservation and sociocultural valuation. Read the free Plain Language Summary for this article on the Journal blog.

Interdependence of ecological and social systems is widely acknowledged, but consideration of how local communities are influenced by processes at other sectors or scales is often omitted. This research addresses this gap by examining the implementation of China’s national environmental programs (NEPs) to combat desertification. We investigate (a) the changes in local social-ecological systems and the role of the NEPs therein since the year 2000; (b) how the changes have affected local livelihoods and behaviors and attitudes toward the NEPs and the land; and (c) the role of other drivers in the changes and their implications. Interviews and surveys were conducted with scientists, grassroots implementers, and local farmers and herders. Secondary socioeconomic data were used to understand broader changes and drivers. Our results indicate that the NEPs generated both positive and negative biophysical and socioeconomic changes, and that they were both supported and disrupted by institutions at other sectors and scales. Although farmers and herders appreciated an improved environment and living standards, they suffered from other changes, such as reduced arable land area, rising costs of living and production, precarious markets, and extreme weather events. Absence of social security and limited social capital made farmers and herders unable to engage in long-term practices that support land conservation and their well-being. The findings highlight the need to foster systemic resilience in local communities through the provision of social security and social capital building to navigate the changing world.

Transforming Growth Factor-β (TGF-β) can have both tumour-promoting and tumour-suppressing activity in breast cancer. Elucidating the key downstream mediators of pro-tumorigenic TGF-β signalling in this context could potentially give rise to new therapeutic opportunities and/or identify biomarkers for anti-TGF-β directed therapy. Here, we identify C1orf106 (also known as innate immunity activator INAVA) as a novel TGF-β target gene which is induced in a SMAD3-dependent but SMAD2/SMAD4-independent manner in human and murine cell lines. C1orf106 expression positively correlates with tumourigenic or metastatic potential in human and murine breast cancer cell line models, respectively, and is required for enhanced migration and invasion in response to TGF-β stimulation. C1orf106 promoted self-renewal and colony formation in vitro and may promote tumour-initiating frequency in vivo. High C1orf106 mRNA expression correlates with markers of aggressiveness and poor prognosis in human breast cancer. Taken together, our findings indicate that C1orf106 may act as a tumour promoter in breast cancer.

Abstract Biomedical sciences PhDs pursue a wide range of careers inside and outside academia. However, there is little data regarding how career interests of PhD students relate to the decision to pursue postdoctoral training or to their eventual career outcomes. Here, we present the career goals and career outcomes of 1452 biomedical sciences PhDs who graduated from Vanderbilt University between 1997 and 2021. We categorized careers using an expanded three‐tiered taxonomy and flags that delineate key career milestones. We also analyzed career goal changes between matriculation and doctoral defense, and the reasons why students became more‐ or less‐interested in research‐intensive faculty careers. We linked students' career goal at doctoral defense to whether they did a postdoc, the duration of time between doctoral defense and the first non‐training position, the career area of the first non‐training position, and the career area of the job at 10 years after graduation. Finally, we followed individual careers for 10 years after graduation to characterize movement between different career areas over time. We found that most students changed their career goal during graduate school, declining numbers of alumni pursued postdoctoral training, many alumni entered first non‐training positions in a different career area than their goal at doctoral defense, and the career area of the first non‐training position was a good indicator of the job that alumni held 10 years after graduation. Our findings emphasize that students need a wide range of career development opportunities and career mentoring during graduate school to prepare them for futures in research and research‐related professions.

Background: The management of pediatric dermatological conditions such as alopecia areata (AA), psoriasis, atopic dermatitis (AD), and hidradenitis suppurativa (HS) has significantly evolved with the introduction of biologics and small molecule targeted therapies. The advancement in understanding the immunopathogenesis of these chronic skin conditions has led to the development and approval of novel biologics and small molecule therapies. Initially approved by the United States Food and Drug Administration (FDA) for adults, most of these therapies are now being evaluated in clinical trials for safety and efficacy in adolescents and children, expanding new treatment options for pediatric patients. The role of the FDA in drug approval is multifaceted from drug inception, ensuring that research, data, and evidence show that the proposed drug is effective and safe for the intended use. Objective: The goal of this review article is to provide an overview of the recently FDA-approved and potential biologic and oral small molecule therapies in clinical trials for AA, psoriasis, AD, and HS in pediatric patients. Methods: The search for this review included keywords in ClinicalTrials.gov, PubMed, and Google Scholar for the latest research and clinical trials relevant to these conditions and treatments without the PRISMA methodology. Results: For pediatric AA, ritlecitinib is FDA-approved, while baricitinib and updacitinib are in phase 3 clinical trials for pediatric approval. The FDA-approved drugs for pediatric psoriasis include secukinumab, ustekinumab, ixekizumab, etanercept, and apremilast. Other phase 3 clinical trials for pediatric psoriasis include risankizumab, guselkumab, tildrakizumab, brodalumab, and deucravacitinib. For pediatric AD, the FDA-approved drugs are dupilumab, tralokinumab, abrocitinib, and upadacitinib, with many other drugs in phase 3 trials. Adalimumab is an FDA-approved biologic for pediatric HS, with various clinical trials ongoing for adults. The approved biologics and small molecule therapies had higher efficacy and improved safety profiles compared to traditional medications. Conclusions: With numerous ongoing trials, the success of these clinical trials could lead to their inclusion in treatment guidelines for these chronic skin conditions. Biologics and small molecule therapies offer new avenues for effective disease management, enabling personalized therapeutic interventions and improving pediatric health outcomes.

Laysan (Phoebastria immutabilis) and Black-footed Albatrosses (P. nigripes) nest primarily on low-lying atolls in the Northwestern Hawaiian Islands that are threatened by inundation from sea level rise and increasing storm surge associated with climate change. Restoration or creation of breeding colonies on higher islands is among the highest priority conservation actions for these species. A previous structured decision-making analysis identified the California Channel Islands as a possible restoration site for Black-footed Albatross. The California Current is part of the natural foraging ranges of Laysan and Black-footed albatrosses. Archaeological evidence indicates both species were present in the California Channel Islands prehistorically, yet neither currently nests in the Channel Islands. We assessed the feasibility of creating albatross breeding colonies in the Channel Islands using social attraction and translocation, and the suitability of each island. We used a risk analysis framework developed for the U.S. National Park Service to evaluate the potential ecological risks of this action. Creating an albatross colony in the Channel Islands is feasible using available methods. Santa Barbara and San Nicolas islands would be most suitable for albatross. Social attraction is less expensive and might be effective for creating a Laysan Albatross colony because that species is already visiting some islands. Translocation would be necessary to create a Black-footed Albatross colony. The risks associated with attempting to establish albatross breeding colonies in the Channel Islands were deemed to be generally low, but the risk of no action is high to these albatrosses. This can be a useful assisted colonization case study that can inform decisions by land managers and agencies regarding conservation of North Pacific albatrosses and other species.

Rising gold prices have led artisanal and small-scale gold mining (ASGM) operations to proliferate in sub-Saharan Africa, extending into agricultural areas. Little is known about the interactions between agriculture and mining in these new frontiers. This study aimed to investigate the impacts of ASGM on natural and physical livelihood capitals, ASGM's interactions with agriculture at household, community and institutional levels and the drivers underpinning those interactions, and the policy implications for the co-existence of sustainable agriculture and ASGM. Alongside literature review, field-work took place in Atiwa West District and Koforidua, Ghana using environmental field surveys, questionnaires, focus group discussions and interviews. Questionnaire and field survey data were analysed using descriptive statistics, with thematic analysis of interviews and focus group data. Findings revealed that most miners were unregulated, mined irresponsibly and degraded land, waterways, and farm roads. Over one-third of farmers (38%) suffered land degradation, and 79% of affected farmers' lands were not reclaimed. Farmers diversified into ASGM, and mining proceeds boosted farming. Young farmers (18-40 years) shifted into ASGM full-time because it is more lucrative. Yet, ASGM is not replacing agriculture: cocoa farming remains a vital economic activity. Informal ASGM generates short-term income at household level for some but imposes long-term costs at community level, linked to cumulative loss of agricultural land and degradation of forest areas and water bodies, creating tensions, and increasing vulnerability. Financial hardships faced by farmers, landowners' desire to benefit directly from gold and lack of law enforcement drive informal ASGM. There are no institutional linkages between the agricultural and mining sectors. More joined up governance across agriculture and mining is needed and between formal and informal (traditional) institutions. ASGM should be incorporated into broader rural development policy reforms that support farmers, incentivise miners to operate legally and responsibly and ensure effective stakeholder engagement.

BackgroundCash transfers are a promising but understudied intervention that may protect cognitive function in adults. Although South Africa has a rapidly ageing population, little is known about the nature of association between cash transfers and cognitive function in this setting.ObjectivesWe leveraged age-eligibility expansions to South Africa's Child Support Grant (CSG) to investigate the association between duration of CSG eligibility and cognitive function of biological mothers of child beneficiaries in South Africa.MethodsWe analysed 2014/2015 baseline data from 944 women, aged 40-59 years with at least one CSG-eligible child, enrolled in the population-representative HAALSI cohort in Agincourt, South Africa. Duration of CSG eligibility for each mother was calculated based on the birth dates of all their children and the CSG age-eligibility expansion years (2003-2012). Cognitive function was measured using a cognitive battery administered at the HAALSI baseline interview. Linear regression was used to estimate the association between duration of CSG eligibility, dichotomized as low (≤10 years) and high (>10 years) eligibility, and cognitive function z-scores of the mothers.ResultsHigh vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores in the full sample [β: 0.15 SD units; 95% CI: 0.04, 0.26; p-value = 0.01]. In mothers with one to four lifetime children, but not five or more, high vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores [β: 0.19 SD units; 95% CI: 0.05, 0.34, p-value = 0.02].ConclusionGovernment cash transfers given to support raising children may confer substantial protective effects on the subsequent cognitive function of mothers. Further studies are needed to understand how parity may influence this relationship. Our findings bring evidence to policymakers for designing income supplementation programmes to promote healthy cognitive ageing in low-income settings.

Background Health concordance within couples presents a promising opportunity to design interventions for disease management, including hypertension. We compared the concordance of prevalent hypertension within middle‐aged and older heterosexual couples in the United States, England, China, and India. Methods and Results Cross‐sectional dyadic data on heterosexual couples were used from contemporaneous waves of the HRS (US Health and Retirement Study, 2016/17, n=3989 couples), ELSA (English Longitudinal Study on Aging, 2016/17, n=1086), CHARLS (China Health and Retirement Longitudinal Study, 2015/16, n=6514), and LASI (Longitudinal Aging Study in India, 2017/19, n=22 389). Concordant hypertension was defined as both husband and wife in a couple having hypertension. The prevalence of concordant hypertension within couples was 37.9% (95% CI, 35.8–40.0) in the United States, 47.1% (95% CI, 43.2–50.9) in England, 20.8% (95% CI, 19.6–21.9) in China, and 19.8% (95% CI, 19.0–20.5) in India. Compared with wives married to husbands without hypertension, wives married to husbands with hypertension were more likely to have hypertension in the United States (prevalence ratio, 1.09 [95% CI, 1.01– 1.17), England (prevalence ratio, 1.09, 95% CI, 0.98–1.21), China (prevalence ratio, 1.26 [95% CI, 1.17–1.35), and India (prevalence ratio, 1.19 [95% CI, 1.15–1.24]). Within each country, similar associations were observed for husbands. Across countries, associations in the United States and England were similar, whereas they were slightly larger in China and India. Conclusions Concordance of hypertension within heterosexual couples was consistently observed across these 4 socially and economically diverse countries. Couple‐centered interventions may be an efficient strategy to prevent and manage hypertension in these countries.

Climate smart agriculture (CSA) has been promoted by governments and international development institutions as an intervention to address climate change and deliver triple wins. Yet, the trade-offs and synergies associated with CSA practices have not been explored. This study develops composite indices for prioritizing CSA practices to better inform policy about their trade-offs, synergies and acceptability. The aim of this study was to examine smallholder farmers’ uptake of CSA practices, the drivers of such uptake and the benefits (positive and negative) of CSA practices on agriculture, livelihoods and the environment. We employed the Analytic Hierarchy Process with workshop participants across two study districts in Ghana’s transitional and Sudan savannah agroecological zones. Results showed differences in CSA practices prioritized for achieving the productivity, adaptive capacity and mitigation goals between the two agroecological zones. Results also showed synergies and trade-offs associated with the implementation of CSA interventions, for example, irrigation may increase farm productivity (synergy) while contributing to the emission of greenhouse gases (GHGs) simultaneously (trade-off). Additionally, there are various perceived acceptance and efficiency levels of CSA practices by smallholder farmers and agricultural development officers. These results have implications for the implementation of future CSA action plans in vulnerability hotspots in dryland farming systems.

Abstract The origins of wound myofibroblasts and scar tissue remains unclear, but it is assumed to involve conversion of adipocytes into myofibroblasts. Here, we directly explore the potential plasticity of adipocytes and fibroblasts after skin injury. Using genetic lineage tracing and live imaging in explants and in wounded animals, we observe that injury induces a transient migratory state in adipocytes with vastly distinct cell migration patterns and behaviours from fibroblasts. Furthermore, migratory adipocytes, do not contribute to scar formation and remain non-fibrogenic in vitro, in vivo and upon transplantation into wounds in animals. Using single-cell and bulk transcriptomics we confirm that wound adipocytes do not convert into fibrogenic myofibroblasts. In summary, the injury-induced migratory adipocytes remain lineage-restricted and do not converge or reprogram into a fibrosing phenotype. These findings broadly impact basic and translational strategies in the regenerative medicine field, including clinical interventions for wound repair, diabetes, and fibrotic pathologies.

Abstract Currently available anti-erosive agents only provide partial protection, emphasizing the need to enhance their performance. By characterizing erosive enamel wear at the nanoscale, the aim of this in vitro study was to assess the anti-erosive effects of SnF2 and CPP-ACP both individually and synergistically. Erosion depths were assessed longitudinally on 40 polished human enamel specimens after 1, 5, and 10 erosion cycles. Each cycle comprised one-min erosion in citric acid (pH 3.0) and one-min treatment in whole saliva (control group) or a slurry of one of the three anti-erosive pastes (10% CPP-ACP; 0.45% SnF2 (1100 ppm F); or SnF2/CPP-ACP (10% CPP-ACP + 0.45% SnF2)) (n = 10 per group). Scratch depths were assessed longitudinally in separate experiments using a similar protocol after 1, 5, and 10 cycles. Compared with the control groups, all slurries reduced erosion depths after 1 cycle (p ≤ 0.004) and scratch depths after 5 cycles (p ≤ 0.012). The order of anti-erosive potential was SnF2/CPP-ACP > SnF2 > CPP-ACP > control for erosion depth analysis, and SnF2/CPP-ACP > (SnF2 = CPP-ACP) > control for scratch depth analysis. These data provide ‘proof of concept’ evidence that SnF2/CPP-ACP has superior anti-erosive potential compared to SnF2 or CPP-ACP alone.

Abstract Background Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies. Methods Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1–17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study. Results As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. Conclusions There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.

Climate change is increasing pressure on communities that are already experiencing high levels of vulnerability and poverty, threatening their subsistence. Among the most vulnerable are smallholder farmers in the Global South, who rely on their yields for food and income. Smallholders need to adapt to changes in rainfall, temperature, and weather patterns and their knock-on effects, and at the same time, ensure that their on-farm climate adaptations do not make climate change worse by increasing greenhouse gas emissions. The Intergovernmental Panel on Climate Change (IPCC) emphasises the need for Climate Resilient Development Pathways (CRDPs) to support vulnerable communities, including smallholder farmers, in balancing climate adaptation, mitigation and development. CRDPs comprise reactive and/or preventive actions that key stakeholders (e.g., government, business, civil society and individuals, including smallholder farmers) can take to become more resilient in the context of a changing climate while not compromising their development or increasing emissions. The CRDP framework has so far remained conceptual, providing little information on how to actually create these pathways in practice. This paper addresses this gap, and with a focus on agroforestry projects and smallholders in the Global South, assesses how CRDPs can become more concrete and actionable through a focus on agroforestry: the voluntary combination of crop and/or pasture with trees and/or shrubs, considering its contribution to climate adaptation, mitigation and development. We draw on literature review and focus group data, analysed using Atlas.ti 23 and a coding process to present a tool relevant to project designers, policymakers and researchers to assess agroforestry projects according to different aspects of climate resilient development, with particular focus on smallholder farmers in the Global South. Evaluation of the tool found it is relevant and useful for project developers and funders to check that their projects follow the components of CRD, but the tool needs to be translated to the local context to better address local demands and reflect regional specificities, which focus group participants deemed possible.

[This corrects the article DOI: 10.1371/journal.pmed.1003793.].

BackgroundKinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown.MethodsTo understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy.ResultsC. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells.ConclusionWe report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.

ABSTRACT A crucial phase in the life cycle of tick-borne pathogens is the time spent colonizing and persisting within the arthropod. Tick immunity is emerging as a key force shaping how transmissible pathogens interact with the vector. How pathogens remain in the tick despite immunological pressure remains unknown. In persistently infected Ixodes scapularis, we found that Borrelia burgdorferi (causative agent of Lyme disease) and Anaplasma phagocytophilum (causative agent of granulocytic anaplasmosis) activate a cellular stress pathway mediated by the endoplasmic reticulum receptor PKR-like ER kinase (PERK) and the central regulatory molecule eIF2α. Disabling the PERK pathway through pharmacological inhibition and RNA interference (RNAi) significantly decreased microbial numbers. In vivo RNAi of the PERK pathway not only reduced the number of A. phagocytophilum and B. burgdorferi colonizing larvae after a bloodmeal but also significantly reduced the number of bacteria that survive the molt. An investigation into PERK pathway-regulated targets revealed that A. phagocytophilum and B. burgdorferi induce activity of the antioxidant response regulator, nuclear factor erythroid 2-related factor 2 (Nrf2). Tick cells deficient for nrf2 expression or PERK signaling showed accumulation of reactive oxygen and nitrogen species in addition to reduced microbial survival. Supplementation with antioxidants rescued the microbicidal phenotype caused by blocking the PERK pathway. Altogether, our study demonstrates that the Ixodes PERK pathway is activated by transmissible microbes and facilitates persistence in the arthropod by potentiating an Nrf2-regulated antioxidant environment. IMPORTANCE Recent advances demonstrate that the tick immune system recognizes and limits the pathogens they transmit. Innate immune mediators such as antimicrobial peptides and reactive oxygen/nitrogen species are produced and restrict microbial survival. It is currently unclear how pathogens remain in the tick, despite this immune assault. We found that an antioxidant response controlled by the PERK branch of the unfolded protein response is activated in ticks that are persistently infected with Borrelia burgdorferi (Lyme disease) or Anaplasma phagocytophilum (granulocytic anaplasmosis). The PERK pathway induces the antioxidant response transcription factor, Nrf2, which coordinates a gene network that ultimately neutralizes reactive oxygen and nitrogen species. Interfering with this signaling cascade in ticks causes a significant decline in pathogen numbers. Given that innate immune products can cause collateral damage to host tissues, we speculate that this is an arthropod-driven response aimed at minimizing damage to “self” that also inadvertently benefits the pathogen. Collectively, our findings shed light on the mechanistic push and pull between tick immunity and pathogen persistence within the arthropod vector.

Nitric oxide (NO) is a critical signaling molecule that has been implicated in the pathogenesis of neurocognitive diseases. Both excessive and insufficient NO production have been linked to pathology. Previously, we have shown that argininosuccinate lyase deficiency (ASLD) is a novel model system to investigate cell-autonomous, nitric oxide synthase–dependent NO deficiency. Humans with ASLD are at increased risk for developing hyperammonemia due to a block in ureagenesis. However, natural history studies have shown that individuals with ASLD have multisystem disease including neurocognitive deficits that can be independent of ammonia. Here, using ASLD as a model of NO deficiency, we investigated the effects of NO on brain endothelial cells in vitro and the blood-brain barrier (BBB) in vivo. Knockdown of ASL in human brain microvascular endothelial cells (HBMECs) led to decreased transendothelial electrical resistance, indicative of increased cell permeability. Mechanistically, treatment with an NO donor or inhibition of Claudin-1 improved barrier integrity in ASL-deficient HBMECs. Furthermore, in vivo assessment of a hypomorphic mouse model of ASLD showed increased BBB leakage, which was partially rescued by NO supplementation. Our results suggest that ASL-mediated NO synthesis is required for proper maintenance of brain microvascular endothelial cell functions as well as BBB integrity.

Priorities and programmes in the City of Cape Town’s Integrated Development Plan (2022–2027) demonstrate progress towards operationalising local level planning for climate-resilient development. These developments provide lessons of process and focus on transformative outcomes for cities seeking equitable and just development while implementing climate change adaptation and mitigation.

Change in mangrove extent and condition has potential consequences for social disparity in terms of who can adapt to change in ecosystem services and places perceived important for providing them. Participatory GIS can elicit spatial variation in the importance attached to ecosystem service places, but disaggregated research that can reveal difference over the small spatial extents often covered by mangroves is underdeveloped. Using mixed-methods (quantitative, qualitative and spatial) in a rehabilitated mangrove system in Vietnam, this study assesses if and why perspectives about ecosystem services and their providing places vary among households with different capacities to adapt to mangrove change.Three household groups with different adaptive capacities were characterised using quantitative adaptive capacity indicators, demographic and economic data, and trajectory interviews spanning three decades: accumulating, coping and flexible households Coastal protection was identified as beneficial by all, and sediment, habitat provisioning and food services were also frequently associated with mangroves. Only food was identified significantly more or less by different groups. Spatial hotspots generated for each group by quantifying overlap in places perceived important for providing these four services, revealed greatest difference in locations important for food. Interviews indicated change in the characteristics of mangrove localities and different abilities to adapt to them enabled some households to prosper while others struggled. We consider adaptive capacities that helped temper mangrove change, and who might be most impacted by continuing change. We conclude by identifying ways forward for rehabilitation strategies centred on local people’s differential adaptive capacity and multiple ecosystem service needs.

T1-weighted structural MRI is widely used to measure brain morphometry (e.g., cortical thickness and subcortical volumes). Accelerated scans as fast as one minute or less are now available but it is unclear if they are adequate for quantitative morphometry. Here we compared the measurement properties of a widely adopted 1.0 mm resolution scan from the Alzheimer's Disease Neuroimaging Initiative (ADNI = 5′12’’) with two variants of highly accelerated 1.0 mm scans (compressed-sensing, CSx6 = 1′12’’; and wave-controlled aliasing in parallel imaging, WAVEx9 = 1′09’’) in a test-retest study of 37 older adults aged 54 to 86 (including 19 individuals diagnosed with a neurodegenerative dementia). Rapid scans produced highly reliable morphometric measures that largely matched the quality of morphometrics derived from the ADNI scan. Regions of lower reliability and relative divergence between ADNI and rapid scan alternatives tended to occur in midline regions and regions with susceptibility-induced artifacts. Critically, the rapid scans yielded morphometric measures similar to the ADNI scan in regions of high atrophy. The results converge to suggest that, for many current uses, extremely rapid scans can replace longer scans. As a final test, we explored the possibility of a 0′49’’ 1.2 mm CSx6 structural scan, which also showed promise. Rapid structural scans may benefit MRI studies by shortening the scan session and reducing cost, minimizing opportunity for movement, creating room for additional scan sequences, and allowing for the repetition of structural scans to increase precision of the estimates.

Abstract INTRODUCTION We used cultural neuropsychology‐informed procedures to derive and validate harmonized scores representing memory and language across population‐based studies in the United States and Mexico. METHODS Data were from the Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS‐HCAP) and the Mexican Health and Aging Study (MHAS) Ancillary Study on Cognitive Aging (Mex‐Cog). We statistically co‐calibrated memory and language domains and performed differential item functioning (DIF) analysis using a cultural neuropsychological approach. We examined relationships among harmonized scores, age, and education. RESULTS We included 3170 participants from the HRS‐HCAP (Mage = 76.6 [standard deviation (SD): 7.5], 60% female) and 2042 participants from the Mex‐Cog (Mage = 68.1 [SD: 9.0], 59% female). Five of seven memory items and one of twelve language items demonstrated DIF by study. Harmonized memory and language scores showed expected associations with age and education. DISCUSSION A cultural neuropsychological approach to harmonization facilitates the generation of harmonized measures of memory and language function in cross‐national studies. HIGHLIGHTS We harmonized memory and language scores across studies in the United States and Mexico. A cultural neuropsychological approach to data harmonization was used. Harmonized scores showed minimal measurement differences between cohorts. Future work can use these harmonized scores for cross‐national studies of Alzheimer's disease and related dementias.

IntroductionSeldom has work investigated systematic biases in adults’ truth and lie judgments of children’s reports. Research demonstrates that adults tend to exhibit a bias toward believing a child is telling the truth, but it is unknown whether this truth bias applies equally to all children. Given the pervasiveness of racial prejudice and anti-Black racism in the United States, the current study examined whether adults are more or less likely to believe a child is telling the truth based on the race of the child (Black or White), the race of the adult perceiver (Black or White), and the perceiver’s concerns regarding appearing unprejudiced.MethodsUsing an online data-collection platform, 593 Black and White American adults reviewed fictitious vignettes in which a child denied committing a misbehavior at school (e.g., damaging a laptop). The race of the child in the vignette was manipulated using an AI-generated photo of either a Black child or a White child. After reading each story, participants provided a categorical veracity judgment by indicating whether they believed the child in the story was lying (and therefore committed the misdeed) or telling the truth (and was innocent), as well as rated how honest or deceptive the child was being on a continuous scale. Participants also completed questionnaires assessing their internal (personal) and external (normative) motivations to respond in non-prejudiced ways.Results and discussionResults indicated that systematic racial biases occur in adults’ veracity judgments of children’s statements. Both Black and White participants exhibited a truth bias in their veracity judgments of Black children, but not when evaluating the deceptiveness of White children. Consistent with the prejudice-related concerns hypothesis, the observed truth bias toward Black children was moderated by individual differences in participants’ desire to respond without prejudice and whether those motivations stem from external or internal sources. The current findings present novel evidence regarding racial bias and prejudice-related concerns as potential barriers to making veracity judgments of children’s statements and, ultimately, successful lie detection.

Background. Health systems must collect equity-relevant sociodemographic variables to measure and mitigate health inequities. The specific variables collected by organ donation organizations (ODOs) across Canada, variable definitions, and processes of the collection are not defined. We undertook a national health information survey of all ODOs in Canada. These results will inform the development of a standard national dataset of equity-relevant sociodemographic variables. Methods. We conducted an electronic, self-administered cross-sectional survey of all ODOs in Canada from November 2021 to January 2022. We targeted key knowledge holders familiar with the data collection processes within each Canadian ODO known to Canadian Blood Services. Categorical item responses are presented as numbers and proportions. Results. We achieved a 100% response rate from 10 Canadian ODOs. Most data were collected by organ donation coordinators. Only 2 of 10 ODOs reported using scripts explaining why sociodemographic data are being collected or incorporated training in cultural sensitivity for any given variable. A lack of cultural sensitivity training was endorsed by 50% of respondents as a barrier to the collection of sociodemographic variables by ODOs, whereas 40% of respondents identified a lack of training in sociodemographic variable collection as a significant barrier. Conclusions. Few programs routinely collect sufficient data to examine health inequities with an intersectional lens. Most data collection occurs midway through the ODO interaction, creating a missed opportunity to better understand differences in social identities of patients who register their intention to donate in advance or who decline the donation. National standardization of equity-relevant data collection definitions and processes of the collection is needed.

Background and objectivesElevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia.MethodsIn a pooled cross-sectional sample of the Health and Retirement Study (n = 9,923), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24 vs. ≤1.24 mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, other biomarkers, and chronic conditions. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity.ResultsOverall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.2; 95% CI: 1.0, 1.5). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 0.7 (95% CI: −0.1, 2.4), the attributable proportion was 0.1 (95% CI: −0.2, 0.4), and the synergy index was 1.1 (95% CI: 0.8, 1.8) in a fully adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: −0, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 8% (95% CI: −5, 22%). Analyses for Hispanic relative to non-white participants suggested moderation by race/ethnicity, but not mediation.DiscussionElevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White.

Increasing aridity can sharply reduce vegetation productivity in drylands, but elevated CO _2 and warming can enhance vegetation growth. However, the extent to which these positive effects counteract the negative effects of heightened aridity on vegetation productivity remains uncertain. Here, we used space-for-time substitution to assess the responses of 15 ecosystem variables to aridity in China’s drylands and predicted vegetation productivity under future aridity, temperature, precipitation, nitrogen deposition, and CO _2 . The results showed that vegetation productivity decreased abruptly as aridity (1-precipitation/potential evapotranspiration) increased to the threshold of 0.7, which corresponds to the vegetation decline stage in the dryland ecosystem’s response to increasing aridity. Future projections suggest that 12.8% of China’s drylands will cross aridity thresholds (0.7, 0.8, and 0.95) by 2100, in which vegetation productivity will significantly increase by 40.0%. Elevated CO _2 will stimulate vegetation growth, but continuously rising temperature and CO _2 by 2100 will have adverse effects, particularly in regions with limited nitrogen and water. This study suggests that effective adaptation and mitigation actions should be developed for regions crossing aridity thresholds, to ensure that drylands maintain the capacity to provide essential ecosystem services required to support the increasing population.

The contents of this Special Issue provide a broad overview of the current landscape of psoriasis and atopic dermatitis (AD) treatment in pediatric populations, highlighting the challenges and recent advances [...]

A horizon scan was used to explore possible impacts of robotics and automated systems on achieving the UN Sustainable Development Goals. Positive effects are likely. Iterative regulatory processes and continued dialogue could help avoid environmental damages and increases in inequality.

Abstract The prevalence of obesity continues to rise, underscoring the need to better understand the pathways mediating adipose tissue (AT) expansion. All‐trans‐retinoic acid (atRA), a bioactive vitamin A metabolite, regulates adipogenesis and energy metabolism, and, in rodent studies, aberrant vitamin A metabolism appears a key facet of metabolic dysregulation. The relevance of these findings to human disease is unknown, as are the specific enzymes implicated in vitamin A metabolism within human AT. We hypothesized that in human AT, family 1A aldehyde dehydrogenase (ALDH1A) enzymes contribute to atRA biosynthesis in a depot‐specific manner. To test this hypothesis, parallel samples of subcutaneous and omental AT from participants (n = 15) were collected during elective abdominal surgeries to quantify atRA biosynthesis and key atRA synthesizing enzymes. ALDH1A1 was the most abundant ALDH1A isoform in both AT depots with expression approximately twofold higher in omental than subcutaneous AT. ALDH1A2 was detected only in omental AT. Formation velocity of atRA was approximately threefold higher (p = 0.0001) in omental AT (9.8 [7.6, 11.2]) pmol/min/mg) than subcutaneous AT (3.2 [2.1, 4.0] pmol/min/mg) and correlated with ALDH1A2 expression in omental AT (β‐coefficient = 3.07, p = 0.0007) and with ALDH1A1 expression in subcutaneous AT (β‐coefficient = 0.13, p = 0.003). Despite a positive correlation between body mass index (BMI) and omental ALDH1A1 protein expression (Spearman r = 0.65, p = 0.01), BMI did not correlate with atRA formation. Our findings suggest that ALDH1A2 is the primary mediator of atRA formation in omental AT, whereas ALDH1A1 is the principal atRA‐synthesizing enzyme in subcutaneous AT. These data highlight AT depot as a critical variable for defining the roles of retinoids in human AT biology.

The modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy at 3 years following the four-shot immunization series, coupled with rapid waning of putative immune correlates of decreased infection risk. New strategies to increase magnitude and durability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evaluated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients after 6-8 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone, or ALVAC-HIV + AIDSVAX B/E gp120). Previous reports demonstrated that this regimen elicited higher binding, antibody Fc function, and cellular responses than the primary RV144 regimen. However, the impact of the canarypox viral vector in driving antibody specificity, breadth, durability and function is unknown. We performed a follow-up analysis of humoral responses elicited in RV305 to determine the impact of the different booster immunogens on HIV-1 epitope specificity, antibody subclass, isotype, and Fc effector functions. Importantly, we observed that the ALVAC vaccine component directly contributed to improved breadth, function, and durability of vaccine-elicited antibody responses. Extended boosts in RV305 increased circulating antibody concentration and coverage of heterologous HIV-1 strains by V1V2-specific antibodies above estimated protective levels observed in RV144. Antibody Fc effector functions, specifically antibody-dependent cellular cytotoxicity and phagocytosis, were boosted to higher levels than was achieved in RV144. V1V2 Env IgG3, a correlate of lower HIV-1 risk, was not increased; plasma Env IgA (specifically IgA1), a correlate of increased HIV-1 risk, was elevated. The quality of the circulating polyclonal antibody response changed with each booster immunization. Remarkably, the ALVAC-HIV booster immunogen induced antibody responses post-second boost, indicating that the viral vector immunogen can be utilized to selectively enhance immune correlates of decreased HIV-1 risk. These results reveal a complex dynamic of HIV-1 immunity post-vaccination that may require careful balancing to achieve protective immunity in the vaccinated population. Trial registration: RV305 clinical trial (ClinicalTrials.gov number, NCT01435135). ClinicalTrials.gov Identifier: NCT00223080.

Newell’s Shearwater (Puffinus auricularis newelli; NESH) and Hawaiian Petrel (Pterodroma sandwichensis; HAPE) are listed under the U.S. Endangered Species Act and have declined by 94% and 78%, respectively, since 1993 due to habitat degradation, predation by introduced predators, collisions with powerlines and light attraction. Given the challenges in protecting nesting birds in their rugged montane habitats, it has long been desirable to create populations of both species in more accessible locations that offer a higher level of protection. We translocated 110 HAPE and 86 NESH chicks over a six-year period from 2015-2020 to a 2.5-ha predator-free enclosure on Kaua`i, Hawai`i. In addition to invasive plant removal and native plant out-planting, we installed 76 artificial burrows to provide nesting sites. Chicks were tube fed 1-20% of their body weight daily in the form of a slurry comprised of squid, fish, salmon oil, and Pedialyte. All NESH and 96% (N=106) of HAPE survived to fledging. Eight HAPE, including three breeding pairs, and one NESH have returned as adults to the translocation site and HAPE have bred at the site, resulting in the first predator-free breeding colony of this species.

Abstract Untargeted metabolomics is a global molecular profiling technology that can be used to screen for inborn errors of metabolism (IEMs). Metabolite perturbations are evaluated based on current knowledge of specific metabolic pathway deficiencies, a manual diagnostic process that is qualitative, has limited scalability, and is not equipped to learn from accumulating clinical data. Our purpose was to improve upon manual diagnosis of IEMs in the clinic by developing novel computational methods for analyzing untargeted metabolomics data. We employed CTD, an automated computational diagnostic method that “connects the dots” between metabolite perturbations observed in individual metabolomics profiling data and modules identified in disease­specific metabolite co-perturbation networks learned from prior profiling data. We also extended CTD to calculate distances between any two individuals (CTDncd) and between an individual and a disease state (CTDdm), to provide additional network-quantified predictors for use in diagnosis. We show that across 539 plasma samples, CTD-based network-quantified measures can reproduce accurate diagnosis of 16 different IEMs, including adenylosuccinase deficiency, argininemia, argininosuccinic aciduria, aromatic l-amino acid decarboxylase deficiency, cerebral creatine deficiency syndrome type 2, citrullinemia, cobalamin biosynthesis defect, GABA-transaminase deficiency, glutaric acidemia type 1, maple syrup urine disease, methylmalonic aciduria, ornithine transcarbamylase deficiency, phenylketonuria, propionic acidemia, rhizomelic chondrodysplasia punctata, and the Zellweger spectrum disorders. Our approach can be used to supplement information from biochemical pathways and has the potential to significantly enhance the interpretation of variants of uncertain significance uncovered by exome sequencing. CTD, CTDdm, and CTDncd can serve as an essential toolset for biological interpretation of untargeted metabolomics data that overcomes limitations associated with manual diagnosis to assist diagnosticians in clinical decision-making. By automating and quantifying the interpretation of perturbation patterns, CTD can improve the speed and confidence by which clinical laboratory directors make diagnostic and treatment decisions, while automatically improving performance with new case data.

The European Union’s ‘Green Deal’ proposes an ambitious roadmap towards climate neutrality by 2050 and the adoption of a circular economy. Functional AgroBiodiversity (FAB) measures, which balance food production with minimised impacts on nature, are a promising way to achieve this on farmland. Here, we undertake a rapid evidence assessment to highlight Functional Agro-Biodiversity (FAB) management measures which help to realise biodiversity, climate neutrality, efficiency in use of natural resources and the circular economy. We report evidence on the effectiveness of 10 common FAB measures employed in Europe following a resurgence of interest and increased availability of data on their impact. The review found that the outcomes of implementing FAB measures were largely positive, with a number of mixed effects. There are evidence gaps, e.g., the impact of FAB measures on yield, the magnitude and timescale of impacts, the effect of landscape context. We signpost the most relevant and well-documented FAB measures, providing a reference for land managers and practitioners to select FAB measures to achieve specific ecological and agricultural outcomes. It is also important to note that a combination of measures implemented in a strategic way can enhance the output success.

Complexity of African agrarian systems necessitates that agricultural research and development transition to agricultural innovation system [AIS] approaches. While AIS perspectives are embraced across sub-Saharan Africa, engagement of stakeholders in agricultural research and development processes as espoused in AIS paradigm remains limited. This paper aims to analyze key stakeholders in the AIS in Malawi using the case of Conservation Agriculture [CA]. We analyze roles, organizational capacity and collaboration of stakeholders in Malawi’s CA innovation system. Although Government has the most extensive role, NGOs dominate the national CA agenda, while smallholder farmers remain passive recipients of CA interventions. Many CA promoters lack technical and financial capacity, and pursue limited collaboration, which diminish prospects of inclusive stakeholder engagement. While insufficient resources lead to inadequate technical support to smallholders, the limited collaboration hinders integration of programmes, multiple sources of innovation and knowledge required to foster social learning and sustainability of CA. Our findings indicate a need to: (1) strengthen understanding of AIS approaches among CA innovation system stakeholders; (2) build stronger partnerships in CA research and development by strengthening stakeholder platforms and social processes; (3) strengthen collaboration advisory mechanisms to facilitate knowledge-sharing, resource mobilization and joint programme implementation with strengthened feedback loops.

Diversity in specificity of polyclonal antibody (pAb) responses is extensively investigated in vaccine efficacy or immunological evaluations, but the heterogeneity in antibody avidity is rarely probed as convenient tools are lacking. Here we have developed a polyclonal antibodies avidity resolution tool (PAART) for use with label-free techniques, such as surface plasmon resonance and biolayer interferometry, that can monitor pAb-antigen interactions in real time to measure dissociation rate constant (kd) for defining avidity. PAART utilizes a sum of exponentials model to fit the dissociation time-courses of pAb-antigens interactions and resolve multiple kd contributing to the overall dissociation. Each kd value of pAb dissociation resolved by PAART corresponds to a group of antibodies with similar avidity. PAART is designed to identify the minimum number of exponentials required to explain the dissociation course and guards against overfitting of data by parsimony selection of best model using Akaike information criterion. Validation of PAART was performed using binary mixtures of monoclonal antibodies of same specificity but differing in kd of the interaction with their epitope. We applied PAART to examine the heterogeneity in avidities of pAb from malaria and typhoid vaccinees, and individuals living with HIV-1 that naturally control the viral load. In many cases, two to three kd were dissected indicating the heterogeneity of pAb avidities. We showcase examples of affinity maturation of vaccine induced pAb responses at component level and enhanced resolution of heterogeneity in avidity when antigen-binding fragments (Fab) are used instead of polyclonal IgG antibodies. The utility of PAART can be manifold in examining circulating pAb characteristics and could inform vaccine strategies aimed to guide the host humoral immune response.

We aimed to determine the influence of modifiable health behaviors prior to a cancer diagnosis on functional aging trajectories after diagnosis among middle-aged and older cancer survivors in the United States. Data were from biennial interviews with 2,717 survivors of a first incident cancer diagnosis after age 50 in the population-based US Health and Retirement Study from 1998 to 2016. Smoking status, alcohol use, and vigorous physical activity frequency were assessed at the interview prior to cancer diagnosis. Confounder-adjusted multinomial logistic regression was used to determine the associations between each pre-diagnosis health behavior and post-diagnosis trajectories of memory function and limitations to activities of daily living (ADLs), which were identified using group-based trajectory modeling. Overall, 20.7 % of cancer survivors were current smokers, 30.6 % drank alcohol, and 27.1 % engaged in vigorous physical activity >=once a week prior to their diagnosis. In the years following diagnosis, those who had engaged in vigorous physical activity > once a week were less likely to have a medium–high (OR: 0.5; 95 % CI: 0.2–0.9) or medium–low memory loss trajectories (OR: 0.6; 95 % CI: 0.3–1.0) versus very low memory loss trajectory, and were less likely to have a high, increasing ADL limitation trajectory (OR: 0.3; 95 % CI: 0.2, 0.6) versus no ADL limitation trajectory. Vigorous physical activity, but not smoking or alcohol use, was associated with better post-diagnosis functional aging trajectories after a first incident cancer diagnosis in mid-to-later life in this population-based study. Identification of modifiable risk factors can inform targeted interventions to promote healthy aging among cancer survivors.

Earlier pubertal development appears to be one pathway through which childhood trauma contributes to psychopathology in adolescence. Puberty-related changes in neural networks involved in emotion processing, namely the amygdala-medial prefrontal (mPFC) circuit, may be a potential mechanism linking trauma and adolescent psychopathology. Our participants were 227 youth between 10 and 13 years of age who completed assessments of threat and deprivation-related experiences of adversity, pubertal stage, and internalizing and externalizing symptoms. A subset (n = 149) also underwent a functional MRI scan while passively viewing fearful and calm faces. Potential mechanisms linking childhood trauma with psychopathology, encompassing earlier pubertal timing and neural response to aversive stimuli were explored. Earlier pubertal development was associated with childhood trauma as well as increased externalizing symptoms in boys only. Earlier pubertal timing in males and females was negatively associated with activation in bilateral amygdala, hippocampal, and fusiform regions when comparing fearful and calm faces. However, amygdala-mPFC connectivity showed no association with pubertal timing or psychopathology symptoms. These findings do not support accelerated amygdala-mPFC development as a mechanism linking childhood trauma and psychopathology, but instead provide support for the role of pubertal development in normative decreases in limbic activation across development.

The study of cardiac electrophysiology is built on experimental models that span all scales, from ion channels to whole-body preparations. Novel discoveries made at each scale have contributed to our fundamental understanding of human cardiac electrophysiology, which informs clinicians as they detect, diagnose, and treat complex cardiac pathologies. This expert review describes an engineering approach to developing experimental models that is applicable across scales. The review also outlines how we applied the approach to create a set of multiscale whole-body experimental models of cardiac electrophysiology, models that are driving new insights into the response of the myocardium to acute ischemia. Specifically, we propose that researchers must address three critical requirements to develop an effective experimental model: 1) how the experimental model replicates and maintains human physiological conditions, 2) how the interventions possible with the experimental model capture human pathophysiology, and 3) what signals need to be measured, at which levels of resolution and fidelity, and what are the resulting requirements of the measurement system and the access to the organs of interest. We will discuss these requirements in the context of two examples of whole-body experimental models, a closed chest in situ model of cardiac ischemia and an isolated-heart, torso-tank preparation, both of which we have developed over decades and used to gather valuable insights from hundreds of experiments.

Material resources owned by households that affect daily living conditions may be salient for cognitive health during aging, especially in low-income settings, but there is scarce evidence on this topic. We investigated relationships between long-term trends in household material resources and cognitive function among older adults in a population-representative study in rural South Africa. Data were from baseline interviews with 4580 adults aged ≥40 in “Health and Ageing in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI) in 2014/2015 linked to retrospective records on their household material resources from the Agincourt Health and Socio-Demographic Surveillance System (HDSS) from 2001 to 2013. Household material resources were assessed biennially in the Agincourt HDSS using a five-point index that captured dwelling materials, water and sanitation, sources of power, livestock, and technological amenities. Cognitive function was assessed in HAALSI and analyzed as a z-standardized latent variable capturing time orientation, episodic memory, and numeracy. We evaluated the relationships between quintiles of each of the mean resource index score, volatility in resource index score, and change in resource index score and subsequent cognitive function, overall and by resource type. Higher mean household resources were positively associated with cognitive function (βadj = 0.237 standard deviation [SD] units for the highest vs. lowest quintile of mean resource index score; 95% CI: 0.163–0.312; p-trend

Background: The acute impacts of COVID-19-related mental health concerns on cognitive function among middle-aged and older adults are unknown. We investigated whether between-person (BP) differences and within-person (WP) changes in loneliness, anxiety, and worry about COVID-19 were related to cognitive function and abilities in a longitudinal cohort of middle-aged and older United States (US) adults over a nine-month period during the COVID-19 pandemic. Methods: Data were from bimonthly questionnaires in the nationwide COVID-19 Coping Study from August/September 2020 through April/May 2021 (N = 2262 adults aged ≥55). Loneliness was assessed with the 3-item UCLA Loneliness Scale, anxiety with the 5-item Beck Anxiety Inventory, and COVID-19 worry on a 5-point Likert-type scale. Cognitive outcomes were assessed with the 6-item Patient Reported Outcomes Measurement Information System (PROMIS®) Cognitive Function and Abilities scales. Marginal structural models incorporating inverse probability of treatment and attrition weights as well as sampling weights estimated the BP and WP relationships between the mental health predictors and PROMIS® cognitive scores over time. Results: In any given month, experiencing a loneliness or anxiety symptom score higher than the sample mean (BP difference) or higher than one's personal mean across the nine-month period (WP change) was negatively associated with cognitive function and abilities in that month. The observed magnitudes of associations were stronger for BP differences than for WP changes and were the strongest for anxiety symptom scale scores. Conclusions: Elevated loneliness and anxiety symptoms, both relative to other adults and to one's usual levels, were acutely associated with worse perceived cognitive function and abilities over a nine-month period during the COVID-19 pandemic in the United States. The long-term impacts of mental health symptoms experienced during the pandemic for population cognitive health should be explored.

Abstract Objective Immune-mediated inflammatory diseases (IMID) are characterized by systemic inflammation affecting the joints and bodily organs. Studies examining the association between individual IMIDs and the risk of Alzheimer’s disease (AD) have yielded inconsistent findings. This study examines AD risk across a group of IMIDs in a large population-based sample of older adults. Methods Data on a national sample of US adults over age 50 was drawn from the Health and Retirement Study (HRS) and linked Medicare claims from 2006 to 2014. IMIDs include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and related conditions. We identified IMIDs from 2006 to 2009 Medicare claims using International Classification of Diseases (ICD9-CM) codes. The date of incident AD was derived from Chronic Conditions Warehouse (CCW) identifiers. We examined the risk of AD from 2009 to 2014 using Cox proportional hazards models, both unadjusted and adjusted for age, gender, education, race, and the genetic risk factor APOE-e4. Results One hundred seventy-one (6.02%) of the 2842 total HRS respondents with Medicare coverage and genetic data were classified with IMIDs. Over the subsequent 6 years, 9.36% of IMID patients developed AD compared to 8.57% of controls (unadjusted hazard ratio (HR): 1.09, 95% CI .66–1.81, p = 0.74). Adjusted HR 1.27 (95% CI 0.76–2.12, p = 0.35). Age (HR for 10-year increment 3.56, p

Abstract Background The COVID-19 pandemic has had a significant impact on the health system worldwide. The organ and tissue donation and transplantation (OTDT) system is no exception and has had to face ethical challenges related to the pandemic, such as risks of infection and resource allocation. In this setting, many Canadian transplant programs halted their activities during the first wave of the pandemic. Method To inform future ethical guidelines related to the COVID-19 pandemic or other public health emergencies of international concern, we conducted a literature review to summarize the ethical issues. Results This literature review identified three categories of ethical challenges. The first one describes the general ethical issues and challenges reported by OTDT organizations and transplantation programs, such as risks of COVID-19 transmission and infection to transplant recipients and healthcare professionals during the transplant process, risk of patient waitlist mortality or further resource strain where transplant procedures have been delayed or halted, and resource allocation. The second category describes ethical challenges related to informed consent in the context of uncertainty and virtual consent. Finally, the third category describes ethical issues related to organ allocation, such as social considerations in selecting transplant candidates. Conclusion This literature review highlights the salient ethical issues related to OTDT during the current COVID-19 pandemic. As medical and scientific knowledge about COVID-19 increases, the uncertainties related to this disease will decrease and the associated ethical issues will continue to evolve.