Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

How do we achieve blinding in modern electronic and paper medical records during the conduct of transfusion trials?

BACKGROUND: Regulatory aspects of transfusion medicine add complexity in blinded transfusion trials when considering various electronic record keeping software and blood administration processes. The aim of this study is to explore strategies when blinding transfusion components and products in paper and electronic medical records. METHODS: Surveys were collected and interviews were conducted for 18 sites across various jurisdictions in North America to determine solutions applied in previous transfusion randomized control trials. RESULTS: Sixteen responses were collected of which 11 had previously participated in a transfusion randomized control trial. Various solutions were reported which were specific to the laboratory information system (LIS) and electronic medical record (EMR) combinations although solutions could be grouped into four categories which included the creation of a study product code in the LIS, preventing the transmission of data from the LIS to the EMR, utilizing specialized stickers and labels to conceal product containers and documents in the paper records, and modified bedside procedures and documentation. DISCUSSION: LIS and EMR combinations varied across sites, so it was not possible to determine combination-specific solutions. The study was able to highlight solutions that may be emphasized in future iterations of LIS and EMR software as well as procedural changes that may minimize the risk of unblinding.

IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

Exploring the potential harm of varied blood storage on patients undergoing cardiovascular surgery.

BACKGROUND AND OBJECTIVES: Debate exists surrounding the optimal duration of red blood cell (RBC) storage. A hypothesis emerging from previous research suggests that exposure to fresh blood may be harmful to patients undergoing cardiac surgery. This study uses a large transfusion medicine database to explore the association between in-hospital mortality and red cell storage duration. MATERIALS AND METHODS: This is an exploratory retrospective cohort study of all adult patients at Hamilton, Canada, over a 14-year period that received at least one allogeneic red cell transfusion during their hospitalization for cardiac surgery requiring bypass. The primary outcome for the study was in-hospital death. Analysis was performed using multivariate Cox regression modelling with time-dependent and time-independent covariates and stratification variables. Five models with varying definitions for short, intermediate and prolonged duration of RBC storage were tested. RESULTS: From March 2004 to December 2017, 11,205 patients met the inclusion criteria and were included in the regression analyses. No significant effect of short-duration red storage on patient mortality was observed in all statistical models, with the red cells stored for the longest duration as the reference group. When patients who received exclusively fresh (hazard ratio [HR] 1.040, 95% confidence interval [CI] 0.588-1.841, p-value = 0.893) and older aged (HR 1.038, 95% CI 0.769-1.1.402, p-value = 0.0801) RBCs were compared with those who received exclusively mid-age red cells as the reference, statistical significance was similarly not reached. CONCLUSION: Red cells stored for the shortest duration are not associated with increased risk of mortality among cardiac surgery patients.

Current state of technical transfusion medicine practice for out-of-hospital blood transfusion in Canada.

BACKGROUND AND OBJECTIVES: Canadian out-of-hospital blood transfusion programmes (OHBTPs) are emerging, to improve outcomes of trauma patients by providing pre-hospital transfusion from the scene of injury, given prolonged transport times. Literature is lacking to guide its implementation. Thus, we sought to gather technical transfusion medicine (TM)-specific practices across Canadian OHBTPs. MATERIALS AND METHODS: A survey was sent to TM representatives of Canadian OHBTPs from November 2021 to March 2022. Data regarding transport, packaging, blood components and inventory management were included and reported descriptively. Only practices involving Blood on Board programme components for emergency use were included. RESULTS: OHBTPs focus on helicopter emergency medical service programmes, with some supplying fixed-wing aircraft and ground ambulances. All provide 1-3 coolers with 2 units of O RhD/Kell-negative red blood cells (RBCs) per cooler, with British Columbia trialling coolers with 2 units of pre-thawed group A plasma. Inventory exchanges are scheduled and blood components are returned to TM inventory using visual inspection and internal temperature data logger readings. Coolers are validated to storage durations ranging from 72 to 124 h. All programmes audit to manage wastage, though there is no consensus on appropriate benchmarks. All programmes have a process for documenting units issued, reconciliation after transfusion and for transfusion reaction reporting; however, training programmes vary. Common considerations included storage during extreme temperature environments, O-negative RBC stewardship, recipient notification, traceability, clinical practice guidelines co-reviewed by TM and a common audit framework. CONCLUSION: OHBTPs have many similarities throughout Canada, where harmonization may assist in further developing standards, leveraging best practice and national coordination.

Therapeutic plasma exchange in alloimmune platelet refractoriness.

Patients with alloimmune platelet refractoriness can present complex clinical conundrums. Herein we describe a case of platelet refractoriness in the setting of combined HLA and HPA alloimmunization in a patient with acute myeloid leukemia and life-threatening bleeding. We discuss causative antibodies and compare prevailing therapeutic modalities. We highlight plasma exchange as a potentially feasible, repeatable, and personalized treatment option for patients with extensive platelet alloimmunization who require transfusion.

Severe acute haemolytic transfusion reaction secondary to a plasma incompatible group B platelet transfusion.

OBJECTIVES: To report a rare case of acute hemolytic transfusion reaction (AHTR) following an ABO plasma incompatible group B platelet transfusion. BACKGROUND: AHTR is an uncommon, but potentially fatal event. Most reported cases of platelet transfusions associated with AHTR involve group O donors. CASE REPORT: A 34-year-old man, recipient of a group AB haploidentical haematopoietic stem cell transplantation (HSCT), had received re-induction chemotherapy for leukaemia relapse. A group B whole blood-derived buffy coat platelet pool was transfused. He developed rigours/fever, profound hemolytic anaemia, and hemodynamic instability. Serological investigations revealed AHTR from passive transfer of high titre anti-A (256 for IgM and 8192 for IgG). DISCUSSION: This case highlights the potential risks associated with ABO-mismatched transfusions, and the complexity associated with transfusing HSCT recipients and red cell transfusion recipients with dual populations of circulating red cells. The literature on minor ABO plasma incompatible transfusions, challenges in establishing local policies to limit the risks of AHTR and risk mitigation strategies are discussed. CONCLUSION: Clinicians must maintain a high level of suspicion for AHTR after ABO plasma incompatible platelet transfusions. Patients must be aware of the risks of AHTR, and early recognition and diagnosis of this complication may be lifesaving.

Flammability of Ocular Surface Lubricants.

PURPOSE: Surgical fires pose a substantial risk to patients and can cause significant injury, especially in oculofacial surgery. Ocular surface lubricants can potentially act as fuel for an operating room fire. We present an experimental analysis of the flammability of 9 commonly used ophthalmic lubricants under 4 ignition sources used in oculofacial surgery with and without supplemental oxygen. METHODS: The flammability of 9 ophthalmic lubricants were tested under various operating room conditions. Each lubricant was exposed to 4 different ignition sources: an open flame lighter, monopolar cautery, bipolar cautery, and hand-held high temperature cautery, and the response of the lubricant was recorded. The testing was conducted both in room air and with 6 L/minute of 100% oxygen directed at the lubricant through a nasal cannula. Any reaction in which there was ignition, sparking, smoking, or a transient or permanent change in appearance of the lubricant was deemed notable. RESULTS: Of the 9 lubricants tested, 4 displayed a reaction to the ignition source. Without supplemental oxygen, 100% petrolatum and neomycin-polysporin-bacitracin-hydrocortisone ointment produced some smoke when applied with the high temperature cautery. Notably, under both the conditions of no supplemental oxygen and with the addition of 6 L/minute of 100% oxygen, the carboxymethylcellulose drops and lidocaine jelly both conducted and sparked with the monopolar cautery leaving visible burn marks on the paper. CONCLUSIONS: The overall fire hazard posed by ocular surface lubricants is low. Some topical lubricants can conduct electricity from monopolar cautery, which could increase the risk of inadvertent electrical burns. Certain lubricants could potentially become a fuel source when used in combination with hand-held high temperature battery cautery. Bipolar cautery was not associated with either increased conductivity or flammability with any of the lubricants tested.

Orbital Dermoid Cysts in Monozygotic Twins.

Two healthy 12-year-old monozygotic twin sisters presented with strikingly similar, painless orbital masses along their frontozygomatic suture line that had been slowly enlarging since birth. The masses were clinically consistent with orbital dermoid cysts and the patients underwent excision of their lesions, with the diagnosis confirmed by histological analysis. There are prior case reports of both nasal and ovarian dermoid cysts in twins, however, no prior case of orbital dermoid cysts in twins have been described. These dermoid cysts are generally thought to be a sporadic disorder of embryogenesis, yet the authors' case suggests genetics may play a role in the underlying etiology of dermoid cysts.

A human secretome library screen reveals a role for Peptidoglycan Recognition Protein 1 in Lyme borreliosis.

Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete Borrelia burgdorferi. Infection begins in the skin following a tick bite and can spread to the hearts, joints, nervous system, and other organs. Diverse host responses influence the level of B. burgdorferi infection in mice and humans. Using a systems biology approach, we examined potential molecular interactions between human extracellular and secreted proteins and B. burgdorferi. A yeast display library expressing 1031 human extracellular proteins was probed against 36 isolates of B. burgdorferi sensu lato. We found that human Peptidoglycan Recognition Protein 1 (PGLYRP1) interacted with the vast majority of B. burgdorferi isolates. In subsequent experiments, we demonstrated that recombinant PGLYRP1 interacts with purified B. burgdorferi peptidoglycan and exhibits borreliacidal activity, suggesting that vertebrate hosts may use PGLYRP1 to identify B. burgdorferi. We examined B. burgdorferi infection in mice lacking PGLYRP1 and observed an increased spirochete burden in the heart and joints, along with splenomegaly. Mice lacking PGLYRP1 also showed signs of immune dysregulation, including lower serum IgG levels and higher levels of IFNγ, CXCL9, and CXCL10.Taken together, our findings suggest that PGLYRP1 plays a role in the host's response to B. burgdorferi and further demonstrate the utility of expansive yeast display screening in capturing biologically relevant interactions between spirochetes and their hosts.

DeepPocket: Ligand Binding Site Detection and Segmentation using 3D Convolutional Neural Networks.

A structure-based drug design pipeline involves the development of potential drug molecules or ligands that form stable complexes with a given receptor at its binding site. A prerequisite to this is finding druggable and functionally relevant binding sites on the 3D structure of the protein. Although several methods for detecting binding sites have been developed beforehand, a majority of them surprisingly fail in the identification and ranking of binding sites accurately. The rapid adoption and success of deep learning algorithms in various sections of structural biology beckons the usage of such algorithms for accurate binding site detection. As a combination of geometry based software and deep learning, we report a novel framework, DeepPocket that utilizes 3D convolutional neural networks for the rescoring of pockets identified by Fpocket and further segments these identified cavities on the protein surface. Apart from this, we also propose another data set SC6K containing protein structures submitted in the Protein Data Bank (PDB) from January 1st, 2018, until February 28th, 2020, for ligand binding site (LBS) detection. DeepPocket's results on various binding site data sets and SC6K highlight its better performance over current state-of-the-art methods and good generalization ability over novel structures.

A, B, C's of Trk Receptors and Their Ligands in Ocular Repair.

Neurotrophins are a family of closely related secreted proteins that promote differentiation, development, and survival of neurons, which include nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. All neurotrophins signal through tropomyosin receptor kinases (TrkA, TrkB, and TrkC) which are more selective to NGF, brain-derived neurotrophic factor, and neurotrophin-3, respectively. NGF is the most studied neurotrophin in the ocular surface and a human recombinant NGF has reached clinics, having been approved to treat neurotrophic keratitis. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are less studied neurotrophins in the ocular surface, even though brain-derived neurotrophic factor is well characterized in glaucoma, retina, and neuroscience. Recently, neurotrophin analogs with panTrk activity and TrkC selectivity have shown promise as novel drugs for treating dry eye disease. In this review, we discuss the biology of the neurotrophin family, its role in corneal homeostasis, and its use in treating ocular surface diseases. There is an unmet need to investigate parenteral neurotrophins and its analogs that activate TrkB and TrkC selectively.

Glyceollins Trigger Anti-Proliferative Effects in Hormone-Dependent Aromatase-Inhibitor-Resistant Breast Cancer Cells through the Induction of Apoptosis.

Aromatase inhibitors (AIs) are standard treatment for estrogen-dependent postmenopausal breast tumors; however, resistance develops leading to tumor relapse and metastasis. We previously demonstrated that glyceollin inhibits proliferation, survival, and migration of hormone-independent letrozole-resistant breast cancer. Since many AI-resistant tumors remain hormone-dependent, identifying distinctions between estrogen-receptor-positive (ER+) and ER-negative (ER-) AI-resistant tumor response to therapy is critical. We hypothesize that treating ER+ letrozole-resistant T47D breast cancer cells (T47DaromLR) with a combination of 10 µM glyceollin and 0.5 µM lapatinib (a dual EGFR/HER2 inhibitor) will decrease cell proliferation through induction of apoptosis. The T47DaromLR cells were found to overexpress HER2 and MAPK while maintaining aromatase and ER levels compared to their letrozole-sensitive (T47Darom) counterparts. In the absence of estrogen stimulation, glyceollin ± lapatinib had no effect on the proliferation of the T47Darom cells, while glyceollin treatment caused 46% reduction in the proliferation of T47DaromLR cells, which was further diminished when combined with lapatinib. While neither agent influenced cell migration, glyceollin and lapatinib reduced S and G2/M phase cell entry and exclusively induced apoptosis by 1.29-fold in the T47DaromLR cells. Taken together, these results suggest that glyceollins and lapatinib may have potential as a novel combination therapeutic approach for hormone-dependent, letrozole-resistant tumors.

Educating Caregivers to Reduce Complications and Improve Outcomes of Stroke Patients (ECCOS) - A Cluster-Randomized Trial.

OBJECTIVES: Stroke constitutes a significant public health problem in developing countries. Caregivers provide an important support system for patient care but usually lack knowledge and skill to attend their stroke patients. We assessed whether a caregiver-directed educational intervention would reduce hospital-acquired complications and improve stroke patients' outcomes. MATERIALS AND METHODS: We randomly assigned two Neurology inpatient wards to receive either standard care or an educational intervention. The coprimary outcomes included incidence of hospital-acquired complications and in-hospital mortality. Secondary outcomes included the modified Rankin Scale and mortality at three months. RESULTS: Among 164 patients recruited, 82 received intervention, and standard care each. The mean (Standard deviation) Glasgow coma scale of patients was 11.01 (3.4), and National Institute of Health Stroke Scale was 19.17 (8.54). The incidence of complications (72 in the intervention versus 81 in the control group; p=0.56) was not different. Ten patients (12.2%) in the intervention group and 16 (19.5%) in the control group (p=0.20) died in-hospital. Twenty patients (27.8%) in the intervention and twelve (18.2%) in the control group attained modified Rankin Scale 0-2 at three months (p=0.12). The mortality at three months (20 [24.4%] in the intervention versus 25 [30.5%] in the control group) was not different (p=0.38). The intervention group had fewer complications (42 versus 68 in the control group; p=0.01) during the initial ten days of hospital stay, but adjusted analysis revealed no difference. CONCLUSION: A structured educational intervention did not reduce the incidence of hospital-acquired complications, mortality, or morbidity. However, there was a trend towards fewer complications in the initial days of hospital stay. Extended hospital stay, caregiver fatigue, and dilution of the intervention over time might be reasons for the apparent lack of effect. CLINICAL TRIAL REGISTRATION-URL: http://www.ctri.nic.in. Unique identifier: CTRI/2018/11/016312.

Polymeric Nanoparticles Active against Dual-Species Bacterial Biofilms.

Biofilm infections are a global public health threat, necessitating new treatment strategies. Biofilm formation also contributes to the development and spread of multidrug-resistant (MDR) bacterial strains. Biofilm-associated chronic infections typically involve colonization by more than one bacterial species. The co-existence of multiple species of bacteria in biofilms exacerbates therapeutic challenges and can render traditional antibiotics ineffective. Polymeric nanoparticles offer alternative antimicrobial approaches to antibiotics, owing to their tunable physico-chemical properties. Here, we report the efficacy of poly(oxanorborneneimide) (PONI)-based antimicrobial polymeric nanoparticles (PNPs) against multi-species bacterial biofilms. PNPs showed good dual-species biofilm penetration profiles as confirmed by confocal laser scanning microscopy. Broad-spectrum antimicrobial activity was observed, with reduction in both bacterial viability and overall biofilm mass. Further, PNPs displayed minimal fibroblast toxicity and high antimicrobial activity in an in vitro co-culture model comprising fibroblast cells and dual-species biofilms of Escherichia coli and Pseudomonas aeruginosa. This study highlights a potential clinical application of the presented polymeric platform.

A tutorial on Bayesian multi-model linear regression with BAS and JASP.

Linear regression analyses commonly involve two consecutive stages of statistical inquiry. In the first stage, a single 'best' model is defined by a specific selection of relevant predictors; in the second stage, the regression coefficients of the winning model are used for prediction and for inference concerning the importance of the predictors. However, such second-stage inference ignores the model uncertainty from the first stage, resulting in overconfident parameter estimates that generalize poorly. These drawbacks can be overcome by model averaging, a technique that retains all models for inference, weighting each model's contribution by its posterior probability. Although conceptually straightforward, model averaging is rarely used in applied research, possibly due to the lack of easily accessible software. To bridge the gap between theory and practice, we provide a tutorial on linear regression using Bayesian model averaging in JASP, based on the BAS package in R. Firstly, we provide theoretical background on linear regression, Bayesian inference, and Bayesian model averaging. Secondly, we demonstrate the method on an example data set from the World Happiness Report. Lastly, we discuss limitations of model averaging and directions for dealing with violations of model assumptions.

Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling. Transcriptional Regulation by SOX and HIF-2α.

We previously demonstrated involvement of NAMPT (nicotinamide phosphoribosyltransferase) in pulmonary arterial hypertension (PAH) and now examine NAMPT regulation and extracellular NAMPT's (eNAMPT's) role in PAH vascular remodeling. NAMPT transcription and protein expression in human lung endothelial cells were assessed in response to PAH-relevant stimuli (PDGF [platelet-derived growth factor], VEGF [vascular endothelial growth factor], TGF-ß1 [transforming growth factor-ß1], and hypoxia). Endothelial-to-mesenchymal transition was detected by SNAI1 (snail family transcriptional repressor 1) and PECAM1 (platelet endothelial cell adhesion molecule 1) immunofluorescence. An eNAMPT-neutralizing polyclonal antibody was tested in a PAH model of monocrotaline challenge in rats. Plasma eNAMPT concentrations, significantly increased in patients with idiopathic pulmonary arterial hypertension, were highly correlated with indices of PAH severity. eNAMPT increased endothelial-to-mesenchymal transition, and each PAH stimulus significantly increased endothelial cell NAMPT promoter activity involving transcription factors STAT5 (signal transducer and activator of transcription 5), SOX18 (SRY-box transcription factor 18), and SOX17 (SRY-box transcription factor 17), a PAH candidate gene newly defined by genome-wide association study. The hypoxia-induced transcription factor HIF-2α (hypoxia-inducible factor-2α) also potently regulated NAMPT promoter activity, and HIF-2α binding sites were identified between -628 bp and -328 bp. The PHD2 (prolyl hydroxylase domain-containing protein 2) inhibitor FG-4592 significantly increased NAMPT promoter activity and protein expression in an HIF-2α-dependent manner. Finally, the eNAMPT-neutralizing polyclonal antibody significantly reduced monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-κB activation. eNAMPT is a novel and attractive therapeutic target essential to PAH vascular remodeling.

An Ixodes scapularis Protein Disulfide Isomerase Contributes to Borrelia burgdorferi Colonization of the Vector.

Borrelia burgdorferi causes Lyme disease, the most common tick-transmitted illness in North America. When Ixodes scapularis feed on an infected vertebrate host, spirochetes enter the tick gut along with the bloodmeal and colonize the vector. Here, we show that a secreted tick protein, I. scapularisprotein disulfide isomerase A3 (IsPDIA3), enhances B. burgdorferi colonization of the tick gut. I. scapularis ticks in which ispdiA3 has been knocked down using RNA interference have decreased spirochete colonization of the tick gut after engorging on B. burgdorferi-infected mice. Moreover, administration of IsPDIA3 antiserum to B. burgdorferi-infected mice reduced the ability of spirochetes to colonize the tick when feeding on these animals. We show that IsPDIA3 modulates inflammatory responses at the tick bite site, potentially facilitating spirochete survival at the vector-host interface as it exits the vertebrate host to enter the tick gut. These data provide functional insights into the complex interactions between B. burgdorferi and its arthropod vector and suggest additional targets to interfere with the spirochete life cycle.

Combatting antibiotic-resistant bacteria using nanomaterials.

The dramatic increase in antimicrobial resistance for pathogenic bacteria constitutes a key threat to human health. The Centers for Disease Control and Prevention has recently stated that the world is on the verge of entering the "post-antibiotic era", one where more people will die from bacterial infections than from cancer. Recently, nanoparticles (NPs) have emerged as new tools that can be used to combat deadly bacterial infections. Nanoparticle-based strategies can overcome the barriers faced by traditional antimicrobials, including antibiotic resistance. In this tutorial review, we have highlighted multiple nanoparticle-based approaches to eliminate bacterial infections, providing crucial insight into the design of elements that play critical roles in creating antimicrobial nanotherapeutics. In particular, we have focused on the pivotal role played by NP-surface functionality in designing nanomaterials as self-therapeutic agents and delivery vehicles for antimicrobial cargo.

A Hybrid Experimental-Computational Modeling Framework for Cardiovascular Device Testing.

Significant advances in biomedical science often leverage powerful computational and experimental modeling platforms. We present a framework named physiology simulation coupled experiment ("PSCOPE") that can capitalize on the strengths of both types of platforms in a single hybrid model. PSCOPE uses an iterative method to couple an in vitro mock circuit to a lumped-parameter numerical simulation of physiology, obtaining closed-loop feedback between the two. We first compared the results of Fontan graft obstruction scenarios modeled using both PSCOPE and an established multiscale computational fluid dynamics method; the normalized root-mean-square error values of important physiologic parameters were between 0.1% and 2.1%, confirming the fidelity of the PSCOPE framework. Next, we demonstrate an example application of PSCOPE to model a scenario beyond the current capabilities of multiscale computational methods-the implantation of a Jarvik 2000 blood pump for cavopulmonary support in the single-ventricle circulation; we found that the commercial Jarvik 2000 controller can be modified to produce a suitable rotor speed for augmenting cardiac output by approximately 20% while maintaining blood pressures within safe ranges. The unified modeling framework enables a testing environment which simultaneously operates a medical device and performs computational simulations of the resulting physiology, providing a tool for physically testing medical devices with simulated physiologic feedback.