SGD-OD: investigating the potential oxygen demand of submarine groundwater discharge in coastal systems.

Submarine groundwater discharge (SGD) supplies nutrients, carbon, metals, and radionuclide tracers to estuarine and coastal waters. One aspect of SGD that is poorly recognized is its direct effect on dissolved oxygen (DO) demand in receiving waters, denoted here as SGD-OD. Sulfate-mediated oxidation of organic matter in salty coastal aquifers produces numerous reduced byproducts including sulfide, ammonia, dissolved organic carbon and nitrogen, methane, and reduced metals. When these byproducts are introduced to estuarine and coastal systems by SGD and are oxidized, they may substantially reduce the DO concentration in receiving waters and impact organisms living there. We consider six estuarine and coastal sites where SGD derived fluxes of reduced byproducts are well documented. Using data from these sites we present a semiquantitative model to estimate the effect of these byproducts on DO in the receiving waters. Without continued aeration with atmospheric oxygen, the study sites would have experienced periodic hypoxic conditions due to SGD-OD. The presence of H2S supplied by SGD could also impact organisms. This process is likely prevalent in other systems worldwide.

Quantitative Model-Based Assessment of Multiple Sickle Cell Disease Therapeutic Approaches Alone and in Combination.

Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3-BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense-state sickle hemoglobin that contributes to polymer formation. Induction of 30% HbF is seen as the gold standard because 30% endogenous expression is associated with a lack of symptoms. However, the level of intervention required to achieve equivalent polymerization protection by the other strategies is uncertain, and there is little understanding of how these approaches could work in combination. We sought to develop an oxygen saturation model that could assess polymerization protection of all three approaches alone or in combination by extending the Monod-Wymann-Changeux model to include additional mechanisms. Applying the model to monotherapies suggests 51% sickle hemoglobin (HbS) occupancy with an oxyHb stabilizer or lowering RBC 2,3 BPG concentrations to 1.8 mM would produce comparable polymerization protection as 30% HbF. The model predictions are consistent with observed clinical response to the oxyHb stabilizer voxelotor and the 2,3-BPG reducer etavopivat. The model also suggests combination therapy will have added benefit in the case of dose limitations, as is the case for voxelotor, which the model predicts could be combined with 20% HbF or 2,3-BPG reduction to 3.75 mM to reach equivalent protection as 30% HbF. The proposed model represents a unified framework that is useful in supporting decisions in preclinical and early clinical development and capable of evolving with clinical experience to gain new and increasingly confident insights into treatment strategies for SCD.

Increasing awareness of adverse childhood experiences in nurse practitioner students.

ABSTRACT: Adverse childhood experiences (ACEs) are reported in most children, and significant ACEs are associated with neurological changes and chronic conditions. Despite this, routine screening for early identification and intervention is rare. To increase screening frequency, education for providers including nurse practitioners is critical. This project provided asynchronous education on ACEs for family nurse practitioner (FNP) students with preeducation and posteducation survey links. The survey items focused on three key areas: knowledge, skills, and attitudes (KSAs). T-tests were run to determine improvements in knowledge and skills questions and for Likert scale ratings on the attitude questions. Statistical significance was found in skills questions and in knowledge questions for one implementation site, and overall increases were seen in all areas from preeducation to posteducation results. This improvement in KSAs toward ACEs for FNP students showed that increased knowledge and understanding of skills also increased the reported willingness to screen patients in primary care to improve overall health outcomes.

Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy.

BACKGROUND: Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed. METHODS: We developed a model of dynamic TTR concentrations in plasma to relate TTR occupancy by tafamidis to TTR stabilisation. We then developed population pharmacokinetic-pharmacodynamic models to characterise the relationship between stabilisation and measures of disease progression. RESULTS: Modelling individual patient data of tafamidis exposure and increased plasma TTR confirmed that single-site binding provides complete tetramer stabilisation in vivo. The approved dose was estimated to reduce unbound TTR tetramer by 92%, and was associated with 53%, 56% and 49% decreases in the rate of change in NT-proBNP, KCCQ-OS, and six-minute walk test disease progression measures, respectively. Simulating complete TTR stabilisation predicted slightly greater reductions of 58%, 61% and 54%, respectively. CONCLUSIONS: These findings support the value of TTR stabilisation as a clinically beneficial treatment option in ATTR-CM and the ability of tafamidis to realise nearly the full therapeutic benefit of this mechanism. CLINICALTRIALS.GOV IDENTIFIER: NCT01994889.

Impact of local rivers on coastal acidification.

Coastal ecosystems are highly dynamic areas for carbon cycling and are likely to be negatively impacted by increasing ocean acidification. This research focused on dissolved inorganic carbon (DIC) and total alkalinity (TA) in the Mississippi Sound to understand the influence of local rivers on coastal acidification. This area receives large fluxes of freshwater from local rivers, in addition to episodic inputs from the Mississippi River through a human-built diversion, the Bonnet Carré Spillway. Sites in the Sound were sampled monthly from August 2018 to November 2019 and weekly from June to August 2019 in response to an extended spillway opening. Prior to the 2019 spillway opening, the contribution of the local, lower alkalinity rivers to the Sound may have left the study area more susceptible to coastal acidification during winter months, with aragonite saturation states (Ωar) < 2. After the spillway opened, despite a large increase in TA throughout the Sound, aragonite saturation states remained low, likely due to hypoxia and increased CO2 concentrations in subsurface waters. Increased Mississippi River input could represent a new normal in the Sound's hydrography during spring and summer months. The spillway has been utilized more frequently over the last two decades due to increasing precipitation in the Mississippi River watershed, which is primarily associated with climate change. Future increases in freshwater discharge and the associated declines in salinity, dissolved oxygen, and Ωar in the Sound will likely be detrimental to oyster stocks and the resilience of similar ecosystems to coastal acidification.

Considering Abundance, Affinity, and Binding Site Availability in the NF-κB Target Selection Puzzle.

The NF-κB transcription regulation system governs a diverse set of responses to various cytokine stimuli. With tools from in vitro biochemical characterizations, to omics-based whole genome investigations, great strides have been made in understanding how NF-κB transcription factors control the expression of specific sets of genes. Nonetheless, these efforts have also revealed a very large number of potential binding sites for NF-κB in the human genome, and a puzzle emerges when trying to explain how NF-κB selects from these many binding sites to direct cell-type- and stimulus-specific gene expression patterns. In this review, we surmise that target gene transcription can broadly be thought of as a function of the nuclear abundance of the various NF-κB dimers, the affinity of NF-κB dimers for the regulatory sequence and the availability of this regulatory site. We use this framework to place quantitative information that has been gathered about the NF-κB transcription regulation system into context and thus consider questions it answers, and questions it raises. We end with a brief discussion of some of the future prospects that new approaches could bring to our understanding of how NF-κB transcription factors orchestrate diverse responses in different biological contexts.

Membrane Potential Depolarization Alters Calcium Flux and Phosphate Signaling During Osteogenic Differentiation of Human Mesenchymal Stem Cells.

Background: Membrane potential (Vmem) changes accompany important events in embryonic development and organ regeneration. Recent studies have pointed to its function as a potent regulator of cell proliferation, differentiation, migration, and tissue regeneration. We have previously reported that Vmem depolarization and hyperpolarization control the osteogenic (OS) differentiation potential of human mesenchymal stem cells (hMSCs). Materials and Methods: In this study, we sought to understand the mechanism(s) underlying voltage regulation of hMSC differentiation. We investigated the role of calcium and phosphate ion flux in the depolarization response of OS-differentiating hMSCs, as these ions are the two major inorganic components of the bone mineral matrix and are indicative of mature osteoblast function. Results: Our results suggest that inorganic phosphate levels play a larger role than calcium flux in mediating hMSC response to depolarization and that the expression of stanniocalcin 1 (STC1), a protein that regulates calcium and phosphate homeostasis in osteoblasts, is functionally required for the depolarization response during the early stages of differentiation. Conclusion: Depolarization alters hMSC differentiation through a phosphate signaling pathway involving STC1. This study enriches our mechanistic understanding of hMSC response to endogenous voltage cues.

Is Stroke Early Supported Discharge still effective in practice? A prospective comparative study.

OBJECTIVE: Randomised controlled trials have shown the benefits of Early Supported Discharge (ESD) of stroke survivors. Our aim was to evaluate whether ESD is still beneficial when operating in the complex context of frontline healthcare provision. DESIGN: We conducted a cohort study with quasi experimental design. A total of 293 stroke survivors (transfer independently or with assistance of one, identified rehabilitation goals) within two naturally formed groups were recruited from two acute stroke units: 'ESD' n=135 and 'Non ESD' n=158 and 84 caregivers. The 'ESD' group accessed either of two ESD services operating in Nottinghamshire, UK. The 'Non ESD' group experienced standard practices for discharge and onward referral. Outcome measures (primary: Barthel Index) were administered at baseline, 6 weeks, 6 months and 12 months. RESULTS: The ESD group had a significantly shorter length of hospital stay (P=0.029) and reported significantly higher levels of satisfaction with services received (P<0.001). Following adjustment for age differences at baseline, participants in the ESD group (n=71) had significantly higher odds (compared to the Non ESD group, n=85) of being in the ⩾90 Barthel Index category at 6 weeks (OR = 1.557, 95% CI 2.579 to 8.733), 6 months (OR = 1.541, 95% CI 2.617 to 8.340) and 12 months (OR 0.837, 95% CI 1.306 to 4.087) respectively in relation to baseline. Carers of patients accessing ESD services showed significant improvement in mental health scores (P<0.01). CONCLUSION: The health benefits of ESD are still evident when evidence based models of these services are implemented in practice.