Protective Assets Reinforced With Integrated Care and Technology (PARITY): Protocol for a Randomized Controlled Trial.

BACKGROUND: Black women are significantly more likely to experience severe maternal morbidity and are 3 times as likely to die from pregnancy-related causes compared to White women. Using a strengths-based wellness approach within an integrated supportive care program provided by a community doula could offer pragmatic solutions for Black maternal disparities. The Protective Assets Reinforced with Integrated Care and Technology (PARITY) program consists of a wellness technology platform, including informational links to wellness content and reinforcing motivational SMS text messages, as well as community-based doula support delivered both in person and through the technology platform to improve Black maternal wellness. OBJECTIVE: This pilot randomized controlled trial (RCT) and mixed methods evaluation aims to (1) determine the feasibility and acceptability of the PARITY intervention; (2) investigate the preliminary efficacy of the PARITY intervention on clinical outcomes (maternal blood pressure, gestational weight gain, and cesarean birth); and (3) investigate changes to wellness behavioral outcomes (nutrition, physical activity, sleep, and health care adherence) and empowered strengths (self-efficacy, social support, motivation, resilience, problem-solving, and self-regulation) in the intervention group compared to a control group. METHODS: A 2-arm RCT and mixed methods evaluation will be conducted. Overall, 60 Black pregnant individuals will be randomized in a ratio of 1:1 to either the intervention or informational control group. Participants in the intervention group will receive access to the technology platform over a 12-week period that ends before birth. Intervention participants will be assigned a doula interventionist, who will meet with them 4 times during the intervention. All participants (intervention and control) will receive a referral for a birth doula at no cost, printed materials about having a healthy pregnancy, and community resources. Feasibility and acceptability will be assessed at the end of the program. Measures will be obtained at baseline (20-28 weeks), the 36th week of pregnancy, birth, and 6-12 weeks post partum. Summary statistics and distribution plots will be used to describe measured variables at each time point. A generalized linear mixed model with a shared random component will be used to analyze the effects of PARITY on clinical, wellness behavioral, and empowered strength outcomes, including baseline nutrition, physical activity, and sleep measures as covariates. For significant effects, post hoc contrasts will be adjusted using the Holm method to maintain comparison-wise error at or <.05. Missing data will be addressed using a pattern-mixture model. RESULTS: The National Institute of Nursing Research funded this pilot RCT. Recruitment, enrollment, and data collection are ongoing, and the estimated study completion date is October 2024. CONCLUSIONS: The expected results of this study will provide the feasibility and preliminary efficacy of the PARITY intervention, to be used in a larger trial with a 12-month PARITY program intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05802615; https://clinicaltrials.gov/study/NCT05802615. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/58580.

Revealing the principles of inter- and intra-domain regulation in a signaling enzyme via scanning mutagenesis.

Multi-domain enzymes can be regulated by both inter-domain interactions and structural features intrinsic to the catalytic domain. The tyrosine phosphatase SHP2 is a quintessential example of a multi-domain protein that is regulated by inter-domain interactions. This enzyme has a protein tyrosine phosphatase (PTP) domain and two phosphotyrosine-recognition domains (N-SH2 and C-SH2) that regulate phosphatase activity through autoinhibitory interactions. SHP2 is canonically activated by phosphoprotein binding to the SH2 domains, which causes large inter-domain rearrangements, but autoinhibition can also be disrupted by disease-associated mutations. Many details of the SHP2 activation mechanism are still unclear, the physiologically-relevant active conformations remain elusive, and hundreds of human variants of SHP2 have not been functionally characterized. Here, we perform deep mutational scanning on both full-length SHP2 and its isolated PTP domain to examine mutational effects on inter-domain regulation and catalytic activity. Our experiments provide a comprehensive map of SHP2 mutational sensitivity, both in the presence and absence of inter-domain regulation. Coupled with molecular dynamics simulations, our investigation reveals novel structural features that govern the stability of the autoinhibited and active states of SHP2. Our analysis also identifies key residues beyond the SHP2 active site that control PTP domain dynamics and intrinsic catalytic activity. This work expands our understanding of SHP2 regulation and provides new insights into SHP2 pathogenicity.

Crafting Unnatural Peptide Macrocycles via Rh(III)-Catalyzed Carboamidation.

Contemporary developments in the field of peptide macrocyclization methodology are imperative for enabling the advance of drug design in medicinal chemistry. This report discloses a Rh(III)-catalyzed macrocyclization via carboamidation, reacting acryloyl-peptide-dioxazolone precursors and arylboronic acids to form complex cyclic peptides with concomitant incorporation of noncanonical α-amino acids. The diverse and modular technology allows for expedient access to a wide variety of cyclic peptides from 4 to 15 amino acids in size and features simultaneous formation of unnatural phenylalanine and tyrosine derivatives with up to >20:1 diastereoselectivity. The reaction showcases an expansive substrate scope with 45 examples and is compatible with the majority of standard protected amino acids used in Fmoc-solid phase peptide synthesis. The methodology is applied to the synthesis of multiple peptidomimetic macrocyclic analogs, including derivatives of cyclosomatostatin and gramicidin S.

Emerging Medical Technologies and Their Use in Bionic Repair and Human Augmentation.

As both the proportion of older people and the length of life increases globally, a rise in age-related degenerative diseases, disability, and prolonged dependency is projected. However, more sophisticated biomedical materials, as well as an improved understanding of human disease, is forecast to revolutionize the diagnosis and treatment of conditions ranging from osteoarthritis to Alzheimer's disease as well as impact disease prevention. Another, albeit quieter, revolution is also taking place within society: human augmentation. In this context, humans seek to improve themselves, metamorphosing through self-discipline or more recently, through use of emerging medical technologies, with the goal of transcending aging and mortality. In this review, and in the pursuit of improved medical care following aging, disease, disability, or injury, we first highlight cutting-edge and emerging materials-based neuroprosthetic technologies designed to restore limb or organ function. We highlight the potential for these technologies to be utilized to augment human performance beyond the range of natural performance. We discuss and explore the growing social movement of human augmentation and the idea that it is possible and desirable to use emerging technologies to push the boundaries of what it means to be a healthy human into the realm of superhuman performance and intelligence. This potential future capability is contrasted with limitations in the right-to-repair legislation, which may create challenges for patients. Now is the time for continued discussion of the ethical strategies for research, implementation, and long-term device sustainability or repair.

Pediatric Hematology and Oncology Patients on Extracorporeal Membrane Oxygenation: Outcomes in a Multicenter, Retrospective Cohort 2009-2021.

OBJECTIVE: To describe characteristics associated with survival for pediatric patients with an oncologic diagnosis or hematopoietic cell transplant (HCT) supported with extracorporeal membrane oxygenation (ECMO). DESIGN: Multicenter, retrospective study. SETTING: Sixteen PICUs in the United States and Israel. PATIENTS: We included patients aged younger than 19 years with an oncologic diagnosis or HCT who required ECMO support between 2009 and 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 149 patients were included in the study cohort. There were 118 patients with an oncologic diagnosis and 31 that received HCT. The indications for ECMO were respiratory failure (46%), combined respiratory and cardiac failure (28%), and cardiac failure (25%). Venovenous (V-V) ECMO was used in 45% of patients, with 53% of patients being placed on venoarterial (V-A) ECMO. For oncologic and HCT groups, survival to ECMO decannulation was 52% (62/118) and 64% (20/31), and survival to hospital discharge was 36% (43/118) and 42% (13/31), respectively. After adjusting for other factors, requiring cardiopulmonary resuscitation was associated with greater odds ratio of mortality (3.0 [95% CI, 1.2-7.7]). CONCLUSIONS: Survival to ECMO decannulation of pediatric oncologic and HCT patients in this study was 52-64%, depending upon diagnosis. However, survival to hospital discharge remains poor. Future research should prioritize understanding factors contributing to this survival gap within these patient populations.

Allosteric regulation of the tyrosine phosphatase PTP1B by a protein-protein interaction.

The rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter cell signaling or protein function. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized. Alternatively, protein-protein interactions can allosterically regulate function, enhancing or suppressing activity in response to binding. In this work, we investigate the interaction between the tyrosine phosphatase PTP1B and the adaptor protein Grb2, which have been annotated as binding partners in a number of proteomics studies. This interaction has been postulated to co-localize PTP1B with its substrate IRS-1 by forming a ternary complex, thereby enhancing the dephosphorylation of IRS-1 to suppress insulin signaling. Here, we report that Grb2 binding to PTP1B also allosterically enhances PTP1B catalytic activity. We show that this interaction is dependent on the proline-rich region of PTP1B, which interacts with the C-terminal SH3 domain of Grb2. Using NMR spectroscopy and hydrogen-deuterium exchange mass spectrometry (HDX-MS) we show that Grb2 binding alters PTP1B structure and/or dynamics. Finally, we use MS proteomics to identify other interactors of the PTP1B proline-rich region that may also regulate PTP1B function similarly to Grb2. This work presents one of the first examples of a protein allosterically regulating the enzymatic activity of PTP1B and lays the foundation for discovering new mechanisms of PTP1B regulation in cell signaling.

The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.

Mutations in the tyrosine phosphatase Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting autoinhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8 to 10 Å from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine-binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein-protein interaction specificity that alters enzyme activation.

Atorvastatin-Associated Eosinophilic Spongiosis: A Case Report and a Relevant Literature Review of Dermatological Manifestations.

Atorvastatin, a widely prescribed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (HMG-CoA reductase inhibitor), is associated with various adverse effects, including many dermatologic manifestations. We present the case of a 73-year-old man who developed eosinophilic spongiosis shortly after initiating atorvastatin therapy, an adverse effect which to our knowledge has not yet been reported in association with atorvastatin. Our investigation explores the clinical and histopathologic characteristics of eosinophilic spongiosis induced by atorvastatin, delving into potential mechanisms behind statin-induced eosinophilia. A literature review, focusing on atorvastatin's dermatological side effects, revealed a limited number of relevant studies, emphasizing the scarcity of documented cases. Our aim is to raise awareness of eosinophilic spongiosis as a potential side effect of atorvastatin, emphasizing its impact on patients' quality of life. This case prompts further research into the mechanisms underlying such dermatologic reactions, contributing to a better understanding of atorvastatin's diverse adverse effects.

Digital health's influence on the association between birth preference and vaginal birth.

BACKGROUND: Women's preferred mode of birth during pregnancy is predictive of their actual mode of birth. Digital prenatal care services are a promising method for educating women on mode of birth to reduce elective cesareans. This study aimed to evaluate the influence of digital health on the association between birth preference and mode of birth. METHODS: Data come from 5409 pregnant women enrolled in a digital platform for women's and family health. Multi-trajectory modeling identified trajectories of digital health usage throughout pregnancy. Adjusted logistic regression models tested associations between birth preferences and mode of birth. The modifying effect of digital health usage on the association between birth preference and mode of birth was assessed on the multiplicative scale. RESULTS: Four distinct trajectories of digital service usage were identified and labeled as: (1) baseline users (52%): the reference group; (2) just-in timers (16%): high usage during the third trimester; (3) learners (26%): high educational resource usage (e.g., articles and classes) throughout pregnancy; and (4) super users (6%): high usage of both education and care resources throughout pregnancy. Overall, preferred mode of birth at enrollment was predictive of actual mode of birth; however, digital health usage moderated this association, whereby super users and learners who preferred a cesarean at enrollment were more likely to deliver vaginally, compared to baseline users who preferred a cesarean. CONCLUSION: For the increasing proportion of women considering an elective cesarean, education through a prenatal digital health platform may help to encourage vaginal birth and reduce cesarean births.

Reclaiming narratives of empowerment around Black maternal health: a strengths-based, community-informed focus group study.

OBJECTIVES: Research on Black maternal populations often focuses on deficits that can reinforce biases against Black individuals and communities. The research landscape must shift towards a strengths-based approach focused on the protective assets of Black individuals and communities to counteract bias. This study engaged the local Black community using a strengths-based approach to discuss the assets of Black maternal populations and to inform the design of a future clinical trial focused on reducing Black maternal health disparities. DESIGN: Guided by the Theory of Maternal Adaptive Capacity, we conducted three purposive focus group sessions with Black adult community members. The focus groups were semi-structured to cover specific topics, including the strengths of the local community, strengths specific to pregnant community members, how the strengths of community members can support pregnant individuals, and how the strengths of pregnant community members can facilitate a healthy pregnancy. The focus group interviews were transcribed verbatim and analyzed using thematic content analysis. RESULTS: Three focus group sessions were conducted with sixteen female individuals identifying as Black or African American. Central themes include (1) the power of pregnancy and motherhood in Black women, (2) challenging negative perceptions and media representation of Black mothers, (3) recognizing history and reclaiming cultural traditions surrounding birth, and (4) community as the foundation of Black motherhood. CONCLUSION: Black community members identified powerful themes on Black maternal health through a strengths-based lens. These focus groups fostered relationships with the Black community, elucidated possible solutions to improve Black women's health and wellness, and offered direction on our research design and intervention.

Treatment of Symptomatic Carotid Webs: A Single-Center Review.

BACKGROUND: Carotid webs are abnormal thin shelf-like or flap-like tissue in the carotid bulb (proximal internal carotid artery). Rarely are carotid webs detected prior to symptoms since routine carotid artery surveillance is not performed in younger individuals without traditional risk factors for carotid disease. The cause and natural history remain unknown. In general, they are not common but should be considered in the differential diagnosis of a patient who presents with ischemic neurologic symptoms. The web can create a flow disturbance, potentiating local thrombus formation, which can embolize producing resulting in cerebral ischemia. Current treatment is to reduce thrombus formation (antithrombotics and/or anticoagulation) or to alter the flow disturbance caused by the web (surgical removal or stent). METHODS: We retrospectively identified all patients presenting with acute ischemic stroke to our Comprehensive Stroke Center that were diagnosed with carotid web from January 2020 to December 2023. Patient demographics, presentation, hospital course including treatment and complications were collected and reported. RESULTS: Fifteen patients presented with carotid web and stroke from 2020 to 2023 and 13 underwent carotid artery stenting or endarterectomy with no periprocedural complications. Most (40%) carotid webs were not primarily identified by the initial radiology interpretation. CONCLUSIONS: We discuss our experience of carotid web and its management as well as review of the current literature.

Neurologic Statistical Prognostication and Risk Assessment for Kids on Extracorporeal Membrane Oxygenation-Neuro SPARK.

This study presents Neuro-SPARK, the first scoring system developed to assess the risk of neurologic injury in pediatric and neonatal patients on extracorporeal membrane oxygenation (ECMO). Using the extracorporeal life support organization (ELSO) registry, we applied robust machine learning methodologies and clinical expertise to a 10 years dataset. We produced separate models for veno-venous (V-V ECMO) and veno-arterial (V-A ECMO) configurations due to their different risk factors and prevalence of neurologic injury. Our models identified 14 predictor variables for V-V ECMO and 20 for V-A ECMO, which demonstrated moderate accuracy in predicting neurologic injury as defined by the area under the receiver operating characteristic (AUROC) (V-V = 0.63, V-A = 0.64) and good calibration as measured by the Brier score (V-V = 0.1, V-A = 0.15). Furthermore, our post-hoc analysis identified high- and low-risk groups that may aid clinicians in targeted neuromonitoring and guide future research on ECMO-associated neurologic injury. Despite the inherent limitations, Neuro-SPARK lays the foundation for a risk-assessment tool for neurologic injury in ECMO patients, with potential implications for improved patient outcomes.

Nanosecond solvation dynamics in a polymer electrolyte for lithium batteries.

Solvation dynamics critically affect charge transport. Spectroscopic experiments and computer simulations show that these dynamics in aqueous systems occur on a picosecond timescale. In the case of organic electrolytes, however, conflicting values ranging from 1 to several 100 picoseconds have been reported. We resolve this conflict by studying mixtures of an organic polymer and a lithium salt. Lithium ions coordinate with multiple polymer chains, resulting in temporary crosslinks. Relaxation of these crosslinks, detected by quasielastic neutron scattering, are directly related to solvation dynamics. Simulations reveal a broad spectrum of relaxation times. The average timescale for solvation dynamics in both experiment and simulation is one nanosecond. We present the direct measurement of ultraslow dynamics of solvation shell break-up in an electrolyte.

Photocatalytic Activation of Aryl(trifluoromethyl) Diazos to Carbenes for High-Resolution Protein Labeling with Red Light.

State-of-the-art methods in photoproximity labeling center on the targeted generation and capture of short-lived reactive intermediates to provide a snapshot of local protein environments. Diazirines are the current gold standard for high-resolution proximity labeling, generating short-lived aryl(trifluoromethyl) carbenes. Here, we present a method to access aryl(trifluoromethyl) carbenes from a stable diazo source via tissue-penetrable, deep red to near-infrared light (600-800 nm). The operative mechanism of this activation involves Dexter energy transfer from photoexcited osmium(II) photocatalysts to the diazo, thus revealing an aryl(trifluoromethyl) carbene. The labeling preferences of the diazo probe with amino acids are studied, showing high reactivity toward heteroatom-H bonds. Upon the synthesis of a biotinylated diazo probe, labeling studies are conducted on native proteins as well as proteins conjugated to the Os photocatalyst. Finally, we demonstrate that the conjugation of a protein inhibitor to the photocatalyst also enables selective protein labeling in the presence of spectator proteins and achieves specific labeling of a membrane protein on the surface of mammalian cells via a two-antibody photocatalytic system.

The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.

Mutations in the tyrosine phosphatase SHP2 are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting auto-inhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that, while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8-10 Å from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein-protein interaction specificity that alters enzyme activation.

Association Between Doula Use on a Digital Health Platform and Birth Outcomes.

OBJECTIVE: To examine the association between the use of virtual doula appointments on a comprehensive digital health platform and users' mode of birth and their birth experiences, among all platform users and Black platform users. METHODS: Data for this retrospective cohort study were extracted from individuals who enrolled in a comprehensive digital health platform, between January 1, 2020, and April 22, 2023. Multivariable logistic regression models were used to estimate the association between number of virtual doula appointments completed on the digital health platform and odds of cesarean birth and user-reported birth experience outcomes, which included help deciding a birth preference, receiving a high level of support during pregnancy, learning medically accurate information about pregnancy complications and warning signs, and managing mental health during pregnancy, stratified by parity. The interaction of doula utilization by race for each outcome was also tested. RESULTS: Overall 8,989 platform users were included. The completion of at least two appointments with a virtual doula on the digital health platform was associated with a reduction in odds of cesarean birth among all users (adjusted odds ratio [aOR] 0.80, 95% CI, 0.65-0.99) and among Black users (aOR 0.32, 95% CI, 0.14-0.72). Among platform users with a history of cesarean birth, completion of any number of doula visits was associated with a reduction in odds of repeat cesarean birth (one visit: aOR 0.35, 95% CI, 0.17-0.72; two or more visits: aOR 0.37, 95% CI, 0.17-0.83). Analyses among all users indicated dose-response associations between increased virtual doula use and greater odds of users reporting support in deciding a birth preference (one visit: aOR 2.35, 95% CI, 2.02-2.74; two or more visits: aOR 3.67, 95% CI, 3.03-4.44), receiving a high level of emotional support during pregnancy (one visit: aOR 1.99, 95% CI, 1.74-2.28; two or more visits: aOR 3.26, 95% CI, 2.70-3.94), learning medically accurate information about pregnancy complications and warning signs (one visit: aOR 1.26, 95% CI, 1.10-1.44; two or more visits: aOR 1.55, 95% CI, 1.29-1.88), and help managing mental health during pregnancy (one visit: aOR 1.28, 95% CI, 1.05-1.56; two or more visits: aOR 1.78, 95% CI, 1.40-2.26). CONCLUSION: This analysis demonstrates that virtual doula support on a digital health platform is associated with lower odds of cesarean birth and an improved birth experience. Positive findings among Black users and users with vaginal birth after cesarean suggest that doula support is critical for patient advocacy, and that digital health may play a meaningful role in increasing health equity in birth outcomes.

TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments.

T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity.

Role of cardiopulmonary interactions in development of ventilator-induced lung injury-Experimental evidence and clinical Implications.

Ventilator-induced lung injury (VILI) impacts outcomes in ARDS and optimization of ventilatory strategies improves survival. Decades of research has identified various mechanisms of VILI, largely focusing on airspace forces of plateau pressure, tidal volume and driving pressure. Experimental evidence indicates the role of adverse cardiopulmonary interaction during mechanical ventilation, contributing to VILI genesis mostly by modulating pulmonary vascular dynamics. Under passive mechanical ventilation, high transpulmonary pressure increases afterload on right heart while high pleural pressure reduces the RV preload. Together, they can result in swings of pulmonary vascular flow and pressure. Altered vascular flow and pressure result in increased vascular shearing and wall tension, in turn causing direct microvascular injury accompanied with permeability to water, proteins and cells. Moreover, abrupt decreases in airway pressure, may result in sudden overperfusion of the lung and result in similar microvascular injury, especially when the endothelium is stretched or primed at high positive end-expiratory pressure. Microvascular injury is universal in VILI models and presumed in the diagnosis of ARDS; preventing such microvascular injury can reduce VILI and impact outcomes in ARDS. Consequently, developing cardiovascular targets to reduce macro and microvascular stressors in the pulmonary circulation can potentially reduce VILI. This paper reviews the role of cardiopulmonary interaction in VILI genesis.

Chimney-Shaped Phase Diagram in a Polymer Blend Electrolyte.

The phase behavior of polymer blend electrolytes comprising poly(ethylene oxide) (PEO)/poly(methyl methacrylate) (PMMA)/lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) was determined using a combination of light and small angle neutron scattering (SANS) experiments. The results at a fixed temperature (110 °C) are presented on a PEO concentration versus salt (LiTFSI) concentration plot. The blends are miscible at all PEO concentrations in the absence of salt. With added salt, a region of immiscibility is obtained in PEO-lean polymer blend electrolytes; blends rich in PEO remain miscible at most salt concentrations. A narrow region of immiscibility juts into the miscible region, giving the phase diagram a chimney-like appearance. The data are qualitatively consistent with a simple extension of Flory-Huggins theory with a composition-dependent Flory-Huggins interaction parameter, χ, that was determined independently from SANS data from homogeneous blend electrolytes. Phase diagrams like the one we obtained were anticipated by self-consistent field theory calculations that account for correlations between ions. The relationship between these theories and measured χ remains to be established.