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Despite numerous studies on the impacts of climate change in developing economies, scarce research focuses on these spatial effects in the internal regions of these countries. To shed light on this concern, this study aims to analyze the spatial effect of climate change on regional economic disparities in the context of Benin. The secondary data are extracted from the World Bank’s Climate Knowledge Portal and a Beninese local finance database covering the period from 2010 to 2019. A random-effects panel model and a dynamic spatial Durbin model of endogenous growth are used. The results reveal that, in the absence of spatial effects, average temperature reinforces economic disparities by 4.4 points within regions. A one-point increase in precipitation increases economic disparities by 0.001 points. The spatial model reveals both short- and long-term positive spatial externalities. Thus, a one-point positive variation in precipitation in neighboring regions leads to a 0.005% increase in a given region’s own revenue per capita. Similarly, a one-point increase in precipitation in a given region induces a 0.004% rise in own revenues in neighboring regions. Damage caused by climate change in one area encourages positive economic dynamics in neighboring areas. These spatial interactions reinforce economic differences and maintain economic disparities between Benin’s regions.

Abstract Allogrooming is a widespread, pervasive activity among non-human primates. Besides its hygienic function, it is thought to be instrumental in maintaining social bonds and establishing hierarchical structures within groups. However, the question arises as to whether the physiological and social benefits derived from social touch stem directly from body stimulation, or whether other mechanisms come into play. We address this question by analyzing an elaborate social behavior that we observed in two adult male macaques. This behavior demonstrates the existence of a persistent motivation to interact through a form of simulated grooming, as the animals were housed in adjacent enclosures separated by a glass panel preventing direct tactile contact. We find that such virtual grooming produces similar physiological sensations and social effects as allogrooming. We suggest that this behavior engages affective and reward brain circuits to the same extent as real social touch, and that this is probably achieved through high level processes similar to those involved in bodily illusions or synaesthetic phenomena previously described in humans. This observation reveals the unsuspected capacity of non-human primates to invent alternative, quasi-symbolic strategies to obtain effects similar to those provided by direct bodily interaction, which are so important for maintaining social bonds.

Abstract Healthcare datasets are becoming larger and more complex, necessitating the development of accurate and generalizable AI models for medical applications. Unstructured datasets, including medical imaging, electrocardiograms, and natural language data, are gaining attention with advancements in deep convolutional neural networks and large language models. However, estimating the generalizability of these models to new healthcare settings without extensive validation on external data remains challenging. In experiments across 13 datasets including X-rays, CTs, ECGs, clinical discharge summaries, and lung auscultation data, our results demonstrate that model performance is frequently overestimated by up to 20% on average due to shortcut learning of hidden data acquisition biases (DAB). Shortcut learning refers to a phenomenon in which an AI model learns to solve a task based on spurious correlations present in the data as opposed to features directly related to the task itself. We propose an open source, bias-corrected external accuracy estimate, P E s t , that better estimates external accuracy to within 4% on average by measuring and calibrating for DAB-induced shortcut learning.

Abstract Background Participatory research approaches systematically integrate the perspectives of individuals, organizations, or communities that have a direct interest in a study’s processes and outcomes (i.e., stakeholders) in research design and implementation. This supports interventions that are developed “by, not for” end-users, thereby increasing acceptability, uptake, and adherence. However, participatory approaches are relatively under-utilized in intervention development and behavioral change intervention research, in part, due to inadequate reporting of methodology. Therefore, to improve transparency in planning and reporting, we (a) describe how we engaged patients and community organizations (i.e., patient and community partners) in grant development for a self-compassion and physical activity behaviour change intervention for women with cardiovascular risk factors and (b) present a protocol for engaging patient and community partners in the optimization and implementation of the intervention moving forward. Methods Our participatory research approach was guided by the Strategy for Patient-Oriented Research patient engagement framework and our prior stakeholder engagement work. Four patients and three community partners were engaged at the level of Involve, meaning their perspectives informed directions, processes, and decisions at major project milestones. Specifically, patient and community partners engaged in three separate meetings during grant development wherein they: (a) established a Terms of Reference to guide engagement activities and expectations; (b) shaped the grant through guided conversations about research priorities, outcomes, and intervention delivery components that could be targeted for optimization and (c) co-developed a protocol that specifies how relationships will be initiated with future patient partners, proposes engagement activities across the research cycle, and includes plans for formal evaluation of engagement processes. Conclusions Participatory research approaches provide valuable insights into the development of behavioural interventions, especially when stakeholders can partner early and have a meaningful impact. By detailing our engagement activities to date, we hope to model an approach to engaging stakeholders in behavioral intervention development and demonstrate the impacts of doing so.

BackgroundCervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients.ObjectiveWe investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A).MethodsThis single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes.ResultsAmong the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed.ConclusionHPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies.

Summary: Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4+ TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.

Abstract Dissolved inorganic nutrient concentrations in the surface waters (0 to 5 m) of the Northern Gulf of Mexico (NGoM) were analyzed from 1985 to 2019 (> 10,000 observations) to determine spatiotemporal trends and their connection to nutrients supplied from the Mississippi/Atchafalaya River (MAR). In the NGoM, annual mean dissolved inorganic P (DIP) concentrations increased significantly over time, while dissolved inorganic N (DIN) concentrations showed no temporal trend. With greater salinity, mean DIN:DIP decreased from above the Redfield ratio of 16 to below it, reflecting DIN losses and the more conservative behavior of DIP with salinity. Over the same time period, annual mean P (total dissolved P, DIP, dissolved organic P) loading from the MAR to the NGoM significantly increased, annual mean DIN and total dissolved N loading showed no temporal trend, and dissolved organic N loading significantly decreased. Though DIP increased in the MAR, MAR DIP alone was insufficient to explain the surface distribution of DIP with salinity. Therefore, increases in surface DIP in the NGoM are not simply a reflection of increasing MAR DIP, pointing to temporal changes in other DIP sources. The increase in NGoM DIP suggests greater N limitation for phytoplankton, with implications for N fixation and nutrient management.

Abstract Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of a ɑ4-1BB antibody fused to the collagen-binding protein LAIR. While combination treatment with an antitumor antibody (TA99) shows only modest efficacy, simultaneous depletion of CD4+ T cells boosts cure rates to over 90% of mice. Mechanistically, this synergy depends on ɑCD4 eliminating tumor draining lymph node regulatory T cells, resulting in priming and activation of CD8+ T cells which then infiltrate the tumor microenvironment. The cytotoxic program of these newly primed CD8+ T cells is then supported by the combined effect of TA99 and ɑ4-1BB-LAIR. The combination of TA99 and ɑ4-1BB-LAIR with a clinically approved ɑCTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of ɑCTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy.

Abstract Volcanic eruptions generate initially sterile materials where biological processes are absent, allowing for the fresh colonization by new organisms. This review summarizes the characteristics of volcanic habitats that are available for pioneer microbial colonization, including hot springs, fumaroles, lava tubes, and recently cooled rock surfaces and interiors. Eruptions provide unique insight into microbial community development in extreme environments. The trajectories that these ecosystems follow are largely dictated by the initial environmental conditions and identities of the colonizers, rather than the age of the system. The review also discusses how studies of microbial communities in young lava flow fields can provide insights into the possibility of life on Mars, which was volcanically and hydrologically active in the past. Understanding biosignature preservation as well as the metabolisms and survival mechanisms of microorganisms in volcanic systems has implications for how an ecosystem might have developed on early Earth and possibly Mars.

Abstract Background Patient engagement in research (also commonly referred to as patient or patient and public involvement in research) strives to transform health research wherein patients (including caregivers and the public) are regularly and actively engaged as multidisciplinary research team members (i.e. patient partners) working jointly towards improved health outcomes and an enhanced healthcare system. To support its mindful evolution into a staple of health research, this participatory study aimed to identify future directions for Canadian patient engagement in research and discusses its findings in the context of the international literature. Methods The study met its aim through a multi-meeting pan-Canadian virtual workshop. Participants (n = 30) included Strategy for Patient-Oriented Research-funded academic researchers and patient partners identified through a publicly available database, personal and professional networks and social media. All spoke English, could access the workshop virtually, and provided written informed consent. The workshop was composed of four, 1.5–3-h virtual meetings wherein participants discussed the current and preferred future states of Canadian patient engagement in research. Workshop discussions (i.e. data) were video and audio recorded. Themes were generated through an iterative process of inductive thematic analysis that occurred concurrently with the multi-week workshop. Results Our participatory and iterative process identified 10 targetable areas of focus for the future of Canadian patient engagement in research. Five were categorized as system-level (systemic integration; academic culture; engagement networks; funding models; compensation models), one as researcher-level (engagement processes), and four crossed both levels (awareness; diversity and recruitment; training, tools and education; evaluation and impact). System level targetable areas called for reshaping the patient engagement ecosystem to create a legitimized and supportive space for patient engagement to be a staple component of a learning health system. Researcher level targetable areas called for academic researchers and patient partners to collaboratively generate evidence and apply knowledge to inform values and behaviours necessary to foster and sustain supportive health research spaces that are accessible to all. Conclusions Future directions for Canadian patient engagement in research span 10 interconnected targetable areas that require strong leadership and joint action between patient partners, academic researchers, and health and research institutions if patient engagement is to become a ubiquitous component of a learning health system.

The marine cyanobacterium Prochlorococcus can utilize glucose as a source of carbon. However, the relative importance of inorganic and organic carbon assimilation and the timing of glucose assimilation are still poorly understood in these numerically dominant cyanobacteria. Here, we investigated whole microbial community and group-specific primary production and glucose assimilation using incubations with radioisotopes combined with flow cytometry cell sorting. We also studied changes in the microbial community structure in response to glucose enrichments and analyzed the transcription of Prochlorocccus genes involved in carbon metabolism and photosynthesis. Our results showed a diel variation for glucose assimilation in Prochlorococcus, with maximum assimilation at midday and minimum at midnight (~2-fold change), which was different from that of the total microbial community. This suggests that the timing in glucose assimilation in Prochlorococcus is coupled to photosynthetic light reactions producing energy, it being more convenient for Prochlorococcus to show maximum glucose uptake precisely when the rest of microbial populations have their minimum glucose uptake. Many transcriptional responses to glucose enrichment occurred after 12- and 24-h periods, but community composition did not change. High-light Prochlorococcus strains were the most impacted by glucose addition, with transcript-level increases observed for genes in pathways for glucose metabolism, such as the pentose phosphate pathway, the Entner-Doudoroff pathway, glycolysis, respiration, and glucose transport. While Prochlorococcus C assimilation from glucose represented less than 0.1% of the bacteriums photosynthetic C fixation, increased assimilation during the day and glcH gene upregulation upon glucose enrichment indicate an important role of mixotrophic C assimilation by natural populations of Prochlorococcus. IMPORTANCE Several studies have demonstrated that Prochlorococcus, the most abundant photosynthetic organism on Earth, can assimilate organic molecules, such as amino acids, amino sugars, ATP, phosphonates, and dimethylsulfoniopropionate. This autotroph can also assimilate small amounts of glucose, supporting the hypothesis that Prochlorococcus is mixotrophic. Our results show, for the first time, a diel variability in glucose assimilation by natural populations of Prochlorococcus with maximum assimilation during midday. Based on our previous results, this indicates that Prochlorococcus could maximize glucose uptake by using ATP made during the light reactions of photosynthesis. Furthermore, Prochlorococcus showed a different timing of glucose assimilation from the total population, which may offer considerable fitness advantages over competitors temporal niches. Finally, we observed transcriptional changes in some of the genes involved in carbon metabolism, suggesting that Prochlorococcus can use both pathways previously proposed in cyanobacteria to metabolize glucose.

Protist plankton can be divided into three main groups: phytoplankton, zooplankton, and mixoplankton. In situ methods for studying phytoplankton and zooplankton are relatively straightforward since they generally target chlorophyll/photosynthesis or grazing activity, while the integration of both processes within a single cell makes mixoplankton inherently challenging to study. As a result, we understand less about mixoplankton physiology and their role in food webs, biogeochemical cycling, and ecosystems compared to phytoplankton and zooplankton. In this paper, we posit that by merging conventional techniques, such as microscopy and physiological data, with innovative methods like in situ single-cell sorting and omics datasets, in conjunction with a diverse array of modeling approaches ranging from single-cell modeling to comprehensive Earth system models, we can propel mixoplankton research into the forefront of aquatic ecology. We present eight crucial research questions pertaining to mixoplankton and mixotrophy, and briefly outline a combination of existing methods and models that can be used to address each question. Our intent is to encourage more interdisciplinary research on mixoplankton, thereby expanding the scope of data acquisition and knowledge accumulation for this understudied yet critical component of aquatic ecosystems.

4-(tris(4-methyl-1H-pyrazol-1-yl)methyl)aniline was prepared in a 63% yield utilizing a C–F activation strategy from a mixture of 4-(trifluoromethyl)aniline, 4-methylpyrazole, and KOH in dimethylsulfoxide (DMSO). The identity of the product was confirmed by nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, and single-crystal analysis. An analysis of crystals grown from the layering method (CH2Cl2/acetone/pentane) indicated two distinct polymorphs of the title compound. Moreover, density functional theory calculations utilizing the MN15L density functional and the def2-TZVP basis set indicated that 4-(tris(4-methyl-1H-pyrazol-1-yl)methyl)aniline forms with similar energetics to the previously reported unmethylated analog.

Background and purpose: Blood-based biomarkers are a non-invasive solution to predict the risk of conversion of mild cognitive impairment (MCI) to dementia. The utility of free plasma amyloid peptides (not bound to plasma proteins and/or cells) as an early indicator of conversion to dementia is still debated, as the results of studies have been contradictory. In this context, we investigated whether plasma levels of the free amyloid peptides Aβ1–42 and Aβ1–40 and the free plasma Aβ1–42/Aβ1–40 ratio are associated with the conversion of MCI to dementia, in particular AD, over three years of follow-up in a subgroup of the BALTAZAR cohort. We also compared their predictive value to that of total plasma Aβ1–42 and Aβ1–40 levels and the total plasma Aβ1–42/Aβ1–40 ratio. Methods: The plasma Aβ1–42 and Aβ1–40 peptide assay was performed using the INNO-BIA kit (Fujirebio Europe). Free amyloid levels (defined by the amyloid fraction directly accessible to antibodies of the assay) were obtained with the undiluted plasma, whereas total amyloid levels were obtained after the dilution of plasma (1/3) with a denaturing buffer. Free and total Aβ1–42 and Aβ1–40 levels were measured at inclusion for a subgroup of participants (N = 106) with mild cognitive impairment (MCI) from the BALTAZAR study (a large-scale longitudinal multicenter cohort with a three-year follow-up). Associations between conversion and the free/total plasma Aβ1–42 and Aβ1–40 levels and Aβ1–42/Aβ1–40 ratio were analyzed using logistic and Cox Proportional Hazards models. Demographic, clinical, cognitive (MMSE, ADL and IADL), APOE, and MRI characteristics (relative hippocampal volume) were compared using non-parametric (Mann-Whitney) or parametric (Student) tests for quantitative variables and Chi-square or Fisher exact tests for qualitative variables. Results: The risk of conversion to dementia was lower for patients in the highest quartile of free plasma Aβ1–42/Aβ1–40 (≥ 25.8%) than those in the three lower quartiles: hazard ratio = 0.36 (95% confidence interval [0.15–0.87]), after adjustment for age, sex, education, and APOE ε4 (p-value = 0.022). This was comparable to the risk of conversion in the highest quartile of total plasma Aβ1–42/Aβ1–40: hazard ratio = 0.37 (95% confidence interval [0.16–0.89], p-value = 0.027). However, while patients in the highest quartile of total plasma Aβ1–42/Aβ1–40 showed higher MMSE scores and a higher hippocampal volume than patients in the three lowest quartiles of total plasma Aβ1–42/Aβ1–40, as well as normal CSF biomarker levels, the patients in the highest quartile of free plasma Aβ1–42/Aβ1–40 did not show any significant differences in MMSE scores, hippocampal volume, or CSF biomarker levels relative to the three lowest quartiles of free plasma Aβ1–42/Aβ1–40. Conclusion: The free plasma Aβ1–42/Aβ1–40 ratio is associated with a risk of conversion from MCI to dementia within three years, with performance comparable to that of the total plasma Aβ1–42/Aβ1–40 ratio. Threshold levels of the free and total plasma Aβ1–42/Aβ1–40 ratio could be determined, with a 60% lower risk of conversion for patients above the threshold than those below.

Background: People receiving hemodialysis experience high symptom burden that contributes to low functional status and poor health-related quality of life. Management of symptoms is a priority for individuals receiving hemodialysis but limited effective treatments exist. There is emerging evidence that exercise programming can improve several common dialysis-related symptoms. Objective: The primary aim of this study is to evaluate the effect of an exercise rehabilitation program on symptom burden in individuals receiving maintenance hemodialysis. Design: Multicenter, randomized controlled, 1:1 parallel, open label, prospective blinded end point trial. Setting: Three facility-based hemodialysis units in Winnipeg, Manitoba, Canada. Participants: Adults aged 18 years or older with end-stage kidney disease receiving facility-based maintenance hemodialysis for more than 3 months, with at least 1 dialysis-related symptom as indicated by the Dialysis Symptom Index (DSI) severity score >0 (n = 150). Intervention: Supervised 26-week exercise rehabilitation program and 60 minutes of cycling during hemodialysis thrice weekly. Exercise intensity and duration were supervised and individualized by the kinesiologist as per participant baseline physical function with gradual progression over the course of the intervention. Control: Usual hemodialysis care (no exercise program). Measurements: Our primary outcome is change in symptom burden at 12 weeks as measured by the DSI severity score. Secondary outcomes include change in modified DSI severity score (includes 10 symptoms most plausible to improve with exercise), change in DSI severity score at 26 and 52 weeks; time to recover post-hemodialysis; health-related quality of life measured using EuroQol (EQ)-5D-5L; physical activity behavior measured by self-report (Godin-Shepherd questionnaire) and triaxial accelerometry; exercise capacity (shuttle walk test); frailty (Fried); self-efficacy for exercise; and 1-year hospitalization and mortality. Methods: Change in primary outcome will be compared between groups by independent 2-tailed t test or Mann-Whitney U test depending on data distribution and using generalized linear mixed models, with study time point as a random effect and adjusted for baseline DSI score. Similarly, change in secondary outcomes will be compared between groups over time using appropriate parametric and nonparametric statistical tests depending on data type and distribution. Limitations: The COVID-19 pandemic restrictions on clinical research at our institution delayed completion of target recruitment and prevented collection of accelerometry and physical function outcome data for 15 months until restrictions were lifted. Conclusions: The application of an exercise rehabilitation program to improve symptom burden in individuals on hemodialysis may ameliorate common symptoms observed in individuals on hemodialysis and result in improved quality of life and reduced disability and morbidity over the long term. Importantly, this pragmatic study, with a standardized exercise intervention that is adaptable to baseline physical function, addresses an important gap in both clinical care of hemodialysis patients and our current knowledge.