Stem cells hold promise for treating a wide variety of diseases, including degenerative disorders of the eye. The eye is an ideal organ for stem cell therapy because of its relative immunological privilege, surgical accessibility, and its being a self-contained system. The eye also has many potential target diseases amenable to stem cell-based treatment, such as corneal limbal stem cell deficiency, glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa (RP). Among them, AMD and glaucoma are the two most common diseases, affecting over 200 million people worldwide. Recent results on the clinical trial of retinal pigment epithelial (RPE) cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) in treating dry AMD and Stargardt’s disease in the US, Japan, England, and China have generated great excitement and hope. This marks the beginning of the ocular stem cell therapy era. The recent Zhongshan Ophthalmic Center Ocular Stem Cell Symposium discussed the potential applications of various stem cell types in stem cell-based therapies, drug discoveries and tissue engineering for treating ocular diseases. Stem cell research has become a promising area of biology in the last few decades. In the last few years, it has been recognized that the stem cell potential of terminally differentiated cells can be reprogrammed. Systemic and local stem cell-based therapy has been applied in many diseases with encouraging results. Recently, there has been increased interest and activity in exploring stem cell-based therapies as potential approaches for the treatment for the degenerative eye diseases. Therapeutic mechanisms being explored include stem cell-based replacement of lost neurons and other ocular cells, restoration of neural circuits, and paracrine-mediated therapies in which stem cell-derived trophic factors are used as neuroprotective molecules to protect compromised endogenous retinal neurons from death and to induce the growth of new connections.The eye has a unique structure  and is cet al. (1989) [ex vivo expansion of LSCs as an alternative.The corneal epithelium is a unique non-keratinized epithelial cell in an orderly arrangement, which is crucial to the maintenance of corneal transparency . It is w. (1989)  were theHong Ouyang, Professor of Cell Biology at Zhongshan Ophthalmic Center, discussed LSC research. In 1999, LSCs were cultured on a feeder layer of lethally irradiated mouse 3T3 cells . Upon trMaintenance of tissue homeostasis relies on accurate self-renewal and lineage commitment of adult stem cells. Pathological changes in LSCs usually cause the corneal surface to turn into an opaque keratinized skin-like epithelium. It has been reported that DKK2, an antagonist of canonical Wnt signaling and Notch1, can support the maintenance of corneal epithelial cell (CEC) fate during repair in injured mouse corneas . In 2008Ouyang suggested that stem cell-based therapy offers promising benefits to corneal regenerative medicine. In particular, LSCs have been approved as a commercial product for eye burns in Europe. In addition, in an effort to treat bilateral LSCD, a tissue-engineered cell sheet composed of autologous oral mucosal epithelium has been applied as a substitutive source of cells for the reconstruction of the corneal surface ,17,18. ii.e., squamous metaplasia [Wei Li, Professor of Ophthalmology at the Eye Institute of Xiamen University, discussed the corneal stem cell niche that is located in a defined limbal structure termed the Palisades of Vogt . This nitaplasia . They hataplasia .ex vivo LSC expansion by functioning as a surrogate niche. Previous studies used cryopreserved AMs, which contain devitalized stromal and/or epithelial cells [ex vivo expansion of LSCs, and found that limbal epithelial cells growing on LAM exhibited more homogeneous, compact, and smaller in size. The colony formation efficiency of the cells expanded on LAM was significantly higher than that on the dead denuded AM (DAM) lacking live stromal cells. The LAM increased long-term BrdU labeled LSCs but not short-term BrdU labeled differentiated corneal epithelial cells. K14, p63, and Ki67 expression was higher in epithelial cells expanded on the LAM. K12 was negative in the basal epithelium on the LAM, while there was strong immunoreaction in the epithelium on the DAM. Furthermore, the epithelial cells on the LAM could be easily separated as an intact cell sheet and successfully used to reconstruct the ocular surface in the LSCD rabbit model, while the cells on the DAM could not generate intact cell sheets. The data from Li’s team indicates that the LAM can facilitate ex vivo LSC expansion possibly via a niche mechanism. Currently they are utilizing the culture system combining air-exposure, low oxygen, and the LAM culture system to generate tissue engineered corneal epithelium for a clinical trial, which shows promising outcome in the treatment of LSCD. Jeffrey L Goldberg, Professor and Chair of Ophthalmology at Stanford University, presented an update on the progress in using stem cells for glaucoma treatment. Retinal ganglion cells  have been broadly used as carrier for al cells . Li and ls RGCs,  degeneraLate in glaucoma or other optic nerve degenerations, however, a significant number of RGCs will have already died. Neurotrophic or neuroprotection approaches will be less useful at such later stages, but cell replacement therapies will be very promising for vision restoration ,30. Herein vivo in rodent models. In collaboration with his collaborator Ken Muller at the University of Miami, and led by his graduate student Praseeda Venugopalan, his team began by asking whether RGCs can be transplanted and integrate into the mature retina [in vivo by intravitreal injection. Goldberg presented data demonstrating that transplanted RGCs acquired morphologic features of endogenous ones, with axons growing towards the optic nerve head of the host retina and dendrites extending into their target zones in the inner plexiform layer. Preliminary data showed GFP+ axons extending within the host optic nerves and optic tract to the superior colliculus and the lateral geniculate nucleus, two primary synaptic targets in the brain. Goldberg also shared data from electrophysiological recordings from transplanted RGCs, which demonstrated their electrical excitability. Light responses were also similar to host ON, ON-OFF and OFF RGCs, although less rapid and with greater adaptation. These data presented a promising approach to developing cell replacement strategies in diseased retinas with degenerating RGCs [Goldberg presented his laboratory group’s latest work on RGC transplantation and integration e retina ,33. Theying RGCs .The retina is the visual information sensing, primary processing and projecting neural tissue in the eye. Similar to other parts of the nervous system in our body, all the retinal neurons are generated during development, and the adult human retina shows little regeneration activity . On the in vivo approaches for regenerating photoreceptors in the degenerative diseases. There are two different ways for replenishing the lost photoreceptors in age- AMD and RP patients: transplantation of in vitro stem cell-derived photoreceptors and regeneration in vivo from existing cells. Retinal pigment epithelial (RPE) cells, Müller cells and Lgr5-positive amacrine cells could be ideal cell sources for generating photoreceptors because of their in vivo close proximity to endogenous photoreceptors . In the adult zebrafish retina, Müller cells have been shown to have remarkable ability to produce new retinal neurons, including photoreceptors, in response to light-induced injury ,41. ReceShuyi Chen, Principal Investigator of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, further discussed the field of endogenous retinal repair and regeneration. She pointed out that many clues to the cellular and molecular features of retinal regeneration come from studies in lower vertebrates, especially teleost fishes. The retina in fish continuously grows throughout lifetime, and can recover all types of retinal cells after injury, exhibiting tremendous regeneration ability . The regin vitro expanded retinal cells partially restore visual response to photoreceptor degenerated mice [As noted above, researchers have recently focused more attention on developing Müller cells as a source of RSCs. A number of reasons support this increased interest in Müller cells: first, Müller cells in lower vertebrates function as RSCs during homeostasis and upon injury ,50; secoted mice .in situ.Though Müller cells share multiple molecular characteristics with retinal progenitor cells, their transcriptomes are significantly different from each other, which may explain, at least partially, the limited regeneration activity of these cells . Recent Guo-Tong Xu, Professor of Ophthalmology and Regenerative Medicine and Dean of Tongji University School of Medicine, presented his group’s data on transplantation of (A) bone-marrow mesenchymal stem cells (MSCs) with or without gene modification; (B) adipose-derived stem cells (ADSCs); and (C) embryonic stem cells (ESCs) in rats with retinal degeneration (the RCS rats). All three donor stem-cell types, after transplantation into the subretinal space, demonstrated promising therapeutic effects in terms of protection of retinal structure and function in RCS rats. MSCs could differentiate into retinal cells and replaced some of the injured host cells. ASDCs appear to function primarily through paracrine effects. The rat ESCs (rESC) differentiated to two types of retinal progenitor cells (RPCs): the rESC-RPC1 contained more glia while the rESC-RPC2 was retinal neuron enriched . The rECWei Li, Chief of Retinal Neurobiology Section at National Eye Institute, National Institutes of Health, presented work led by his post-doctoral fellow Jingxing Ou in which they developed a ground squirrel iPSC system to study “hibernation in a dish”. Hibernation is a trait that some animals have evolved to cope with harsh winter environments. By lowering their metabolic rate and utilizing lipid fuels accumulated during the summer and fall, mammals such as ground squirrels seal themselves underground and survive the cold winter with little food and water intake. This is an amazing biological feat, as hibernators have to alternate between two vastly different metabolic states multiple times. Studying hibernation can help us not only to understand this fascinating biological phenomenon, but also to provide invaluable information about mechanisms of metabolic regulation that are critical for adapting to metabolic challenges. Such challenges are frequently brought upon in diseases and pathological conditions.Li’s lab studies adaptive changes in the ground squirrel retina during hibernation ,73,74,75in vitro by differentiating them into signature cell types of the three germ layer cells . In addition, positive results for teratoma formation further confirmed the pluripotency of the cells in vivo. Finally, karyotyping experiments suggested that the cell lines are genetically stable. This work by Li’s team represents the first example of successful generation of iPSC cell lines from a hibernating mammal.To generate iPSC lines, postnatal neural precursor cells were transduced with Sendai vectors to express the four classic Yamanaga transcription factors . These iPSC cells were positive for expression of pluripotency markers such as OCT3/4 (POU5F1) and NANOG. Li’s team tested their pluripotency Using iPSC-derived neuronal culture, preliminary data indicate that ground squirrel iPSC-derived neurons differ from human iPSC-derived neurons in that they are able to largely maintain their cytoskeletal structure when subjected to low temperature culturing (6 °C) for up to five days. Human iPSC-derived neurons, on the other hand, could not withstand low temperature culturing for as little as 10–12 h. Using pharmacology, genetics, and systems biology approaches, Li’s team is currently exploring the molecular mechanism(s) of this cold resistance feature of ground squirrel iPSC-derived neurons.Kang Zhang, Professor of Ophthalmology and Genetics and the founding Director of the Institute for Genomic Medicine at the University of California at San Diego, summarized his work in genetics, epigenetics, stem cell and 3D printing -based therapy for retinal blindness. His group demonstrated that the HTRA1 locus at chromosome 10q26 strongly impact AMD risk , and shoin vitro and treating ocular degenerative diseases including AMD and glaucoma [Zhang believes that stem cell research shows great promise in modeling disease glaucoma . Interesglaucoma ,81. 3D pglaucoma ,82. The glaucoma .Donald Zack, Professor of Genetic Engineering and Molecular Ophthalmology at Wilmer Eye Institute, Johns Hopkins University presented a talk entitled “Use of Human Stem Cell-Derived Retinal Cells for Drug Discovery” in which he highlighted the power of combining human retinal stem cell systems with high content screening approaches, both for increasing our understanding of retinal development and disease pathogenesis as well as for facilitating drug discovery. Zack first described work from his lab on efforts to identify RGC neuroprotective molecules for the treatment of glaucoma and other forms of optic nerve disease . These iZack also described a parallel series of studies being led by Karl Wahlin to use 3D stem cell technology to generate, via human stem cell-derived retinal cups, photoreceptor cell populations suitable for use in high content screening ,86. He oAs a third cellular system to demonstrate the potential power of combining retinal stem cell biology with small molecule screening technology, Zack described work led by Julien Maruotti in which a high throughput quantitative polymerase chain reaction (qPCR) assay was used to identify chetomin, an inhibitor of hypoxia inducible factors, as a strong promoter of differentiation of stem cells into RPE cells . This fiLastly, Robert B. Nussenblatt, Chief of Immunology Laboratory at National Eye Institute, National Institutes of Health raised his concern on stem cell transplantation that the eye is not always “privileged”. The eye has been put forward as one of the premier areas in stem cell technology to use this approach. Of great interest has been the use of RPE to treat several disorders, including inherited retinal degenerations and age related macular degeneration. This heightened interest has often centered around the concept that the eye is sequestered from the rest of the body and entertains a “privileged” relationship with the immune system. Indeed, the eye does maintain a special relationship with the immune system, but it is rather that of constant feedback and interchange. Under normal circumstances the eye attempts to maintain a downregulatory environment and several factors in the retina provide this “privilege” . Many ocStem cell generation may present challenges as well. It has been noted that there can be abnormal gene expression in some iPSCs, so that T-cell mediated immune responses can be elicited even in syngeneic hosts . A seconThe Symposium provided a welcome environment to connect among the authorities and audience. The ten leading experts shared their knowledge, perspectives, innovation and insight on ocular stem cell research. Due to the characteristics of unlimited proliferation and differentiation ability for multiple cell types, stem cells represent a promising approach for vision restoration. Different sources of stem cells used include ESCs, iPSCs, retinal progenitor cells, and LSCs. These stem cells have the potential to treat a wide range of ocular diseases, such as LSCD, glaucoma, retinal degeneration and AMD. Transplantation of stem cells in animal models of eye diseases and early clinical trials has demonstrated the effectiveness of stem-cell-based treatments. Although a successful replacement of dysfunctional cells by transplantation holds great hope for patients, problems still exist which may compromise their efficacy. For example, controlling the direction of stem cell differentiation remains a challenge, which involves the use of complex factors and takes many steps. In addition, immune rejection of grafted cells is also a considerable cause of transplantation failure.


Central venous pressure (CVP) and right atrial pressure (RAP) are important parameters in the complete hemodynamic assessment of a patient. Sonographic measurement of the inferior vena cava (IVC) diameter is a non-invasive method of estimating these parameters, but there are limited data summarizing its diagnostic accuracy across multiple studies. We performed a comprehensive review of the existing literature to examine the diagnostic accuracy and clinical utility of sonographic measurement of IVC diameter as a method for assessing CVP and RAP.We performed a systematic search using PubMed of clinical studies comparing sonographic evaluation of IVC diameter and collapsibility against gold standard measurements of CVP and RAP. We included clinical studies that were performed in adults, used current imaging techniques, and were published in English.Twenty one clinical studies were identified that compared sonographic assessment of IVC diameter with CVP and RAP and met all inclusion criteria. Despite substantial heterogeneity in measurement techniques and patient populations, most studies demonstrated moderate strength correlations between measurements of IVC diameter and collapsibility and CVP or RAP, but more favorable diagnostic accuracy using pre-specified cut points. Findings were inconsistent among mechanically ventilated patients, except in the absence of positive end-expiratory pressure.Sonographic measurement of IVC diameter and collapsibility is a valid method of estimating CVP and RAP. Given the ease, safety, and availability of this non-invasive technique, broader adoption and application of this method in clinical settings is warranted. Measurement of central venous pressure (CVP) is a critical component of the complete hemodynamic assessment of a patient. CVP is considered equivalent to right atrial pressure (RAP) when the vena cava is continuous with the right atrium . CentralThe inferior vena cava (IVC) is a compliant vessel whose size and shape vary with changes in CVP and intravascular volume . TherefoEarly standards for sonographic IVC assessment called for measurements of the maximum IVC diameter (IVCmax) and the minimum IVC diameter (IVCmin) during the respiratory cycle . An IVC A number of clinical studies have evaluated IVC diameter measurements as a method to estimate CVP and RAP, but the overall reliability and accuracy of this technique has not been systemically compared across multiple studies. We provide a comprehensive review of the existing literature to examine the reliability and accuracy of sonographic measurement of IVC diameter as a method for assessing CVP and RAP.We performed a systematic literature search in PubMed with search terms “ultrasound of inferior vena cava and central venous pressure” and “ultrasound of inferior vena cava and right atrial pressure” to identify clinical studies that compared ultrasound measurement of IVC diameter and collapsibility against gold standard measurements of CVP and RAP. Only clinical research studies among adults that pertained to our objective, used up-to-date imaging techniques, and were published in English were included in our review. For each study, we collected data on study design, patient population, and major findings, including the correlation between invasive pressure measurements and IVC measurement parameters.Our literature search returned 214 journal articles, of which we excluded 13 studies that were performed in pediatric/fetal populations, 13 that were not clinical research studies, 149 that were unrelated to our objective, 17 that were not published in English, and 1 that used an obsolete imaging technique (Fig. In all studies, IVC measurements were taken from the supine position, using the subcostal view Table . Howeverp-values for the correlation reported statistically significant results at α = 0.05.The majority of studies reported statistically significant positive correlations between sonographic measurements of IVC diameter and CVP or RAP. All studies that examined the relationship between ultrasound measurements of maximum IVC diameter and CVP or RAP across the entire respiratory cycle, at end-expiration, or at end-inspiration reported positive correlations Table . All stuMultiple studies also reported statistically significant negative correlations between IVCCI and CVP or RAP Table . AlthougSeveral studies have also identified threshold levels of IVC size and collapsibility by which to estimate CVP or RAP Table . AlthougThe reported correlations between IVC dimension and CVP in mechanically ventilated patients are generally weak and inconsistent across studies Table . ApproxiOverall, these findings support the use of sonographic measurements of IVC diameter to estimate CVP or RAP in spontaneously ventilating patients. Positive correlations were consistently reported between IVC size and CVP or RAP, and negative correlations were consistently reported between IVCCI and CVP or RAP. Although the correlations were generally only moderately strong, the diagnostic performance of pre-specified cut-points was superior, and justifies the current guideline recommendations for estimation of right-sided filling pressure. Importantly, there was substantial heterogeneity across the studies reviewed in the timing of IVC size measurement with respect to the respiratory cycle. Although IVCe has previously been recommended as the preferred IVC parameter by which to estimate CVP or RAP , the strThe correlations between IVC dimension and CVP in mechanically ventilated patients were generally weak and inconsistently observed. Furthermore, the use and magnitude of PEEP varied greatly across studies of mechanically ventilated patients. Positive pressure ventilation leads to increased intrathoracic pressure, decreased systemic venous return, and increased volume of venous blood in the IVC. The dimension and distensibility of the IVC is consequently affected. Therefore, the use of IVC measurements to estimate RAP in mechanically ventilated patients is usually unreliable. Accordingly, 2015 guidelines from the American Society of Echocardiography recommend against their routine application in this setting . HoweverThere are a few other notable circumstances in which IVC diameter may not correlate with CVP or RAP. First, the IVC may be dilated in young elite athletes with normal RAP, particularly swimmers. One study showed a mean IVC diameter of 2.3 cm in elite athletes compared to 1.3 cm in control subjects . In addiThere was substantial heterogeneity across the reviewed studies with respect to patient population. Importantly, the validity of IVC measurements for CVP or RAP estimation may not be equivalent in all patient subgroups. One population with limited data includes patients with atrial fibrillation, in whom venous inflow Doppler pattern is altered due to the loss of the atrial relaxation wave. Only four studies included patients with atrial fibrillation –18, withThere are only limited data suggesting an effect of body size on IVC diameter , and to One valuable application of non-invasive sonographic estimation of CVP may lie in serial measurements. IVC diameter has been shown to increase after fluid resuscitation and in association with concomitant increases in CVP . AdditioSimplification of IVC measurements could improve their standardization and application in clinical practice. In a pilot study, Martin et al. demonstrated success in training hospitalists to perform sonographic IVC measurements using an online module and a 1-day training session . After tUltrasound measurement of the IVC at the point of care provides insight into hemodynamics in a rapid and non-invasive manner and can impact clinical decision making. Assessment of CVP, historically requiring invasive intervention, can be performed non-invasively with reasonable accuracy in most, but not all, clinical settings. Additional validation of IVC measurements for estimation of CVP may be indicated in specific subgroups of patients. Measurement of the IVC with portable ultrasound devices as well as additional health care provider training may allow for expansion of filling pressure estimation as an extension of the routine bedside clinical examination of all patients.AF, atrial fibrillation; BSA, body surface area; CCU, critical care unit; CVP, central venous pressure; ER, emergency room; ICU, intensive care unit; IM, internal medicine; IVC, inferior vena cava; IVCCI, inferior vena cava collapsibility index; IVCe, maximum diameter of the inferior vena cava at end-expiration; IVCi, maximum diameter of the inferior vena cava at end-inspiration; IVCmax, maximum diameter of the inferior vena cava across the respiratory cycle; MD, medical doctor; N, sample size; n/a, not applicable; PEEP, positive end-expiratory pressure; RAP, right atrial pressure; RN, registered nurse; ROC, receiver operating characteristic; TEE, transesophageal echocardiogram; TR, tricuspid regurgitation.


Advances in mechanical circulatory support have significantly expanded the treatment options for patients with heart failure, whether acute or chronic. There are numerous devices available that offer patients short-, intermediate-, and long-term duration of support depending on their clinical needs and cardiac recovery. Each device has its own technical considerations and the decision which device to use depends on several factors, including what is available, the degree of support required, and expected duration of support. Additional issues that need to be considered in choosing level of support include right heart function, respiratory failure, and multi-organ derangements. A widespread availability of short-term ventricular assist devices and timely institution for effective hemodynamic support will translate into improved patient outcomes whether that is successful transfer to a tertiary care facility or recovery of inherent cardiac function. Implantable ventricular assist devices have and will continue to evolve into smaller and more durable devices, and the future for patients with advanced heart failure looks ever-more promising. The limited efficacy of medical therapy to treat end-stage heart failure (ESHF), shortage of available donor hearts, and the increasing number of patients who do not qualify for transplant candidacy despite worsening heart failure have all fueled the evolution of mechanical circulatory support. Currently, long-term implantable left ventricular assist devices (LVAD) have significantly expanded treatment options for patients with ESHF as a bridge-to-decision, recovery, transplant, or destination therapy (DT) . MirroriThe immediate goal for patients in cardiogenic shock is the re-establishment of normal hemodynamics and restoring vital organ perfusion. Cardiogenic shock can occur as a result of myocardial ischemia, valvular heart disease, myocardial disorders , or mechanical complications of myocardial infarction. Ideally, left ventricular support in this setting should be easy to institute, able to rapidly stabilize the patient, able to be transported with the patient, and allow adequate duration of support to address organ derangements and evaluation of neurologic status. A common approach in these patients is conservative, stepwise escalation of support before committing the patient to a more effective mechanical circulatory support (MCS), ie, maximal inotropes, followed by intra-aortic balloon pump, then followed by consideration of VAD therapy. This approach arguably poses a significant delay in reversing malperfusion in these critically ill patients.Percutaneously implanted devices include the Impella 2.5 and 5.0 , TandemHeart , and extracorporeal membrane oxygenation (ECMO). The Impella, a microaxial flow pump, is inserted through a 13-French catheter in the femoral artery and placed across the aortic valve. The Impella 2.5 has been successfully used for left ventricular support during high-risk coronary intervention and for patients with myocardial infarction and cardiogenic shock (The TandemHeart is another percutaneously placed VAD. The inflow cannula 17 French) is placed into the femoral vein and advanced into the left atrium under fluoroscopic guidance by a transseptal puncture. The outflow cannula (15 of 17 French) is inserted into the femoral artery. This pump has been successfully used for high-risk coronary intervention, post-cardiotomy heart failure, bridge-to-bridge (BTB), and bridge-to-transplant (BTT) 7 French . A majorThere is considerable experience with ECMO utilized for the treatment of cardiogenic shock. The major addition to the ECMO circuit is an oxygenator and it is the device of choice when patients have both cardiac and respiratory failure. Cannulation depends on the clinical situation; central cannulation is used in the post-cardiotomy setting and percutaneous cannulation through the femoral, subclavian, or neck vessels is more commonly used for cardiogenic shock. ECMO can provide full cardiopulmonary support, but disadvantages of this device strategy include bleeding because of the strict need for intense anticoagulation, limb ischemia when peripheral cannulation is employed, incomplete left ventricular decompression, and difficulty during patient transportation if the circuit is not compact and simplified. This type of support can be used as bridge-to-recovery (BTR), BTB, or BTT.The Biomedicus Bio-pump  is a centrifugal pump that has been in use since the 1980s. One major advantage of this pump is its widespread availability in most centers that perform cardiac surgery. It is easy to implant and transport patients on this system. However, this pump is prone to fibrin formation in the circuit, and other types of circulatory devices have emerged.The Abiomed BVS5000 is a pneumatically-driven assist device which consists of a filling chamber (fills passively) and blood returns to the patient via a pumping chamber. Pulsatile flow is not usually in concert with native cardiac contraction and can produce flows up to 6 L/min. The pump head requires exchange every week even with adequate anticoagulation. This device can similarly be used as support until weaning, and as a bridge to longer-term implantable VAD, or BTT.A newer external VADs based on improved centrifugal technology is the CentriMag . Patients with CentriMag can be supported until weaning, as a bridge to a longer-term implantable VAD, or transplant . AnticoaAs previously discussed, LVAD selection mainly depends on the indication for mechanical circulatory support. In the United States, long-term, implantable ventricular assist devices have been approved for clinical use on two indications, either as BTT or DT. This section focuses on long-term implantable devices, which have received FDA approval for these clinical scenarios.The clinical indications for use of implantable ventricular assist devices as BTT mainly parallel the eligibility criteria for cardiac transplantation, but its primary therapeutic aim is reducing transplant wait list mortality. Various VADs based on pulsatile pump technology were approved for BTT; these included both paracorporeal pumps such as the Thoratec PVAD  and the Berlin Heart Excor , and implantable devices such as the HeartMate XVE and Novacor VAD . More recently, The HeartMate II, an axial flow pump, has proven to be effective in improving functional status, quality of life, and survival in those who clinically deteriorated while awaiting transplantation . The thiOn the other hand, the majority of patients with advanced ESHF simply do not become eligible for heart transplantation due to the limited number of suitable donor hearts. The HeartMate XVE was the first device FDA approved based largely on the results of the REMATCH trial in which transplant-ineligible patients were randomized to either optimal medical management or LVAD therapy . At 1 anLVAD technology has evolved from large, pulsatile pumps into smaller, continuous-flow pumps. The HeartMate 2 has proven to be significantly more durable than the HeartMate XVE, and survival and quality of life were significantly improved in those supported on the new axial flow pumps . CurrentA unique device, which is also FDA approved for BTT, is the pneumatic total artificial heart Cardiowest TAH . Indications for TAH implantation differ from those of most VADs. This pump is mainly for patients with severe cardiogenic shock resulting in profound multiple organ derangements, extensive myocardial infarction resulting in biventricular failure, left ventricular failure with extensive intraventricular thrombi, or select cases of primary graft failure or rejection following transplantation.As discussed earlier, these implantable devices, which are currently FDA approved for long-term VAD support for either BTT or DT, are typically implanted in patients with chronic heart failure after a thorough evaluation process. However, in patients that are transferred on the aforementioned temporary support instituted for cardiogenic shock or post cardiac surgery, the evaluation process is quite different and their treatment pathway is dependent on several factors . Upon arPatient presentation and acuity of illness dictate the appropriateness of which device is selected for support. Temporary devices can serve as a bridge in order to stabilize patients and facilitate a work-up for candidacy for long-term implantable devices. This field continues to evolve as do the indications for their use


Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects. Owing to reduced bioavailability otential . Thus, totential ). The fiotential . In the otential ), are hiotential . Later wotential .The ability of CPPs to deliver large cargo to the intracellular environment provides an opportunity to deliver intracellular, therapeutically active proteins, thus providing a novel platform for the development of medical treatments using molecules that had thus far been considered improbable for therapy. This review will focus on the potential therapeutic uses of CPPs in promoting the uptake of biologically active proteins important in both inherited or acquired forms of protein deficiency. We will also describe the barriers that must be overcome before these CPP-protein therapies can become therapeutically useful.The mechanisms by which CPPs promote uptake of associated molecules are influenced by the physico-chemical properties of the different penetrating peptides, the associated molecular cargo, and the variety of cells and tissues being treated. Two general models of uptake have been proposed: energy-independent direct translocation across the plasma membrane to the cytosolic compartment ,8 and enMechanisms of CPP-mediated cellular uptake have been discussed extensively in previous reviews, including an article on membranotropic peptides in the current CPP special issue, to which the reader is referred for more extensive detail ,15,19. Ietc. Proteins that function intracellularly, however, may also be used as therapeutic molecules if cellular uptake of an intact, enzymatically active form can be achieved. Conjugation of cell-penetrating peptides to these proteins or even concurrent delivery of CPPs with other proteins can potentially circumvent this issue, thus facilitating the development of novel therapies. This review focuses on advancements made in CPP-aided protein therapies as new tools for medicine.The availability of CPPs to deliver therapeutically active cargo to the intracellular environment provides a novel platform for the development of medical treatments using molecules that would otherwise be ineffective without cellular entry. Proteins used as potential therapeutic molecules have traditionally been limited to those that function at the cell surface through ligand-receptor interaction, such as insulin, growth hormone, interferon, Therapeutic proteins can be delivered enterally or parenterally through intravenous, subcutaneous or inhaled routes of entry. Proteins must traverse mucosal barriers in some cases, travel through the extracellular space into the bloodstream, before entering target cells. Conjugation of CPPs to biotherapeutics or co-administration of CPPs can resolve some of the commonly encountered problems with systemic routes, by increasing cellular absorption and ensuring bioavailability to otherwise impenetrable organs, such as the brain .d-form of penetratin to facilitate intestinal uptake after oral administration. The oral route is the least invasive method of administration and would more closely mimic endogenous spikes of insulin seen in healthy people. Orally administered peptides are subject to enzymatic degradation in the intestinal fluid and the authors addressed this by examining the resistance to degradation of l- and d-forms of penetratin, as well as insulin, in intestinal fluid. While both forms of penetratin decreased the degradation rate for insulin, d-penetratin showed an increased resistance compared to l-penetratin and led to the highest amount of bioavailability, which in this case was limited to 18% [Insulin is a circulating polypeptide hormone that acts at the surface of the cell through binding to its receptor tyrosine kinase to promote the uptake of glucose into the cell. In diabetes mellitus, insulin deficiency or insulin resistance is often treated with administration of subcutaneous insulin, which is then absorbed into the bloodstream and circulates to target tissues. To maintain circulating glucose homeostasis, insulin must usually be administered subcutaneously several times a day for prolonged periods, which can lead to patient discomfort. Nasal co-administration of insulin and penetratin in rats leads to 50% bioavailability and significant lowering of blood glucose, while intranasal administration of insulin alone does not lead to a decrease in blood glucose concentration . The pred to 18% .Therapeutic protein and peptide-based vaccines typically induce a humoral antibody response but not a cell-mediated immune response, based on antigen processing through primarily the endocytic pathway and presentation via the MHC class II pathway. Activation of the cytotoxic T-cell lymphocyte (CTL) response requires antigen processing through the MHC class I pathway. CPPs have been shown to promote cytosolic uptake of vaccine antigens, resulting in cross-presentation by the MHC I pathway, thereby enhancing the cytolytic response. For example, a non-covalently bound cell-penetrating peptide, LAH4, facilitated the cellular entry of a tyrosinase-related protein 2 (TRP2) peptide vaccine, resulting in enhanced cross-presentation to CTLs, leading to antitumor effects against TRP2-expressing tumors in a mouse model .in vitro and reduction of tumor growth in vivo [Autoantibodies against double-stranded DNA can mediate cell penetration and target to the nucleus without pathological effects on the cell. A single chain variable fragment (scFv) from one such antibody, 3E10, can facilitate cell entry of therapeutic proteins and has been used to construct bispecific antibodies targeting cancer cell growth by enhancing p53 tumor suppressor function . Mutatio in vivo .Pseudomonas Aeruginosa, p28 demonstrates protein transduction domain capabilities with an affinity for cancer cells and antitumor effects. P28 can promote uptake of heterologous proteins such as green fluorescent protein and glutathione S-transferase into cultured cells [Another compound aimed at preventing p53 degradation in tumors is a novel amphipathic CPP, p28. Originally derived from amino acids 50−77 of azurin, a redox protein from the pathogen ed cells . The acted cells . p28 bined cells . After ded cells . Becauseed cells . This isA class of emerging therapeutics introduces exogenous enzymes into cells deficient in those proteins. Enzyme replacement therapy (ERT) is commercially available for various lysosomal storage diseases (LSDs) and represents a potentially exciting avenue for other inherited enzyme deficiency disorders that currently lack available treatments. Enzyme replacement therapies have the benefit of well-understood safety profiles when compared with gene therapies and also generally show increased specificity compared with small molecule mimetics . ERTs cu.In neutrophils, an intact phagocyte NADPH oxidase (PHOX) complex is required to produce reactive oxygen species (ROS) that facilitate clearing of bacterial infections by promoting destruction of phagocytized bacteria. In chronic granulomatous disease (CGD), phagocytic cells are unable to destroy internalized bacteria efficiently due to mutations in one of the four essential subunits of the PHOX complex. Honda and colleagues restored the ability to produce ROS in CGD patient-derived neutrophils by transducing them with one of two of the essential subunits of the PHOX complex (p47 or p67) linked to the PTD Hph-1. These proteins are normally localized in the cytosol and translocate to the plasma membrane, the site of ROS production, only upon neutrophil activation. The exogenously delivered proteins localized in the cytosol in control cells and did not produce excess ROS. These recombinant enzymes only translocated to the membrane after neutrophils were activated with phorbol myristate acetate treatment, and subsequently restored the ability of the neutrophils to produce ROS .et al. have reported on efforts to develop a frataxin-Tat enzyme replacement therapy with encouraging results in mice [Lipoamide dehydrogenase  deficiency is an inherited mitochondrial disorder with a variable clinical course resulting in severe metabolic disturbances. The LAD protein is part of several large complexes in the mitochondrial matrix responsible for the metabolism of amino acids and carbohydrates. Lorberboum and colleagues reported the successful delivery of two different Tat-coupled mitochondrial enzymes, LAD and nicotinamide adenine dinucleotide dehydrogenase complex I assembly factor (NDUFAF4) to mice and patient cells, respectively ,37. Coup in mice .X-linked myotubular myopathy (XLMTM) is a rare form of congenital myopathy resulting from mutations in the lipid phosphatase myotubularin. Lawlor and co-workers showed that a small amount of exogenous myotubularin linked to the 3E10Fv PTD identified by Weisbart , deliveret al. included a Tat CPP downstream of the gene encoding the missing enzyme, α-Galactosidase A, demonstrating that the recombinant α-Gal A-Tat enzyme is able to diffuse to neighboring cells that may not have been transduced by the virus [CPPs have also been used as adjuncts to gene therapy in LSDs. LSDs are a group of inherited metabolic disorders arising from mutations that result in lysosomal accumulation of metabolic intermediates. Current treatment for these disorders consists of enzyme replacement by delivering the missing enzymes, tagged with mannose-6-phosphate, which promotes uptake and delivery to lysosomes mediated by the mannose-6-phosphate receptor . More rehe virus . NeonataCPP-mediated enzyme replenishment can also be used in non-inherited conditions. Reduced mitochondrial complex I activity has been linked to ischemia/reperfusion-induced damage after myocardial infarction . In a raSystemic delivery of therapeutic proteins may in some situations be undesirable, such as when organ-specific deficiencies need to be addressed and also when potential therapies have toxic or off-target effects in certain tissues. CPPs that target specific tissues would circumvent these issues and have been reported for the heart , althougTraditionally, drug development approaches have not favored proteins as therapeutics, due to the difficulty of delivering them into cells, focusing instead on mimetic small molecule drugs . While sOne major challenge in the use of proteins for therapy is delivering them to the appropriate site of action; this challenge is twofold—getting the protein to the target tissue/cells and ensuring localization of the exogenous protein to the correct extra- or intracellular compartment. CPPs have been developed that reportedly deliver cargo to certain cell types/tissues, either by using CPPs which target specific cells or by taking advantage of unique features of the target microenvironment. Two different CPPs, p28 and NGR, have been reported to preferentially target cancer cells and tumor vasculature, respectively ,47. SeveAttachment of a CPP could impact its function in live cells. It has been proposed that the presence of CPPs acidifies the environment in endosomes, thus facilitating escape. This same effect could also disrupt microdomains or organellar environments where a particular enzyme localizes. In addition, depending on where the CPP is conjugated to the protein, it could also prevent membrane-embedded enzymes from attaching to the membrane. A system in which the CPP is cleaved off once the protein reaches the intracellular environment would theoretically circumvent these issues. Efforts to develop cleavable CPPs, however, have thus far been limited.Although coupling of an exogenous enzyme with a CPP can promote its entry into cells, endogenous targeting signals are usually relied upon for further trafficking to its subcellular compartment. One consequence of attaching polycationic CPPs to proteins is their propensity to direct localization to the nucleus; if the therapeutic enzyme is destined for a different subcellular location, then attachment of a CPP could interfere with its proper localization. Development of a class of synthetic mitochondrial and other organelle-specific targeting peptides is a potential solution for this problem ,51,52,53et al. have described a class of peptides comprised of both synthetic and natural residues known as mitochondria-penetrating peptides (MPPs) [Horton s (MPPs) . These ps (MPPs) . Due to More recently, a dual role antioxidant and mitochondria-penetrating peptide, mtCPP-1, was developed based on the Szeto-Schiller (SS) tetrapeptide antioxidants ,55. Likeet al. based their dual peptide design on the MTS of the mitochondrially destined protein, aldehyde dehydrogenase, and the intracellular targeting properties of polyarginine peptides [Another approach focuses on combining existing CPP motifs with mitochondrial-targeting sequences (MTS) to promote cellular entry and targeting to the mitochondria. Lin peptides . The compeptides ,57. TFAMpeptides . Treatmeet al. used the well-studied NLS from simian virus 40 large-T antigen in combination with octa-arginine in order to increase DNA delivery to the nuclear compartment. The NLS-octa-arginine compound effectively delivered luciferase DNA to two different cell lines [Similarly, a nuclear localization signal (NLS) was used in conjunction with a polyarginine CPP to direct nuclear targeting. Wang ll lines .A cyclical new peptide, cyc 3, is able to show localization to the nucleolus. Cyc 3 is a cyclical CPP based on the cationic antimicrobial peptide (CAP18), which takes advantage of the recent observations that peptide rigidity plays a role in its uptake efficiency . Upon inet al., three of the most commonly used CPPs—Tat, penetratin and transportan—were examined for potential innate immunity induction. Epithelial cells from skin, lung and intestine, the cells most likely to first come into contact with systemically administered CPP therapeutics, were incubated with albumin conjugated to one of the three CPPs evaluated. Although the cells internalized the CPP and cargo, their viability was unaltered. Furthermore, they failed to produce an innate immune response as assessed by lack of activation of phosphorylated NF-κB, a signaling molecule downstream of toll-like receptors, and failure to secrete epithelial-specific interleukins, IL-6 and IL-8 [CPP sequences are in many cases novel to the organism to which they are being administered and it is thus possible that they could elicit an immune response. It is therefore important to establish the potential immunogenic effects of CPP administration. In a study by Carter and IL-8 .et al. These peptides were incubated with human white blood cells either alone or with plasmid or siRNA. In all cases, no immune response was observed, as measured by cytokine release. These results were confirmed in mice and, similarly, there were no increases in cytokines detected in serum [The immunogenicity of Tat, transportan and some synthetic derivatives of transportan was also evaluated by Suhorutsenko in serum .These studies showed that it is possible to deliver CPPs without eliciting an immune reaction; however, given the breadth and diversity of available CPPs, assessment of immunogenicity should be performed for each individual CPP. Additionally, coupling of a CPP with cargo can result in generation of novel epitopes such that even if an individual isolated CPP does not elicit an immune response, it may do so when conjugated to a particular cargo. Penetratin alone, for example, does not cause an immune reaction, but when coupled to an siRNA, the complex does elicit an innate immune response. The same siRNA complexed with Tat, however, did not elicit a response . These dIn vitro studies on the cytotoxicity of CPPs show that cationic CPPs are less toxic and can be tolerated by the cells at much higher concentrations than amphipathic CPPs, such as transportan and model amphipathic peptide (MAP). Commonly used assays, such as cell viability, proliferation and leakage of lactate dehydrogenase (LDH) demonstrate virtually no toxic effects of Tat and penetratin. In contrast, MAP and transportan show an effect on cell viability and membrane integrity at relatively low concentrations, such as those used for intracellular delivery [delivery ,65. Simidelivery . As within vivo toxicity studies for CPPs are generally not available, a small number of published animal studies as well as the approval of several CPP formulations for use in clinical trials attest to the general safety of therapeutic CPP molecules at the doses studied [in vivo study using intravenously delivered nona-arginine (r9), in which mice experienced immediate respiratory collapse and death [Although comprehensive  studied ,68,69. Ond death . At lowend death . Histolond death .in vivo so long as careful consideration is given to potentially novel effects of conjugating a CPP to a previously untested cargo.As recently noted by Verdurmen and Brock, several compounds involving CPPs have been tested in humans with no serious adverse effects . KAI-980Numerous studies using cell-penetrating peptides demonstrate the feasibility and efficacy of using CPP-tagged proteins as therapeutic agents in experimental systems. To the best of our knowledge, however, no CPP-tagged proteins have yet entered human clinical trials. Nevertheless, given the numerous CPP-peptides that have entered clinical trials, we are cautiously optimistic that CPP-proteins will eventually be useful therapeutic agents. Expanding the use of therapeutic proteins can address many unmet needs and has potential for higher therapeutic specificity with acceptable safety. In addition, CPPs can reduce the dosing necessary to achieve therapeutic levels and can be used to facilitate delivery to specialized cells, thus reducing overall toxicity. The ongoing discovery of numerous CPPs, the extensive use of CPP-protein therapy in experimental disease models and the fact that CPP-aided therapies have entered human clinical trials speaks to their potential impact on developing novel CPP-protein therapies for human disease.


The development of the cardiopulmonary bypass (CPB) revolutionized cardiac surgery and contributed immensely to improved patients outcomes. CPB is associated with the activation of different coagulation, proinflammatory, survival cascades and altered redox state. Haemolysis, ischaemia, and perfusion injury and neutrophils activation during CPB play a pivotal role in oxidative stress and the associated activation of proinflammatory and proapoptotic signalling pathways which can affect the function and recovery of multiple organs such as the myocardium, lungs, and kidneys and influence clinical outcomes. The administration of agents with antioxidant properties during surgery either intravenously or in the cardioplegia solution may reduce ROS burst and oxidative stress during CPB. Alternatively, the use of modified circuits such as minibypass can modify both proinflammatory responses and oxidative stress. The development of the cardiopulmonary bypass (CPB) revolutionized cardiac surgery and contributed immensely to improved patients outcomes , 2.It is accepted that CPB exposes patients to a complex set of nonphysiological conditions during which organs are subjected to severe functional alterations. CPB is associated with the activation of different coagulation, proinflammatory, survival cascades and altered redox state –5 Figur. Despite2−•), hydrogen peroxide (H2O2), hydroxyl radicals (•OH), and peroxynitrite (ONOO−). Although hydrogen peroxide is not a free radical it is considered a ROS due to its highly reactive nature.Free radicals are molecules with unpaired electrons making them highly reactive. They can be derived from oxygen, nitrogen, or sulfur molecules. Free radicals derived from oxygen are usually called reactive oxygen species (ROS) , 9. The ROS can be formed as a natural byproduct of normal metabolism of oxygen as aerobic metabolism results in the production of ROS in the mitochondria during ATP formation. Nonetheless, cells are normally able to shield themselves against ROS through different defense mechanisms that include enzymatic and free radical scavenging activities to neutralize these radicals resulting in a balance (redox state) between ROS production and cells ability to detoxify ROS or to repair any subsequent damage. During periods of stress, however, ROS levels can increase drastically leading to substantial damage to many cellular molecules such as lipids, proteins, and DNA –10.2•− and oxygen sensing. Redox signalling is involved in multiple processes such as homoeostasis, stress response pathways, and cardiac remodeling and fibrosis  than control mitochondria. The result of a randomised trial designed to address the effect of adding propofol to cardioplegia solution in patients undergoing cardiac surgery will report shortly [Animal studies demonstrated that propofol increases the antioxidant capacity of the liver, kidney, heart, and lung by decreasing t-BHP-induced TBARS formation in an ischaemia and reperfusion model –58, 63.  shortly .2O2 production suggesting an increase in bioavailability of NO [2 uptake and reduced malondialdehyde (MDA) extraction [L-Arginine is an amino acid that can play an important role in immune function and vascular homeostasis as a precursor for the synthesis of nitric oxide (NO). It is recognised that cardiac surgical patients have arginine/nitric oxide pathway impairment evident by increased levels of nitric oxide inhibitor asymmetric dimethylarginine , 69. Thety of NO . Such chty of NO . When L-traction , 73. In traction .2O2, HOCl-, and lucigenin levels were significantly lower than the control group. Furthermore, tumour necrosis factor-alpha levels were significantly decreased as a result of NAC administration [NAC is another effective scavenger of free radicals with neutrophil aggregation inhibitory properties. When NAC is used as intravenous infusion during CABG surgery, it was noted that luminol, Hstration , 76. Morstration . When adstration –79.Levosimendan is a calcium sensitizer that enhances myocardial contractility without increasing myocardial oxygen. Its function involves the activation of mitochondria ATP-sensitive potassium (mito-KATP) channels and production of eNOS-dependent NO through Akt and MAPK , 81.+ ions into the matrix and preventing Ca2+ accumulation in the matrix, thus blunting the opening of mPTP and its deleterious effects (as discussed above). Furthermore, the activation of mito-KATP can protect cells from damage induced by ROS and reduce cell apoptosis [KATP channels belong to the ATP-binding cassette transporter superfamily. Two KATP channel subtypes coexist in the myocardium, with one subtype located in the sarcolemma (sarc-KATP) membrane and the other in the inner membrane of the mito-KATP . Under hpoptosis –86. Clinpoptosis –90. Furtpoptosis .Recent years have witnessed the use of mitochondrial targeted antioxidants such as Mitoquinone mesylate (MitoQ). MitoQ is made up of a lipophilic triphenylphosphonium (TPP) cation covalently attached to a ubiquinone antioxidant moiety. The positive charge on the TPP cation means that it is rapidly and extensively taken up by mitochondria due to the large membrane potential across the mitochondrial inner membrane. Within mitochondria, the ubiquinone moiety of MitoQ is rapidly reduced by complex II of the mitochondrial respiratory chain to the active antioxidant ubiquinol form and, after detoxifying a ROS, it is converted to the ubiquinone form which is then rapidly recycled back to the active antioxidant , 93.MitoQ has been used in a wide range of animal studies and demonstrated efficacy in preventing mitochondrial oxidative damage in the heart, liver, kidney, and brain , 94–97. The impact of surface contact activation, air-fluid interface, and cell damage by cardiotomy suction associated with conventional bypass on the activation of proinflammatory and survival cascades has led to the development of minimised cardiopulmonary bypass circuit (mini-CPB). The design is a closed CPB system characterised by reduced surface area and thus priming volume, elimination of cardiotomy suction, and prevention of air-blood contact. The use of mini-CPB is associated with delayed or reduced secretion of different proinflammatory cytokines, attenuated complement activation, and blunted leukocytes activation compared to conventional circuit , 100.The utilization of mini-CPB is associated with significant reduction in red blood cell damage (as measured by free Hb), activation of coagulation cascades, and blunted fibrinolytic and proinflammatory activities. Furthermore, serum concentration of MDA and allantoin/urate ratio as markers of oxidative stress tend to be reduced in patients undergoing surgery using mini-CPB when compared to conventional circuit , 102.Cardiopulmonary bypass, although not perfect, remains an essential part of cardiac surgery. The utilization of CPB is associated with the production of ROS and oxidative stress.Haemolysis, ischaemia, and perfusion injury and neutrophils activation during CPB play a pivotal role in oxidative stress and the associated activation of proinflammatory and proapoptotic signalling pathways which can affect the function and recovery of multiple organs such as the myocardium, lungs, and kidneys and influence clinical outcomes.The administration of agents with antioxidant properties during surgery either intravenously or in the cardioplegia solution may reduce ROS burst and oxidative stress during CPB. Alternatively, the use of modified circuits such as minibypass can modify both proinflammatory responses and oxidative stress. More in-depth research and adequately powered randomised clinical studies with strict CPB protocols are still required.


Patient information and education, such as decision aids, are gradually moving toward online, computer-based environments. Considerable research has been conducted to guide content and presentation of decision aids. However, given the relatively new shift to computer-based support, little attention has been given to how multimedia and interactivity can improve upon paper-based decision aids.The first objective of this review was to summarize published literature into a proposed classification of features that have been integrated into computer-based decision aids. Building on this classification, the second objective was to assess whether integration of specific features was associated with higher-quality decision making.Relevant studies were located by searching MEDLINE, Embase, CINAHL, and CENTRAL databases. The review identified studies that evaluated computer-based decision aids for adults faced with preference-sensitive medical decisions and reported quality of decision-making outcomes. A thematic synthesis was conducted to develop the classification of features. Subsequently, meta-analyses were conducted based on standardized mean differences (SMD) from randomized controlled trials (RCTs) that reported knowledge or decisional conflict. Further subgroup analyses compared pooled SMDs for decision aids that incorporated a specific feature to other computer-based decision aids that did not incorporate the feature, to assess whether specific features improved quality of decision making.Of 3541 unique publications, 58 studies met the target criteria and were included in the thematic synthesis. The synthesis identified six features: content control, tailoring, patient narratives, explicit values clarification, feedback, and social support. A subset of 26 RCTs from the thematic synthesis was used to conduct the meta-analyses. As expected, computer-based decision aids performed better than usual care or alternative aids; however, some features performed better than others. Integration of content control improved quality of decision making . In contrast, tailoring reduced quality of decision making . Similarly, patient narratives also reduced quality of decision making . Results were varied for different types of explicit values clarification, feedback, and social support.Integration of media rich or interactive features into computer-based decision aids can improve quality of preference-sensitive decision making. However, this is an emerging field with limited evidence to guide use. The systematic review and thematic synthesis identified features that have been integrated into available computer-based decision aids, in an effort to facilitate reporting of these features and to promote integration of such features into decision aids. The meta-analyses and associated subgroup analyses provide preliminary evidence to support integration of specific features into future decision aids. Further research can focus on clarifying independent contributions of specific features through experimental designs and refining the designs of features to improve effectiveness. Over the past decade, health care has shifted from paper-based practice to electronic health records . PatientConsiderable research has been conducted to guide content and presentation of decision aids ,6-18. InTheory suggests that integration of media rich or interactive features into computer-based decision aids can have a positive impact on quality of decision making by engaging patients in decision making beyond traditional static approaches . TherefoFour databases  were searched for all relevant studies published from 1946-2013. Three main concepts of decision support, the patient, and computer were mapped to the most relevant controlled vocabulary using Medical Subject Headings (MeSH), and free-text terms were added where necessary. Full search strategies are outlined in The review identified studies that evaluated computer-based decision aids for adults faced with a preference-sensitive medical decision  and that reported at least one quality of decision-making outcome . Disagreements were resolved by discussion and consensus between the 2 reviewers. Overall kappa score was calculated to assess interrater reliability .One reviewer completed data abstraction (AS), which focused on citation information, study design, decision context, interventions, controls , components being tested, and quality of decision-making outcomes. If an article included in the review cited a development paper or webpage, then information from these sources was used to supplement data abstracted from the article.All studies identified for the systematic review were included in the thematic analysis. Data abstracted from the articles was used to create a proposed classification of features that have been integrated into computer-based decision aids to date. The classification was developed based on logical groupings and informed by themes from decision aid literature ,7.Selection of groupings was completed by 1 reviewer (AS), guided by steps outlined by Thomas & Harden for conducting thematic analysis: (1) line-by-line coding of articles to record components, (2) development of descriptive themes, and (3) creation of analytical themes . Componed effect size) was calculated for each study [Only randomized controlled trials (RCTs) that reported knowledge or decisional conflict were included in the quantitative synthesis. Decisional certainty, satisfaction with decision making, and decisional self-efficacy were not included due to the lower number of studies that reported these outcomes. The standardized mean difference . Studies were pooled using inverse variance weighting and random effects models with 95% confidence intervals. Heterogeneity of pooled SMDs was assessed based on Iatistics .Subgroup analyses were conducted to test whether specific features (or types of components) could explain some of the heterogeneity in the overall effect. Subgroup analyses compared pooled SMDs for decision aids that incorporated a specific feature to other computer-based decision aids that did not incorporate the feature to assess whether specific features were associated with improvements in quality of decision making. The Review Manager test for subgroup differences was used to assess statistical significance.The search identified 3541 eligible articles. The title and abstract screen retained 135 articles. Full text screening identified 58 studies that met the target criteria and were included in the thematic synthesis. The overall kappa score for screening was 0.60, reflecting moderate interrater agreement . A subseData abstracted from articles are presented in Studies assessed quality of decision making by measuring knowledge , decisional conflict , decisional certainty , satisfaction with decision making , and decisional self-efficacy . Studies compared computer-based decision aid performance to usual care , alternative aids , or based on pre-assessments .The thematic analysis identified six main features that have been integrated into computer-based decision aids: content control, tailoring, patient narratives, explicit values clarification, feedback, and social support. A proposed classification for these features and types of components is presented in The majority of studies included in the thematic analysis provided content control . Two-thirds tailored information to the patient , and almost half incorporated patient narratives . Over half of the studies provided explicit values clarification , feedback , or social support . One third of the studies incorporated five  or all six  of these features.P<.001). A forest plot is presented in Eighteen studies were included in the meta-analysis to assess whether or not use of computer-based decision aids improved knowledge. The studies included were published between 2001 and 2013. Most computer-based decision aids performed significantly better than usual care or alternative aid controls ; the performance of the remaining decision aids was not significantly different from controls. Overall, computer-based decision aids were associated with significant improvements in knowledge with a pooled SMD of 0.54 . A forest plot is presented in We included 21 studies in the meta-analysis to assess whether or not use of computer-based decision aids improved decisional conflict. The studies included were published between 2002 and 2013. Most computer-based decision aids performed significantly better than usual care or alternative aid controls ; the performance of the remaining decision aids was not significantly different from controls. Overall, computer-based decision aids were associated with significant improvements in decisional conflict with a pooled SMD of 0.35 . However, specific types had differing effects. Knowledge and decisional conflict were negatively affected by offering navigation , whereas knowledge and decisional conflict both improved by providing clarity around evidence , optional in-depth information , or access to external resources .Overall, integration of content control was positively associated with quality of decision making, although the association was only significant for knowledge . This association was consistent across all types; both knowledge and decisional conflict were negatively affected by tailoring based on patient demographics , clinical condition , or values, preferences, and beliefs .Conversely, tailoring was negatively associated with knowledge and decisional conflict (P=.005). Both knowledge and decisional conflict were negatively affected by presenting patient stories , or behavior modeling .Similarly, patient narratives reduced quality of decision making; however, the association was significant only for decisional conflict (P=.42) but did not affect decisional conflict. However, effects varied for different types. Both knowledge and decisional conflict improved by integrating notebooks , or trade-off exercises . Knowledge was reduced by providing weighting exercises (P=.18) or social matching (P=.47), with no effect on decisional conflict. Likewise, personal reflection reduced knowledge (P=.47).Explicit values clarification reduced knowledge . Again, effects varied by type. Reporting progress through the decision aid improved decisional conflict (P=.32). Likewise, both knowledge and decisional conflict improved by providing knowledge feedback . Providing a summary of preferences did not affect decisional conflict. Optimal choice feedback reduced knowledge (P=.44), but improved decisional conflict (P=.54). Both knowledge and decisional conflict were negatively affected by providing feedback around decisional consistency , or providing a summary of decision aid activity .Overall, providing feedback was negatively associated with knowledge and decisional conflict (P=.67) but did not affect decisional conflict. Both knowledge and decisional conflict improved by providing community support . Integration of family support did not affect knowledge but improved decisional conflict (P=.54). Both knowledge and decisional conflict were negatively affected by facilitation of shared decision making .Social support improved knowledge  statement simply states that authors should report sufficient information to ensure replicability, including detail around how and when interventions were administered . The CONAs expected, computer-based decision aids were associated with significant improvements in knowledge and decisional conflict compared to usual care or alternative aids . The subOverall, content control improved quality of decision making. All types of content control performed better than other features, with the exception of navigation. Content control is intended to provide patients with control over order, detail, and type of evidence presented . The conInterestingly, navigation reduced quality of decision making compared to other features. Given that navigation is a foundational piece of computer-based interventions, this may represent a reporting bias. As a result of journal space limitations, navigation may have been underreported in exchange for reporting novel or impressive decision aid components. This relates back to the need for a classification to ensure that all features are reported; otherwise, important features may be overlooked as a result of biased evaluations.Tailoring reduced quality of decision making, with all subgroups performing worse than other features. In general, tailoring is intended to translate evidence into patient-specific information to improve engagement. The effects of tailoring can be split into two categories: (1) effects on calculation of risk estimates, and (2) effects on presentation of information.Tailoring can be used to frame evidence in terms of patient demographics or clinical condition to present only viable treatment options with more accurate estimates of associated risks and benefits. Ideally, this should provide a better understanding of personal situations and lead to high-quality decision making. However, evidence around the benefits of tailoring risk estimates is varied . TailoriTailoring can also be used to present evidence in terms of patient preferences or to address knowledge deficits, in an effort to facilitate understanding or to correct misinformation. However, this form of tailoring may limit the amount or type of evidence that is presented. For example, decision aids can be tailored to information-seeking style   or inforSimilarly, patient narratives reduced quality of decision making. Patient narratives are intended to provide insight into patient experiences and bring attention to important evidence to consider throughout the decision-making process. In addition, information presented through patient narratives is processed differently than written information and can improve understanding and retention of evidence ,20,109. In this study, both patient stories and behavior modeling scenarios reduced quality of decision making. Shaffer and Zikmund-Fisher have developed a taxonomy for patient narratives outlining dimensions that are expected to impact decision making: (1) purpose of the narrative, (2) content of the narrative, and (3) evaluative valence  . This taThe negative effects of tailoring and patient narratives on quality of decision making in decision aids were unexpected, considering the positive impact of tailoring and patient narratives when employed in behavior change interventions -113. A pSpecific types of explicit values clarification had a positive effect on quality of decision making. Explicit values clarification methods are intended to guide patients through specific tasks to identify personal values and preferences . Few havSpecific types of feedback were also associated with improvements in quality of decision making. Feedback is intended to provide the patient with important information around decision making based on interactions with the decision aid. Progress through the decision aid and knowledge feedback both improved quality of decision making. Both are intended to ensure that the patient is well informed by confirming that all necessary information is reviewed by the patient and to correct misinformation, respectively. Summary of preferences, optimal choice, and decisional consistency are types of feedback that are specific to explicit values clarification methods. Summary of preferences provides feedback around how patients personally value risks and benefits integral to decision making. Optimal choice builds on summary of preferences, by suggesting which option is best based on patients’ values and preferences, which had a positive effect on decisional conflict. Similarly, research has shown that providing implications of stated values  may have a positive effect on decision making . In contSpecific types of social support improved quality of decision making. This feature is intended to reinforce that the patient is not alone in their experiences or decision making. Social support is a recurring theme throughout patient needs assessments for medical care -117, andBased on the study findings, content control should be integrated into decision aids to allow patients to select the order, level of detail, and type of information presented. This approach allows the patient to directly access topics of interest, view alternative presentations of information for clarity, and access optional information or external resources. However, to ensure balanced representation of all options, it is important to integrate safeguards to ensure that the patient reviews all necessary evidence  prior to making a final decision.Tailoring, as currently developed and presented, should be used with caution, as it may reduce quality of decision making. Ineffective tailoring may have resulted from superficial or non-transparent tailoring, which patients did not believe reflected their true risk. Allowing patients to “self-tailor” through content control may be a viable option until effective strategies for tailoring information are established.Patient narratives should also be used with caution, as they may reduce quality of decision making. Patient narratives may unintentionally present unbalanced or biased information, which may undermine statistical data presented in the decision aid or encourage patients to focus on factors that are not in line with personal values or preferences. Further research should focus on identifying types of narrative content and presentation that facilitate quality decision making.Further research is also needed in the areas of feedback, explicit values clarification, and social support to guide future integration. There was substantial heterogeneity in effects between types of components within each of these features, which may reflect artificial grouping of components. In addition, small sample sizes limited appropriate assessments, with many components having been tested only in one decision aid, which limited guidance for integration of these features into decision aids.Studies included in the meta-analyses had a high level of heterogeneity with regard to patient populations, decision context, characteristics of the interventions, and components being tested, as well as choice of usual care or alternative aid controls. Studies were selected for inclusion based on testing a computer-based decision aid intervention, evaluating quality of decision making by measuring either knowledge or decisional conflict, and using an RCT design. For each subgroup analysis, decision aids that incorporated a specific feature (or type of component) were compared to decision aids that did not incorporate the feature. Effectively, this approach compared groupings of studies that tested various complex decision aids against very different control groups. Therefore, results from this study should be interpreted as “hypothesis-generating” and should be considered preliminary evidence to guide future work in this area.Small numbers of studies incorporated certain types of components, which reduced the power to detect significant subgroup differences but also increased the probability of false positives. Nevertheless, subgroup analyses were conducted for all features and types of components for completion, and the number of studies in each subgroup was considered when interpreting the results.Similarly, the study did not adjust for numerous comparisons generated through the subgroup analyses, which also increased the probability of false positives. However, given the exploratory nature of the study, such adjustments may not be necessary, since findings will require further research to establish independent contributions of each feature .Given that the majority of decision aids incorporated multiple features, conducting subgroup analyses limited the capacity to disentangle the effects of specific features or to assess whether specific bundles of features were more effective for improving quality of decision making. Ideally, conducting a meta-regression, similar to the analysis described by Michie et al, would address these shortcomings . HoweverIntegration of media rich or interactive features into computer-based decision aids can improve quality of preference-sensitive decision making beyond traditional static approaches. However, this is an emerging field with limited evidence to guide implementation. The systematic review and thematic synthesis identified features used in available computer-based decision aids, in an effort to facilitate reporting of these features and to promote integration of such features into decision aids. The meta-analyses and associated subgroup analyses provide preliminary evidence to support integration of specific features into future decision aids. Further research can focus on clarifying independent contributions of specific features through experimental designs and refining the designs of features to improve effectiveness.


Targeted therapies have become an important therapeutic paradigm for multiple malignancies. The rapid development of resistance to these therapies impedes the successful management of advanced cancer. Due to the redundancy in angiogenic signaling, alternative proangiogenic factors are activated upon treatment with anti-VEGF agents. Higher doses of the agents lead to greater stimulation of compensatory proangiogenic pathways that limit the therapeutic efficacy of VEGF-targeted drugs and produce escape mechanisms for tumor. Evidence suggests that dose intensity and schedules affect the dynamics of the development of this resistance. Thus, an optimal dosing regimen is crucial to maximizing the therapeutic benefit of antiangiogenic agents and limiting treatment resistance. A systems pharmacology approach using multiscale computational modeling can facilitate a mechanistic understanding of these dynamics of angiogenic biomarkers and their impacts on tumor reduction and resistance. Herein, we discuss a systems pharmacology approach integrating the biology of VEGF-targeted therapy resistance, including circulating biomarkers, and pharmacodynamics to enable the optimization of antiangiogenic therapy for therapeutic gains. Therapeutic intervention in diseases takes place within a milieu of factors, including drug pharmacokinetics, signaling pathways, mechanisms of drug action, and compensatory processes. Studying any single pathway, mechanism of action, or interactive process in isolation has limited value in improving our understanding of the complexity of disease physiology. This is evident in the redundancy of signaling networks, feedback, and cross talk between multiple regulatory processes . A systeAngiogenesis is critical for tumor growth and metastasis. VEGF signaling is an extensively studied pathway for blocking tumor angiogenesis. Several antiangiogenic agents targeting the VEGF-pathways have been approved and are important modalities in the management of advanced cancers. Bevacizumab, a therapeutic antibody targeting VEGF and various VEGF receptor tyrosine kinase inhibitors (TKIs), have shown clinical benefit in solid tumors. However, the benefits of VEGF-targeted agents are short-lived and resistance to anti-VEGF agents rapidly emerges after an initial response phase, leading to restored tumor growth and progression. This rapid development of resistance to therapy constitutes a major clinical obstacle to providing extended therapeutic benefits with this class of drugs. Thus, effective strategies are needed to delay or prevent resistance to VEGF antiangiogenics.Resistance to antiangiogenic agents arises through multiple mechanisms, including the activation of compensatory responses that are mediated by malignant cells and stroma cells within the microenvironment. Angiogenesis is a highly adaptive biological process. Tumors can resume angiogenesis and progress using diverse angiogenic signaling, including VEGF, FGF, HGF, PDGF, PlGF, and several proangiogenic cytokines. Numerous compensatory angiogenic factors are upregulated upon anti-VEGF therapy in a dose-dependent manner , suggestOncology drug development often involves the maximum-tolerated dose (MTD)-based paradigm, even when data suggest that a drug maximally inhibits its target at lower doses. The recent analysis by the U.S. Food and Drug Administration (FDA) showed that inappropriate dose selection was the major cause of post-marketing requirements for oncology drugs approved between 2011 and 2013 . ClinicaHigher doses of anti-VEGF therapies can lead to pronounced anti-vascular effects and, subsequently, hypoxia in the tumor, e.g., treatment-induced hypoxia. Treatment-induced hypoxia stimulates several compensatory biological processes to circumvent continued VEGF inhibition, leading to resistance to therapy . This exThe transient effects of antiangiogenic therapy predominantly result from a redundancy in the angiogenesis signaling that mediates tumor escape from anti-VEGF therapy. Many of the signaling molecules  within these compensatory pathways can be detected systemically in patients treated with VEGF-targeting agents. For example, increases in VEGF and PlGF, and decreases in VEGFR2 can be observed. These changes are considered a “class” effect of VEGF-targeted therapies . Many ofin vivo drug concentrations (PK), changes in the tumors , the biological turnover of signaling molecules, compensatory mechanisms, tumor-independent CAF induction by normal cells in the host body, and the development of resistance. These diverse contributing factors create uncertainty when attempting to use dynamic biomarkers. Mathematical modeling can play an important role in understanding and utilizing the biomarkers to find the optimum biological dose and schedule which can delay the onset of therapy resistance  with their downstream effects in terms of protein formation or pharmacodynamic effects. PK/PD modeling has been used to explain the relationship between pharmacokinetics and the end downstream effects. What is missing is the mechanistic information in between. Limiting our investigation to antiangiogenic therapy, we anticipate three major challenges to filling this gap: (1) determining the interaction of ligands to their receptors and perturbation by drug molecules, (2) integrating the ensuing signal from these receptors with the downstream protein production machinery, and (3) accounting for interaction between various cell types, that produces pharmacodynamics responses and resistance.Receptor occupancy theory is well-developed and can be readily utilized to integrate this process . We mustSignaling pathways are an important component of a systems pharmacology model, which links receptor-ligand interaction to pharmacodynamic outputs . VEGF biIdeally, signaling events are linked to tumor growth kinetics. Tumor inhibitory effects of anti-VEGF agents can be described by adapting well-established models . In addiThe contributions of host cells and stroma cells within the tumor microenvironment have been increasingly recognized to play an important role in cancer progression and treatment . This shin vivo drug concentrations (PK), target–drug interactions, the biological target pathway, antitumor activity, and compensatory signals leading to treatment resistance , or other imaging techniques to monitor vessel integrity, permeability of blood vessels, and tumor perfusion . Thus, fThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There is little consensus regarding outcomes assessment in borderline personality disorder treatment trials, making comparisons of results and meta-analytic studies difficult and far less generalizable. The current article highlights a range of measures frequently employed and puts forth a set of recommendations for a core battery of outcome measures in BPD treatment efforts. The proposed core battery aims to be comprehensive while minimizing patient burden, clinician time and costs. The relative brevity of the proposed core battery would engender flexibility for adding specific processes and outcome measures unique to targeted interventions and treatment models. Psychotherapies including dialectical behavior therapy and mentalization-based therapy  with adjRecent meta-analyses and reviews highlight the variety of outcomes utilized to operationalize short-term outcomes. Similar to the heterogeneity in the diagnostic phenomenology of BPD, there, too, is significant heterogeneity in outcomes – both in terms of domains measured and in methods of measurement . In their review of psychotherapy trials, Stoffers and colleagues  dichotomLonger-term follow-up studies e.g., -9) sugge sugge9])Based on broader experience with general mental health quality and outcomes efforts, we argue that a variety of additional outcomes may also define the efficacy of BPD treatment. Though infrequently and variably measured, quality of life (QOL) is gaining recognition as a primary treatment outcome, and the general consensus is that QOL is severely impaired in BPD but improves with treatment . Of noteIt is not surprising that such a heterogeneous, debilitating, and stigmatized disorder would have such a varied use of outcomes across its empirical treatment base. Unfortunately, important outcomes are frequently excluded from BPD treatment trials, likely in an effort to reduce participant burden. Though psychotherapy is the only empirically supported treatment for BPD -5, few pcore battery in Table supplementing the core battery with additional self-report and interview-based measures as well as behavioral observation when possible. More in depth measurement will allow for a richer and potentially less-biased appreciation of treatment outcomes  but undoubtedly will be more time, labor and cost intensive.There have been calls for a consensus to identify outcomes measures that capture quality of life, functioning and symptoms that are relevant to both patients and care providers (e.g. ); these