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Abstract Background During aging, the human methylome undergoes both differential and variable shifts, accompanied by increased entropy. The distinction between variably methylated positions (VMPs) and differentially methylated positions (DMPs), their contribution to epigenetic age, and the role of cell type heterogeneity remain unclear. Results We conduct a comprehensive analysis of > 32,000 human blood methylomes from 56 datasets (age range = 6–101 years). We find a significant proportion of the blood methylome that is differentially methylated with age (48% DMPs; FDR

Bullying victimization remains to be a public health concern in the United States, especially among sexual and ethnic minority youth. However, few studies have examined how school outcomes might be associated with bullying victimization among heterosexual and sexual minority African American youth and the factors that may attenuate that relationship. To address this gap, this study surveyed 462 heterosexual and 102 sexual minority African American youth residing in Chicago's Southside neighborhoods, who participated in the Resiliency Project. Study variables included bullying victimization, school outcomes (i.e., school connectedness, and academic grades), and future orientation. Bullying victimization was associated with a significant increase in feeling disconnected from school among both heterosexual and sexual minority adolescents; however, there was no significant association observed between bullying victimization and receiving low grades among either group. Future orientation did not moderate the association between bullying victimization and school outcomes among heterosexual adolescents; however, positive future orientation did attenuate the association between bullying victimization and feeling disconnected from school among sexual minority adolescents. Prevention programs that focus on promoting school connectedness need to consider the role of future orientation for sexual minority youth.

Young Black men who have sex with men (YBMSM) are disproportionately impacted by violence, including violence rooted in anti-Black racism, sexual identity bullying, and neighborhood violence rooted in structural racism and inequities. These multiple forms of violence are frequently co-occurring and interactive creating syndemic conditions that can negatively impact HIV care. This qualitative study is based on in-depth interviews with 31 YBMSM, aged 16-30 years, living with HIV in Chicago, IL, to examine how violence has impacted their lives. Using thematic analysis, we identified five themes that reflect how YBMSM experience violence at the intersection of racism, homonegativity, socioeconomic status, and HIV status: (a) the experience of intersectional violence; (b) long histories of violence contributed to hypervigilance, lack of safety, and lack of trust; (c) making meaning of violence and the importance of strength; (d) normalizing violence for survival; and (e) the cyclical nature of violence. Our study highlights how multiple forms of violence can accumulate across an individuals life and contribute to social and contextual situations that further contribute to violence and negatively impact mental health and HIV care.

Light transmission aggregometry (LTA) is a method used to investigate platelet functions in platelet-rich plasma (PRP), notably when screening for platelet disorders. Various national guidelines and recommendations help in setting up the LTA test in specialized laboratories. However, due to the nature of the sample matrix and its subsequent specificities, more accurate positions are needed to achieve LTA accreditation according to the standard NF EN ISO 15 189. We reviewed guidelines and recommendations as they can be useful in the accreditation process, and we conducted a survey on LTA practice among members of the Société Française de Thrombose et d’Hémostase (SFTH) in 2021. We formulated 28 proposals, which have been approved by vote within the SFTH. All aspects to take into consideration for the proper conduct of LTA assays and their accreditation have been covered. Notably, preanalytical, analytical and postanalytical aspects are depicted, including blood sampling, PRP preparation, instruments, agonists, performance assessment, personnel training and data interpretation. This document, essentially representing a French position paper on the current recommendations and subsequent proposals for LTA accreditation, might prove useful also outside France for relevant laboratories and auditors involved in LTA accreditation.

ABSTRACT Introduction Short post‐learning breaks, lasting from 5 to 30 min, transiently enhance procedural motor memory performance in adults. However, the impact of activity type (active vs. passive) during the offline break on sequential motor performance remains poorly investigated in children. Method This study examined the impact of active versus passive post‐learning breaks on procedural motor memory in 116 healthy participants (58 children, aged 9.03 ± 1.19; 58 adults, aged 22.89 ± 1.77 years). Participants practiced a Finger Tapping Task, reproducing a five‐element keypress sequence as fast and accurately as possible. The task included two sessions (S1 and S2) separated by either a short (30 min) or long (4 h) break. The first 30‐min of the post‐learning break included either a passive (remaining still) or an active (engaging in daily activities) condition. Results Repeated‐measures ANOVA revealed significant Session × Age group × Break duration and Session × Break type interaction effects (ps

Abstract Climate change threatens the resource adequacy of future power systems. Existing research and practice lack frameworks for identifying decarbonization pathways that are robust to climate‐related uncertainty. We create such an analytical framework, then use it to assess the robustness of alternative pathways to achieving 60% emissions reductions from 2022 levels by 2040 for the Western U.S. power system. Our framework integrates power system planning and resource adequacy models with 100 climate realizations from a large climate ensemble. Climate realizations drive electricity demand; thermal plant availability; and wind, solar, and hydropower generation. Among five initial decarbonization pathways, all exhibit modest to significant resource adequacy failures under climate realizations in 2040, but certain pathways experience significantly less resource adequacy failures at little additional cost relative to other pathways. By identifying and planning for an extreme climate realization that drives the largest resource adequacy failures across our pathways, we produce a new decarbonization pathway that has no resource adequacy failures under any climate realizations. This new pathway is roughly 5% more expensive than other pathways due to greater capacity investment, and shifts investment from wind to solar and natural gas generators. Our analysis suggests modest increases in investment costs can add significant robustness against climate change in decarbonizing power systems. Our framework can help power system planners adapt to climate change by stress testing future plans to potential climate realizations, and offers a unique bridge between energy system and climate modeling.

Abstract Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Studies suggest that religion is a protective factor for substance misuse and mental health concerns among Black/African American youth despite reported declines in their religious involvement. However, few studies have investigated the associations among religion, substance misuse, and mental health among Black youth. Informed by Critical Race Theory, we evaluated the correlations between gender, depression, substance misuse, and unprotected sex on mental health. Using multiple linear regression, we assessed self-reported measures of drug use and sex, condom use, belief in God, and religiosity on mental health among a sample of Black youth (N = 638) living in a large midwestern city. Results indicated drug use, and sex while on drugs and alcohol, were significant and positively associated with mental health symptoms. Belief in God was negatively associated with having sex while on drugs and alcohol. The studys findings suggest that despite the many structural inequalities that Black youth face, religion continues to be protective for Black youth against a myriad of prevalent problem behaviors.

This study conducted 28 semi-structured, in-depth interviews with Young Black Men who have Sex with Men in Chicago to investigate the impact of COVID-19 on their HIV care and ancillary service access. The qualitative analysis identified both negative and positive effects. The negative effects included: (l) mixed disruptions in linkage to and receipt of HIV care and ancillary services, and (2) heightened concerns about police and racial tensions in Chicago following the murder of George Floyd, contributing to possible disruption of retention in care. The positive effects included: (1) the ability to reflect and socially connect, contributing to heightened self-care and retention in care, and (2) some improvements in receipt of medical care. These findings suggest that while COVID-19 disruptions in care reduced in-person use of HIV care, the expansion of telemedicine allowed more administrative tasks to be handled online and focused in-person interactions on more substantive interactions.

Immunocompromised patients in the hematology department are usually hospitalized in areas protected by the high-efficiency particulate air (HEPA) filtration system. Renovations may require moving these patients at risk for invasive fungal infection to areas without HEPA. Mobile air handling units may be a solution in these cases. For renovation purposes, we evaluated the efficiency of mobile air handling units called Plasmair® as well as their optimization, by comparing two generations of devices.Particle counts were performed to determine a particle cleanliness classification according to the ISO 14644–1 standard (high ISO classes correspond to a degraded particulate cleanliness). Mycological air samples were also taken to determine the percentage of positive samples and the median number of filamentous fungi colonies.Without air treatment, only 18 % (38/216) of particle counts were classified as ISO 6. With the use of mobile air treatment units, this proportion increased to 71 % (205/288). The positivity rate of mycological samples without air treatment was 86 % (31/36) with a median number of fungal colonies of 3 (1–5)/0.5m3. A significant decrease in fungal pressure was observed when using Plasmair®. Percentages of positive air samples and the median number of colonies found between the old generation Plasmair® (T2006) and the new generation Plasmair® (Guardian) were significantly different, respectively 55.6 % (20/36) versus 22.2 % (8/36) and 1(0–1) versus 0 (0–0).Finally, we confirm Plasmair® were effective in reducing airborne fungal pressure, the new generation especially. However, they were not effective enough to obtain negative mycological air samples as usually observed with the HEPA system, whatever the generation.

Abstract IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.

Large-scale hydrological models (LHMs) are commonly used for regional and global assessment of future water shortage outcomes under climate and socioeconomic scenarios. The irrigation of croplands, which accounts for the lion's share of human water consumption, is critical in understanding these water shortage trajectories. Despite irrigation's defining role, LHM frameworks typically impose trajectories of land use that underlie irrigation demand, neglecting potential dynamic feedbacks in the form of human instigation of and subsequent adaptation to water shortages via irrigated crop area changes. We extend an LHM, MOSART-WM, with adaptive farmer agents, applying the model to the continental United States to explore water shortage outcomes that emerge from the interplay between hydrologic-driven surface water availability, reservoir management, and farmer irrigated crop area adaptation. The extended modeling framework is used to conduct a hypothetical computational experiment comparing differences between a model run with and without the incorporation of adaptive farmer agents. These comparative simulations reveal that accounting for farmer adaptation via irrigated crop area changes substantially alters modeled water shortage outcomes, with US-wide annual water shortages being reduced by as much as 42 % when comparing adaptive and non-adaptive versions of the model forced with US climatology from the period 1950–2009.

Energy and water systems are deeply interdependent yet organized and managed into separate sectors. Although technological innovations emerge at the intersection of energy and water, these sectors largely operate independently, despite their mutual importance. This persistent challenge is structural, as the sectors are organized and managed as separate systems. More can be done to integrate these sectors for mutual benefit and resilience. This paper provides an overview and a useful categorization of six research areas that bridge the water and energy sectors: integrated planning, integrated operations, data and analytics, policy and economics, hydropower and marine energy, and resilience. The authors lead the IEEE Power & Energy Society Task Force on Water-Power Systems (WPS), which represents an international and rapidly growing collaboration across both energy and water sectors to find common areas of cooperation and innovation. Through the collective efforts of this Task Force, a comprehensive roadmap on water power systems integration was issued in 2023. The paper presents evidence that coordinated efforts in data analytics, policy, and economic interventions can significantly advance hydropower, marine energy, and energy storage technologies, ultimately enhancing the resilience and efficiency of both water and power infrastructures.

Abstract Pitting corrosion in seawater is one of the most difficult forms of corrosion to identify and control. A workhorse material for marine applications, 316L stainless steel (316L SS) is known to balance resistance to pitting with good mechanical properties. The advent of additive manufacturing (AM), particularly laser powder bed fusion (LPBF), has prompted numerous microstructural and mechanical investigations of LPBF 316L SS; however, the origins of pitting corrosion on as-built surfaces is unknown, despite their utmost importance for certification of LPBF 316L SS prior to fielding. Here, we show that Mn-rich silicate slags are responsible for pitting of the as-built LPBF material in sodium chloride due to their introduction of deleterious defects such as cracks or surface oxide heterogeneities. In addition, we explain how slags are formed in the liquid metal and deposited at the as-built surfaces using high-fidelity melt pool simulations. Our work uncovers how LPBF changes surface oxides due to rapid solidification and high-temperature oxidation, leading to fundamentally different pitting corrosion mechanisms.

Agroecological transition requires research and actions at the scale of local territories, in which agricultural activities interact with the environment and natural resources depending on a territory’s spatial configuration. To support the agroecological transition, there is an urgent need to design and implement new spatial configurations. For this, local public authorities in France can be considered as an interesting level of governance, because of their skills in spatial planning and their interest in agriculture, to ensure the ecological transition of their territory. However, new methodological frameworks need to be developed to support the design of new spatial configurations of territories, by constructing representations of the territory that consider both agricultural and socio-environmental issues, and by involving agricultural and non-agricultural stakeholders so that both can project themselves into the new spatial configurations. We developed a new methodological framework at the interface between landscape agronomy and landscape architects’ approaches, and experimented with applying this framework in the Urban Community of Dunkirk (UCD), which was performing a spatial planning approach called a Landscape Plan and proposing to create an Agricultural Park. The results show that the implementation of the methodological framework enabled the construction of a spatially explicit and place-based representation including the spatial issues of farming systems. These representations enable a local authority’s stakeholders to enhance their knowledge of the agricultural issues and consider changes in the spatial configuration of the Agricultural Park. In the discussion, we question the adaptation of the framework in rural territory and highlight the limitations of local authorities as the level of governance at which to address the agroecological transition at the territorial scale.

Abstract Around 60% of households in Texas currently rely on electricity for space heating. As decarbonization efforts increase, non‐electrified households could adopt electric heat pumps, significantly increasing peak (highest) electricity demand in winter. Simultaneously, anthropogenic climate change is expected to increase temperatures, the potential for summer heat waves, and associated electricity demand for cooling. Uncertainty regarding the timing and magnitude of these concurrent changes raises questions about how they will jointly affect the seasonality of peak demand, firm capacity requirements, and grid reliability. This study investigates the net effects of residential space heating electrification and climate change on long‐term demand patterns and load shedding potential, using climate change projections, a predictive load model, and a direct current optimal power flow (DCOPF) model of the Texas grid. Results show that full electrification of residential space heating by replacing existing fossil fuel use with higher efficiency heat pumps could significantly improve reliability under hotter futures. Less efficient heat pumps may result in more severe winter peaking events and increased reliability risks. As heating electrification intensifies, system planners will need to balance the potential for greater resource adequacy risk caused by shifts in seasonal peaking behavior alongside the benefits (improved efficiency and reductions in emissions).

Advance care planning (ACP) supports individuals in aligning their medical care with personal values and preferences in the face of serious illness. The variety of ACP tools available reflects diverse strategies intended to facilitate these critical conversations, yet evaluations of their effectiveness often show mixed results. Following the Arskey and O’Malley framework, this scoping review aims to synthesize the range of ACP tools targeted at patients and families, highlighting their characteristics and delivery methods to better understand their impact and development over time. Studies included focused on patient-facing ACP tools across all settings and mediums. Exclusions were applied to studies solely targeting healthcare providers or those only aiming at completion of advance directives without broader ACP discussions. Searches were conducted across PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science. Data were extracted using a predesigned spreadsheet, capturing study population, setting, intervention modality, and intervention theme. Tools were categorized by delivery method and further analyzed through a year-wise distribution to track trends and developments. We identified 99 unique patient-facing tools, with those focusing on counseling (31) and video technologies (21) being the most prevalent while others incorporated online platforms, print materials, games, or some combination of different delivery methods. Over half the tools were designed for specific patient groups, especially for various diseases and racial or ethnic communities. Recent years showed a surge in tool variety and innovation, including integrated patient portals and psychological techniques. The review demonstrates a broad array of innovative ACP tools that facilitate personalized and effective ACP. Our findings contribute to an enhanced understanding of their utilization and potential impacts, offering valuable insights for future tool development and policy making in ACP.

IntroductionThe administration of antibiotics can expose the digestive microbiota of humans and animals to sub-inhibitory concentrations, potentially favouring the selection of resistant bacteria. The minimal selective concentration (MSC) is a key indicator to understand this process. The MSC is defined as the lowest concentration of an antibiotic that promotes the growth of a resistant strain over a susceptible isogenic strain. It represents the lower limit of the sub-minimal inhibitory concentration (MIC) selective window, where resistant mutants can be selected. Previous studies focused on determining the MSC under standard culture conditions, whereas our research aimed to determine the MSC in a model that approximates in vivo conditions.MethodsWe investigated the MSC of oxytetracycline (OTC) in Mueller-Hinton broth (MHB) and sterilised intestinal contents (SIC) from the jejunum, caecum and rectum (faeces) of pigs, using two isogenic strains of Escherichia coli (one susceptible and one resistant to OTC). Additionally, the MIC of OTC against the susceptible strain was determined to assess the upper limit of the sub-MIC selective window.ResultsOur study took a novel approach, and the results indicated that MIC and MSC values were lower in MHB than in SIC. In the latter, these values varied depending on the intestinal segment, with distal compartments exhibiting higher MIC and MSC values. Moreover, the sub-MIC selective window of OTC in SIC narrowed from the jejunum to the rectum, with a significantly closer MSC to MIC in faecal SIC.DiscussionThe results suggest that OTC binds to digestive contents, reducing the fraction of free OTC. However, binding alone does not fully explain our results, and interactions between bacteria and intestinal contents may play a role. Furthermore, our findings provide initial estimates of low concentrations facilitating resistance selection in the gut. Finally, this research enhances the understanding of antimicrobial resistance selection, emphasising the intricate interplay between antibiotics and intestinal content composition in assessing the risk of resistance development in the gut.

Whereas immunotherapies have revolutionized the treatment of different solid and hematological cancers, their efficacy in nodal peripheral T-cell lymphomas (PTCLs) is limited, due to a lack of understanding of the immune response they trigger. To fully characterize the immune tumor microenvironment (TME) of PTCLs, we performed spectral flow cytometry analyses on 11 angioimmunoblastic T-cell lymphomas (AITL), 7 PTCL, not otherwise specified (PTCL, NOS) lymph node samples, and 10 non-tumoral control samples. The PTCL TME contained a larger proportion of regulatory T cells and exhausted CD8+ T cells, with enriched expression of druggable immune checkpoints. Interestingly, CD39 expression was up-regulated at the surface of most immune cells, and a multi-immunofluorescence analyses on a retrospective cohort of 43 AITL patients demonstrated a significant association between high CD39 expression by T cells and poor patient prognosis. Together, our study unravels the complex TME of nodal PTCLs, identifies targetable immune checkpoints, and highlights CD39 as a novel prognostic factor.