Injury of the aortic isthmus is the second most frequent cause of death in cases of blunt traumatic injury. Conventional open repair is related to significant morbidity and mortality. Thoracic endovascular aortic repair (TEVAR) has increasing role in traumatic isthmic rupture, as it avoids the thoracotomy-related morbidity, aortic cross clamping, and cardiopulmonary bypass. Additionally to the technical difficulties of open repair, multi-trauma patients may not tolerate the manipulations necessary to undergo open surgery, due to concomitant injuries. TEVAR is a procedure easier to perform compared to open surgery, despite that a considerable degree of expertise is necessary. Direct comparison of the two methods is difficult, but TEVAR appears to offer better results than open repair in terms of mortality, incidence of spinal cord ischemia, renal insufficiency, and graft infection. TEVAR is related to a—statistically not significant—trend for higher re-intervention rates during the follow-up period. Current guidelines support TEVAR as a first-line repair method for traumatic isthmic rupture. Certain specific considerations related to TEVAR, such as the timing of the procedure, the type and oversizing of the endograft, heparinization during the procedure, the necessity of cerebrospinal fluid drainage, type of anesthesia, and the necessary follow-up strategy remain to be clarified. TEVAR should be considered advantageous compared to open surgery, but future developments in endovascular materials, along with accumulating long-term clinical data, will eventually improve TEVAR results in traumatic aortic isthmic rupture (TAIR) cases. This publication reviews the role, outcomes, and relevant issues linked to TEVAR in the repair of TAIR. Blunt traumatic thoracic aortic injury of the aortic isthmus is the second most frequent cause of trauma-related mortality , 2. OpenThoracic endovascular aortic repair (TEVAR) has already been proven to be an accepted option in thoracic aneurysm repair, but it can play a significant a role in other pathologies of the thoracic aorta, such as the traumatic aortic isthmic rupture (TAIR) –8. TEVARIsthmus is the segment of the aorta affected in the vast majority of blunt thoracic injury cases, reaching 80% of TAIR patients . Other aAlthough there is no Level I evidence, TEVAR is gradually gaining ground in treatment of TAIR cases, as the advantages of this procedure in terms of operative complexity when compared to open surgical repair are clear. Open repair usually requires left thoracotomy, single lung ventilation, and aortic cross-clamping with complex cardiorespiratory support. However, in most cases, multi-trauma patients may not tolerate most of the necessary surgical or anesthesiologic periprocedural manipulation, while cervical instability and synchronous presence of multiple fractures could make positioning for left thoracotomy on the surgical table problematic or even impossible . Grave cAdditionally, multi-trauma patients usually arrive at a hospital with limited or no experience in open surgical treatment of thoracic aortic injuries , 15. On Published comparative data between open surgery and TEVAR show a significant advantage of the latter in terms of perioperative morbidity and mortality , 16, 17.On the other hand, data published in multiple single-center studies reports promising outcomes of TEVAR for TAIR. Feezor et al. reported a 0% 30-day mortality and only one serious endograft-related complication in a series of 22 patients undergoing TEVAR for TAIR .A direct comparison of outcomes between open and endovascular repair for TAIR is difficult. Prospective randomized trials have not been published to date. Systematic reviews and meta-analysis of already published literature is the only source of evidence , 25.p < 0.01). End-stage renal disease (ESRD) and spinal cord ischemia (SCI) incidence was reported to be lower in TEVAR compared to open repair . Both systemic and graft infections occurred less frequently in patients treated with TEVAR compared to open surgery . During the follow-up period, TEVAR showed a higher re-intervention trend compared to open surgery, although this trend was not statistically significant (p = 0.07). Under the light of the above mentioned findings, the SVS committee published clinical practice guidelines suggesting that TEVAR in patients presenting with traumatic thoracic aortic injuries is linked to better results regarding mortality and morbidity compared to open repair and, therefore, can be considered the first line of treatment  after TEVAR for traumatic aortic rupture, significantly lower than open thoracic aortic repair , 47. To Despite the fact that TEVAR could be performed under local anesthesia in elective cases, in emergency settings with a multi-trauma patient who is often agitated, non-cooperative, and presents with a number of concomitant injuries of various gravity, local anesthesia is less favorable. Published data support that TEVAR for TAIR should always be performed under general anesthesia .The ideal strategy for long-term follow-up of TAIR patients after TEVAR is still in evolution. Annually performed CTA control for life is considered the best method for elective TEVAR surveillance, but this strategy might not suit patients who underwent TEVAR for TAIR. Opposite to the nature of degenerative thoracic aortic aneurysms, TAIR is not an evolving aortic disease process, but rather a stable injury as a direct result of trauma. Despite current guidelines suggesting the contrary, annual CTA might not be mandatory if TEVAR in TAIR cases is successfully completed and no complications occurred in the short- and midterm follow-up periods . The RESAnatomic variations and anomalies of the arch and its branches are considered rare, but they are reported to reach as high as 15–34% in published TAIR case series . These vEndovascular repair of TAIR should be considered advantageous compared to open repair linked to lower operative mortality, morbidity, and SCI incidence. The quality of evidence though remains relatively low. Besides, current stent-grafts are not designed for use in TAIR and, therefore, they cannot always optimally accommodate the unique anatomy of these young patients. Current key points regarding TEVAR in TAIR can be seen in Table NP is the corresponding author and has contributed in literature research and manuscript writing. AK has contributed in literature research and manuscript writing. CK has the overall responsibility of the manuscript. All authors have accepted the final (submitted) version of the manuscript.The 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.


As an important protein quality control process, autophagy is essential for the degradation and removal of long-lived or injured cellular components and organelles. Autophagy is known to participate in a number of pathophysiological processes including cardiometabolic syndrome. Recent findings have shown compelling evidence for the intricate interplay between autophagy and lipid metabolism. Autophagy serves as a major regulator of lipid homeostasis while lipid can also influence autophagosome formation and autophagic signaling. Lipophagy is a unique form of selective autophagy and functions as a fundamental mechanism for clearance of lipid excess in atherosclerotic plaques. Ample of evidence has denoted a novel therapeutic potential for autophagy in deranged lipid metabolism and management of cardiometabolic diseases such as atherosclerosis and diabetic cardiomyopathy. Here we will review the interplays between cardiac autophagy and lipid metabolism in an effort to seek new therapeutic options for cardiometabolic diseases. Cardiometabolic syndrome, also termed metabolic syndrome (MetS), is a clinical group of inter-related risk factors associated with atherosclerotic cardiovascular disease (ASCVD) and other metabolic diseases such as type 2 diabetes mellitus and stroke. The major risk factors for MetS include abdominal obesity, dyslipidemia, hypertension, insulin resistance and glucose intolerance . AccordiDespite of the improved understanding of the risk factors, the underlying mechanism(s) of cardiometabolic syndrome remains elusive at this point. A number of possible theories have been postulated including genetic and epigenetic factors, oxidative stress, apoptosis, insulin resistance, endothelial dysfunction and dysregulated lipid metabolism , 5. ReceAutophagy is classified into three types, including macroautophagy, microautophagy and chaperone-mediated autophagy. In macroautophagy (or autophagy thereafter), autophagosomes transfer aged or damaged cellular cargo components and organelles to lysosomes for degradation, which serves as an important recycling process to maintain cellular homeostasis. As depicted in Apart from removal of unnecessary protein aggregates and organelles, degradation products such as amino acids and lipids also serve as materials for new synthesis in nutrient deprivation . BesidesLipid overload is a pivotal element of cardiometabolic syndrome and recent evidence has suggested a role for defective autophagy in the dysregulation of lipid metabolism . VariousAutophagy influences lipid metabolism in a number of ways, from lipogenesis to lipolysis . AutophaApart from lipid metabolism, autophagy also plays an essential role in the regulation of lipoprotein metabolism. Lipoprotein contains hydrophobic lipids and amphipathic proteins in order to transfer lipids in circulation, among which low-density lipoprotein (LDL) is commonly considered an independent risk factor of cardiovascular diseases while high-density lipoprotein (HDL) is deemed cardioprotective . It was in vitro and in vivo, while overexpression of STAT3 inhibited starvation-induced autophagy, possibly through its interaction with the dsRNA-activated protein kinase (PKR). STAT3 acted as a competitive inhibitor of PKR to inhibit PKR phosphorylation. Palmitate is capable of disrupting the inhibitory STAT3-PKR interactions and led to phosphorylation of PKR-dependent EIF2α, which promoted autophagic induction  to induce diabetic cardiomyopathy-like hypertrophy and left ventricular dysfunction in mice. SFA diet promoted autophagy indicated by increased LC3II and Beclin1, and sphingolipids are required in the pathogenesis . MoreoveIntracellular lipids including triglycerides and cholesterol are stored in the form of lipid droplets (LDs). Lipids may induce autophagy and undergo autophagic-lysosomal degradation in order to avoid lipotoxicity caused by excessive lipid accumulation, which is often termed as lipophagy, a special form of selective macroautophagy. LDs are transferred by autophagosomes to lysosomes and degraded into free fatty acids and cholesterol, and defective lipophagy results in excessive lipid accumulation. Besides, the amount of lipids targeted for lipophagy varies according to different nutritional status. Studies showed increased association of LC3 with LDs under starvation, and the percentage of autophagosomes containing lipids increased markedly with increased time of energy deprivation. Lipophagy is selectively upregulated when facing extra energy needs, while the breakdown products free fatty acids undergo β-oxidation to supply ATP. Increased lipophagy enables the cell to generate energy timely for cell survival under starvation . Therefoin vitro and in vivo in response to lipid excess, which may become a novel therapeutic target for atherosclerosis , as an essential regulator of lipid metabolism, inflammation and ER stress, is involved in the pathogenesis of atherosclerosis. Expression levels of ORMDL3 were elevated in the Chinese Han population carrying alleles of the rs7216389 and rs9303277, exhibiting overtly elevated atherosclerotic risk. Experimentally, oxidized low-density lipoprotein (ox-LDL) stimulated ORMDL3 expression in endothelial cells. ORMDL3 silencing reduced basal and ox-LDL-induced autophagy, and suppressed BECN1 expression, which is a protein vital to autophagic initiation. Therefore, ORMDL3 mediates ox-LDL-induced autophagy in endothelial cells in atherosclerosis , Parkin (the E3 ligase Parkinson protein-2), Mfn2 , the Nix/Bnip3L-Atg8-LC3II complexes and Fun14 domain containing 1 (FundC1) . PINK1 pAs mitophagy plays a vital role in the clearance of unwanted mitochondria, impaired mitophagy was closely associated with mitochondrial injury and dyslipidemia in cardiometabolic diseases such as atherosclerosis , 42. InfAutophagic-lysosomal degradation pathway is an indispensable mechanism for clearing and recycling waste cellular components to maintain homeostasis and to provide materials for new synthesis. Recent evidence has emphasized a vital role for autophagy in lipid metabolism in cardiometabolic diseases such as atherosclerosis. Lipophagy, as a selective form of autophagy, takes charge of translocating lipids for lysosomal degradation, and prevents excess lipid deposit in macrophages and expansion of atherosclerotic plaques, which should be a promising drug target for the management of cardiometabolic diseases.It is noteworthy that the role of autophagy in cardiometabolic diseases can be complex. Different reports indicate both protective and detrimental roles in atherosclerosis. Most studies do favor a protective role for autophagy in the prevention of atherosclerosis , 43. AutApart from atherosclerosis, autophagy also plays both beneficial and detrimental roles in other cardiometabolic diseases. As depicted in In summary, basal level of autophagy is of great significance to clear damaged cellular components and maintain lipid homeostasis, while excessive autophagy may be detrimental and leads to cell death. Due to its regulatory effects on lipid metabolism, autophagy and lipophagy is considered a novel therapeutic target for cardiometabolic syndrome and atherosclerosis, which deserves to be explored further more.MY drafted and revised the manuscript. YZ revised the manuscript. JR revised the manuscript and provided financial support.The 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.


Mitochondria play a pivotal role in cardioprotection. Here we report some fundamental studies which considered the role of mitochondrial components  in postconditioning cardioprotection. We briefly discuss the role of mitochondria, reactive oxygen species and gaseous molecules in postconditioning. Also the effects of anesthetics—used as cardioprotective substances—is briefly considered in the context of postconditioning. The role of mitochondrial postconditioning signaling in determining the limitation of cell death is underpinned. Issues in clinical translation are briefly considered. The aim of the present mini-review is to discuss in a historical perspective the role of main mitochondria mechanisms in cardiac postconditioning. Mitochondria are fundamental as sources of energy, but also to sustain life being elements involved in cell survival and death. Mitochondrial dysfunction is a critical element of many diseases including ischemia/reperfusion (I/R) and subsequent development of ventricular systolic dysfunction and possible compensatory heart hypertrophy. This article outlines the role of mitochondria as targets for reducing I/R damage in myocardial postconditioning.Cardiac postconditioning has been defined by the seminal work of Vinten-Johansen's group as “repetitive ischemia applied during early reperfusion”  or pharmacological approach to target mitochondria in animals and humans. Also, inhibition of mitochondrial permeability transition to limit the so-called “post-cardiac arrest syndrome,” observed in patients resuscitated from cardiac arrest, has been tested in a pre-clinical study  in lethal reperfusion injury and suggested that this pore is modulated by postconditioning. The study was conducted in anesthetized open-chest rabbits. Mitochondria were isolated from the risk area of myocardium, and calcium-induced mPTP opening was determined using a potentiometric method. Postconditioning inhibited the opening of the mPTP and provided a robust anti-ischemic protection. Later, the same group demonstrated that mitochondrial calcium decreased in pre-conditioning, but increased significantly either in postconditioning or after inhibition of mPTP . The involvement of mitochondria in postconditioning protection has been confirmed in several studies, for Reviews see  contributes to cardioprotection by stimulation of respiration and inhibition of mPTP opening  mice in vivo  have a putative important role in postconditioning cardioprotection  regulates mPTP in isolated perfused rat hearts subjected to a postconditioning protocol , carbon monoxide (CO) and Nitric Oxide (NO) are recognized as three gaseous mediators for cardioprotection. All these molecules have potential cardioprotective effects in the heart. In particular, the beneficial actions were demonstrated against myocardial I/R injury, including infarction, arrhythmia, hypertrophy, fibrosis, and heart failure. These protective effects were mediated by complex pathway and the effects included: anti-oxidative action, anti-inflammatory responses, reduction of apoptosis, angiogenic actions, and regulation of ion channel  and inhibits mPTP opening  is produced by several enzymes, within and outside mitochondria. It seems that H2S produced by cystathionine-gamma-lyase (CSE) from L-cysteine can readily scavenge the ROS and may induced protection with two mechanisms, one reperfusion injury salvage kinase (RISK)-dependent and the other RISK-independent. Therefore, H2S as NO has important antioxidant properties, but in contrast to NO, H2S cannot directly form radicals  is synthesized by hemoxygenases (HO-1 and HO-2) as a consequence of the catabolism of haem and is an important bioactive molecule. It has been observed that CO induces the mitochondrial production of u et al. .sevoflurane given for 2 min at the beginning of reperfusion-induced myocardial protection against myocardial I/R injury. This sevoflurane-postconditioning is mediated, at least in part, by mKATP-channels  mediates myocardial postconditioning protection by isoflurane, thus indirectly modulating mPTP activity . The receptors with ligands migrate to caveolae, where signaling elements are scaffolded into signalosomes that translocate to mitochondria. The signalosome-mitochondria interaction then initiates mKATP channels, increases ROS production, which favors mitochondrial protein kinase C epsilon activation and mPTP inhibition, thus decreasing myocardial injury (Quinlan et al., via mitochondrial import machinery TOM70 (Yang et al., Postconditioning signaling converges on mitochondria, thus limiting all forms of cell death. We have suggested that postconditioning or perfusion of the heart with bradykinin may activate cellular signaling leading to the opening of mKATP channels, increasing ROS production, inhibiting the mPTP and inducing cardioprotection (Penna et al., apoptotic and necrotic cell death (Murphy and Steenbergen, via an interaction between PKCε and calcium-sensing receptors to inhibit endoplasmic and sarcoplasmic reticulum-mitochondria crosstalk (Dong et al., Mitochondria are important players in many types of The influence of mitochondrial dynamics in I/R and cardioprotection, and their potential as targets in treating cardiovascular disease, are also emerging (Boengler et al., Pharmacological and mechanical ischemic postconditioning can be therapeutic options (Pagliaro and Penna, In conclusion, here we have reported several studies which have shown that different signal transduction pathways are switched on or switched off both by ischemic postconditioning and by pharmacological postconditioning. These signaling pathways converge on mitochondria where different components are affected preserving many of the mitochondrial functions after ischemia/reperfusion. Within mitochondria, a central role is played by connexin 43, mKATP channels and mPTP. Mitochondrial dynamics are also of fundamental importance in I/R and cardioprotection (Boengler et al., CP and PP drafted the first version and supervised the manuscript. All authors evaluated retrieved papers and their reference lists to identify additional relevant articles. JP and SF made the figure. All authors revised the manuscript and approved the final version of the manuscript.The 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.


Pluripotent stem cells (PSCs) are defined by their self-renewal potential, which permits their unlimited propagation, and their pluripotency, being able to generate cell of the three embryonic lineages. These properties render PSCs a valuable tool for both basic and medical research. To induce and stabilize the pluripotent state, complex circuitries involving signaling pathways, transcription regulators and epigenetic mechanisms converge on a core transcriptional regulatory network of PSCs, thus determining their cell identity. Among the transcription factors, MYC represents a central hub, which modulates and integrates multiple mechanisms involved both in the maintenance of pluripotency and in cell reprogramming. Indeed, it instructs the PSC-specific cell cycle, metabolism and epigenetic landscape, contributes to limit exit from pluripotency and modulates signaling cascades affecting the PSC identity. Moreover, MYC extends its regulation on pluripotency by controlling PSC-specific non-coding RNAs. In this report, we review the MYC-controlled networks, which support the pluripotent state and discuss how their perturbation could affect cell identity. We further discuss recent finding demonstrating a central role of MYC in triggering epigenetic memory in PSCs, which depends on the establishment of a WNT-centered self-reinforcing circuit. Finally, we comment on the therapeutic implications of the role of MYC in affecting PSCs. Indeed, PSCs are used for both disease and cancer modeling and to derive cells for regenerative medicine. For these reasons, unraveling the MYC-mediated mechanism in those cells is fundamental to exploit their full potential and to identify therapeutic targets. Pluripotent stem cells (PSCs) possess two defining properties: they are able to indefinitely self-renew, thus maintaining their cell identity after cell division, and they are pluripotent, having the potential to differentiate toward all cell lineages of the organism. Those properties have made PSCs an attractive tool in many research areas such as developmental studies Keller, , regenervivo, PSCs are a transient cell population emerging approximately at embryonic day 3.5 (E3.5) in mouse embryos, and are confined to the inner cell mass (ICM) of the blastocyst, which will further differentiate giving rise to all embryonic tissues  derived from the ICM , governing cell identity  was first identified more than 30 years ago as a cellular homolog of the At the functional level, MYC is a relatively weak transcriptional modulator, leading to small changes of its target genes. It exerts its functions by interplaying with a large set of other TFs, co-activators or by recruiting chromatin modifiers  and the central/peripheral nervous systems  and comprised over 500 genes, which were not shared with neither the core nor the polycomb modules  are constitutively active and expressed to significantly elevated levels in mESCs with respect to committed cells, where their expression become cell cycle regulated and oscillates in a strictly periodic manner  and leads to oxidative phosphorylation (Oxphos) Figure . Despites Leese, . Finallys Leese, . The reas Leese,  and metas Leese, ,b.myc−/− mESCs show diminished glycolityc signature. The same molecular mechanism seems to be conserved in humans and favors the reprogramming of human fibroblasts. Gu et al.  proteins, in both mouse and human ESCs  in either mESCs or iPSCs results in their differentiation toward primitive endoderm  fusion protein, activated by 4-hydroxytamoxifenm (OHT)  are primary players in defining PSCs identity  non-coding RNAs (lncRNAs) resemble protein-coding mRNAs and are usually spliced, polyadenylated and possess a 5′cap. They can either act as antisense transcripts, modulate the activity of chromatin modifiers or serve as “sponges” for miRNAs, thus affecting their activity , initially identified by Shinya Yamanaka's lab as sufficient to reprogram differentiated cells to iPSCs, both in mice and humans  re-acquire transcriptional activation, after having been repressed in both MYC-dependent and MYC-derived cells (Figure We recently described a MYC-driven epigenetic memory mechanism, which is able to maintain mESC identity (Fagnocchi et al., p Figure . Importap Figure . By defip Figure . In agrep Figure . By cults Figure . Altogetplethora of interactions with other TFs and chromatin players (Smith et al., Since MYC was first implicated in maintaining mESCs more than 10 years ago (Cartwright et al., Immediately after their first derivation (Takahashi et al., While the feasibility of generating PSC-based models and deriving cells for regenerative medicine have been often reported, much additional work will be required to evaluate the impact of those applications in treating multiple diseases.LF and AZ discussed the subject and wrote the manuscript.The 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.


The development of tissue fibrosis in the context of a wound-healing response to injury is common to many chronic diseases. Unregulated or persistent fibrogenesis may lead to structural and functional changes in organs that increase the risk of significant morbidity and mortality. We will explore the natural history, epidemiology, and pathogenesis of fibrotic disease affecting the lungs, kidneys, and liver as dysfunction of these organs is responsible for a substantial proportion of global mortality. For many patients with end-stage disease, organ transplantation is the only effective therapy to prolong life. However, not all patients are candidates for the major surgical interventions and life-long immunosuppression required for a successful outcome and donor organs may not be available to meet the clinical need. We will provide an overview of the latest treatment strategies for these conditions and will focus on stem or progenitor cell-based therapies for which there is substantial pre-clinical evidence based on animal models as well as early phase clinical trials of cell-based therapy in man. Table 1). Despite an extensive understanding of fibrogenesis in response to injury, no effective anti-fibrotic therapies are currently available. The highly conserved wound healing response is also highly redundant with multiple overlapping pathways suggesting that inhibition of a single candidate molecule or pathway is insufficient and new approaches are required. Based on this notion, cell-based therapies with the potential to alter multiple therapeutic targets are gaining popularity. A broad discussion of all stem cell types is beyond the focus of this mini-review. We will concentrate on mesenchymal stem cells (MSCs), which form the largest experience in cell therapy, as well as our work with placental stem cells.An appropriate response to injury is required for homeostasis. While injury may take many forms, the repair response is typically generic. An understanding of aberrant wound repair has direct relevance to human disease given that organ fibrosis has been estimated to contribute to 45% of all-cause human mortality . While lPulmonary fibrosis is a family of over 200 chronic lung diseases stemming from multiple underlying causes including autoimmune diseases such as scleroderma and rheumatoid arthritis. Pulmonary fibrosis may be a consequence of environmental exposure to inhaled dust, bacteria, or molds, but can also arise following exposure to cancer treatments such as radiation therapy or chemotherapy using bleomycin or methotrexate. However, idiopathic pulmonary fibrosis (IPF), a type of pulmonary fibrosis where the cause is unknown occurs in 3–9 per 100,000 people annually based on conservative estimates from Europe and North America . The incThe clinical progression of IPF is often slow and gradual but an accelerated decline has been reported in some patients, associated with episodes of acute respiratory exacerbations. The median survival rates are historically poor at 2–3 years, with 5-year survival ranging between 30 and 50% . To dateWhile drugs such as nintedanib and pirfenidone appear to reduce disease progression, widespread usage is unlikely due to their high cost and conflicting data surrounding clinical efficacy. Currently, the proposed use of pirfenidone is to bridge between diagnosis and lung transplantation . NintedaMUC5B polymorphism; however, the role of this gene in IPF pathogenesis remains undefined  using stem cells for IPF, predominantly allogeneic bone marrow-derived MSCs . However, placenta and adipose tissue-derived MSCs have also been tested (NCT01385644 and NCT02135380). Interest in MSC-based therapies is attributed to their reported immunomodulatory and anti-fibrotic properties exerted through paracrine mediators. For example, there is recent evidence that MSC can reduce ER stress, thereby improving survival and function of AEC2 through the release of hepatocyte growth factor . One curvere IPF . Similarvere IPF . While tThe epidemic of chronic kidney disease (CKD) and end-stage renal failure (ESRF) is a crisis for global healthcare. There is urgent need for new therapeutic options considering the high morbidity of dialysis, extensive healthcare costs, and donor-kidney shortages. Known risk factors for CKD include age, hypertension, obesity, and diabetes .Regardless of etiology, the common end-point of kidney injury is fibrosis leading to CKD development . An exceStem or progenitor cell therapies offer a strategy for modulating CKD progression by suppressing multiple pathogenic pathways and promoting pro-regenerative mechanisms. MSCs are pursued as a therapeutic tool as they are immunomodulatory, easily obtainable from bone marrow, and can be expanded in culture for use in the clinic . MSCs elEndothelial progenitor cells (EPCs) also have therapeutic potential. EPCs can be mobilized from the bone marrow and adventitial tissue surrounding endothelial cells (ECs), and home toward sites of injury. There, they influence the release of vasoactive substances or directly differentiate into mature ECs to regenerate damaged endothelium. Diabetes-related EPC dysfunction is closely linked to the impaired healing response experienced by many patients with diabetic CKD. Circulating EPCs are low in type 2 diabetic patients and the loss of function of these cells may contribute to the vasodegenerative changes observed in diabetic micro- and macrovasculature disease . TherefoA growing number of clinical trials show that MSCs are safe and well tolerated in diabetes . The exoin vivo creating a more favorable environment for MSC-mediated repair  to combat kidney fibrosis progression and aid in MSC survival . Combined repair . TargetiGlobally in 2013, cirrhosis was the 6th cause of life years lost in developed countries; ranging from 5th in Europe and central Asia, to 9th in southeast Asia and Oceania. In the United States, cirrhosis was the 12th leading cause of death overall and the 5th in adults aged 45–54 years . Common Hepatic fibrosis will progress to cirrhosis in many patients unless the cause of injury is removed. Progressive hepatocyte loss and subsequent disruption of the hepatic vasculature by unregulated ECM expansion result in liver insufficiency characterized by jaundice, coagulopathy, and hypoalbuminemia. Portal hypertension leads to ascites, variceal hemorrhage, and hepatic encephalopathy. The onset of any of these conditions defines hepatic decompensation, which has a significantly higher 1-year mortality than compensated cirrhosis, 20% compared with 5% in one study of 700 patients . In thesHepatic fibrogenesis involves a dynamic interplay among hepatic stellate cells (HSCs), macrophages, and liver progenitor cells (LPCs). HSCs are pericytes that store vitamin A. During chronic liver injury, they transform to myofibroblasts, acquire a contractile phenotype, and accumulate at sites of injury where they secrete large amounts of ECM including collagen. TGFβ is a major fibrogenic cytokine that triggers HSC activation and ECM production and induces hepatocyte apoptosis . Platelelo) that produces high levels of matrix metalloproteinases that contribute to ECM degradation has been described (Kupffer cells (resident liver macrophages) and recruited circulating monocytes contribute to inflammation, fibrogenesis, and fibrosis resolution. Macrophages are capable of distinct activation states and functions, broadly classified as M1  or M2  . M1 macrescribed .LPCs are rare in healthy tissue but proliferate and differentiate into cholangiocytes or hepatocytes during chronic liver injury. The LPC response corresponds with the degree of liver injury  because,Table 2). Trial endpoints commonly include liver tests, ascites volume, or clinical scores . To date, outcomes have yet to translate into clinical practice. Furthermore, there is experimental evidence that bone marrow-derived MSC can contribute to hepatic fibrosis , fetus-derived stem-like cells that arise prior to gastrulation and are easily isolated from the placenta, which is an abundant and ethically undisputed source. hAEC prevent and reverse inflammation and established fibrosis in immunocompetent animal models of liver injury , diminisThe global burden of end-stage fibrotic disease can be seen in the impaired survival of patients with IPF, diabetic CKD, and cirrhosis. Fortunately, the pathogenesis of fibrosis in response to injury is relatively well understood and remarkably similar in different organs, suggesting that an integrated approach may be possible. Control or removal of the injury stimulus should be the primary focus in preventing disease progression, yet for many control is incomplete or unachievable, thus the need for a broadly effective anti-fibrotic therapy that targets multiple fibrogenic pathways remains. Cell-based approaches employing stem cells that are easy to isolate and upscale to sufficient quantities for clinical use have been successfully characterized in animal models of organ fibrosis. While the outcomes of early phase clinical trials indicate that cell-based (primarily MSC) therapies are safe, efficacy data remain scarce. Consequently, cell-based therapies remain largely experimental. The lack of robust efficacy data may be due to the heterogeneity of MSC populations as well as limited agreement regarding differentiation state, doses, and administration regimens. Challenges remain in determining the goals of cell therapy – whether to supply sufficient cells to replace damaged parenchyma, to dampen inflammation with the aim of decreasing fibrosis, or to stimulate endogenous progenitor cells and repair processes. Furthermore, the ability to manufacture, transport, and store stem cells in a cost-effective manner must be considered. Clinical trials will continue to inform us about the most effective stem cell types on which to base therapy as well as the optimal dosages necessary to achieve a clinically meaningful reduction in fibrosis-related organ dysfunction.WS contributed the liver fibrosis section; RL contributed the lung fibrosis section; SR contributed the kidney fibrosis section; and all authors reviewed the manuscript and provided critical intellectual input.The 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.


The modernization and internationalization of Chinese medicines (CMs) are hampered by increasing concerns on the safety and the efficacy. Pharmacokinetic (PK) study is indispensable to establish concentration-activity/toxicity relationship and facilitate target identification and new drug discovery from CMs. To cope with tremendous challenges rooted from chemical complexity of CMs, the classic PK strategies have evolved rapidly from PK study focusing on marker/main drug components to PK-PD correlation study adopting metabolomics approaches to characterize associations between disposition of global drug-related components and host metabolic network shifts. However, the majority of PK studies of CMs have adopted the approaches tailored for western medicines and focused on the systemic exposures of drug-related components, most of which were found to be too low to account for the holistic benefits of CMs. With an area under concentration-time curve- or activity-weighted approach, integral PK attempts to understand the PK–PD relevance with the integrated PK profile of multiple co-existing structural analogs (prototyes/metabolites). Cellular PK–PD complements traditional PK–PD when drug targets localize inside the cells, instead of at the surface of cell membrane or extracellular space. Considering the validated clinical benefits of CMs, reverse pharmacology-based reverse PK strategy was proposed to facilitate target identification and new drug discovery. Recently, gut microbiota have demonstrated multifaceted roles in drug efficacy/toxicity. In traditional oral intake, the presystemic interactions of CMs with gut microbiota seem inevitable, which can contribute to the holistic benefits of CMs through biotransforming CMs components, acting as the peripheral target, and regulating host drug disposition. Hence, we propose a global PK–PD approach which includes the presystemic interaction of CMs with gut microbiota and combines omics with physiologically based pharmacokinetic modeling to offer a comprehensive understanding of the PK–PD relationship of CMs. Moreover, validated clinical benefits of CMs and poor translational potential of animal PK data urge more research efforts in human PK study. Pharmacokinetics (PK) characterizes drug disposition in the body by studying the time-course of drug concentrations in biofluids and cell/tissue/organ samples and factors governing its absorption, distribution, metabolism and excretion (ADME) processes. PK study is a prerequisite to establish relevance of the activities/clinical benefits to the chemical contents. The information obtained is crucial for lead identification and optimization in drug discovery and dosage regimen design and adjustment in clinical practice. Comparing to the PK study of western drugs which are generally single ingredient with known target, PK characterization of Chinese medicines (CMs) is fraught with tremendous challenges rooted from their chemical complexity , undefined targets (multi-target), and unclear mechanisms of actions. These difficulties are further superimposed by interactions with biological systems (different ADME profiles) as well as those among co-existing ingredients. Unraveling PK profiles of CMs requires adopting strategies distinct from that for western medicines, not only coping with the chemical complexity but also treating the CMs and the compound formula as a whole to provide a holistic and mechanistic understanding of the therapeutic benefits of CMs. Recent rapid development in analytical techniques, systems biology, biochemical pharmacology, as well as multivariate data analysis approaches has promoted the evolution of PK strategies to deal with these challenges.The fascination of CMs lies in the art of constructing a prescription with multiple CMs which act as “monarch”, “minister”, “assistant” and “messenger”, respectively, to enhance efficacy or reduce toxicity in the intended disease therapy. Mechanistic understanding of the compatibility in this ancient combination therapy guided by the traditional Chinese medicine (TCM) principles is another focus and challenge and has been attempted from pharmaceutical, pharmacodynamic (PD) and pharmacokinetic perspectives –3. The PPuerariae lobatae (Gegen), not Salvia miltiorrhiza radix (Danshen), offsets the anticoagulant effects of warfarin by accelerating cytochrome P450 (CYP)-mediated metabolism of warfarin, increasing activity and expression of vitamin K epoxide reductase while decreasing those of thrombomodulin in rats [Polygonum multiflorum, could influence the PK and PD of clozapine to alleviate clozapine-induced constipation [Staphylococcus aureus strains through inhibiting NorA-mediated efflux and promoting ciprofloxacin accumulation in the bacteria [PK study is also imperative to predict interactions of CMs with concomitantly dosed western medicines, unravel the PK interactions among co-existing components, validate the different processing methods, as well as guide formulation design. Co-prescription of western medicines and CMs is very common in China. Herbal products are also increasingly incorporated into western health care owing to an increasing awareness of their health-promoting effects and perceived less side effects. Concomitant use of CMs may mimic, magnify, oppose the effect or even cause toxicity of drugs through PD and/or PK mechanisms. Herb-drug interactions (HDI) have received wide attentions in the past decades. For examples, Radix  in rats . Rhein, tipation . Rhein atipation . Non-toxbacteria . Saikosabacteria . Recent bacteria , 13. So The increasing applications of CMs in disease therapy, the tremendous interests in drug discovery from CMs and the growing concerns on the clinical outcome consistency and safety urgently need the development of suitable PK strategies to dissect the multi-component multi-target holistic clinical effects of CMs. This review offers an overview of the evolving PK strategies and provides a perspective on the future PK study of CMs.People believe that, similar to western medicines, CMs also need to meet the following two requirements to elicit effects: significant exposure and suitable retention time in the target organ or tissue. The chemical complexity, unknown targets, combinatorial use tradition guided by esoteric principles (TCM theory), long history of clinical applications of CMs make them distinguishable from western medicines which are usually chemically simple and have definite targets, requesting distinct PK strategies that can establish concentration-activity/toxicity relevance to allow mechanistic insights into the efficacy/toxicity of CMs. However, despite these inherent differences, the majority of previous PK studies of CMs adopted the same strategy tailored for western medicines which usually focus on the systemic exposure (drug levels in blood) of drugs. To cope with the chemical complexity of CMs, major efforts of the PK study of CMs have been laid on selecting representative components as well as improving sensitivity of analytical methods for PK measurement. Thus, considerable research efforts have been devoted to identify or predict in vivo available components of CMs using in silico, in vitro or in vivo approaches and describe their plasma PK profiles . The strThe diverse chemical types and the wide concentration ranges of the components in CMs demand excellent analytical capability in both accurate structural identification and sensitive quantitation. Relying on the availability of analytical instruments and standard compounds, earlier PK study of CMs usually investigate the in vivo fates of single components (in pure or mixed form), and gradually assemble the findings into a whole picture. Quality control marker compounds documented in China Pharmacopoeia and/or major components in the herbs were usually chosen for PK studies because the authentic compounds were more easily obtained. They were either dosed as pure compound or in mixed form (extract or fraction) or both to obtain the PK parameters and identify PK interactions with co-existing components. For example, PK of ferulic acid was depicted in normal and blood-deficiency-syndrome rats receiving Fo-Shou-San which is composed of Danggui and Chuanxiong . PK of ZPanax notoginseng (Sanqi) extract in rats, ginsenosides Ra3, Rb1 and Rd were identified as PK markers for systemic exposure of the herb due to long-circulating and high exposure levels of the three ginsenosides resulted from their slow biliary excretion, low metabolism, and slow renal excretion [S)-protopanaxadiol (PPD) and 20(S)-protopanaxatriol (PPT) were considered as more suitable PK markers which reflect the individual microbial activity, dynamics and inter-individual differences in plasma exposures of respective oxidized metabolites, the major circulating forms of ginsenosides in the blood circulation [Simultaneous determination of PK of multiple components in herbal medicines is technically challenging due to the wide concentration ranges, complex interactions with the body/among the co-existing components in ADME processes, as well as diverse elimination dynamics in vivo. Although poly-PK using classic strategy allows simultaneous determination of multi-components, most of the in vivo available components may not show ideal PK properties due to the following reasons: (1) too low systemic exposures in blood to contribute to the efficacy of CMs (PK–PD disconnection), (2) poor dose-exposure relevance , (3) the metabolites, not the prototypes from CMs, reaching considerable exposure, (4) exposure not relevant to efficacy/safety, (5) unclear targeting tissues/organs/molecules and mechanisms of actions. Moreover, it usually has poor high-throughput (time-consuming), relies on availability of analytical instrument and chemical standards, thus, is not practicable to be applied in other laboratories or readily translated to industry or clinical practice to improve the efficacy, safety, and quality consistency of CMs. In the past decade, Chuan Li’s group has carried out poly-PK studies of many CMs using integrated in vivo–in vitro–in silico approaches , 28–30. xcretion . Howeverculation .Dioscorea bulbifera rhizome extract using AUC- and IC50-weighting approaches, respectively. The IC50-weighting integrated plasma concentration–time profile showed better correlation with the hepatic injury measurement total bile acids [The chemical components of CMs usually fall into several main different chemical types, each containing tens of compounds bearing a same skeleton with varied substituents/conformations. In vivo metabolism of these structural analogs will produce even more metabolites keeping the same skeleton. Owing to the structural similarity, compounds and their metabolites of the same chemical type possibly exhibit similar biological activities with potency varied to different extents. For each single compound, it may not be detectable or the exposure is too low to allow significant contribution to the clinical outcomes. However, when administered together in a mixture (the CM fraction or extract), these components may produce additive/synergistic effect, contributing significantly to the holistic actions of CMs. Thus, comparing to PK of single compound or individual PK data of multiple effective components, integrated PK property of CMs can offer more comprehensive understanding of the exposure-efficacy/toxicity relevance. Cai’s team detected 191 metabolites of taxifolinb, a ubiquitous bioactive constituent of foods and herbs, in rats receiving 3-day consecutive oral dosing of the compound. These metabolites exhibited a wide distribution in the body and more than 60 metabolites were predicted to have similar targets as the prototype does, suggesting that these metabolites which keep the same pharmacophore as the bioactive parent compound may act on the same targets in vivo and hence produce additive effects . An AUC-le acids , suggestMany CMs have well-documented therapeutic benefits and multiple pharmacological activities but elusive targets and mechanisms. The PK profiles of CMs and the PK–PD relationship are key to identify real active components (prototype or metabolite), unravel efficacy/toxicity mechanism of CMs and reveal PK compatibility in a compound formula and predict HDI. An increasing number of studies have included both PK and PD measurements into the efficacy/safety assessment of CMs. Ren et al. found that three chemical types  of Huang-Lian-Jie-Du decoction, a compound formula consisting of Coptidis Rhizoma, Scutellaria Radix, Phellodendri Cortex, Gardenia Fruit, and notable for heat-dispersing and detoxifying effects, showed distinct modes of anti-inflammatory activity by determining the concentration-effect relevance between the plasma PK profiles of 41 drug-related components (prototypes and metabolites) and the levels of 7 cytokines in lipid polysaccharides-induced rat inflammation model . A transMetabolomics is a technology originally developed to inform what did happen to a biological system  through comprehensive unbias analysis of small molecules in a biofluid, cell, organ or organism. It is a promising approach to address the challenges in poly-PK and classic PK–PD of CMs when coupled with multivariate statistical tools. Metabolomics can not only decode biological network perturbation to a stimulus by identifying the most significantly affected endogenous metabolites and their metabolic pathways, but also resolve the relationships between endogenous and xenobiotic metabolic processes . MetabolGinkgo biloba leaves) are much lower than the concentrations required to elicit neuroprotective effects in vitro [2O2 treated neuronal culture, quercetin pretreatment prevented neuronal death from the oxidant exposure although intracellular quercetin or related metabolites were undetectable, suggesting alternative mechanisms of quercetin neuroprotection beyond its long-established ROS scavenging properties [Taxus brevifolia and camptothecin from Camptotheca acuminate. Comparing to imaging techniques, in particular fluorescence imaging, cell fraction approach provides an alternative method for drugs having no fluorescence, offering not only intracellular distribution but also accurate drug concentrations [Poor plasma concentration-efficacy/toxicity relevance is a common issue for CMs. Most drug-related components (prototype or metabolite) showed poor blood exposure owing to low abundance in the original herb or unsatisfactory in vivo ADME property, thus is believed to be impossible to contribute to efficacy/toxicity of CMs. For instances, ginsenoside Rb1 and Rg1 showed extremely low oral bioavailability due to poor absorption, extensive microbial deglycosylation, biliary excretion, acidic degradation , 42. Thein vitro . Althougin vitro . Cellulain vitro . Acidotrin vitro . Compariin vitro . Anti-oxin vitro . In H2O2operties . The celtrations . The dettrations .Acknowledgement of the multifactorial property in the etiology of many chronic diseases has facilitated multi-target drug discovery . A recenIn the past decades, numerous PK studies of CMs have been reported owning to a wider recognition of the crucial roles of PK in mechanistic understanding of the multi-component, multi-target holistic benefits of CMs and new drug discovery from CMs. The PK strategies for CMs also evolve faster to meet the growing demands. The ultimate goal is to establish PK–PD relevance of CMs to ensure suitable quality control, pertinent pharmacological evaluation and consistent clinical output, which undoubtedly is crucial but tremendously challenging due to chemical complexity by nature, undefined targets, complex interactions among co-existing compounds and combinatorial use tradition guided by obscure TCM theory, disconnection between disease site and target site, etc. The rapid advances in systems biology, omics, multivariate data analysis approaches allow us to translate the holistic clinical benefits into modern scientific data and bring our understanding of the mystery of the old tradition to unprecedented depths. The future research efforts may consider improving the PK–PD relevance study in the following two aspects.O-β-d-glucoside suggested the contributions of gut microbiota to both disposition and efficacy of CMs. We conceived that the holistic health benefits of CMs should be attributed to components that can interact with gut microbiota to manipulate intestinal hemeostasis and those, either prototypes or the metabolites formed by gut microbial metabolism, which can reach the blood circulation to elicit effects [The recent rapid advancement of our knowledge in the physiological, pathological and pharmacological roles of gut microbiota in human also promote an in-depth understanding of its multifaceted roles in drug metabolism, efficacy and toxicity  and the  effects . TherefoPhysiologically based pharmacokinetic (PBPK) modeling is a powerful mathematical modeling technique for predicting drug ADME in humans and other animal species through integrating anatomical, physiological, physical, and chemical descriptions . It offeSo far, majority of the PK knowledge of CMs was obtained from animal models. Advances in molecular biology and pharmacogenetics enable a more comprehensive view of interspecies differences in drug disposition and the underlying physiological and pathophysiological mechanisms. Big differences have been reported between humans and animals commonly used  for preclinical PK study . AlthougAn increasing number of human PK studies of CMs were reported. Most studied widely prescribed single herbs or famous compound formulas in healthy volunteers at one single oral dose, with single or a few marker/main compounds measured. The impact of inflammation on host drug metabolizing enzymes has been well documented , 77. ChaThe chemical complexity undoubtedly is the basis of the multi-target holistic action mode of CMs which makes them attractive, in particular, in an era when more diseases are found to be multifactorial and demand combination drug therapy, while on the other hand, it hampers the mechanistic understanding of their holistic therapeutic benefits. The validated clinical benefits/pharmacological activities, the elusive targets and mechanisms, the undesirable ADME properties and the PK–PD disconnection, appeal for a PK strategy that follows a distinct paradigm from the one tailored for western medicines to address these challenges. The rapid advancement of the analytical techniques, systems biology, and multivariate analysis methods have promoted the development of several PK strategies, allowing the study of PK–PD relevance between the disposition of multiple/global drug-related components and the extracellular/membrane targets and intracellular targets. The emerging enormous evidence support the close connections of gut microbiota with many diseases and its multifaceted role in drug disposition, efficacy, and toxicity. The presystemic interactions of gut microbiota are believed to constitute a significant contribution to the holistic therapeutic benefits of CMs. A presystemic PK–PD focusing on gut drug exposure and gut-originated targets should be included into a global PK–PD strategy to complement the current PK–PD strategies to provide a comprehensive mechanistic understanding of the multi-component multi-target holistic clinical outcomes of CMs.


Over the past few decades zinc oxide (ZnO)-based thin films and nanostructures have shown unprecedented performance in a wide range of applications. In particular, owing to high isoelectric point, biocompatibility and other multifunctional characteristics, ZnO has extensively been studied as a transduction material for biosensor development. The fascinating properties of ZnO help retain biological activity of the immobilized biomolecule and help in achieving enhanced sensing performance. As a consequence of recent advancements in this multidisciplinary field, diagnostic biosensors are expanding beyond traditional clinical labs to point-of-care and home settings. Label-free electrical detection of biomarkers has been demonstrated using ZnO-sensing platforms. In this review we highlight the characteristics of ZnO that enable realization of its use in development of point-of-care biosensors toward disease diagnosis, in particular cardiovascular diseases. The goal of this review is to discuss the features of ZnO in enhancing the sensitivity and selectivity of biomarker detection toward the development of point-of-care diagnostic devices. Basic biosensor design features and fabrication of ZnO nanostructures, strategies for surface modifications and its application toward disease diagnosis are discussed. Biosensors and bioanalytical devices are integrated devices that represent ingenious developments in the realm of early management of diseases. Design and development of such analytical devices harness the advantages of multidisciplinary fields such as engineering, chemistry and biology. The basic concept behind the design of these complex bioanalytical devices is their capability to deliver a measurable output signal response for either diagnostic or therapeutic purposes when a biological recognition element interacts with the transducing surface of the sensor. A biological recognition element, commonly known as a biomarker, is usually a biomolecule which represents the pathophysiological condition such as irregularities in cellular regulatory functions, pathological responses or intervention to any therapeutic drugs. Biomarkers are usually detected by employing another biological element known as bioreceptor  immobilized on to surface of transducer, which are sensitive to target analyte as shown in Illustration of the ‘enzyme electrode’ by Leland C Clark in 1962 marked the rise of a new era in healthcare diagnostics . The bioPOC and rapid quantification of biomarkers can offer crucial information in various facets of disease detection, monitoring and analysis . CurrentThe growing prevalence of diseases and increasing demand for sophisticated healthcare infrastructure, as well as need for rapid and reliable disease detection have fueled biosensor research. Advancements in nanotechnology and biotechnology have set the stage for exciting possibilities to help address challenges in conventional biosensor design. The fundamental challenges in biomarker detection have been in achieving; ultrasensitivity, that is, detection of target biomarkers at relatively low concentrations , and selectivity, that is, ability to distinguish target biomarker from other biomolecules present in sample biological fluid. The other challenges include low signal-to-noise ratio of readout mechanism, lower detection limits, low cost, minimal sample volume, long-term monitoring and fast and accurate detection . MiniatuDesign of optimal biosensor devices requires a deeper understanding of both the biosensing concept in general as well as the targeted performance metrics. Miniaturization of biosensor devices is currently trending which has been made possible through advancements in nanofabrication methodologies. Miniaturization helps realize detection of multiple target biomarkers on the same platform and in batch manufacturing at very low cost, thus increasing the overall throughput. However, the transduction mechanism plays a significant role in development of miniaturized and integrated biosensors. Electrical/electrochemical transduction of physiochemical changes are simple and robust making miniaturization possible with limited resources, and unlike in optical biosensors, electrical transduction helps reduce signal interference from other biological molecules ,11. HoweSynergy is the key to developing a perfect POC biosensor addressing the fundamental challenges with sensitivity, selectivity, stability and most importantly biocompatibility of the chosen material. Recent advances in nanofabrication have widened the research on new material synthesis, microfluidic design and understanding the biochemical interactions, all of which can be incorporated with electronics into a portable, miniaturized handheld POC device . NanomatA criterion for material selection is application specific, which includes choosing among metals/metal oxides, polymers/ceramics, hydrogels, etc. . Polymer2, CNT- TiO2, SnO2, ZrO2, etc., have been used in the design of glucose oxidase, cholesterol oxidase and other enzymatic biosensors [The surface topography of material used for transducing the physical or chemical changes due to biomolecular binding is a key feature in biosensor design. Surface topography can be altered by creating nanostructures specifically for size matching with the biomolecules. Nanotextured surfaces have a high impact on sensor performance offering unique features and increased surface area for biomolecular binding . Nanostrosensors . ZnO, duosensors ,23. StruZnO is a key technological material that has attracted profound research in the last decade due to its unique functional and nanomorphological properties. ZnO is an inorganic II–VI binary compound semiconductor with direct wide band gap of 3.37 eV in the near UV spectral region and large exciton binding energy of 60 meV at room temperature ,25. Such2+ and O2- ions are stacked alternatively along the c-axis which confers noncentral symmetric structure to ZnO. This tetrahedral coordination between Zn2+ and O2- ions gives rise to spontaneous polarity effects and induces piezoelectricity [1) polar surfaces that results in different physical and chemical properties. Furthermore, availability of polar and nonpolar planes imparts strong electrical properties to ZnO which can easily be tuned and leveraged toward design of ZnO-based electrical biosensors.Though ZnO crystallizes in three different forms , the structure that is most thermodynamically stable under normal conditions of ambient pressure and temperature is its hexagonal wurtzite structure . In wurtctricity . The lay3 covalent bonding. However, the Zn–O bond also possesses very strong ionic character, which arises from large difference in electronegativity between zinc and oxygen atom. Thus, ZnO lies on the borderline between being classed as a covalent and ionic compound, with an ionicity of fi = 0.616 on the Phillips ionicity scale [Aside from causing the inherent polarity in the ZnO crystal, the tetrahedral coordination is an indicator of spty scale . Furtherty scale ,29. TranIn recent years, ZnO thin films and nanostructures have shown great potential as a suitable material for binding of biological molecules. From a technological viewpoint, ZnO is an excellent candidate material for designing biosensor applications due to the ease of surface engineered terminations, high isoelectric point (IEP), fabricating their nanostructures at low temperatures and biocompatibility along with high electron mobility ,31. PhysBoth ionic and semiconducting characteristics of ZnO can help provide the desired sensitivity for detecting target biomarkers at ultralow concentrations. Also, this particular metal oxide can be grown as nanostructures with current volume scalable manufacturing techniques and at low cost of ownership ,33. TherResearchers have studied an assortment of ZnO nanostructures for biosensing applications since their dimensions are comparable to the size of target biomolecules and thus allows for detection from low sample volume. ZnO nanostructures based on their dimensionality and nanomorphological characteristics offer opportunities for design of integrated biosensors for real-time sensing applications . Such na110), (0110) and (0001) [110) or (0110) and its equivalent directions results in formation of nanobelts, nanoribbons or nanocombs [A diverse group of novel ZnO structures can be grown by tuning the growth rates in one of its three fast growing directions – (2d (0001) . Thin fid (0001) . It has anocombs , as illuThe two main nanofabrication methods for fabrication of nanomaterials can be classified as: top-down  and bot2+ and O2- on to the substrate. Nanostructure synthesis is normally carried out in a gaseous environment at temperatures ranging from 500 to 1500°C in closed chambers [Vapor phase synthesis methods such as physical vapor deposition, chemical vapor deposition, vapor-solid or vapor-liquid-solid, and other epitaxial growth methods yield the best quality ZnO nanostructures . ZnO nanchambers ,43. Growchambers ,45. Thouchambers . Thus, schambers ,46. The et al. have investigated formation of ZnO thin films using RF magnetron sputtering under Argon plasma both in presence and absence of oxygen flow [Vapor phase process generally involves reduction of ZnO inside a reaction chamber. Growth of ZnO nanowires has been demonstrated by reducing a mixture of ZnO powder and graphite in Argon plasma followed by condensation of Zn vapor on Au-coated substrates . Studiesgen flow . The ratgen flow ,49–52.Liquid phase or wet chemical synthesis methods are simple, scalable, cost-effective and requires a very simple equipment ,43 and aet al. were the first to successfully demonstrate synthesis of ZnO microtubes through chemical dissolution and aging process [2- formation is from precursor salts rather than the solvent itself, an alkaline or aqueous environment is essential for decomposition of Zn salts. Nucleation begins when the chemical bath is supersaturated with ZnO nuclei, that is, when Zn2+ and O2- ion concentrations in the solution have reached their critical value of saturation [Vayssieres  process  and ZnO  process . Ever si process ,55–57. Ituration . Thus th2+ ions as well as the thermodynamic equilibrium state of the chemical bath [The type of zinc hydroxyl product formed depends on the concentration of Zncal bath ,61. Whencal bath .2) have high density of positive charges under normal growth conditions and wide range of pH which get adsorbed due to electrostatic attractions on nonpolar facets. On the contrary, citrate ions hinder the growth along the basal plane hindering the growth along the c-axis due to their negative charge density. While the former growth condition results in formation of nanostructures such as nanorods or nanowires or nanotubes, the latter results in formation of plate-like structures such as nanobelts, nanoribbons, etc. Zhang et al. have demonstrated the growth of oriented and hierarchical ZnO nanostructures with subsequent addition of two organic structure-directing agents – citrate ions and diaminopropane [A myriad of ZnO nanostructures can be obtained by addition of additives such as citrate ions , ethylenopropane .ZnO nanostructure surfaces obtained by the above described synthesis methods should be immobilized with a capture probe for detection of target biomarker. Sensitivity and selectivity of detection strongly depend on the stability of the capture probe immobilized on the ZnO nanostructure surfaces. Capture probe immobilization can be obtained either via covalent functionalization with organic molecules known as cross-linker or through physical adsorption. High IEP of ZnO facilitates physical adsorption of low IEP enzymes such as glucose oxidase, cholesterol oxidase, etc., on ZnO nanostructures through attractive electrostatic force. On the other hand, immobilization of capture probes such as antibodies for biosensing purposes rely on chemical binding with cross-linker molecules.2 ends, that facilitates interaction with amino acid residues [Surface functionalization with cross-linkers results in formation of a highly oriented, ordered and packed organic layer on sensing the surface that provides selective surface sites for binding of biorecognition element. A cross-linker molecule is characterized by a reactive head group that covalently attaches to the sensing surface, an alkyl chain that acts as a spacer and a terminal functional group, usually NHS or NHresidues ,65. A scresidues . Severalresidues ,68. Veryresidues . Hence, et al. [Silanization of ZnO surfaces with 3-aminopropyltriethoxysilane (APTES) toward biomarker detection has been demonstrated by few research groups . Though et al. . Extensiet al. ,69,72–74et al. ,75. The 2+ and O2- ions stacked along the polar planes impart strong electrical properties to ZnO which can easily be tuned. As a consequence of direct and wide band gap semiconductor, ZnO has the ability to withstand high temperature and larger electric fields, higher breakdown voltages and high power operation [The oppositely charged Znperation . N-type peration . Synthesperation .The electrical properties of ZnO are strongly influenced by the adsorption of oxygen species from ambient air, which in turn controls the carrier concentration. Either physisorption (does not result in any electronic transfer process) or chemisorption (oxygen species now acts as electron acceptor sites) changes the overall resistance of ZnO material . It is aCharge transfer between the semiconductor and the electrolyte at the interface is key to the development of ZnO-based electrical/electrochemical biosensor. The lattice structure of material under study significantly influences the bulk and interface properties. Due to imperfections in crystal lattice which includes surface states and abrupt lattice terminations, different facets of crystal may come in contact with the electrolyte. This significantly alters the charge distribution at both ZnO electrode and electrolyte side . LocalizC and EV, while constant potential is observed in the bulk of the semiconductor. Hence, it is extremely important to understand the mechanism of charge transfer and correlating them to the effects of biomolecular binding interactions is necessary for quantification of target biomarker concentrations. When an electric potential is applied to ZnO, the charge distribution occurring at the interface due to biomolecular binding events results in a potential drop between the electrode and electrolyte [The majority of charge carriers in an n-type semiconductor are the electrons. So when ZnO nanostructured surface is brought in contact with the electrolyte, there occurs positive charge build up in SCL due to electron transfer from its conduction band to the electrolyte and negative charge build up in the electrolyte. When an electric field is applied, unlike metal the potential drop occurs across both SCL and HL, as shown in ctrolyte . ModulatA group of pathological disorders of the heart and blood vessels affecting not just the coronary artery but the entire arterial circulation is termed cardiovascular disease (CVD). The clinical manifestations of CVD include coronary heart disease, angina, myocardial infarction or heart attack, chronic kidney disease, stroke and carotid artery disease . AccordiVenous blood of the infarcted patients, or patients complaining of chest pain are sampled to test for different markers of AMI. Biomarkers which include proteins, enzymes or metabolites are expected to be released into bloodstream when cardiac muscles experience stress due to ischemia . When thDetection of biomarkers in particular concentration ranges is related to AMI diagnosis and risk stratification of cardiac injury. Enzymes such as aspartate transaminase, lactate dehydrogenase and creatine kinase (CK) are conventional cytoplasmic markers indicative of cardiac tissue injury ,90. Aspa3)2.6H2O) dissolved in water. In c-axis-oriented growth, the polar planes can either be Zn-terminated or O-terminated. Under such conditions, the electrical characteristics of ZnO can be tuned by modifications to their surface, which can effectively be used for biomarker identification. In this study, results showed modulation in charge transfer and effective charge density with varied density of ZnO nanorods, a phenomenon attributed to variation to the number of zinc interstitials and oxygen vacancies. Also, each ZnO nanorod (prepared under 50 mM growth condition) at the sensing platform behaves as an individual nanoelectrode as it facilitated semi-infinite hemispherical diffusion of cardiac troponins to its surface. This behavior thus enhances the sensing ability of nanostructured ZnO electrode as opposed to sensing with nanotextured ZnO surfaces demonstrated previously by our group [In one study, the authors developed a nanostructured sensing platform with ZnO nanorods to demonstrate detection of cTnT based on electrical/electrochemical transduction mechanism . ZnO nanur group .Detection capabilities of the developed nanostructured ZnO biosensor were tested with aliquots of spiked concentrations of cTnT in human serum. Detection was established based on changes in charge distribution at the ZnO electrode/human serum buffer interface. cTnT binding and subsequent polarization cause imbalance in surface electrochemical potential at the interface that was measured as changes to capacitive impedance through electrochemical impedance spectroscopy and Mott–Schottky. The authors show that binding events cause localized positive and negative charge distribution on ZnO (known as SCL) and electrolyte side (known as Helmholtz layer), respectively. Electroionic changes modulate capacitance at both these layers and, hence, demonstrate label-free and sensitive detection of cTnT with detection limit at 0.1 pg/ml using above-mentioned complementary techniques.However, the essential requirement for potential application as a POC biosensor is the ability to work with low sample volume and function with low power which led to incorporation of the above design on flexible polyimide substrates ,74. Simiet al. developed an APTES-functionalized ZnO nanoparticle-based interdigitated electrodes biosensor that was found to detect cTnI biomarker [Detection of cTnI using ZnO nanoparticle-based sensing platform has recently been demonstrated by several other research groups. Tan iomarker . Detectiiomarker . MultiplA key revolution in biosensor development is the integration of structures at the nanoscale to obtain enhanced analytical performance. Nanostructured sensing surfaces have opened up new horizons for biosensing applications. Further, biomolecule immobilization at these nanostructured surfaces can be achieved in a selective and oriented fashion without losing the biological activity of biomolecule. Sensor technologies with integrated nanostructures are becoming increasingly attractive due to their proven potential for development of portable and miniaturized POC biosensor for rapid biomarker detection.Thin films and nanostructures of ZnO, due to their fascinating properties, can offer novel electrical and electrochemical properties. These properties can be exploited through surface engineering of ZnO for achieving high sensitivity and selectivity toward biomarker detection. In addition, scalable manufacturability of ZnO and tailored surface properties make it possible to fabricate ZnO biosensors with excellent detection capabilities. At the nanoscale, ZnO experiences fast electron transport kinetics and, hence, is sensitive to any physicochemical changes occurring at its surface even in presence of ultralow biomarker concentrations. Formation of a biorecognition layer on the surfaces of ZnO through covalent binding is a complex procedure which depends on surface topography and defects in ZnO crystal structure.Conventional diagnoses for cardiovascular diseases have been focused on quantitative determination of its biomarkers in whole blood or heparinized plasma samples. Despite tremendous progress in developing POC diagnostic devices for cardiac disease diagnosis, a substantial number of devices lack methods for standardization, concerns with false positives if sample preparation is inadequate and need for catheter-based blood draw in most cases. Recently, studies have shown scientific evidence relating clinical information from saliva to cardiac biomarkers. Saliva, as a diagnostic fluid offers new directions in development of POC devices for cardiac disease diagnosis. However, design of ZnO-based platforms for diagnosis with saliva may be highly challenging due to their effect on salivary peroxidase enzyme as well in those patients treated for oral conditions.Current efforts are directed toward understanding ZnO sensor architectures, which are focused on achieving low sample handling, high throughput and multiplexed detection. Although most ZnO biosensors discussed in this review meet the clinical need, translation of such devices into routine diagnostic practices is still a long way away. The ability to demonstrate sensitive and selective detection in natural biological buffer is extremely important for practical realization of these devices in the biosensor industry. Nonetheless, the current state-of-the-art technologies will be of great scientific value for further advancing ZnO biosensors performance for POC diagnostics applications.Cardiovascular disease is the leading cause of death worldwide. Development of low-cost and point-of-care diagnostic devices for disease identification is the need of the hour.ZnO exhibits multifunctional characteristics which favors sensitive and selective detection of target biomarkers.Nanostructures of ZnO can be fabricated using low-cost techniques. The structural morphology of grown structures is effectively controlled by various growth parameters.Rapid charge transport at ZnO electrode/electrolyte interfaces can be interpreted toward detection of target biomarkers.


A decision to undertake screening for breast cancer often takes place within the primary care setting, but current controversies such as overdiagnosis and inconsistent screening recommendations based on evolving evidence render this a challenging process, particularly for average-risk women. Given the responsibility of primary care providers in counseling women in this decision-making process, it is important to understand their thoughts on these controversies and how they manage uncertainty in their practice.To review the perspectives and approaches of primary care providers regarding mammography decision-making with average-risk women.This study is a critical interpretive review of peer-review literature that reports primary care provider perspectives on mammography screening decision-making. Ovid MEDLINE®, Ovid PsycInfo, and Scopus databases were searched with dates from 2002 to 2017 using search terms related to mammography screening, uncertainty, counseling, decision-making, and primary health care providers.Nine articles were included following a review process involving the three authors. Using an inductive and iterative approach, data were grouped into four thematic categories: (1) perceptions on the effectiveness of screening, screening initiation age, and screening frequency; (2) factors guiding primary care providers in the screening decision-making process, including both provider and patient-related factors, (3) uncertainty faced by primary care providers regarding guidelines and screening discussions with their patients; and (4) informed decision-making with average-risk women, including factors that facilitate and hinder this process.The discussion of results addresses several factors about the diversity of perspectives and practices of physicians counseling average-risk women regarding breast cancer screening. This has implications for the challenge of understanding and explaining evidence, what should be shared with average-risk women considering screening, the forms of knowledge that physicians value to guide screening decision-making, and the consent process for population-based screening initiatives. Within the data, there was little attention placed on how physicians coped with uncertainty in practice. Given the dual responsibility of physicians in caring for both individuals and the larger population, further research should probe more deeply into how they balance their duties to individual patients with those to the larger population they serve. Organized mammography screening programs have been implemented in most high-income countries since the end of the twentieth century to promote the early detection of breast cancer and reduce mortality rates from this disease. Yet, over the last two decades, the utility of these population-based programs are increasingly being questioned due to growing evidence on the uncertain benefits and potentially substantial harms of screening for average-risk asymptomatic women . Since tA decision to undertake screening for breast cancer often takes place in the primary care setting, but current controversies such as inconsistent recommendations based on available evidence on the harms and benefits of screening render this decision-making process challenging for primary care providers and their patients. One Cochrane review of 7 trials involving 600,000 women assessed the effect of breast cancer screening with mammography on mortality and morbidity . It reveAnother concern is overdiagnosis, causing women to undergo unnecessary testing and treatment of cancers that would not have harmed them during their lifetime . One invChoosing Wisely Canada, a clinician and researcher-led campaign aiming to reduce unnecessary medical tests and treatments, recommended to not perform routine screening mammography for average-risk women aged 40 to 49. In contrast, the American Cancer Society [Basing its recommendations on the best available evidence , 10, in  Society  and The  Society  continue Society .Norris et al. studied the relationship between screening guideline panel members, their conflicts of interest, and screening recommendations for asymptomatic average-risk women aged 40 to 49 . They foIn light of these inconsistencies in guidelines available to primary care providers, and the increasing evidence on the harms of overdiagnosis, the decision of whether or when to screen is no longer clinically or ethically obvious for average-risk women. Little is known about how primary care providers deal with these challenges in their clinical practice despite their important role in the promotion of preventive health services such as mammography screening . Since pThe primary aim of our review is to explore the perspectives and approaches of primary care providers regarding mammography screening decision-making with average-risk women. Specifically in this paper, the question of what are the perspectives of primary care providers with respect to mammography screening decision-making with average-risk women will be explored.Additionally, with respect to screening discussions with average-risk women, this review will seek information on what factors guide primary care providers in their practice and how primary care providers understand and manage clinical uncertainty, including their experiences with support of patient decision-making. To date, no review of primary care providers’ perspectives on mammography screening and decision-making with their patients has yet been published.A critical interpretive review of peer-review literature regarding primary care provider perspectives on mammography screening decision-making was conducted. This type of review was specifically developed for bioethics research, which typically requires the exploration of a wide range of interdisciplinary sources. The flexibility needed to conduct this review cannot function within the rigid approach of a systematic review. Instead, critical interpretive reviews offer a thorough and rigorous approach to scan literature in an effort to identify “key ideas” in a particular area of study and theorize around this knowledge, in order to answer a specific research question .A search strategy was developed to identify articles capturing the perspectives of primary care providers on mammography screening recommendations and decision-making with average-risk women. In this study, the term “perspective” was broadly defined as a thought, viewpoint, or belief. Specifically, articles that examined qualitatively or quantitatively these perspectives of primary care providers about any aspect of mammography screening or mammography screening decision-making were included. Articles that discussed elements that influenced primary care providers when making screening decisions with their patients were therefore also selected. Inclusion criteria for articles were being published in English and discussing mammography screening in healthcare systems of high-income countries  because similar population-based screening programs have been implemented in these settings. We wished to focus the scope of this study to current perspectives based on current evidence. Since numerous mammography screening guidelines from various professional organizations and cancer societies have been published since 2002 , 19–21, Ovid MEDLINE(R) search 2002–present: Mammography/ or mammogr* or breast cancer screening AND mass screening or early detection of cancer; OR screen*; AND Counseling or counsel* or (overdiagnos* or over diagnos*) or practice patterns, physicians’/ or decision-making or decid* or informed decision-making or informed consent or consent* or Uncertainty/ or uncertain* AND (family or physician$).af. or practice$.mp. or primary care.af. or exp. Primary Health Care/ or primary.mp. or general pract$.af. or gp.tw. or gps.tw. or nurses/ or nursing/ or nurs*.Ovid PsycInfo search 2002–present: Mammography/ or mammogr* or breast cancer screening AND Cancer screening or screening or screen* AND Counseling or counsel* or (overdiagnos* or over diagnos*) or decision-making/ or decid* or informed decision-making or informed consent/ or consent* or Uncertainty/ or uncertain* AND (family or physician$).af. or practice$.mp. or primary care.af. or exp. Primary Health Care/ or primary.mp. or general pract$.af. or gp.tw. or gps.tw. or nurses/ or nursing/ or nurs*.Scopus search 2002–present: TITLE-ABS-KEY(mammogr* OR “breast cancer”) AND TITLE-ABS-KEY(screen*) AND TITLE-ABS-KEY(counsel* OR decid* OR decision* OR uncertain* OR consent* OR overdiagnosis) AND TITLE-ABS-KEY.The databases Ovid MEDLINE(R), PsycInfo, and Scopus were scanned from 2002 to 2017 on 23 February 2018 using categories of search terms relating to mammography screening, counseling, decision-making, overdiagnosis, consent, and those covering primary health care provider terms. All combinations of terms were covered, and mappings to headings were made wherever possible. The Cochrane database was also scanned for potential relevant articles, but this search did not identify any eligible papers. The specific search strategies for the three databases were as follows:Following an in-depth reading of the results sections of all included articles, data were organized into sections that sub-divided the main objective of the review. The thematic development in critical interpretive reviews requires an inductive and iterative analytical approach. Through this process, the analysis was revised and refined until all relevant elements from the articles were appropriately captured into three final sections. Drawing on Sally Thorne’s interpretive descriptive framework , contentThe database searches resulted in 1423 articles. After removal of duplicates, the three database searches yielded a total of 761 articles. One team member (SS) then reviewed the titles and abstracts of these articles and retained those that seemed to address the aim of this study. This search strategy identified 50 articles. Two team members (SS and CE) then independently reviewed these 50 articles in more depth and met in person to discuss which of these should be included based on our criteria. We also reviewed the reference lists of these retained articles to identify any other relevant articles that were not captured through our database searches. When needed, a third team member (GB) was consulted to reach consensus on whether an article should be included. Following this process, we identified a total of nine empirical studies –34.Since all participants in the included articles were physicians working in primary care, for simplicity, we report the results and follow using the term “primary care physicians” (PCP) and in some places “physicians”. The analysis of data in the nine articles resulted in a grouping of results into four thematic categories. The first grouping includes general clinical perspectives and approaches from physicians on screening such as their perceptions on the effectiveness of screening and at what age they initiated screening with average-risk women. The second group includes data on the multiple factors guiding physicians in the screening decision-making process. This category was the richest in data, and findings touched on physician- and patient-related factors, the influence of best practice guidelines and physicians’ sub-specialty organizations, as well as non-medical factors such as physicians’ colleagues’ influence on their practice. The third category of results reports on data relating to the uncertainty faced by physicians with regard to guidelines and screening discussions with their patients. The last thematic grouping includes all data discussing decision-making approaches. Physicians’ thoughts on their willingness to support women in informed decision-making and the factors facilitating and hindering the informed decision-making for average-risk women are presented.Table Table In two articles , 30, phyData reporting on the general perspectives and approaches of PCPs regarding mammography screening for average-risk women are shown in Table The participating physicians in three articles found mammography guidelines unclear or conflicting , 27, 32.Table Three of the included studies –30 colleOne of these studies, however, showed that PCPs in the USA were most influenced by their sub-specialty cancer screening guidelines . In one Furthermore, three of the studies revealed that physicians would recommend screening if their colleagues recommended this test , 27, 29.Three of the articles , 27, 32 In these studies, physicians found mammography guidelines unclear, contradictory, and changing. One study showed that the difficulty of reconciling divergent organizational guidelines was strongly associated with recommending screening to women aged 45–49 . The stuLastly, the physicians’ perspectives on the mammography decision-making process between physicians and patients are found in Table Four of the articles highlighted time as a factor affecting the screening decision-making process , 31, 32.The reviewed literature offers an overview of the current mammography screening landscape from the perspective of PCPs. These physicians approach mammography screening with average-risk women in different ways and hold diverse views with respect to screening decision-making with their patients, based on differing beliefs and varying factors influencing their practice. This research is useful to further understand what guides physicians when clinical guidelines are unclear and conflicting and sheds light on the extent to which other factors consequently play a role in decision-making. By narrowing in on the patient-PCP relationship, this research illustrates what actually occurs in physicians’ offices, regardless of public health messages or population-based mammography program goals. It can inform next steps on identifying what physicians need to improve the mammography screening decision-making process with average-risk women in order to respect ethical and professional obligations towards their patients.The PCP data revealed that more than 50% of physicians in three of the nine included studies found mammography guidelines unclear, conflicting, or ambiguous. We expected studies to report on this clinical uncertainty in the recommendations, but interestingly, the physician data did not extensively elaborate on the ways in which physicians coped with clinical uncertainty in mammography decisions. Only one article  revealedData from two studies , 30 showPCPs have discussed this issue of presenting evidence on risk reductions associated with tests or interventions as absolute versus relative risk and how this difference has an impact on the capability of women to make informed choices. Woloshin and Schwartz  affirm tYet, even if providers are equipped with the necessary information to share with women considering screening, disagreements on what exactly should be shared with women remains a problem. For instance, in Parker et al.’s work on breast cancer screening communication , the mosRegardless of what specific information is presented to patients, using evidence to guide practice requires proper knowledge and understanding of statistics on the provider’s part to distinguish between relevant and irrelevant data. In a survey of over 400 PCPs in the USA , nearly While this research addresses screening from the perspective of PCPs, it is relevant to consider that in high-income countries, many women are invited to enter mammography screening programs through government-based initiatives. Provincial mammography screening programs across Canada do not offer or advise women to seek counseling prior to entering their programs. In Quebec, at the age of 50, women receive an invitation to enroll in the province’s official screening program. Although the Quebec program offers psychosocial support to women once registered in the program, there is limited access to pre-screening counseling. Once women register in these programs, their physicians typically receive alerts for subsequent mammograms, which are ordered automatically. Few opportunities may exist for women to revisit an initial decision to start screening. For women who discuss screening with their PCP, uncertainty around what information to present to inform decisions remains an important issue. Yet, in the Canadian Medical Association Code of Ethics , articleWhen balancing the benefits and trade-offs of a screening test becomes less clear, such as in breast cancer screening, primary care experts are increasingly recommending shared decision-making . ThroughLastly, our review revealed that physicians may have strong intentions to support women in making informed decisions about mammography screening , but somOur study captures articles using diverse methodologies and methods and various outcome measures, resulting in a difficult harmonization of findings. Although all nine included articles are empirical, comparing the results of these studies that measure different outcomes becomes somewhat difficult. Our use of a Critical Interpretive approach  allows fFurthermore, the varying terminology used to describe similar data in our included studies challenged the comparing and contrasting of findings. We were not always able to effectively group data into consistent themes. For instance, in one study, authors measured whether or not physicians ‘offered’ screening , whereasIn conducting this critical interpretive review, we aimed to rigorously gather information on the beliefs and approaches of physicians regarding mammography screening decision-making with average-risk women. As stated in article 3 of the Code of Ethics of Physicians in Quebec , physiciUpcoming work led by this research group aims to continue this examination, by analyzing comments from physicians in response to clinical evidence on mammography screening. These perspectives, stemming from the Patient Oriented Evidence that Matters (POEMs) dataset, will provide further insight on the decision-making processes occurring during visits with primary care providers and the values guiding the practice of these professionals.


Schizophrenia is a debilitating syndrome characterised by three main symptom categories: positive, negative and cognitive. Cognitive symptoms emerge first, and currently do not have appropriate treatments, despite being a strong predictor of the severity and progress of the illness. Cognitive deficits are thought to be partly attributed to impaired synchronization of gamma frequency oscillatory activity. Gamma oscillations are generated by a subclass of GABAergic interneuron that expresses the calcium binding protein, parvalbumin (PV). PV-interneurons are supported by Brain Derived Neurotrophic Factor (BDNF) and recent evidence has found that cessation of BDNF support in PV- interneurons impairs gamma oscillations. All of these factors have been demonstrated to have a role in cognitive processing, but their dynamic relationship is not completely understood.The aims of this study were: 1) To generate transgenic mice where 50% of BDNF receptor (TrkB) gene is excised from PV-expressing neurons using the cre-lox recombination system and 2) To investigate the cognitive and behavioural consequences of disrupted BDNF signalling at inhibitory PV-expressing interneurons. Male and female mice underwent a battery of tests including: Y-Maze, Novel Object Recognition Task (NORT), Elevated Plus Maze, Locomotor and Cheeseboard Maze.Sex-specific spatial memory impairments were found in PV-Cre x TrkB floxed mice with only males showing no preference for the novel arm in the Y-maze paradigm. Furthermore, male PV-Cre x TrkB floxed mice displayed a lack of cognitive flexibility in the cheeseboard maze for long term spatial memory. No significant differences were observed in measures of anxiety and activity, indicating that these were not confounding variables for cognitive measures.This mouse line has not been cognitively characterised before and the results are of major interest. Subtle changes to cognition were observed and were sex-dependent. Interestingly, only males were observed to have changes in cognition, in line with human data. Human males with schizophrenia tend to exhibit more severe cognitive symptoms. Overall, the evidence from this study supports a role for BDNF-TrkB signalling at PV interneurons in regulating spatial memory performance. Future work will be investigating spatial search strategies of the Cheeseboard Maze, in order to elucidate further any cognitive differences between the genotypes. Additionally, future work will aim to specifically disrupt BDNF-TrkB signalling in the hippocampus and/or prefrontal cortex, as these two areas are highly implicated in both cognition and schizophrenia. It would also be of interest to use this genotype in a two-hit model, to further investigate the interaction of multiple factors and their impact on cognitive functions.