Higher substance use is associated with low executive control neural activity and higher inflammation.

Individuals with substance use problems show lower executive control and alterations in prefrontal brain systems supporting emotion regulation and impulse control. A separate literature suggests that heightened inflammation also increases risk for substance use, in part, through targeting brain systems involved in executive control. Research on neural and inflammatory signaling in substance use, however, has occurred in parallel. Drawing on recent neuroimmune network models, we used fMRI to examine the relationships between executive control-related brain activity (as elicited by an n-back working memory task), peripheral inflammation, as quantified by inflammatory cytokines and C-reactive protein (CRP), and substance use for the past month in 93 participants [mean age = 24.4 (SD = 0.6)]. We operationalized low executive control as a neural inefficiency during the n-back task to achieve normative performance, as reflected in higher working memory-related brain activity and lower activity in the default mode network (DMN). Consistent with prediction, individuals with low executive control and high inflammation reported more substance use over the past month, controlling for behavioral performance on the n-back, sex, time between assessments, body-mass-index (BMI), and personal socioeconomic status (SES) (interaction between inflammation and working memory-related brain activity, b = 0.210, p = 0.005; interaction between inflammation and DMN, b = -0.219, p < 0.001). Findings suggest that low executive control and high inflammation may be associated with higher substance use. This has implications for understanding psychological, neural, and immunological risk for substance use problems and the development of interventions to target each of these components.

Altered Glucose Kinetics Occurs With Aging, A New Outlook on Metabolic Flexibility.

Our purpose was to determine how age affects metabolic flexibility and underlying glucose kinetics in healthy young and older adults. Therefore, glucose and lactate tracers, along with pulmonary gas exchange data were used to determine glucose kinetics and respiratory exchange ratios (RER=CO2/O2) during a 2-hour 75-gram oral glucose tolerance test (OGTT). After an 12-hour overnight fast, 28 participants, 15 young (21-35 yr.; 7 men and 8 women) and 13 older (60-80 yr.; 7 men and 6 women) received venous primed-continuous infusions of [6,6-2H]glucose, and [3-13C]lactate with a H13CO3- bolus. Following a 90-minute metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. Arterialized glucose concentrations ([glucose]) started to rise 15 minutes post-glucose consumption, peaked at 60 minutes, and remained elevated. As assessed by rates of appearance (Ra), disposal (Rd) and metabolic clearance (MCR) glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population following the oral glucose challenge. Lastly, there were no differences in 12-hr fasting baseline or peak RER values following an oral glucose challenge in older compared to young men and women, making RER an incomplete measure of metabolic flexibility in the volunteers we evaluated. Our study revealed that glucose kinetics are significantly altered in a healthy aged population following a glucose challenge. Further, those physiological deficits are not detected from changes in RER during an OGTT.

Spatial and life history variation in a trait-based species vulnerability and impact model.

Anthropogenic pressures threaten biodiversity, necessitating conservation actions founded on robust ecological models. However, prevailing models inadequately capture the spatiotemporal variation in environmental pressures faced by species with high mobility or complex life histories, as data are often aggregated across species' life histories or spatial distributions. We highlight the limitations of static models for dynamic species and incorporate life history variation and spatial distributions for species and stressors into a trait-based vulnerability and impact model. We use green sea turtles in the Greater Caribbean Region to demonstrate how vulnerability and anthropogenic impact for a dynamic species change across four life stages. By incorporating life stages into a trait-based vulnerability model, we observed life stage-specific vulnerabilities that were otherwise unnoticed when using an aggregated trait value set. Early life stages were more vulnerable to some stressors, such as inorganic pollution or marine heat waves, and less vulnerable to others, such as bycatch. Incorporating spatial distributions of stressors and life stages revealed impacts differ for each life stage across spatial areas, emphasizing the importance of stage-specific conservation measures. Our approach showcases the importance of incorporating dynamic processes into ecological models and will enable better and more targeted conservation actions for species with complex life histories and high mobility.

A concept for international societally relevant microbiology education and microbiology knowledge promulgation in society.

EXECUTIVE SUMMARY: Microbes are all pervasive in their distribution and influence on the functioning and well-being of humans, life in general and the planet. Microbially-based technologies contribute hugely to the supply of important goods and services we depend upon, such as the provision of food, medicines and clean water. They also offer mechanisms and strategies to mitigate and solve a wide range of problems and crises facing humanity at all levels, including those encapsulated in the sustainable development goals (SDGs) formulated by the United Nations. For example, microbial technologies can contribute in multiple ways to decarbonisation and hence confronting global warming, provide sanitation and clean water to the billions of people lacking them, improve soil fertility and hence food production and develop vaccines and other medicines to reduce and in some cases eliminate deadly infections. They are the foundation of biotechnology, an increasingly important and growing business sector and source of employment, and the centre of the bioeconomy, Green Deal, etc. But, because microbes are largely invisible, they are not familiar to most people, so opportunities they offer to effectively prevent and solve problems are often missed by decision-makers, with the negative consequences this entrains. To correct this lack of vital knowledge, the International Microbiology Literacy Initiative-the IMiLI-is recruiting from the global microbiology community and making freely available, teaching resources for a curriculum in societally relevant microbiology that can be used at all levels of learning. Its goal is the development of a society that is literate in relevant microbiology and, as a consequence, able to take full advantage of the potential of microbes and minimise the consequences of their negative activities. In addition to teaching about microbes, almost every lesson discusses the influence they have on sustainability and the SDGs and their ability to solve pressing problems of societal inequalities. The curriculum thus teaches about sustainability, societal needs and global citizenship. The lessons also reveal the impacts microbes and their activities have on our daily lives at the personal, family, community, national and global levels and their relevance for decisions at all levels. And, because effective, evidence-based decisions require not only relevant information but also critical and systems thinking, the resources also teach about these key generic aspects of deliberation. The IMiLI teaching resources are learner-centric, not academic microbiology-centric and deal with the microbiology of everyday issues. These span topics as diverse as owning and caring for a companion animal, the vast range of everyday foods that are produced via microbial processes, impressive geological formations created by microbes, childhood illnesses and how they are managed and how to reduce waste and pollution. They also leverage the exceptional excitement of exploration and discovery that typifies much progress in microbiology to capture the interest, inspire and motivate educators and learners alike. The IMiLI is establishing Regional Centres to translate the teaching resources into regional languages and adapt them to regional cultures, and to promote their use and assist educators employing them. Two of these are now operational. The Regional Centres constitute the interface between resource creators and educators-learners. As such, they will collect and analyse feedback from the end-users and transmit this to the resource creators so that teaching materials can be improved and refined, and new resources added in response to demand: educators and learners will thereby be directly involved in evolution of the teaching resources. The interactions between educators-learners and resource creators mediated by the Regional Centres will establish dynamic and synergistic relationships-a global societally relevant microbiology education ecosystem-in which creators also become learners, teaching resources are optimised and all players/stakeholders are empowered and their motivation increased. The IMiLI concept thus embraces the principle of teaching societally relevant microbiology embedded in the wider context of societal, biosphere and planetary needs, inequalities, the range of crises that confront us and the need for improved decisioning, which should ultimately lead to better citizenship and a humanity that is more sustainable and resilient. ABSTRACT: The biosphere of planet Earth is a microbial world: a vast reactor of countless microbially driven chemical transformations and energy transfers that push and pull many planetary geochemical processes, including the cycling of the elements of life, mitigate or amplify climate change (e.g., Nature Reviews Microbiology, 2019, 17, 569) and impact the well-being and activities of all organisms, including humans. Microbes are both our ancestors and creators of the planetary chemistry that allowed us to evolve (e.g., Life's engines: How microbes made earth habitable, 2023). To understand how the biosphere functions, how humans can influence its development and live more sustainably with the other organisms sharing it, we need to understand the microbes. In a recent editorial (Environmental Microbiology, 2019, 21, 1513), we advocated for improved microbiology literacy in society. Our concept of microbiology literacy is not based on knowledge of the academic subject of microbiology, with its multitude of component topics, plus the growing number of additional topics from other disciplines that become vitally important elements of current microbiology. Rather it is focused on microbial activities that impact us-individuals/communities/nations/the human world-and the biosphere and that are key to reaching informed decisions on a multitude of issues that regularly confront us, ranging from personal issues to crises of global importance. In other words, it is knowledge and understanding essential for adulthood and the transition to it, knowledge and understanding that must be acquired early in life in school. The 2019 Editorial marked the launch of the International Microbiology Literacy Initiative, the IMiLI. HERE, WE PRESENT: our concept of how microbiology literacy may be achieved and the rationale underpinning it; the type of teaching resources being created to realise the concept and the framing of microbial activities treated in these resources in the context of sustainability, societal needs and responsibilities and decision-making; and the key role of Regional Centres that will translate the teaching resources into local languages, adapt them according to local cultural needs, interface with regional educators and develop and serve as hubs of microbiology literacy education networks. The topics featuring in teaching resources are learner-centric and have been selected for their inherent relevance, interest and ability to excite and engage. Importantly, the resources coherently integrate and emphasise the overarching issues of sustainability, stewardship and critical thinking and the pervasive interdependencies of processes. More broadly, the concept emphasises how the multifarious applications of microbial activities can be leveraged to promote human/animal, plant, environmental and planetary health, improve social equity, alleviate humanitarian deficits and causes of conflicts among peoples and increase understanding between peoples (Microbial Biotechnology, 2023, 16(6), 1091-1111). Importantly, although the primary target of the freely available (CC BY-NC 4.0) IMiLI teaching resources is schoolchildren and their educators, they and the teaching philosophy are intended for all ages, abilities and cultural spectra of learners worldwide: in university education, lifelong learning, curiosity-driven, web-based knowledge acquisition and public outreach. The IMiLI teaching resources aim to promote development of a global microbiology education ecosystem that democratises microbiology knowledge.

Conserved patterns of sequence diversification provide insight into the evolution of two-component systems in Enterobacteriaceae.

Two-component regulatory systems (TCSs) are a major mechanism used by bacteria to sense and respond to their environments. Many of the same TCSs are used by biologically diverse organisms with different regulatory needs, suggesting that the functions of TCS must evolve. To explore this topic, we analysed the amino acid sequence divergence patterns of a large set of broadly conserved TCS across different branches of Enterobacteriaceae, a family of Gram-negative bacteria that includes biomedically important genera such as Salmonella, Escherichia, Klebsiella and others. Our analysis revealed trends in how TCS sequences change across different proteins or functional domains of the TCS, and across different lineages. Based on these trends, we identified individual TCS that exhibit atypical evolutionary patterns. We observed that the relative extent to which the sequence of a given TCS varies across different lineages is generally well conserved, unveiling a hierarchy of TCS sequence conservation with EnvZ/OmpR as the most conserved TCS. We provide evidence that, for the most divergent of the TCS analysed, PmrA/PmrB, different alleles were horizontally acquired by different branches of this family, and that different PmrA/PmrB sequence variants have highly divergent signal-sensing domains. Collectively, this study sheds light on how TCS evolve, and serves as a compendium for how the sequences of the TCS in this family have diverged over the course of evolution.

Alternate typhoid toxin assembly evolved independently in the two Salmonella species.

AB5-type toxins are a diverse family of protein toxins composed of an enzymatic active (A) subunit and a pentameric delivery (B) subunit. Salmonella enterica serovar Typhi's typhoid toxin features two A subunits, CdtB and PltA, in complex with the B subunit PltB. Recently, it was shown that S. Typhi encodes a horizontally acquired B subunit, PltC, that also assembles with PltA/CdtB to produce a second form of typhoid toxin. S. Typhi therefore produces two AB5 toxins with the same A subunits but distinct B subunits, an evolutionary twist that is unique to typhoid toxin. Here, we show that, remarkably, the Salmonella bongori species independently evolved an analogous capacity to produce two typhoid toxins with distinct B subunits. S. bongori's alternate B subunit, PltD, is evolutionarily distant from both PltB and PltC and outcompetes PltB to form the predominant toxin. We show that, surprisingly, S. bongori elicits similar levels of CdtB-mediated intoxication as S. Typhi during infection of cultured human epithelial cells. This toxicity is exclusively due to the PltB toxin, and strains lacking pltD produce increased amounts of PltB toxin and exhibit increased toxicity compared to the wild type, suggesting that the acquisition of the PltD subunit potentially made S. bongori less virulent toward humans. Collectively, this study unveils a striking example of convergent evolution that highlights the importance of the poorly understood "two-toxin" paradigm for typhoid toxin biology and, more broadly, illustrates how the flexibility of A-B interactions has fueled the evolutionary diversification and expansion of AB5-type toxins. IMPORTANCE: Typhoid toxin is an important Salmonella Typhi virulence factor and an attractive target for therapeutic interventions to combat typhoid fever. The recent discovery of a second version of this toxin has substantial implications for understanding S. Typhi pathogenesis and combating typhoid fever. In this study, we discover that a remarkably similar two-toxin paradigm evolved independently in Salmonella bongori, which strongly suggests that this is a critical aspect of typhoid toxin biology. We observe significant parallels between how the two toxins assemble and their capacity to intoxicate host cells during infection in S. Typhi and S. bongori, which provides clues to the biological significance of this unusual toxin arrangement. More broadly, AB5 toxins with diverse activities and mechanisms are essential virulence factors for numerous important bacterial pathogens. This study illustrates the capacity for novel A-B interactions to evolve and thus provides insight into how such a diverse arsenal of toxins might have emerged.

Enteric and systemic postprandial lactate shuttle phases and dietary carbohydrate carbon flow in humans.

Dietary glucose in excess is stored in the liver in the form of glycogen. As opposed to direct conversion of glucose into glycogen, the hypothesis of the postprandial lactate shuttle (PLS) proposes that dietary glucose uptake is metabolized to lactate in the gut, thereby being transferred to the liver for glycogen storage. In the present study, we provide evidence of a PLS in young healthy men and women. Overnight fasted participants underwent an oral glucose tolerance test, and arterialized lactate concentration and rate of appearance were determined. The concentration of lactate in the blood rose before the concentration of glucose, thus providing evidence of an enteric PLS. Secondary increments in the concentration of lactate in the blood and its rate of appearance coincided with those of glucose, which indicates the presence of a larger, secondary, systemic PLS phase driven by hepatic glucose release. The present study challenges the notion that lactate production is the result of hypoxia in skeletal muscles, because our work indicates that glycolysis proceeds to lactate in fully aerobic tissues and dietary carbohydrate is processed via lactate shuttling. Our study proposes that, in humans, lactate is a major vehicle for carbohydrate carbon distribution and metabolism.

Alkyl-templated cocrystallization of long-chain 1-bromoalkanes by lipid-like ionic liquids.

The serendipitous discovery of an unorthodox ionic cocrystallization system using 2-mercaptothiazolium-based ionic liquids as a crystallization milieu paves the way for the first report of crystal structures of long-chain 1-bromoalkanes. We used single crystal X-ray diffraction to determine the structures of 1-bromo-hexadecane and 1-octadecane with the aid of ionic liquids with alkyl side chains of equivalent length to the bromoalkane at room temperature. Long alkyl chains in combination with σ-hole interactions from strategically placed sulfur motifs synergistically function to crystallize the 1-bromoalkanes.

Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward.

BACKGROUND: Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. METHODS: 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood - C-reactive protein, tumor necrosis factor-a, and interleukins-6, -8, and -10 - and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. RESULTS: Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. CONCLUSIONS: Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

Multicenter Comparison of the Safety and Efficacy of Clopidogrel Versus Ticagrelor for Neuroendovascular Stents.

BACKGROUND: Dual antiplatelet therapy (DAPT) is commonly employed for neuroendovascular stenting due to the significant risk of thromboembolism. Clopidogrel and aspirin are most often selected as initial DAPTs; however, there is limited literature available to support guidance of DAPT in this setting. The objective of this study was to evaluate safety and efficacy in patients whose final regimen included either DAPT with aspirin and clopidogrel (DAPT-C) or DAPT with aspirin and ticagrelor (DAPT-T). METHODS: This was a multicenter, retrospective cohort of patients who underwent neuroendovascular stenting and received DAPT between July 1, 2017, and October 31, 2020. Study participants were allocated into groups based on discharge DAPT regimen. The primary outcome was incidence of stent thrombosis at 3-6 months on DAPT-C versus DAPT-T, as defined by the presence of thrombus on imaging or new onset stroke. Secondary outcomes included major and minor bleeding and death within 3-6 months after the procedure. RESULTS: Five hundred and seventy patients were screened across 12 sites. Of those, 486 were included (DAPT-C n = 360, DAPT-T n = 126). There was no difference in the primary outcome of stent thrombosis between the DAPT-C and DAPT-T groups (8% vs. 8%, p = 0.97) and no difference in any of the secondary safety outcomes. CONCLUSIONS: Using DAPT-C or DAPT-T regimens in a broad population of neuroendovascular stenting procedures appears to have similar safety and efficacy profiles. Further prospective evaluation is warranted to streamline the practice of DAPT selection and monitoring to determine the impact on clinical outcomes.

The effect of NK3-Saporin injection within the arcuate nucleus on puberty, the LH surge, and the response to Senktide in female sheep†.

The timing of puberty onset is reliant on increased gonadotropin-releasing hormone (GnRH). This elicits a corresponding increase in luteinizing hormone (LH) due to a lessening of sensitivity to the inhibitory actions of estradiol (E2). The mechanisms underlying the increase in GnRH release likely involve a subset of neurons within the arcuate (ARC) nucleus of the hypothalamus that contain kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons). We aimed to determine if KNDy neurons in female sheep are critical for: timely puberty onset; the LH surge; and the response to an intravenous injection of the neurokinin-3 receptor (NK3R) agonist, senktide. Prepubertal ewes received injections aimed at the ARC containing blank-saporin (control, n = 5) or NK3-saporin (NK3-SAP, n = 6) to ablate neurons expressing NK3R. Blood samples taken 3/week for 65 days following surgery were assessed for progesterone to determine onset of puberty. Control ewes exhibited onset of puberty at 33.2 ± 3.9 days post sampling initiation, whereas 5/6 NK3-SAP treated ewes didn't display an increase in progesterone. After an artificial LH surge protocol, surge amplitude was lower in NK3-SAP ewes. Finally, ewes were treated with senktide to determine if an LH response was elicited. LH pulses were evident in both groups in the absence of injections, but the response to senktide vs saline was similar between groups. These results show that KNDy cells are necessary for timely puberty onset and for full expresson of the LH surge. The occurrence of LH pulses in NK3-SAP treated ewes may indicate a recovery from an apulsatile state.

The complex interactions between nutrition, immunity and infection in insects.

Insects are the most diverse animal group on the planet. Their success is reflected by the diversity of habitats in which they live. However, these habitats have undergone great changes in recent decades; understanding how these changes affect insect health and fitness is an important challenge for insect conservation. In this Review, we focus on the research that links the nutritional environment with infection and immune status in insects. We first discuss the research from the field of nutritional immunology, and we then investigate how factors such as intracellular and extracellular symbionts, sociality and transgenerational effects may interact with the connection between nutrition and immunity. We show that the interactions between nutrition and resistance can be highly specific to insect species and/or infection type - this is almost certainly due to the diversity of insect social interactions and life cycles, and the varied environments in which insects live. Hence, these connections cannot be easily generalised across insects. We finally suggest that other environmental aspects - such as the use of agrochemicals and climatic factors - might also influence the interaction between nutrition and resistance, and highlight how research on these is essential.

Predicting Time to Evaluation After Pediatric Concussion: Factors Affecting Specialty Concussion Care.

Background: The timing of clinical evaluation after pediatric concussion represents an important and potentially modifiable clinical milestone for diagnosis, selection of appropriate treatment pathways, and recovery prognosis. Patient demographics, socioeconomic status, or medical history may affect the time to the initial evaluation and subsequently influence recovery outcomes. Purpose/Hypothesis: The purpose of this investigation was to evaluate the association of patient characteristics with the time to specialty evaluation after a concussion. It was hypothesized that patients with a history of concussion, a preexisting relationship with our specialty concussion program, or a higher ZIP code-based income estimate would present for care more quickly after a concussion than patients without these characteristics. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Included were patients with a concussion between 6 and 18 years old who were seen for care at a single sports medicine center between January 1 and December 31, 2019. Patient demographic, socioeconomic, injury, and clinical characteristics were collected through a retrospective review of the medical records. The primary outcome was the number of days between the date of the concussion and the patient's initial specialty evaluation. Results: Overall, 220 patients (mean age, 14.4 ± 2.5 years; 46% female) were seen for care at a mean of 9.7 ± 5.6 days (range, 1-21 days) after concussion. A shorter time to specialty evaluation was associated with a history of concussion (ß = -1.72 [95% CI, -3.24 to -0.20]; P = .03) and a prior clinical relationship with the treating clinical department (ß = -1.85 [95% CI, -3.52 to -0.19]; P = .03). Referral by a primary care provider was associated with a longer time to evaluation (ß = 3.86 [95% CI, 2.39-5.33]; P < .0001). Conclusion: A history of concussion and having a preexisting clinical relationship with the deparment were associated with a shorter time to evaluation after concussion. Referral from a primary care physician was associated with a longer time to evaluation. Issues may exist in the propensity to access care after an injury, resulting in delays for initiating early treatment.

Underfeeding Alters Brain Tissue Synthesis Rate in a Rat Brain Injury Model.

Brain injuries (BI) are highly disruptive, often having long lasting effects. Inadequate standard of care (SOC) energy support in the hospital leads to dietary energy deficiencies in BI patients. However, it is unclear how underfeeding (UF) affects protein synthesis post-BI. Therefore, in a rat model, we addressed the issue of UF on the protein fractional synthesis rate (fSR) post-BI. Compared to ad libitum (AL)-fed animals, we found that UF decreased protein synthesis in hind-limb skeletal muscle and cortical mitochondrial and structural proteins (p ≤ 0.05). BI significantly increased protein synthesis in the left and right cortices (p ≤ 0.05), but suppressed protein synthesis in the cerebellum (p ≤ 0.05) as compared to non-injured sham animals. Compared to underfeeding alone, UF in conjunction with BI (UF+BI) caused increased protein synthesis rates in mitochondrial, cytosolic, and whole-tissue proteins of the cortical brain regions. The increased rates of protein synthesis found in the UF+BI group were mitigated by AL feeding, demonstrating that caloric adequacy alleviates the effects of BI on protein dynamics in cortical and cerebellar brain regions. This research provides evidence that underfeeding has a negative impact on brain healing post-BI and that protein reserves in uninjured tissues are mobilized to support cortical tissue repair following BI.

Corridor-based approach with spatial cross-validation reveals scale-dependent effects of geographic distance, human footprint and canopy cover on grizzly bear genetic connectivity.

Understanding how human infrastructure and other landscape attributes affect genetic differentiation in animals is an important step for identifying and maintaining dispersal corridors for these species. We built upon recent advances in the field of landscape genetics by using an individual-based and multiscale approach to predict landscape-level genetic connectivity for grizzly bears (Ursus arctos) across ~100,000 km2 in Canada's southern Rocky Mountains. We used a genetic dataset with 1156 unique individuals genotyped at nine microsatellite loci to identify landscape characteristics that influence grizzly bear gene flow at multiple spatial scales and map predicted genetic connectivity through a matrix of rugged terrain, large protected areas, highways and a growing human footprint. Our corridor-based modelling approach used a machine learning algorithm that objectively parameterized landscape resistance, incorporated spatial cross validation and variable selection and explicitly accounted for isolation by distance. This approach avoided overfitting, discarded variables that did not improve model performance across withheld test datasets and spatial predictive capacity compared to random cross-validation. We found that across all spatial scales, geographic distance explained more variation in genetic differentiation in grizzly bears than landscape variables. Human footprint inhibited connectivity across all spatial scales, while open canopies inhibited connectivity at the broadest spatial scale. Our results highlight the negative effect of human footprint on genetic connectivity, provide strong evidence for using spatial cross-validation in landscape genetics analyses and show that multiscale analyses provide additional information on how landscape variables affect genetic differentiation.

Phase 3 Clinical Trial Comparing the Safety and Efficacy of Netarsudil to Ripasudil in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: Japan Rho Kinase Elevated Intraocular Pressure Treatment Trial (J-ROCKET).

INTRODUCTION: A clinical trial evaluated ocular hypotensive efficacy and safety of netarsudil 0.02% once daily (QD) relative to ripasudil 0.4% twice daily (BID). METHODS: This was a single-masked, randomized, phase 3, superiority study. Japanese patients were randomized to either the netarsudil 0.02% group or the ripasudil 0.4% group in a 1:1 ratio and treated for 4 weeks. The primary efficacy variable was mean diurnal intraocular pressure (IOP) (average of diurnal time points at 09:00, 11:00, and 16:00) at Week 4. RESULTS: A total of 245 patients were included in the primary analysis. At Week 4, least squares (LS) mean of diurnal IOP adjusted for baseline was 15.96 and 17.71 mmHg in the netarsudil 0.02% and ripasudil 0.4% groups, respectively, demonstrating the superiority of netarsudil 0.02% QD over ripasudil 0.4% BID by a margin of - 1.74 mmHg (p < 0.0001). Mean reduction from baseline in mean diurnal IOP at Week 4 was 4.65 and 2.98 mmHg, respectively. Adverse events (AEs) occurred less frequently in netarsudil 0.02% than in ripasudil 0.4%, with the incidence of ocular AEs being 59.8% and 66.7%, respectively. The most frequently reported AE was conjunctival hyperemia in both groups, with an incidence of 54.9% and 62.6%, respectively. No serious eye-related AEs were reported. CONCLUSION: Netarsudil ophthalmic solution 0.02% dosed QD (p.m.) was well tolerated and more effective in reducing IOP than ripasudil ophthalmic solution 0.4% dosed BID. Netarsudil 0.02% QD may become an important option for the treatment of Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04620135.

Retrospective evaluation of dexmedetomidine dosing in a cohort of neurologically injured obese critically ill patients.

Background: Dexmedetomidine is used in neurocritical care units (NCCUs) due to the light, dose-dependent sedation, and anxiolysis provided. It is unknown how to dose dexmedetomidine in obese patients. The primary objective is to assess the ability to achieve the goal Richmond Agitation Sedation Scale (RASS) measurements in obese patients with a neurological injury who are solely on dexmedetomidine before and after an institutional dosing change from actual body weight (ABW) to adjusted body weight (AdjBW). Methods: This study included patients admitted to the NCCU with a neurological condition, required dexmedetomidine for at least 8 h as a sole sedative, and weighed ≥120% of ideal body weight. Percentage of RASS measurements within the goal range (-1 to +1) during the first 48 h while on dexmedetomidine were compared between patients dosed on ABW and on AdjBW. Results: Sixty-eight patients in the ABW cohort and 72 patients in the AdjBW cohort were included. There were no statistical differences between the two groups (ABW vs. AdjBW) in the percent of RASS measurements in the goal range (53.2% ± 34.8% vs. 55% ± 37%; P = 0.78), mean weight (99.2 ± 26 vs. 96.8 ± 20.9 kg; P = 0.55), or the average dose of dexmedetomidine required to achieve first goal RASS score (0.4 ± 0.3 vs. 0.4 ± 0.3 mcg/kg/h; P = 0.98). Conclusions: Dosing dexmedetomidine using AdjBW in obese critically ill neurologically injured patients for ongoing sedation resulted in no statistical difference in the percent of RASS measurements within the goal when compared to ABW dosing. Further studies are warranted.

The Association of Intravitreal Anti-VEGF Injections With Kidney Function in Diabetic Retinopathy.

Purpose: To examine whether patients with diabetic retinopathy receiving intravitreal anti-VEGF injections are at increased risk of kidney function decline. Design: Retrospective cohort study. Participants: Included 187 patients who received intravitreal anti-VEGF injections for proliferative diabetic retinopathy (PDR) and/or diabetic macular edema (DME), and 929 controls with non-PDR who did not receive injections, at a large tertiary care center in Chicago, Illinois. Methods: We queried our institutional enterprise data warehouse to identify patients with diabetic retinopathy, determined whether they received intravitreal anti-VEGF injections, and followed kidney function for all patients over time. Main Outcome Measures: We assessed time to sustained 40% decline in estimated glomerular filtration rate (eGFR) from baseline in patients receiving intravitreal anti-VEGF injections and compared it with controls using Kaplan-Meier and multivariable adjusted Cox proportional hazards regression models. Results: This study included 1116 patients (565 female [50.6%]; mean [standard deviation {SD}] age, 57.3 [13.6] years; mean [SD] eGFR, 65.3 [32.1] ml/min/1.73 m2). Of these, 187 patients received ≥ 1 intravitreal anti-VEGF injection (mean [SD], 11.4 [13.1] injections) for PDR and/or DME, and 929 controls with non-PDR received no injections. Intravitreal anti-VEGF injection use was not associated with an increased risk of kidney function decline (hazard ratio [HR], 1.44; 95% confidence interval [CI], 0.97-2.15). Subgroup analyses revealed that use of intravitreal anti-VEGF injections was associated with increased risk of kidney function decline in male patients (HR, 1.87; 95% CI, 1.11-3.14) but not female patients (HR, 0.97; 95% CI, 0.50-1.89). Intravitreal anti-VEGF injection use was also associated with an increased risk of kidney function decline in patients with baseline eGFR > 30 ml/min/1.73 m2 (HR, 1.86; 95% CI, 1.15-3.01), but not in individuals with baseline eGFR ≤ 30 ml/min/1.73 m2 (HR, 0.97; 95% CI, 0.45-2.10). Among patients who received injections, receiving ≥ 12 injections was not associated with risk of kidney function decline (HR, 1.13; 95% CI, 0.52-2.49). Conclusions: Intravitreal anti-VEGF injections for patients with diabetic retinopathy are overall well-tolerated with respect to kidney function, but the use of intravitreal anti-VEGF injections was associated with an increased risk of kidney function decline in certain subgroups of patients. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Conceptualizing socially-assistive robots as a digital therapeutic tool in healthcare.

Artificial Intelligence (AI)-driven Digital Health (DH) systems are poised to play a critical role in the future of healthcare. In 2021, $57.2 billion was invested in DH systems around the world, recognizing the promise this concept holds for aiding in delivery and care management. DH systems traditionally include a blend of various technologies, AI, and physiological biomarkers and have shown a potential to provide support for individuals with various health conditions. Digital therapeutics (DTx) is a more specific set of technology-enabled interventions within the broader DH sphere intended to produce a measurable therapeutic effect. DTx tools can empower both patients and healthcare providers, informing the course of treatment through data-driven interventions while collecting data in real-time and potentially reducing the number of patient office visits needed. In particular, socially assistive robots (SARs), as a DTx tool, can be a beneficial asset to DH systems since data gathered from sensors onboard the robot can help identify in-home behaviors, activity patterns, and health status of patients remotely. Furthermore, linking the robotic sensor data to other DH system components, and enabling SAR to function as part of an Internet of Things (IoT) ecosystem, can create a broader picture of patient health outcomes. The main challenge with DTx, and DH systems in general, is that the sheer volume and limited oversight of different DH systems and DTxs is hindering validation efforts (from technical, clinical, system, and privacy standpoints) and consequently slowing widespread adoption of these treatment tools.

Multicenter comparison of antiplatelet treatment strategies for urgent/emergent neuroendovascular stenting.

BACKGROUND: Emergent neuroendovascular stenting presents challenges for the utilization of antiplatelet agents. METHODS: This was a multicenter, retrospective cohort of patients who underwent emergent neuroendovascular stenting. The primary endpoints were thrombotic and bleeding events in relation to the timing of antiplatelet administration, route of administration, and choice of intravenous (IV) agent and the study investigated practice variability in antiplatelet utilization. RESULTS: Five-hundred and seventy patients were screened across 12 sites. Of those, 167 were included for data analysis. For patients who presented with ischemic stroke, artery dissection and emergent internal carotid artery (ICA) stenting who received an antiplatelet agent prior to or during the procedure, 57% were given an IV antiplatelet agent; for patients who were given an antiplatelet agent after the procedure, 96% were given an oral agent. For patients who presented for aneurysm repair and received an antiplatelet agent prior to or during the procedure, 74% were given an IV agent; patients who were given an antiplatelet agent after the completion of the procedure were given an oral antiplatelet agent 90% of the time. In patients who presented with ischemic stroke, artery dissection and emergent ICA stenting who received oral antiplatelet agents post-procedure were more likely to have thrombotic events compared to those who received oral antiplatelet agents prior to or during the procedure (29% vs 9%; p = 0.04). There were no differences in the primary outcomes observed when comparing other antiplatelet treatment strategies. CONCLUSION: The optimal timing of antiplatelet administration in relation to stent placement and route of administration of antiplatelet agents is unclear. Timing and route of administration of antiplatelet agents may have an effect on thrombosis in emergent neuroendovascular stenting. Significant practice variation exists in antiplatelet agent utilization in emergent neuroendovascular stenting.