Invasive Implanted Hemodynamic Monitoring in Patients With Complex Congenital Heart Disease: State-of-the-Art Review.

As the number of patients with congenital heart disease (CHD) continues to increase, the burden of heart failure (HF) in this population requires innovative strategies to individualize management. Given the success of implanted invasive hemodynamic monitoring (IHM) with the CardioMEMSTM HF system in adults with acquired HF, this is often suggested for use in patients with CHD, though published data are limited to case reports and case series. Therefore, this review summarizes the available published reports on the use of IHM in patients with complex CHD, describes novel applications, and highlights future directions for study. In patients with CHD, IHM has been used across the lifespan, from age 3 years to adulthood, with minimal device-related complications reported. IHM uses include (1) prevention of HF hospitalizations; (2) reassessment of hemodynamics after titration of medical therapy without repeated cardiac catheterization; (3) serial monitoring of at-risk patients for pulmonary hypertension to optimize timing of heart transplant referral; (4) and hemodynamic assessment with exercise (5) or after ventricular assist device placement. IHM has the potential to reduce the number of cardiac catheterizations in anatomically complex patients and, in patients with Fontan circulation, IHM pressures may have prognostic implications. In conclusion, though further studies are needed, as patients with CHD age and HF is more prevalent, this tool may assist CHD physicians in caring for this complex patient population.

Surgical Considerations in Adult Congenital Heart Disease Heart Failure.

Surgical intervention is often used in the management of heart failure in patients with adult congenital heart disease. This review addresses anatomic variations and complications due to prior surgical interventions, including sternal reentry, collateral vessels, and the neo-aortic root after the Damus-Kaye-Stansel procedure. Surgical considerations for systemic atrioventricular valvular surgery, Fontan revision, and advanced heart failure therapies including ventricular assist devices, heart transplant, and combined heart-liver transplant are discussed, with a focus on unique patient populations including those with systemic right ventricles and those with Fontan circulation.

Novel uses for implanted haemodynamic monitoring in adults with subaortic right ventricles.

BACKGROUND: Pulmonary hypertension (PH) is a common complication in patients with complete dextro-transposition of the great arteries (TGA) after atrial switch (D-TGA/AS) and congenitally corrected TGA (ccTGA). In this population with subaortic right ventricles (sRVs), echocardiography is a poor screening tool for PH; implantable invasive haemodynamic monitoring (IHM) could be used for this purpose, but data are limited. The aim of this study is to report on novel uses of IHM in patients with sRV. METHODS: This retrospective study describes the uses of IHM, impact of IHM on heart failure hospitalisation (HFH) and device-related complications in adults with sRV from a single centre (2015-2022). RESULTS: IHM was placed in 18 patients with sRV (median age 43 (range 30-54) years, 8 female, 16 with D-TGA/AS, 2 with ccTGA); 16 had moderate or severe sRV systolic dysfunction, 13 had PH on catheterisation. IHM was used for (1) Medical therapy titration, (2) Medical management after ventricular assist device in patients with transplant-limiting PH and (3) Serial monitoring of pulmonary artery pressures without repeat catheterisations to help identify the optimal time for heart transplant referral. In follow-up (median 23 months), HFHs/year were similar to the year prior to IHM (median 0 (IQR 0-1.0) before vs 0 (0-0.8) after, p=0.984). Device migration occurred in one, without long-term sequelae. CONCLUSIONS: Uses of IHM in patients with sRV are described which may minimise the need for serial catheterisations in a population where PH is prevalent. HFHs were low overall but not impacted by IHM. One device-related complication occurred without long-term consequence.

EBV dUTPase: A Novel Modulator of Inflammation and the Tumor Microenvironment in EBV-Associated Malignancies.

There is increasing evidence that put into question the classical dogma that the Epstein-Barr virus (EBV) exists in cells as either a lytic virus in which new progeny is produced or in a latent state in which no progeny is produced. Notably, a third state has now been described, known as the abortive-lytic phase, which is characterized by the expression of some immediate early (IE) and early (E) genes, but no new virus progeny is produced. While the function of these IE and E gene products is not well understood, several recent studies support the concept they may contribute to tumor promotion by altering the tumor microenvironment (TME). The mechanisms by which these viral gene products may contribute to tumorigenesis remain unclear; however, it has been proposed that some of them promote cellular growth, immune evasion, and/or inhibit apoptosis. One of these EBV early gene products is the deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by BLLF3, which not only contributes to the establishment of latency through the production of activin A and IL-21, but it may also alter the TME, thus promoting oncogenesis.

Diffusiophoresis-enhanced particle deposition for additive manufacturing.

The ability to govern particle assembly in an evaporative-driven additive manufacturing (AM) can realize multi-scale features fundamental to creating printed electronics. However, existing techniques remain challenging and often require templates or contaminating solutes. We explore the control of particle deposition in 3D-printed colloids by diffusiophoresis, a previously unexplored mechanism in multi-scale AM. Diffusiophoresis can introduce spontaneous phoretic particle motion by establishing local solute concentration gradients. We show that diffusiophoresis can play a dominant role in complex evaporative-driven particle assembly, enabling a fundamentally new and versatile control of particle deposition in a multi-scale AM process.

Machine learning-enabled feature classification of evaporation-driven multi-scale 3D printing.

The freeform generation of active electronics can impart advanced optical, computational, or sensing capabilities to an otherwise passive construct by overcoming the geometrical and mechanical dichotomies between conventional electronics manufacturing technologies and a broad range of three-dimensional (3D) systems. Previous work has demonstrated the capability to entirely 3D print active electronics such as photodetectors and light-emitting diodes by leveraging an evaporation-driven multi-scale 3D printing approach. However, the evaporative patterning process is highly sensitive to print parameters such as concentration and ink composition. The assembly process is governed by the multiphase interactions between solutes, solvents, and the microenvironment. The process is susceptible to environmental perturbations and instability, which can cause unexpected deviation from targeted print patterns. The ability to print consistently is particularly important for the printing of active electronics, which require the integration of multiple functional layers. Here we demonstrate a synergistic integration of a microfluidics-driven multi-scale 3D printer with a machine learning algorithm that can precisely tune colloidal ink composition and classify complex internal features. Specifically, the microfluidic-driven 3D printer can rapidly modulate ink composition, such as concentration and solvent-to-cosolvent ratio, to explore multi-dimensional parameter space. The integration of the printer with an image-processing algorithm and a support vector machine-guided classification model enables automated, in-situ pattern classification. We envision that such integration will provide valuable insights in understanding the complex evaporative-driven assembly process and ultimately enable an autonomous optimisation of printing parameters that can robustly adapt to unexpected perturbations.

Deceleration and Trapping of SrF Molecules.

We report on the electrostatic trapping of neutral SrF molecules. The molecules are captured from a cryogenic buffer-gas beam source into the moving traps of a 4.5-m-long traveling-wave Stark decelerator. The SrF molecules in X^{2}Σ^{+}(v=0,N=1) state are brought to rest as the velocity of the moving traps is gradually reduced from 190 m/s to zero. The molecules are held for up to 50 ms in multiple electric traps of the decelerator. The trapped packets have a volume (FWHM) of 1 mm^{3} and a velocity spread of 5(1) m/s, which corresponds to a temperature of 60(20) mK. Our result demonstrates a factor 3 increase in the molecular mass that has been Stark decelerated and trapped. Heavy molecules (mass>100 amu) offer a highly increased sensitivity to probe physics beyond the standard model. This work significantly extends the species of neutral molecules of which slow beams can be created for collision studies, precision measurement, and trapping experiments.

A supersonic laser ablation beam source with narrow velocity spreads.

A supersonic beam source for SrF and BaF molecules is constructed by combining the expansion of carrier gas (a mixture of 2% SF6 and 98% argon) from an Even-Lavie valve with laser ablation of a barium/strontium metal target at a repetition rate of 10 Hz. Molecular beams with a narrow translational velocity spread are produced at relative values of Δv/v = 0.053(11) and 0.054(9) for SrF and BaF, respectively. The relative velocity spread of the beams produced in our source is lower in comparison with the results from other metal fluoride beams produced in supersonic laser ablation sources. The rotational temperature of BaF is measured to be 3.5 K. The source produces 6 × 108 and 107 molecules per steradian per pulse in the X2Σ+ (ν = 0, N = 1) state of BaF and SrF molecules, respectively, a state amenable to Stark deceleration and laser cooling.

Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

PURPOSE: Neuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), affecting 85%-90% of all patients, yet the underlying mechanism or mechanisms responsible for the initiation and/or promotion of this process is largely unknown. Multiple reports, however, have suggested a role for Epstein-Barr virus (EBV), in particular, in ME/CFS, but its potential role, if any, in the neuroinflammatory process has not been addressed. In support of this premise, studies by our group have found that the EBV protein deoxyuridine triphosphate nucleotidohydrolase (dUTPase) induces anxiety and sickness behaviors in female mice. We also found that a small subset of patients with ME/CFS exhibited prolonged and significantly elevated neutralizing antibodies against EBV dUTPase protein in serum, which inversely correlated with ME/CFS symptoms. A larger ME/CFS case-control cohort study further confirmed that a significant percentage of patients with ME/CFS (30.91%-52.7%) were simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or human dUTPase. Altogether, these findings suggest that EBV dUTPase protein may be involved in the neuroinflammatory process observed in ME/CFS. Thus, the aim of the present study was to determine whether the EBV dUTPase protein could contribute to neuroinflammation by altering the expression of genes involved with maintaining blood-brain barrier (BBB) integrity and/or modulating synaptic plasticity. METHODS: With the use of human immortalized astrocytes, microglia, and cerebral microvascular endothelial cells, we conducted time-course (0-24 h) experiments with EBV dUTPase protein (10 µg/mL) to determine what effect(s) it may have on the expression of genes involved with BBB permeability, astrocytes and microglia cell function, tryptophan metabolism, and synaptic plasticity by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In parallel, in vivo studies were conducted in female C57Bl/6 mice. Mice were injected by the intraperitoneal route with EBV dUTPase protein (10 µg) or vehicle daily for 5 days, and the brains were collected and processed for further qRT-PCR analysis of the in vivo effect of the dUTPase on the dopamine/serotonin and γ-aminobutyric acid/glutamate pathways, which are important for brain function, using RT2 Profiler PCR Arrays. FINDINGS: EBV dUTPase protein altered the expression in vitro (12 of 15 genes and 32 of 1000 proteins examined) and in vivo (34 of 84 genes examined) of targets with central roles in BBB integrity/function, fatigue, pain synapse structure, and function, as well as tryptophan, dopamine, and serotonin metabolism. IMPLICATIONS: The data suggest that in a subset of patients with ME/CFS, the EBV dUTPase could initiate a neuroinflammatory reaction, which contributes to the fatigue, excessive pain, and cognitive impairments observed in these patients.

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP) Proteins with Implications for Human Disease.

The human herpesviruses are ubiquitous viruses and have a prevalence of over 90% in the adult population. Following a primary infection they establish latency and can be reactivated over a person's lifetime. While it is well accepted that human herpesviruses are implicated in numerous diseases ranging from dermatological and autoimmune disease to cancer, the role of lytic proteins in the pathophysiology of herpesvirus-associated diseases remains largely understudies. Only recently have we begun to appreciate the importance of lytic proteins produced during reactivation of the virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase), as key modulators of the host innate and adaptive immune responses. In this review, we provide evidence from animal and human studies of the Epstein-Barr virus as a prototype, supporting the notion that herpesviruses dUTPases are a family of proteins with unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer.

Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop.

Respiratory syncytial virus (RSV) is the most common cause of serious acute lower respiratory illness in infants and young children and a significant cause of disease burden in the elderly and immunocompromised. There are no licensed RSV vaccines to address this significant public health need. While advances in vaccine technologies have led to a recent resurgence in RSV vaccine development, the immune correlates of protection against RSV and the immunology of vaccine-associated enhanced respiratory disease (ERD) remain poorly understood. FDA's Center for Biologics Evaluation and Research (CBER) and NIH's National Institute of Allergy and Infectious Diseases (NIAID) organized and co-sponsored an RSV Vaccines Workshop in Bethesda, Maryland on June 1 and 2, 2015. The goal of the conference was to convene scientists, regulators, and industry stakeholders to discuss approaches to RSV vaccine development within the context of three target populations - infants and children, pregnant women, and individuals >60years of age. The agenda included topics related to RSV vaccine development in general, as well as considerations specific to each target population, such as clinical and serological endpoints. The meeting focused on vaccine development for high income countries (HIC), because issues relevant to vaccine development for low and middle income countries (LMIC) have been discussed in other forums. This manuscript summarizes the discussion of clinical, scientific, and regulatory perspectives, research gaps, and lessons learned.

An analytical model for the underwater sound pressure waveforms radiated when an offshore pile is driven.

An analytical model has been developed for the pile vibration and consequent sound pressure and particle velocity radiated underwater when an offshore cylindrical pile is struck by a drop hammer. The model, which is based on the coupled equations of motion for axial and radial vibration of a thin cylindrical shell, yields frequency-dependent phase velocity and attenuation of these vibrations. The amplitude of the pulse of axial and radial displacement that travels down a pile following an axial impact is described in terms of the hammer properties. Solutions are obtained for the radiated sound pressure and particle velocity, using Junger and Feit's Transform Formulation of the Pressure Field of Cylindrical Radiators [(Acoustical Society of America, New York, 1993), p. 216]. The model is applied to published data on radiated noise from offshore driving of a steel pile. The modeled pressure waveforms at 12-m horizontal range and at 9 hydrophone depths correlate significantly with the measured waveforms. The modeled pressures of the initial positive peaks (appropriately low-pass filtered) agree with data to within 1 dB. The initial negative peaks however exceed the data by up to 7 dB, and as hydrophone depth increases, the model negative peaks have a maximum at 7 m, whereas the data have a maximum at 9 m.

An investigation of the support needs of men and partners throughout the prostate cancer journey.

OBJECTIVE: Prostate cancer is one of the mostly commonly diagnosed cancers in men. Unfortunately, the treatment for this cancer can have a number of negative side effects, both for the man himself and his partner. This study investigated the support needs of both men and partners throughout the prostate cancer journey and how this journey may be optimally managed. METHODS: Thirty-one men who had undergone prostate cancer treatment within the last 6 years and 31 partners answered a questionnaire, which explored support care issues as identified in the literature and from focus groups. RESULTS: Men and partners were moderately satisfied with information given regarding diagnosis, treatment and side effects, but partners were more satisfied with information relating to the particular chosen treatment. Men's understanding of their chosen treatment's potential side effects was significantly different from their understanding of diagnosis, cancer outcome, treatment options and selected treatment. Timing of information delivery was preferred by men at diagnosis, whereas partners preferred after the diagnosis. Men wanted more time to think about the diagnosis and treatment, whereas partners wanted an opportunity to discuss the diagnosis. The management of common side effects such as emotional changes, incontinence and erectile dysfunction was rated as 'somewhat' satisfactory. CONCLUSION: Men and partners may have different educational and supportive needs throughout the prostate cancer journey that require attention and tailored management.

Human herpesviruses-encoded dUTPases: a family of proteins that modulate dendritic cell function and innate immunity.

We have previously shown that Epstein-Barr virus (EBV)-encoded dUTPase can modulate innate immune responses through the activation of TLR2 and NF-κB signaling. However, whether this novel immune function of the dUTPase is specific for EBV or a common property of the Herpesviridae family is not known. In this study, we demonstrate that the purified viral dUTPases encoded by herpes simplex virus type 2 (HSV-2), human herpesvirus-6A (HHV-6A), human herpesvirus-8 (HHV-8) and varicella-zoster virus (VZV) differentially activate NF-κB through ligation of TLR2/TLR1 heterodimers. Furthermore, activation of NF-κB by the viral dUTPases was inhibited by anti-TLR2 blocking antibodies (Abs) and the over-expression of dominant-negative constructs of TLR2, lacking the TIR domain, and MyD88 in human embryonic kidney 293 cells expressing TLR2/TLR1. In addition, treatment of human dendritic cells and PBMCs with the herpesviruses-encoded dUTPases from HSV-2, HHV-6A, HHV-8, and VZV resulted in the secretion of the inflammatory cytokines IL-1ß, IL-6, IL-8, IL-12, TNF-α, IL-10, and IFN-γ. Interestingly, blocking experiments revealed that the anti-TLR2 Ab significantly reduced the secretion of cytokines by the various herpesviruses-encoded dUTPases (p < 0.05). To our knowledge, this is the first report demonstrating that a non-structural protein encoded by herpesviruses HHV-6A, HHV-8, VZV and to a lesser extent HSV-2 is a pathogen-associated molecular pattern. Our results reveal a novel function of the virus-encoded dUTPases, which may be important to the pathophysiology of diseases caused by these viruses. More importantly, this study demonstrates that the immunomodulatory functions of dUTPases are a common property of the Herpesviridae family and thus, the dUTPase could be a potential target for the development of novel therapeutic agents against infections caused by these herpesviruses.

Methyl CpG binding domain ultra-sequencing: a novel method for identifying inter-individual and cell-type-specific variation in DNA methylation.

Experience-dependent changes in DNA methylation can exert profound effects on neuronal function and behaviour. A single learning event can induce a variety of DNA modifications within the neuronal genome, some of which may be common to all individuals experiencing the event, whereas others may occur in a subset of individuals. Variations in experience-induced DNA methylation may subsequently confer increased vulnerability or resilience to the development of neuropsychiatric disorders. However, the detection of experience-dependent changes in DNA methylation in the brain has been hindered by the interrogation of heterogeneous cell populations, regional differences in epigenetic states and the use of pooled tissue obtained from multiple individuals. Methyl CpG Binding Domain Ultra-Sequencing (MBD Ultra-Seq) overcomes current limitations on genome-wide epigenetic profiling by incorporating fluorescence-activated cell sorting and sample-specific barcoding to examine cell-type-specific CpG methylation in discrete brain regions of individuals. We demonstrate the value of this method by characterizing differences in 5-methylcytosine (5mC) in neurons and non-neurons of the ventromedial prefrontal cortex of individual adult C57BL/6 mice, using as little as 50 ng of genomic DNA per sample. We find that the neuronal methylome is characterized by greater CpG methylation as well as the enrichment of 5mC within intergenic loci. In conclusion, MBD Ultra-Seq is a robust method for detecting DNA methylation in neurons derived from discrete brain regions of individual animals. This protocol will facilitate the detection of experience-dependent changes in DNA methylation in a variety of behavioural paradigms and help identify aberrant experience-induced DNA methylation that may underlie risk and resiliency to neuropsychiatric disease.

Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach.

The hypothetical 'AXAS' gene network model that profiles functional patterns of heterogeneous DNA variants overrepresented in autism spectrum disorder (ASD), X-linked intellectual disability, attention deficit and hyperactivity disorder and schizophrenia was used in this current study to analyze whole exome sequencing data from an Australian ASD cohort. An optimized DNA variant filtering pipeline was used to identify loss-of-function DNA variations. Inherited variants from parents with a broader autism phenotype and de novo variants were found to be significantly associated with ASD. Gene ontology analysis revealed that putative rare causal variants cluster in key neurobiological processes and are overrepresented in functions involving neuronal development, signal transduction and synapse development including the neurexin trans-synaptic complex. We also show how a complex gene network model can be used to fine map combinations of inherited and de novo variations in families with ASD that converge in the L1CAM pathway. Our results provide an important step forward in the molecular characterization of ASD with potential for developing a tool to analyze the pathogenesis of individual affected families.

Current and potential immune therapies and vaccines in the management of psoriasis.

Psoriasis is a chronic, immune skin disease associated with significant morbidity. Development of psoriasis is influenced by numerous genes, one allele is HLA-CW*0602. Other genes and single nucleotide polymorphisms affect immunologic pathways and antimicrobial peptide synthesis. Dendritic cells initiate psoriasis by activating T-cells toward a Th1 and Th17 response, with increased cytokines including TNF-α, IL-6, -12, -17, -22, and -23. IL-22 appears to promote keratinocyte dedifferentiation and increased antimicrobial peptide synthesis while TNF-α and IL-17 induce leukocyte localization within the psoriatic plaque. These recent insights identifying key cytokine pathways have led to the development of inhibitors with significant efficacy in the treatment of psoriasis. While a strategy for vaccine modulation of the immune response in psoriasis is in progress, with new technology they may provide a cost-effective long-term treatment that may induce tolerance or targeted self-inhibition for patients with autoimmune disorders, such as psoriasis.

Detecting new Buffel grass infestations in Australian arid lands: evaluation of methods using high-resolution multispectral imagery and aerial photography.

We assess the feasibility of using airborne imagery for Buffel grass detection in Australian arid lands and evaluate four commonly used image classification techniques (visual estimate, manual digitisation, unsupervised classification and normalised difference vegetation index (NDVI) thresholding) for their suitability to this purpose. Colour digital aerial photography captured at approximately 5 cm of ground sample distance (GSD) and four-band (visible­near-infrared) multispectral imagery (25 cm GSD) were acquired (14 February 2012) across overlapping subsets of our study site. In the field, Buffel grass projected cover estimates were collected for quadrates (10 m diameter), which were subsequently used to evaluate the four image classification techniques. Buffel grass was found to be widespread throughout our study site; it was particularly prevalent in riparian land systems and alluvial plains. On hill slopes, Buffel grass was often present in depressions, valleys and crevices of rock outcrops, but the spread appeared to be dependent on soil type and vegetation communities. Visual cover estimates performed best (r 2 0.39), and pixel-based classifiers (unsupervised classification and NDVI thresholding) performed worst (r 2 0.21). Manual digitising consistently underrepresented Buffel grass cover compared with field- and image-based visual cover estimates; we did not find the labours of digitising rewarding. Our recommendation for regional documentation of new infestation of Buffel grass is to acquire ultra-high-resolution aerial photography and have a trained observer score cover against visual standards and use the scored sites to interpolate density across the region.

Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells.

We have recently demonstrated that Epstein-Barr virus (EBV)-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTPase) modulates innate immunity in human primary monocyte-derived macrophages through toll-like receptor (TLR) 2 leading to NF-κB activation and the production of pro-inflammatory cytokines. Our previous depletion studies indicated that dendritic cells (DCs) may also be a target of the EBV-encoded dUTPase. However, the role of EBV-encoded dUTPase in DC activation/function and its potential contribution to the inflammatory cellular milieu characteristic of EBV-associated diseases remains poorly understood. In the present study, we demonstrate that EBV-encoded dUTPase significantly altered the expression of genes involved in oncogenesis, inflammation and viral defense mechanisms in human primary DCs by microarray analysis. Proteome array studies revealed that EBV-encoded dUTPase modulates DC immune responses by inducing the secretion of pro-inflammatory TH1/TH17 cytokines. More importantly, we demonstrate that EBV-encoded dUTPase is secreted in exosomes from chemically induced Raji cells at sufficient levels to induce NF-κB activation and cytokine secretion in primary DCs and peripheral blood mononuclear cells (PBMCs). Interestingly, the production of pro-inflammatory cytokines in DCs and PBMCs was TLR2-dependent. Together these findings suggest that the EBV-encoded dUTPase may act as an intercellular signaling molecule capable of modulating the cellular microenvironment and thus, it may be important in the pathophysiology of EBV related diseases.