Atherosclerosis as the leading cause of the cardiovascular disease is closely related to cholesterol deposition within subendothelial areas of the arteries. Significantly, early atherosclerosis intervention is the critical phase for its reversal. As atherosclerosis progresses, early foam cells formation may evolve into fibrous plaques and atheromatous plaque, ulteriorly rupture of atheromatous plaque increases risks of myocardial infarction and ischemic stroke, resulting in high morbidity and mortality worldwide. Notably, amphiphilic apolipoproteins (Apos) can concomitantly combine with lipids to form soluble lipoproteins that have been demonstrated to associate with atherosclerosis. Apos act as crucial communicators of lipoproteins, which not only can mediate lipids metabolism, but also can involve in pro-atherogenic and anti-atherogenic processes of atherosclerosis via affecting subendothelial retention and aggregation of low-density lipoprotein (LDL), oxidative modification of LDL, foam cells formation and reverse cholesterol transport (RCT) in macrophage cells. Correspondingly, Apos can be used as endogenous and/or exogenous targeting agents to effectively attenuate the development of atherosclerosis. The article reviews the classification, structure, and relationship between Apos and lipids, how Apos serve as communicators of lipoproteins to participate in the pathogenesis progression of early atherosclerosis, as well as how Apos as the meaningful targeting mass is used in early atherosclerosis treatment. Atherosclerosis is considered to be a chronic inflammatory disease of abnormal accumulation of cholesterol, mainly in the large and medium arteries, leading to high morbidity and mortality worldwideTherapeutic strategies for early atherosclerosis mostly revolve around the reduction of lipids levels. The lipids serve as the source of energy and nutrient for the body, mainly including cholesterol, triglycerides (TG) and phospholipids (PL), which are insoluble in water and cannot exist independently in plasma. More importantly, plasma amphiphilic apolipoproteins (Apos) possess the property of interacting with both lipids and water, and act as indispensable carriers of lipids transport. Lipoproteins can be formed by the bind of lipids and Apos, including chylomicron (CM), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), which can transport lipids to various tissues of the body for metabolism and utilizationAccumulating evidences demonstrate that Apos are closely associated with atherosclerotic disease and serve vital regulatory roles in a broad spectrum of key events in early atherosclerosisApos, as communicators of lipoproteins, play crucial functions in the process of early atherosclerosis. It is worth noting that Apos may be triggered as meaningful targeting mass to ameliorate atherosclerosis via masking the adverse properties of atherogenic Apos and sufficiently amplifying the advantageous properties of anti-atherogenic Apos. Two therapeutic strategies could be taken to synergistically confront the development of early atherosclerosis, one is to regulate endogenous Apos expression and the other is turning to exogenous anti-atherogenic Apos mimetic peptides. In this review, we summarize the classification, structure, and relationship of Apos with lipids, how Apos act as communicators of lipoproteins to affect the development of early atherosclerosis, and even how Apos act as meaningful targeting mass applied for atherosclerosis treatment.Apos are diverse and possess a variety of biological functions. The amphiphilic nature of Apos enables to interact with lipids and water. Since cholesterol, PL, TG and other lipids are insoluble in water and cannot exist alone in plasma, Apos can combine with lipids to form soluble lipoproteins, and the lipids are transported to body tissues in the form of lipoproteins for metabolism and utilizationApos are generally classified into five categories, such as A, B, C, D and E, each of which has subcategories, such as AI, AII, AIV and AV in class A, B48 and B100 in class B, CI, CII and CIII in class C, E2, E3 and E4 in class E. So far, more than 20 Apos have been foundApos are also divided into exchangeable and non-exchangeable Apos based on their movement and exchange properties between different lipoproteins. Exchangeable Apos can be separated from one lipoprotein and recombined with another lipoprotein during circulation, apparently confering lipoproteins orientation and the ability to interact with cell surface receptorsExchangeable Apos, sharing unique structure related to their biological functions, are soluble in aqueous solutions and transport between various lipoproteins depending on changes in lipoproteins size and lipids composition1 domain, while Apo B100 contains both β1 and β2 domainsThe Apo B, non-exchangeable apolipoprotein, possesses alternative AαHs and amphipathic β-sheet (AβS) domainsApo are important serum proteins embedded on the surface of lipoproteins particles, endowing lipids with a soluble form. Apos, as communicators of lipoproteins, are also involve in lipids metabolism through modulating enzymes activity and binding to cellular receptors.41. Apo J also referred to as clusterin acts extracellularly or intracellularly as a chaperone and is mainly carried by HDL, LDL and VLDLApos combine with lipids in order to form various densities and sizes of lipoproteins that enable to transport hydrophobic mediators in hydrophilic plasma. Lipoproteins are classified into CM, VLDL, IDL, LDL and HDL in ascending order according to hydrated densityin vitroApos act as communicators of lipoproteins to regulate lipid metabolism in lipoproteins by activating or suppressing enzymes. Examples are Apo AI, Apo AIV, Apo AV, Apo CI and Apo E, they may act as activators of lecithin cholesterol acyltransferase (LCAT), which induces free cholesterol (FC) on HDL surface esterified into cholesterol esters (CE) and facilitates CE to get into nascent HDL core to form mature HDLApos, as communicators of lipoproteins, may initiate or inhibit lipid uptake from lipoprotein particles by interacting with specific cellular receptors. Apo B as a ligand is essential for LDL binding to LDL receptor (LDLR), facilitating cholesterol ingestion in peripheral tissues and the liverApo B acts as a major communicator of LDL can spark subendothelial retention of excessive LDL by interacting with ECM components PGs, which is an initial step of atherosclerosisThe endothelial layer maintains integrity upon the majority of atherosclerotic progression, whereas it is highly permeable to LDL and the exact molecular mechanism promoting this increase in permeability is unclear. Other than LDL particles, the small Apo B-containing lipoproteins with sizes about 70 nm, such as CM remnants, VLDL and IDL, could effectively pass through ECsFollowing subendothelial retention, lipoproteins are more easily modified by phospholipases and proteases, including sphingomyelinases (SMase), phospholipaseA2 (PLA2) and α-chymotrypsin (α-CT). These enzymes promote the formation of hydrophobic domains in Apo B of lipoproteins, facilitating aggregation and fusion of retained lipoproteinsAlthough some Apos accelerate atherosclerotic progression via promoting lipoproteins accumulation within the subendothelial space, several Apos exhibit inhibition of lipoproteins aggregation and anti-atherogenic effects. Apo AI could potently bind LDL surface lipids, thereby interfering with surface lipid distribution and stabilizing the conformation of Apo B100, which interrupts aggregation induced by SMasein vivo. One is involved in oxidative stress-associated signaling pathways that directly remove free radicals and prevent LDL oxidation, and the other interacts with oxidant and LDL oxidation byproducts and blocks their harm in atherosclerosis  production and lead to the generation of atherogenic ox-LDL that has been widely identified as a major determinant driving the pathogenesis of atherosclerosis. Indeed, ox-LDL and its bioactive oxidized byproducts, such as lipid peroxides, aldehydes, hydroxyl sterols, and lysophosphatidylcholine, exhibit pro-atherogenic properties and contribute to atherogenesis by affecting manifold biological processes, containing the induction of cholesterol accumulation in macrophages as well as potent proinflammatory, proapoptotic and cytotoxic activitiess Figure .On most occasions, LDL circulating in plasma is protected from oxidation with the presence of antioxidantsTo maintain the prooxidant-antioxidant balance, several Apos also act as communicators of lipoproteins to synergistically attenuate oxidative damage by inhibiting oxidative stress-related signaling pathways. Apo J is enhanced in atherosclerosis as a protein sensor of oxidative stress, which significantly inhibits ROS production stimulated by ox-LDL through lowering expression related to nicotinamide adenine dinucleotide phosphate (NADPH) oxidasein vitro than in wild-type mice. Evidence of amplified oxidative stress and specific epitopes of LDL oxidation in aortic lesions has been found in Apo E-deficient mice. Although the mechanism is acquainted imperfectly, the antioxidant properties of Apo E are ascribed to bind to copper and iron ions, which may isolate them and thus restrain their involvement in the oxidation processExcept for inhibiting oxidative stress-related signaling pathways mediated by Apos, other antioxidative properties of Apos that interact with oxidant and LDL oxidation byproducts are well established. Apo AI may act directly as an antioxidant owning to contain multiple methionine groups and it suppresses the formation of lipid hydrogen peroxide, oxidized CE and PL, which lowers cytokines levels such as MCP-1 and macrophage colony-stimulating factor, as well as inhibits monocytes adhesion to ECs mediated by oxidative lipids, further blocking deleterious effects of them in atherosclerosis processSeveral Apos as communicators of lipoproteins are involved in inflammatory-related signaling pathways to incite robust proinflammatory activity, contributing to the occurrence of several key events involved in foam cells formation, such as ECs activation, monocytes recruitment and activation, as well as SMCs migration and proliferation. Macrophages are mainly derived from activated monocytes and SMCs that migrate from arterial media to intima. Subsequently, macrophages can avidly engulf ox-LDL by the Apos binding to cellular receptors, leading to the formation of lipid-rich foam cells that are typical hallmarks of early atherosclerosis.in vitroex vivo cultured carotid plaques through evoking MAPK and Ca2+-dependent signaling pathways, which incites the release of multiple cytokines containing IL-6, IL-8 and MCP-1 involved in monocytes recruitment in atherosclerotic lesionsApos serve as communicators of lipoproteins to participate in multiple inflammatory responses through motivating ECs-monocytes interactions and exert specific effects on atherogenesis. Research has verified that Apo CIII alone or as a lipoproteins component induced ECs activation and monocytes adhesion The aforesaid findings reveal that some Apos as dangerous signals participate in foam cell formation. Meanwhile, cytoprotective Apos as communicators of lipoproteins may adjust manifold associated signal transduction pathways and actuate resistance to cellular atherogenic response Figure . As a muin vivo and its anti-proliferative effects are partly attributed to the inhibition of the cell cycleExcessive migration and proliferation of SMCs from arterial media to intima are also one of the critical factors promoting atherosclerotic foam cells formation. Inflammatory cytokines derived from Apos-mediated activation of ECs and monocytes stimulate SMCs migration and proliferation. SMCs express various cytokines containing fractalkine, ICAM-1, MCP-1, VCAM-1 and matrix metalloproteinase-9 (MMP-9) under pathological conditionsIt is well established that the continuous influx of cholesterol ultimately exceeds the metabolic capacity of macrophages and thus induces foam cells formation. RCT is responsible for motivating excessive cholesterol efflux from extrahepatic tissues and returns to the liver for further metabolism and excretionThe initial step of RCT is to mobilize cholesterol efflux from macrophages or foam cells. Lipid-poor Apo AI is the dominant acceptor of cellular FC and PL in an adenosine triphosphate-binding cassette transporter A1 (ABCA1) dependent manner to form nascent discoidal pre-β-HDL that serves as a more active FC acceptorIn the second step, LCAT catalyzes CE formation on the pre-β-HDL surface via transferring fatty acids from lecithin to FC. Since CE is less soluble than TG, it cannot circulate in exposure to a water environment, thereby it migrates from lipoprotein particles surface to hydrophobic core, rendering discoidal pre-β-HDL into mature spherical HDLin vitroIn the final step, HDL is transported to the liver for metabolism. CE on HDL is mainly eliminated through hepatic surface receptor SR-BIApos as communicators of lipoproteins play important roles in the pathogenesis of early atherosclerotic development. Correspondingly, they may serve as meaningful targeting mass to reverse atherosclerosis via covering up their unfavorable features and fully augmenting their beneficial features. There are two main available strategies triggering Apos for the treatment of early atherosclerosis. One reasonable approach is to regulate the expression of endogenous Apos to inhibit atherosclerosis via reducing the level of endogenous atherogenic Apos or mutating them and urging the synthesis of endogenous anti-atherogenic Apos. When the generation of endogenous Apos is insufficient or difficult to reverse the progression of atherosclerosis, the application of exogenous Apos mimetic peptides exhibiting similar biological features to native Apos is considered to be another supplementary and desirable approach for atherosclerotic therapeutic option.in vivoConsidering that Apos are bound up with the occurrence and progression of early atherosclerosis due to their atherogenic and anti-atherogenic properties, corresponding interventions such as reducing or mutating endogenous atherogenic Apos, as well as elevating endogenous anti-atherogenic Apos levels could retard atherosclerotic development. Remarkably, anti-Apos antisense oligonucleotide (ASO), aiming at Apos mRNA and reducing plasma Apos levels, offers an intriguing therapy for cardiovascular protection. An anti-Apo B ASO effectively lessens hepatic Apo B synthesis and lowers plasma cholesterol, achieving a basic elimination of plasma LDL in LDLR-deficient mice with atherosclerotic lesions. LDL concentrations declined rapidly within 3 days of administration. After 7 days of ASO treatment, the reduction of plasma Apo B concentrations lowered aortic LDL permeability, possibly further reducing LDL retention and aggregation within subendothelial space, which is prior to any detectable changes in foam cells content and size of aortic atherosclerotic plaquesin vitro and in vivo, and its mechanism is related to inhibiting LXRα and expediting hepatocyte nuclear factor-1α. The regulation of Apo M may be a new way for statins to enhance HDL level and facilitate RCT to prevent atherosclerosis , stroke and peripheral artery disease, resulting in high morbidity and mortality worldwide. In this review, we mainly pay attention to the biological characteristics of Apos, the roles of Apos in the pathogenesis of early atherosclerosis, and Apos as the meaningful targeting mass in the treatment of early atherosclerosis. It indicates that Apos serve as critical communicators of lipoproteins for the pro-atherogenic and anti-atherogenic processes of early atherosclerosis through influencing LDL retention and aggregation, oxidative modification of LDL, foam cells formation, and RCT in macrophage cells or foam cells. Correspondingly, Apos may be applied as the meaningful targeting mass in endogenous and/or exogenous manners for the effective treatment of early atherosclerosis.Although the early intervention of atherosclerosis may achieve the desired therapeutic effect, long-term clinical silence may delay the optimal treatment time because atherosclerosis is a chronic progressive disease. If early treatment is not timely, acute myocardial infarction, ischemic stroke, pulmonary embolism and other severe complication may occur


Soil-disturbing animals are common globally and play important roles in creating and maintaining healthy functional soils and landscapes. Yet many of these animals are threatened or locally extinct due to habitat loss, predation by non-native animals or poaching and poisoning. Some reintroduction and rewilding programmes have as their core aims to increase animal populations and reinstate processes that have been lost due to their extirpation. Here we use a meta-analytical approach to review the effects of soil-disturbing vertebrates on ecosystem processes, and advance the argument that they can be used to rehabilitate degraded ecosystems by altering mainly composition and function, but with fewer positive effects on structure. We describe four examples where the loss or reintroduction of soil-disturbing vertebrates leads to ecosystem state changes and highlight the role of spatial scale, covarying management changes, and species co-occurrence in modulating their effects. We discuss the advantages and disadvantages of using soil-disturbing vertebrates over mechanized engineering approaches such as pitting and furrowing, considering some advantages to include more self-sustainable and heterogeneous disturbances, creation of new habitats and added recreational values. Finally, we identify key knowledge gaps in our understanding of the use of soil-disturbing vertebrates for rehabilitating degraded ecosystems. These two types of structures have marked effects on soil and ecological properties and processes, including changes in vegetation and soil biota composition, nutrient accumulation rates or water infiltration capacity . Many of these soil-disturbing vertebrates  are severely threatened by exotic predators, habitat loss, hunting and even poisoning. Populations of many species of soil-disturbing vertebrates have abruptly declined over the past few decades ), or natHere we produce an overview of the current extent and composition of soil-disturbing vertebrates globally, review existing literature on their impacts on a range of ecological processes  and describe four examples that illustrate how their activity and extirpation can lead to ecosystem state changes. Finally, we discuss where and how the reintroduction of these animals can help to restore biodiversity and ecosystem processes more cheaply and sustainably than engineering-based restoration techniques such as furrowing and pitting.. 2−1 for solitary marsupials [−1 for colonial pocket gophers [−1 for feral pigs [Animal foraging mobilizes sediment that is either trapped in the mound (the ejecta sediment) or transported through the landscape by wind and water . Globally, contemporary rates of soil formation are orders of magnitude less than rates of soil loss, so soil disturbance by animals has the potential to lead to the formation of novel soil horizons. Annual rates of soil movement vary widely among taxa from 0.1 t harsupials  to 22 t  gophers  and morePits and depressions moderate hydrological processes by retarding runoff ,7 and thOverall, greater soil moisture and fertility within pits create favourable microsites for seed germination and establishment ,13,18–20. 3et al. [vice versa. The RII values of all attributes were used separately , then pooled into three categories (for the 12 most common soil-disturbing vertebrates). These categories provide measures of ecosystem structure , function (measures that support ecosystem processes such as decomposition and hydrology) and composition .To assess the balance between the positive and negative effects of soil-disturbing vertebrates, we updated a global database  to incluet al.  by (i) cet al. , electroparately a,b, thenb). Overall effects of soil disturbance on composition were generally positive, increasing biocrust richness, invertebrates and vertebrate abundance, and invertebrate richness, but with non-significant effects on plant richness (b). Effects of soil-disturbing vertebrates on function were generally positive (0.06 ± 0.02) but mixed. Soil nitrogen, infiltration and soil water were greater, and likely account for the increased plant production. However, runoff and soil compaction also increased. Evidence to date clearly suggests that rewilding with soil-disturbing vertebrates can greatly benefit biodiversity but that it may come with environmental costs associated with the loss of important attributes of ecosystem structure and functions related to soil compaction, erosion and runoff.The mean value of structural attributes  declined significantly under the action of soil-disturbing vertebrates , mainly due to the negative effects on biocrust and plant abundance, plant height and litter cover, although soil-disturbing animals also enhanced plant densities b. Overalrichness b. EffectWe also found strong species-dependency in the overall effects of soil-disturbing vertebrates on ecosystems. The effects of soil-disturbing vertebrates ranged from predominantly positive effects on ecosystem composition, function and structure in the presence of porcupines, mongooses, prairie dogs and bandicoots, to predominantly negative responses seen in rabbits, pikas or zokors. Rabbits and prairie dogs had generally positive effects on function, but negative effects on structure  could strongly modulate the sign and intensity of the effects of soil-disturbing vertebrates on ecosystems, which warrants further research  to aid p. 4We now illustrate some of the factors that potentially modulate the direction and strength of the effects of soil-disturbing vertebrates with three relatively well-known examples including density-dependence, complementary effects and the need for additional restoration practices.Ochotona curzoniae) is a widely distributed keystone species across the Tibetan plateau and a significant prey item of plateau carnivores. Its burrows are important refugia for birds and reptiles (a) and the mounds play important roles in soil and vegetation dynamics [The Plateau pika  steppe is an important biome in North America. Over the past century plant composition has been dramatically altered by overgrazing, invasion by Eurasian exotic grasses (Bromus tectorum) and wildfire [Spermophilus spp.) construct small tunnels that enhance water flow into the soil [Taxidea taxus), in turn, predates upon ground squirrels, excavating their burrows and creating large mounds of excavated soil (b) that occupy up to 8% of the landscape and have soils with a greater C : N ratio (approx. 25–30) than undisturbed soils  at the expense of weeds. Mounds therefore provide suitable patches from which native plants can re-establish after overgrazing or fire. Hence, there are clear co-benefits of simultaneously rewilding with these two soil-disturbing vertebrates . The hitebrates , and theDipodomys spectablis) is an important soil-disturbing mammal (rodent) from North America's Chihuahuan Desert (c). The nutrient-rich soils associated with its burrows support unique microbial communities and are preferred sites for desert plants [c) by penetrating the impermeable carbonate layer near the surface, allowing shrubs to access water. Declines in green grass following encroachment force the rats to abandon their mounds [The banner-tailed kangaroo rat , suggesting that their reintroduction could have widespread future benefits. Reintroductions of soil-disturbing vertebrates have been sometimes intentional and with native animals, such as the case of bettongs (Bettongia spp.) and bilbies (Macrotis lagotis) in Australia [Soil-disturbing vertebrates occur across a wide range of ecosystems globally a, suggesustralia , and somustralia . The extTachyglossus aculeatus) have a similar configuration to those constructed by the tyne pitter, a mechanical device used to restore degraded soils worldwide (e.g. [a), reductions in soil erosion at large spatial scales can be valued through the avoided cost of desilting dams.Soil-disturbing animals may be cheaper and more effective tools for rehabilitation than mechanical methods. For example, the foraging pits of the short-beaked echidna (de (e.g. ), but ecde  the longer time period required to ‘treat’ an area equivalent to one mechanically treated, (ii) suitable habitat must be provided to support them , (iii) feral animals  must be controlled and (iv) the foregone costs of not using the land for more productive purposes. Additionally, many soil-disturbing animals also exert strong trophic-level effects on ecosystems and may compete with livestock. Experimental comparisons of the effects of mechanical and ecological structures on ecosystem functions are needed to promote sustainable and successful reintroduction .Given both their trophic and non-trophic effects, we would expect that high densities of soil-disturbing animals would degrade ecosystems, particularly in the absence of natural predators, which is typical in the early days of rewilding programmes . We needb), and thus reintroduction of the latter will be ineffective without the former.The literature on rewilding with megafauna can help to improve our understanding of the usefulness of soil-disturbing vertebrates for restoration. For example, the tools developed to establish potential reference states  for megFigure 2a), and their contrasting effects on ecosystem attributes , it is reasonable to consider the potential for ‘complementarity diversity effects’  suggest that rewilding with these animals offers a unique opportunity for cheaper and more enduring ecological restoration, with benefits exceeding those using mechanical approaches. However, these potential benefits may depend on the composition of species used and whether high densities can be avoided in the absence of natural predators. There are also potential conflicts with alternative land uses  and disservices that need to be accounted for in order to reduce conflict resulting from rewilding. Substantial opportunity exists to explore reference compositions and densities as targets for these rewilding programmes, and to better understand and predict their effects based upon their functional traits and the prevailing environmental and management conditions.


Transdiaphragmatic intercostal hernia is a rare disease. It is usually caused by trauma and is rarely caused by coughing. Although a few cases of intercostal hernia induced by coughing have been reported, our case of a non traumatic acquired acute transdiaphragmatic intercostal and abdominal hernia induced by coughing is very rare. A 77-year-old woman presented with sudden-onset left lower chest pain after an episode of violent coughing. She had risk factors for intercostal hernia, including obesity, chronic obstructive pulmonary disease, oral steroid use, and diabetes mellitus. Computed tomography showed herniation of the lung and intra-abdominal organs into the thoracic and abdominal wall through a ruptured diaphragm, as well as the intercostal and abdominal muscles. Surgery was completed with interrupted sutures to close the defects after the reduction of the herniated organs. Our experience suggests that careful examinations, including the assessment of risk factors and computed tomography imaging, were essential for establishing an accurate diagnosis, and that the repair of a ruptured diaphragm with simple interrupted sutures without any prosthetic materials seems to be feasible in selected patients with a transdiaphragmatic intercostal hernia. Dear Sir,Recently, an unusual case of transdiaphragmatic intercostal hernia (TDIH) with delayed onset and history of blunt trauma incurred in a high-speed motor vehicle accident has been reported . TDIH is9/L) and serum creatine phosphokinase . CT showed herniation of the basal portion of the lower lobe of the left lung and intra-abdominal organs, including the stomach, left colon, and mesenteric fat, into the thoracic and abdominal walls through the ruptured diaphragm, as well as the abdominal and ninth intercostal muscles (Fig. A 77-year-old obese woman with a history of long-term steroid use for asthma and diabetes mellitus presented with sudden-onset left lower chest pain after an episode of violent coughing. She had no history of blunt trauma to the chest or abdomen. Physical examination revealed soft tissue bulging on the left lower chest wall. The chest wall exhibited ecchymosis. The laboratory results showed increased levels of white blood cells (11.80, 4.0–10.0 × 10TDIH is commonly caused by trauma involving motor vehicle accidents, and it may be diagnosed during admission to the emergency department . MohandaAlthough a few cases of cough-induced intercostal hernia have been reported –7, our cThere are several surgical options for the treatment of TDIH including primary closure, using mesh, and closure with prosthetic or autologous material . In acutIn summary, we encountered a rare case of an extensive transdiaphragmatic intercostal and abdominal hernia without a trauma history to the thoracoabdominal wall, with the sudden onset of symptoms after an episode of violent coughing. Through our experience, we would like to emphasize that careful examinations, including suspicion based on symptom history, the assessment of risk factors, physical examination, and CT imaging, are essential for establishing an accurate diagnosis of spontaneous TDIH and that the repair of a ruptured diaphragm with simple interrupted sutures without any prosthetic materials seems to be feasible in selected patients with a TDIH.


Aggregatibacter actinomycetemcomitans (D7S-1), Centipeda periodontii, Campylobacter gracilisi, Fusobacterium nucleatumi, Slackia exigua,Prevotella intermedia, Tannerella forsythia, Staphylococcus aureus, Bacteroides fragilis, and Bacteroides fragilis. Hence, a user-defined query was used to conduct analysis on the providedbacterial strains whose molecular data available in the STITCH database. Thus, we used the STITCH tool to examine protein interactions and the VirulentPred tool to assess pathogenicity using the known molecular data on glycrhizzin and peri implantpathogens. Data shows that glycyrrhizin interacts with peri implant pathogens.Glycyrrhizin is present in the root extract of the licorice plant used for various conditions, including gastric ulcers. Therefore, it is of interest to document the STITCH enabled molecular interaction of glycrhizzin with peri-implant microbiota.The peri implant pathogens includes  Dental implants are prostheses with close resemblance of a natural tooth. The survival rates of implants are also about 96.4% to 99%  over a pAggregatibacter actinomycetemcomitans (D7S-1), Centipeda periodontii, Campylobacter gracilisi, Fusobacterium nucleatumi,Prevotella intermediaSlackia exigua, , Tannerella forsythia, Staphylococcus aureus, Bacteroides fragilis, and Bacteroides fragilis using known molecular data. Hence, auser-defined query was used to conduct analysis on the provided bacterial strains whose molecular data available in the STITCH database [It is of interest to study the interaction of glycyrrhizin with database .A. actinomycetemcomitans (D7S-1), B. fragilis (ATCC 25285), C. gracilis (RM 3268), F. nucleatum (ATCC 43037).14The STITCH database (Version 5) is an open-source platform with an extensive collection of data about interactions, both physical and functional associations made possible by computational prediction of interactions from primary databases, therepertoire of proteins which interact with Cell surface proteins are of particular interest because they can be used as novel drug targets. Subcellular localization of proteins aids in the identification of drug targets and could serve as a potential target for new medications. Analgorithm called Gneg-mPLoc uses an amino acid sequence to determine the likely location of a protein , 15.Cell surface proteins are of particular interest because they can be used as cutting-edge drug targets, and subcellular localization of proteins aids in the identification of drug targets and could serve as a potential target for new medications.Using a given amino acid sequence, the algorithm Gneg-mPLoc predicts the likely location of a protein's localization. The STITCH v5 tool was used to assess the interaction between the microbe and the element of interest. The protein target derivatives of the reactions were then further processed with the VICMpred and Virulentpred algorithms. It has beendiscovered that the molecule glycyrrhizin interacts with proteins crucial to cellular metabolism and other processes. It is intriguing to note that the element of interest also interacted with the peri-implant pathogens' virulence factors. Theenzymes responsible for free radical production, glutaminase, glutamine synthetase, and the superoxide group of enzymes were involved in most interactions. The ten virulent factors' subcellular localization and epitope analysis were also performedin addition to these predictions.Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Aggregatibacteractinomycetemcomitans, Prevotella intermedia, Fusobacterium nucleatumi, Campylobacter species, and Bacteroides species. Because of constant contact with tissues and body fluids, which act as asource for electrochemical interactions, mechanical loading of the implant leads to loss of ions by friction and electrochemical exchange, a process known as bio tribocorrosion It has also been suggested that long-term accumulation of biofilms andmechanical strain causes implant surfaces to degrade. Presence of high levels of dissolved titanium was detected in submucosal plaque around implants when compared to intervention free sites, thus indicating an association between Ti dissolution andperi-implantitis .The oxide corrosion products were found in newly formed trabecular bone and peri-implant vasculature and were systemically distributed. The oxide particles are cytotoxic, having an effect on immune cells, and it has been noted that thesmaller the particle size, the greater the toxicity. Other researchers have observed peri implantitis in situations where the microbial threat is removed or controlled through frequent supportive measures. There is evidence that titanium oxide debriscauses immune-modulatory changes that cause degenerative changes in osseous and periodontal tissues. This is due to the fact that immune cells around the implant, such as poly morpho nuclear neutrophils, macrophages, and monocytes, recognize titaniumoxide debris. However it is interesting to note that TiO2 has a continuous photocatalytic antimicrobial activity against pathogens. Metal oxide alone or in combination with other metals like silver, copper or zinc is shown to have antimicrobial propertyand the same has been explored to a lesser extent In the present study we observe a good number of interactions between TiO2 and common peri-implant pathogens the target was mostly enzymes involved in cellular nitrogen metabolism which in turn bringsabout alteration in protein synthesis hindering the ability of bacteria cause virulence , thus it can be taken that titanium modifies peri implant microbiome and has potential antibacterial activity much light has to be shed on this aspect and thesame would be clinically useful in management of peri implant disease by modifying implant surfaces or and we can deduce that peri implantitis is a complex disorder which has multifactorial causation, and more experimental exploration on this aspectto be carried out to produce effective treatment outcomes.Initial colonization of peri-implant surfaces by bacteria can happen in a matter of 2 weeks , the micData shows that the glycrrhyzin has virulence features against the protein of the oral microbes. This shows that glycyrrhizin have degenerative features. Thus, it has the potential to modify the peri implant microflora by interfering with theirmetabolic processes and could potentially increase the auto-immune response.The first author (S Karthickraj) performed the analysis and interpretation and wrote the manuscript. The second author (Sahana Selvaganesh) contributed to conception, data design, analysis, interpretation and critically revised the manuscript.Third author (N Thiyaneswaran) critically reviewed the manuscript. All the authors have discussed results and revised the manuscript.


Prodrug-based drug development strategy has become a well-established tool to improve the physiochemical , pharmacokinetic (PK), pharmacodynamics (PD) and pharmaceutical (PH) properties  of biologically active agents. It is estimated that over 10% of all the marketed drugs to now are prodrugs. Herein, we launch this Research Topic on a relatively small scale to summarize the latest important advances and some newly emerging technologies in the design of prodrugs and their therapeutic applications.Prodrugs are chemically derived versions of biologically active molecules, which are inherently indolent but capable of being chemically and/or enzymatically converted to their active counterparts upon triggered by endogenous , Law et al.).This Research Topic provides 7 articles, including 2 review articles and 5 original research articles contributed by 62 authors worldwide. The reviews cover Research Topics related to prodrugs in traditional Chinese medicinal herbs and nanotechnology. Obesity as a global health problem has attracted widespread attention, and contributes to the occurrence of various diseases including cardiovascular disease, metabolic syndrome, diabetes and certain cancers. Chinese medicinal herbs-derived molecules such as resveratrol, berberine, artemisinin, curcumin and celastrol are found to be potent therapeutics for obesity. However, these naturally derived compounds have limitations including weak aqueous solubility, low bioavailability, poor stability and strong systematic toxicity. Further derivation and/or modification to the corresponding prodrugs of these herbs-based molecules have the potential to address the above mentioned issues and provide improved biological activities .5-aminolevulinic acid (ALA) is a clinically approved prodrug predominally used in photodynamic therapy (PDT) and fluorescence-assisted photodynamic diagnosis (PDD). Although ALA itself possesses certain advantages such as better aqueous solubility and enhanced stability compared with the parental drug Protoporphyrin IX (PpIX), it has limitations including weak lipophilicity, poor bioavailability and nonselectivity. The recent emerging nanotechnology opens the avenue for amplifying the effects of ALA-based prodrugs in improved PDT  inhibitors, which provided improved solubility, stability and kinase activity . Similarly, Pinzaru et al. prepared nutraceutical prodrugs using Novozyme® 435-catalyzed esterification of Rutin with unsaturated fatty acids. The resulted Rutin bioconjugates possess improved physiochemical properties, as well as enhanced biosafety and bioavailability .Besides, a diverse of original studies on this Research Topic has given various aspects of different prodrug designs and their therapeutic applications. For instance, Toti et al. developed a strategy by the installation of novel lipid terminal motifs featuring various oxygen contents to an acyclic nucleoside phosphonate tenofovir (TFV)-an approved antiviral agent, which showed enhanced metabolic stability while maintaining the antiviral activity of TFV . Such a strategy indicates that small modifications to alter the metabolic soft spots of lipid prodrugs, can bring substantial improvements in PK profiles, thereby enabling molecules that are otherwise undevelopable as potential therapeutics for human diseases.It is known that lipid-based technology for enhancement of bioavailability has been widely utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. However, one of the major limitations of current lipid-based prodrugs is the rapid metabolism of fatty acids in the liver, which greatly shortens the duration of action. Hugele et al. investigated the possible enzymes and effectors  on bioconversion of L-type amino acid transporter 1 (LAT1) using amide-based prodrugs in different biological media . Aminopeptidase B was identified as a potent enzyme for the bioconversion of amide-based prodrugs containing aromatic promoieties (L-Phe), but not for those prodrugs containing aliphatic amino acids. This study is useful for design of siteselective prodrug delivery system and identification of potent organ-selective enzymes in future. Additionally, virtual screening is a computational technology that analyzes libraries of small molecules to identify potential hit candidates. By combination of machine learning activity prediction and virtual screening, followed by efficient in vitro and in vivo models of activity evaluation, it can also assist in the discovery and design of innovative prodrugs .Although the stimuli-responsive feature is one of the major advantages of prodrug-based therapeutics, the uncontrolled bioconversion/release of the parental drug from a prodrug often fails to achieve the desired therapeutic effect. In particular, little is known about the bioconversion enzymes that cleave specific bonds in prodrugs. prodrug design and therapeutic applications”. It is hoped that this interdisciplinary Research Topic will provide useful information and guidelines for academic and industrial researchers to improve drug efficacy, reduce undesirable side effects and develop innovative therapeutics for the treatment of various diseases.Overall, the current Research Topic summarizes aspects of “


Editorial on the Research TopicExecutive functions in sportsThe concept of executive functions has been an important focus for sport and exercise scientists for over two decades . During Following a thorough review process, four original articles were accepted for publication. The 16 contributing authors represented diverse geographical backgrounds, including China, Spain, Italy, and Germany. Each article explores the theme of executive functions in sports from a different scientific as well as cultural perspective. This diversity is reflected in the applied research methodologies, cognitive assessments employed, and participant profiles, encompassing school pupils, college students, adolescents, and elite adult athletes. The two published cross-sectional and the two published intervention studies are summarized below.Zeng et al. examined the association between muscular strength and executive functions in children and adolescents in rural areas of China. In a cross-sectional study, 1,335 students aged 13–15 underwent a comprehensive battery of tests that included numerous strength measurements and executive function tasks. In summary, students with greater muscular strength exhibited shorter reaction times in executive functions and a reduced risk of developing executive dysfunction. The study results offer valuable recommendations for promoting the physical and mental well-being of children and adolescents.Fleddermann et al. investigated whether elite team sport athletes show improved motor inhibition with increased expertise. A sample of 106 elite athletes from various team sports completed the stop-signal reaction time task for hands and feet. The elite athletes with higher expertise demonstrated better motor inhibition than elite athletes of lower expertise. This effect was limited to motor inhibition of the hands. It is argued that the demands of the sport may have led to this result, as elite athletes of team sports were selected in which the use of the hands dominates.The inhibition of initiated motor actions in response to new game situations is regarded as a crucial executive function for success in team sports. Ballester-Ferrer et al. investigated the effect of acute exercise intensity on cognitive inhibition among female college students. This research examined the mechanisms underlying the cognitive response to physical exercise, considering both physiological and psychological parameters. Data analyses revealed that high-intensity interval training produced a significantly greater positive effect on inhibitory control compared to moderate continuous training and a non-exercise control condition. The improvement in inhibitory control was notably correlated with increased lactate release, indicating a connection between cognitive and physiological processes. This relationship was more pronounced in the congruent condition than in the incongruent condition of the Stroop task, suggesting that the enhanced cognitive function was primarily due to increased processing speed rather than improved cognitive inhibition. Additionally, the change in subjective vitality significantly correlated with the change in reaction time, but only in the congruent condition. These findings underscore the importance of considering physiological and psychological variables when investigating the exercise-cognition relationship.Using a within-subject repeated measures design, Heilmann et al. concentrated on the application of cognitive training for executive functions in youth academy soccer players, addressing a common debate among researchers, applied sport psychologists, and coaches. This study investigated the effects of an eight-week smartphone-based, domain-generic cognitive training intervention on executive functions using a pre-post design with intervention and control groups. The results revealed that the evaluated smartphone game “Fruit Ninja” had no significant impact on working memory, inhibition, or cognitive flexibility. These findings align with the current body of research, which suggests inconclusive evidence regarding smartphone-based cognitive games' ability to enhance executive functions. The study also raises questions about the potential benefits of sport-specific cognitive perception tasks for improving executive functions, which, in turn, could enhance performance in sports-related situations.The scientific works presented here provide significant contributions to our understanding of executive functions in sports while simultaneously prompting new research inquiries. Specifically, there is a call for in-depth exploration of the neurophysiological mechanisms underlying both acute and chronic effects to gain a clearer understanding of the specific impacts of exercise and sports on executive functions . This kn


Authors of this study aimed to develop a novel method for conducting TIC-focused PM.Trauma-Informed Care (TIC) is an evidence-based approach for improving health outcomes by providing systematic, trauma- sensitive and -responsive care. Because TIC adoption varies by setting and population, Implementation Science (IS) is particularly well-suited to guide roll-out efforts. Process Mapping (PM) is an IS model for creating shared visual depictions of systems as A real-life TIC implementation study is presented to show how TIC-focused PM was conducted in the case example of a pediatric HIV clinic in a Southern urban area with a high burden of psychological trauma among youth with HIV. A five-phase PM model was applied to evince clinic standards of care, including Preparation, planning and process identification; Data and information gathering; Map generation; Analysis; and Taking it forward. Practices and conditions from four TIC domains were assessed, including Trauma responsive services; Practices of inclusivity, safety, and wellness; Training and sustaining trauma responsiveness; and Cultural responsiveness.The TIC-focused PM method indicated the case clinic provided limited and non-systematic patient trauma screening, assessment, and interventions; limited efforts to promote professional quality of life and elicit and integrate patient experiences and preferences for care; no ongoing efforts to train and prepare workforce for trauma- sensitive or -responsive care; and no clinic-specific efforts to promote diversity, equity, and inclusion for patients and personnel.Principles and constructs of resilience-focused TIC were synthesized with a five-phase PM model to generate a baseline depiction of TIC in a pediatric HIV clinic. Results will inform the implementation of TIC in the clinic. Future champions may follow the TIC-focused PM model to guide context-tailored TIC adoption. Populations burdened by high rates of psychological trauma require more culturally sensitive health care services to promote optimum wellness. Trauma refers to lasting effects  of adverse events, such as catastrophes , personal violations , or life-threatening situations in which escape is difficult  is well-suited for guiding TIC, but IS has been infrequently applied to TIC adoption . Both ISthey are to identify rate-limiting steps of intervention adoption  is an IS tool for creating shared visual depictions of systems as adoption . ExperieA case example is provided to illustrate how to apply TIC-focused PM. Compared with the general population, persons with HIV (PWH) are exposed to disproportionately more trauma, suffer worse effects, and face unique additional trauma exposures related to diagnosis and serostatus , cumulatTIC is as an under-utilized approach with potential to attenuate the syndemic relationship between HIV and trauma. Its implementation has been connected with improvements in patient and provider trauma symptoms and health outcomes  meeting regularly with clinic site-PI [together multiple-PI (mPI)], which led to receiving verbal and written support for the project from the clinic director. The PI held a hospital-wide Grand Rounds presentation to share broadly with the institution housing the clinic about the significance, principles, and implementation domains of TIC. Plans to engage the community were presented during developmental stages, as part of an established community advisory group, which comprises researchers, practitioners, people living with HIV, and other community members. The multi-PIs held a kickoff meeting with clinic personnel to share information about the intent of the project. The PI met monthly with an NIH-assigned Implementation Science Hub with the University of Alabama at Birmingham Center for AIDS Research to discuss engagement strategies and plans for PM meetings. Finally, demographics and psychosocial characteristics, as well as appointment no-show rates and HIV outcomes of patients were reviewed by mPIs to assess outcomes and potential service areas of greatest need for change.PM discussion guides were developed from the TIP 57 to guide discussions around four OTR dimensions, including: 1) Trauma Responsive Services, probing for trauma exposure screening and effects assessments and clinical interventions; 2) Practices of Inclusivity, Safety, and Wellness, probing for efforts to promote professional quality of life and elicit patient experiences and preferences for care; 3) Training and sustaining trauma responsiveness, probing for workforce development efforts; and 4) Cultural Responsiveness, probing for efforts to promote diversity, equity, and inclusion at the clinic-level for patients and personnel.PM discussions were conducted first through face-to-face site visits and virtual workgroups. Information was recorded through note taking  and physical documentation of protocols and instruments employed. Virtual meetings additionally included audio recordings for later review. Meals and snacks were provided during face-to-face meetings to incentivize participation.Patient representatives were engaged as one group, with all being members of a community advisory group with an existing relationship working with HIV providers in the community to guide care for youth. Members of this group were recruited by study team members via verbal and electronic invitations to participate. Because each member of this group had varying familiarity with the workflow of the HIV clinic, the mPIs utilized an experiential activity to generate feedback about workflow. The group was shown a randomized list of clinic services and activities associated with initial and follow-up patient meetings and asked to prioritize the sequential steps for which they would prefer to receive care and discuss how they would like the care administered. Once preferences were identified, the group was then shown the clinic’s actual current workflow and asked to compare and contrast the two  systems as a means for eliciting how they might want services to evolve to be more patient-focused or choice-driven.who is responsible for each phase of care and what type of care is provided. See Supplemental Table 1 for a list of topics, questions, and prompts applied during groups. Follow-up groups then focused on gaining a deeper understanding of how care is provided, and providers were engaged in small service group discussions so that each discipline/service area could describe their team approach and typical workflow: this included separate meetings for Patient Registration, Clinic Nurses/ Advanced Practice Providers, physicians, social workers/psychosocial services, research assistants, and pharmacists/pharmacy technicians to specifically explore shared understandings of standards of care related to the aforementioned OTR domains.Introductory personnel meetings focused on fleshing out An initial map was created based on discussions between study mPIs. Standardized PM symbols and structures found in the literature were utilized to construct the map aesthetically .To analyze findings from PM activities, the map was iteratively refined during and immediately following each work group, to ensure changes were made based on the integration of group member feedback. This was done by reviewing thick notes from discussion meetings and organizing discussion points by the TIP 57 and OTR dimensions. Map drafts were validated or checked for accuracy with a member of each service area as well as the patient representative group.Results from PM discussions were applied to develop an overall plan for moving TIC implementation forward in the case clinic setting. Findings helped to generate a list of action items, an implementation action plan with timelines, identify individuals who might be responsible for actions, and tailor a one-on-one interview guide to further explore TIC dimensions that presented as too sensitive to be assessed in group discussion formats, including Culture of Trust and Support, Collaboration and Empowerment, and further probe into Cultural Responsiveness. Final PM findings were shared clinic-wide with personnel to generate recommendations for long-term actions  and short-term actions .A total of 47 personnel and eight patient representatives participated in PM discussion groups. About a third of participant engagement occurred in-person in December 2021. The remaining group discussions occurred virtually in 2022. The final Process Map is depicted in Clinic personnel were responsible for administering care for a patient census of ~ 250 youth with HIV. Providers included physicians, advanced practice providers , clinic nurses, support staff , mental health practitioners , outreach staff, and pharmacy technicians/pharmacists. Finally, there were research assistants and ancillary personnel working in other campus locations but engaging with patients, including security guards, environmental services, transportation administration and drivers, and patient scheduling.APPs reported being primary medical care providers for patients, with physicians conducting twice-weekly rounds and leading clinical staffing discussions in oversight of medical care provided by APPs. Clinic nurses coordinate patient medical care, take histories via health screening assessments and referrals, gather labs, administer medications, and facilitate clinic flow. Medical assistants prepare medical rooms, prepare medical rooms for patients, collect specimens, and take vitals. Patient care representatives register/check-in patients to prepare for visits. Community outreach staff meet patients upon initial diagnosis and link them to clinical care.All patients were connected with a clinical social worker who provided case management and psychosocial support, including bi-annual psychosocial assessments  and annual Adverse Childhood Experience (ACE) questionnaire screeners . Those eThe psychologist was the only mental health provider practicing a trauma-specific patient treatment modality. However, social workers expressed enthusiastic support for TIC implementation and prior interest in/involvement with it. One had certification in trauma intervention and others had training in trauma-sensitive approaches.When asked about current systems for eliciting/integrating patient and personnel feedback, a hospital-wide satisfaction survey for patients was described but personnel were unsure how the data were utilized or shared. Similarly, hospital-wide employee satisfaction surveys were conducted and shared at larger department-levels, but there were no current practices to elicit clinic personnel satisfaction. Some clinic processes had been amended in response to informal patient verbal feedback , but systematic patient feedback was not routinely gathered or integrated into clinic processes. Personnel and patient representatives suggested the need for clinic administrators to regularly solicit patient feedback  and use it to guide programming. Numerous areas in which patients have authority over their own care were identified, including request for/engagement in psychosocial services, medical care engagement, administration of sexually transmitted infection swabs , vaccine uptake, and ART initiation. Regarding workforce development, numerous security guards and nursing administrators were trained every 1.5 years in Crisis Prevention and Intervention to assist when/if a patient becomes escalated behaviorally. When asked about culturally responsive policies and procedures, personnel reported not currently having clinic-specific policies but that the larger hospital system did have some things in place, including basic annual education about legal protections against discrimination, other bias awareness trainings, and opportunities to participate in group discussions and book clubs on cultural topics.Patients are seen for routine care every three months to meet with medical providers, get labs drawn, and sometimes receive psychosocial support or engage in clinical research with research staff. Community outreach staff work with new patients to explore potential barriers to care by utilizing Motivational Interviewing   to provide education/de-stigmatize HIV. This outreach occurs in medical clinics, patient homes, other public places, or local HIV service organizations.Annual ACE questionnaires are administered within six months of patients initiating care, often during the second visit. This timeframe was set so sensitive questions would be asked after rapport had been built and psychoeducation provided on childhood adversity . Personnel reported questionnaires were inconsistently conducted—due to limited staff resources and patient and personnel discomfort with the questionnaire items—and no identified structured protocols for how repeated screenings are conducted or systematic methods for sharing information with clinic personnel. Multiple providers, spanning different service categories, reported conducting informal risk assessments of new patients during initial engagement. These topics included verbal questions about current domestic violence risk and/or suicidal or homicidal ideation. Responses were documented in the patient’s medical record. Several personnel, spanning different positions, discussed spending lengthy session times with patients during the first and second appointments to obtain patient history as part of formal and informal psychosocial assessments. Advanced practice providers and physicians identified the need to have improved ease of access to patient responses about trauma exposures, mental health needs, and social determinants of health.Providers reported engaging in professional development independently, without any clinic-level group trainings being offered specific to TIC and state that leaders would have to elevate this need to ensure clinic-wide training was feasible . Personnel from several positions expressed desire for the social workers’ roles to be expanded beyond primarily case management, into provision of more clinical/therapeutic modalities. A noted benefit to this was that this expansion would be supported as a reimbursable service, which could increase the clinic’s ability to provide greater mental health support.Initiatives to promote professional quality of life were limited and relied on institution-wide efforts such as tangible treats from a care cart . Personnel reported appreciating this service but found it alone to be insufficient, occurring infrequently, and not specific to the clinic. Staff burnout and high levels of attrition and turnover were common topics, as was the need for more self-care training and institutional- and clinic-level initiatives to prevent burnout.The patient representative group generated three recommendations regarding how the clinic might consider integrating patient-centered care, including offering patients a menu of options for the order of services received during first visits , limiting the number of providers patients encounter in the first visit, and including a navigator or ambassador to remain with the patient on the first visit to escort them across campus through each appointment during the day.A systematic method for conducting TIC-focused PM has been presented and includes a synthesis of a five-phase PM model, the TIP 57, and OTR dimensions. Findings from the case clinic are summarized below with comparisons drawn with literature to contextualize findings. Recommendations are provided in-text and summarized in needed . Strengths of the ACE questionnaire include its parsimony and ability to help identify adversity among youth predictive of future comorbidities , so that young patients may be connected with mental health care instrumental in disrupting the formation of comorbidities  provided as bidities . Limitatbidities , an uninPractices in the case clinic appear to generally follow federal governing body recommendations; both SAMHSA and Health Resources and Services Administration (HRSA) make recommendations for HIV care to include universal mental health screening  approaches are recommended, as conducted by non-clinical staff . The SBIRT approach enables trauma identification and referral to treatment while freeing up clinicians to work at the top of their license to administer complex assessments and interventions upon referral. However, this case clinic could reduce duplicative screeners around suicide risk, as excessive discussions around sensitive subjects can be trauma-activating. Second, mental health and trauma assessments should be administered following trauma screeners , with trIn the case clinic, the social workers are well poised to provide trauma treatment in conjunction with the psychologist and psychiatrist. Overreliance on social workers for case management services can hinder the expansion of mental health services . Numerous interventions have been tested with adults with HIV  and coulIn the case clinic, limited efforts were identified as having been intentionally designed to elicit/integrate personnel or patient experiences or promote professional quality of life. According to a recent HIV Service Organization (HSO) study, 55% of HSOs in the South have mechanisms for engaging clients as organizational decision-makers, though it is unclear what / how systematic those mechanisms are, and if results are integrated system-wide . ServiceObserved clinic findings for trauma training  are consistent with the literature. A recent study shows only 44% of sampled community-based HIV organizations provide TIC training (frequency or regularity not specified). Importantly, those having received training were ten times more likely to have implemented TIC , and finA significant component of implementing and sustaining a trauma-resilient workforce is conducting evaluation to guide continuous quality improvement. At the patient-level, interventions focus on changing health outcomes and patient perception of care, with a recommended instrument, the Organizational Trauma Resilience – Patient Reported Experience Measure (OTR-PREM), for measuring the extent to which patients find the organization to be safe, stable, and nurturing . At the provider-level, interventions largely focus on changing personnel knowledge, attitudes, practices, and professional quality of life, with recommended instruments including Attitudes Related to TIC (ARTIC), TICOmeter (practices affecting patients) and Professional Quality of Life (Pro-QOL) scale  . InterveThe current case example indicated no specific clinic-based cultural responsiveness efforts were identified, despite racial minorities accounting for 97% of the clinic patient population. These findings are consistent with the literature showing racial trauma is often overlooked during trauma screenings and assessments , in inteThere are several notable limitations to methods applied during PM discussions. Initial discussions were conducted as mixed groups  that potentially did not reap the most reliable results; discussions rarely brought attention to challenges or perceived problems, which could be attributed to a perceived fear of leadership reprisal. However, during the second phase of discussions, groups were intentionally conducted by job role to better promote safe dialogue spaces. Future TIC-focused PM should organize groups intentionally to reduce power dynamics that may impede transparent discussions. Because of these group discussion limitations, certain topics requiring more confidential settings—including the OTR dimensions of Culture of Trust and Support and Collaboration and Empowerment—were not explored as part of the current work. Therefore, there may be salient processes that could influence TIC adoption that were not uncovered during PM activities. Hence, process maps should be followed with one-on-one interview, with findings synthesized with PM results. Finally, case study findings only apply to the participating clinic, but the TIC PM methods are hypothesized to be generally applicable for use in other Ryan White-funded clinics in the Southeast U.S.who, what, and how of clinic workflow and validate findings through member checking. Findings enumerate systematic methods for conducting TIC-focused PM in healthcare settings and mark an expansion of the TIC knowledge base. Recommendations for TIC adoption via implementation science have been provided and may be of use for large numbers of clinics. Recommendations focus attention on multiple levels throughout the clinic, underscoring actions that may be taken to enhance patient and personnel experiences, filling a particular gap in knowledge relative to youth-focused trauma-informed HIV care. Overall, findings have the potential to meaningfully inform future TIC implementation.Findings present a systematic method for conducting TIC-focused PM and provide an illustration of how the method was applied within a clinic serving youth with HIV, who are disproportionately affected by trauma. Personnel and patient representatives of the pediatric HIV clinic were engaged for group discussions, following a five-phase approach, meeting ten quality metrics, to explore the


Spontaneous coronary artery dissection (SCAD) primarily affects women younger than age 50 years, is often misdiagnosed or undiagnosed, and research on this topic is limited.A literature review was conducted to identify unique factors that can facilitate pregnancy-related SCAD (P-SCAD) diagnosis as well as differentiate it from nonpregnancy-related SCAD (NP-SCAD).spontaneous coronary artery dissection, misdiagnosis, and women, along with postpartum and pregnancy. The Let Evidence Guide Every New Decision quality assessment tool was applied to all reviews.A literature search was conducted on PubMed, Medline, Embase, The Cochrane Database of Systematic Reviews, and Google Scholar databases that focused on NP-SCAD and P-SCAD cases reported in North America between 2006 and 2021 using the terms A total of 108 journal articles reporting on individual cases, case series examining independent SCAD registries, as well as literature reviews were identified. These included 1547 SCAD cases in women, 510 of which were identified as P-SCAD. SCAD occurs predominantly in women, and thus presents a diagnostic challenge because women are not typically considered at risk for developing cardiovascular diseases and may present with symptoms that mimic other medical conditions. This issue is further exacerbated when SCAD develops during pregnancy or the postpartum period  because P-SCAD patients often present with less typical cardiac symptoms yet tend to experience more severe illness that can jeopardize their health and that of their baby. P-SCAD was associated with higher ST-segment elevation myocardial infarction rates, higher troponin levels, and a greater risk of cardiogenic shock compared with NP-SCAD cohorts. It was also evident that the failure rates associated with invasive procedures such as percutaneous coronary intervention and coronary artery bypass graft surgery were higher in P-SCAD patients, whereas the mortality rates are comparable to NP-SCAD cohorts if diagnosed and treated appropriately.Curr Ther Res Clin Exp. 2023; 84:XXX–XXX)Because younger women are rarely screened, they are at greater risk from SCAD, especially if this condition develops during pregnancy or ≤30 days following delivery. It is essential that medical professionals providing care for pregnant women understand P-SCAD risk factors and provide medical counseling for pregnant women or those planning a pregnancy to be better equipped to recognize its more subtle signs and symptoms, thus facilitating timely specialist referral, diagnosis, and treatment. ( Its further aim is to assess the effectiveness of different treatments and the likelihood of SCAD recurrence after pregnancy.spontaneous coronary artery dissection, spontaneous coronary artery dissection and pregnancy, misdiagnosis, and women along with postpartum and pregnancy.The literature included in this review was obtained by searching PubMed, Medline, Embase, The Cochrane Database of Systematic Reviews, and Google Scholar online databases using the terms Precedence was given to articles describing NP-SCAD and/or P-SCAD cases reported in North America between 2006 and 2021, literature reviews, and case series examining independent SCAD registries. P-SCAD was based on SCAD occurring during pregnancy, up to 12 weeks thereafter, unless a longer period was otherwise noted. Portions of reviews which contained male and female patients with SCAD were excluded if symptoms and treatment data was not differentiated between men and women. Individual case series included in literature reviews were excluded to avoid double counting of results, as were restatements of prior studies that contained duplicative results.As a result of this strategy, 108 articles, literature reviews, and case series referencing the search terms were reviewed.Descriptive statistics were summarized as mean (SD), median (interquartile range), or counts and percentages.For the SCAD cases identified, data were sorted by women and further sorted by P-SCAD cases, which were reviewed to establish the main symptoms, treatments, and outcomes. The results shown reflect the data identified in the review only and may not include all cases of P-SCAD occurring during the period. The author reviewed, collected, and collated the data.For all identified cases, the patient's age, family history, and traditional cardiac risk factors , as well as history of hyperlipidemia were gathered, along with pregnancy-related data if applicable/available, including preeclampsia, use of oral contraceptives, hormone therapy, time of SCAD occurrence during and after pregnancy, prior pregnancies, and SCAD recurrence. Timing of pregnancy, miscarriage, or postpartum status, and associated pathologies such as fibromuscular dysplasia (FMD), systemic inflammatory disease, and connective tissue disorder, as well as presence of chest pain, troponin levels, and emotional and physical stressors, were also recorded if reported by the original investigators.A total of 108 articles were identified from all search engines, of which 6 were duplicates. After exclusion of 48 articles and 6 duplicates, 54 articles were reviewed, including 13 case series and 6 case reports. This totalled 1547 female SCAD patients, of whom 510 were P-SCAD patients.Before commencing the review, the data pertaining to 1547 female SCAD patients identified in extant literature was examined to segregate P-SCAD patients (n = 510) from NP-SCAD patients (n = 1037) to compare and contrast the findings with the aim of aiding timely diagnosis and treatment. With the exception of 1 article reporting on a prospective studyAs can be seen from ,,,,The findings pertaining to SCAD onset are reported in Table 3As can be seen from When P-SCAD and NP-SCAD cases were compared with respect to known stress factors that can precipitate SCAD , it was There was no specific alternative diagnosis strategy described in P-SCAD. No meaningful separate data on P-SCAD diagnostic methods was reported. Diagnostic methods used to identify SCAD were reported as follows: angiography on initial diagnosis (n = 670) was reported in 495 cases (73.9%), optical coherence tomography (n = 670) in 41 cases (6.1%), and intravascular ultrasound (n = 670) in 18 cases (2.7%).As can be seen from Treatment involving conservative approach also differs considerably depending on whether SCAD occurs during pregnancy or postpartum, or at another time in a woman's life, as indicated in Tweet et al'sExpanding the 2017 study in 2020, Tweet et al,14,Given the potentially devastating consequences of SCAD, especially during pregnancy, its recurrence was also investigated,,Beyond the Tweet et al,,,Because SCAD affects young women not otherwise presenting with traditional cardiovascular disease risk factors, it has recently gained considerable attention among researchers and practitioners. Available evidence indicates that women account for 87% to 95% of all recorded SCAD cases,,22SCAD during pregnancy can pose a significant risk, putting about 1.8% of every 100,000 pregnant women in the United States in danger.To assist with this process, Sharma et al,,,,These assertions are supported by the findings yielded by a number of SCAD/pregnancy-focused studies, including Saw et al's,, Saw et alAvailable evidence further indicates that pregnancy-related physiological changes present risk factors for SCAD.As was demonstrated earlier, troponin is elevated in all women who are ultimately diagnosed with SCAD, but much higher levels are noted in P-SCAD patients.,,,,,P-SCAD patients are also more likely to present with ST-elevation MI than non-ST-elevation MI patients and their ST values tend to be higher than in NP-SCAD cases.Because P-SCAD most frequently occurs during the last semester and the first week following delivery,,,,,,In the 2017 Mayo Clinic SCAD registry study, Tweet et al,,,,,Associated pathologies such as FMD, systemic inflammatory disease, and connective tissue disorder are commonly present in SCAD patients,,,,,Although the available data point to a significant variance in the presence of FMD between P-SCAD and NP-SCAD cases,,,,Because FMD affects the artery walls, causing them to lose flexibility and become weak,Although some SCAD patients have inheritable connective tissue disorders such as Marian syndrome, Ehlers-Danlos, and Loeys-Dietz,In a 2019 study, Saw et al,,Because pregnancy, emotional stress, and physical stress are known stressors for SCAD, they are expected to exacerbate P-SCAD. Extant findings counter this assumption because they are mostly based on self-reports by women and their reliability is questionable.,,,,Given that SCAD is a multifactorial disease, several diagnostic methods and data evaluation strategies should be utilized to ensure accurate diagnosis. Angiography is considered the gold standardBecause high progesterone levels during pregnancy and hormonal changes immediately upon delivery have been shown to contribute to P-SCAD emergence, additional care is required when treating women that have a history of multiple births and preeclampsia.,,,,,,More research is needed to discover potential triggers during pregnancy, which is also supported by Tweet et al,,Elevated progesterone levels during pregnancy could weaken the normal elasticity of arterial walls,,,,Pregnancy causes increased cardiac output and a higher level of blood volume in the circulatory system. This, together with the effects of hormone changes during pregnancy, increase the risk of SCAD in pregnant women due to the greater stress on already weakened arteries.,,,Because SCAD is not specifically limited to premenopausal women,,,,,,,The fact that P-SCAD most commonly occurs in later stages of pregnancy and in the immediate postpartum period is attributed to the rapid hormonal changes during and after birth,,,,,,,,Conservative, noninvasive SCAD treatment approach is recommended for stable patients with good blood flow.,,PCI is recommended only if there is poor coronary flow, persistent chest pain, or persistent ST elevation, and in case of hemodynamic instability. Although it is deemed appropriate by some authors in cases of acute SCAD,,Havakuk et al,,,,,,,,Generally, pharmacologic treatment for SCAD is an extension of conservative treatment and is typically based on medical treatment protocols similar to those adopted for ACS patients.,,SCAD recurrence is defined as a subsequent de novo SCAD in a different location within 12 monthsThis study is based on available data reported in articles, literature reviews, and case series pertaining to the occurrence of SCAD in women, particularly P-SCAD in North America during 2006 to 2021. The study is limited by its design and data collected mostly from single case reports and smaller case series. Because this was not a meta-analysis systematic review, the results shown reflect the data identified in the reviews only and may not include all cases of P-SCAD and NP-SCAD occurring during the time frame studied. The data could reflect a selection bias for submission and publishing complicated cases. Some studies did not differentiate between P-SCAD and NP-SCAD for all predisposing conditions and associated pathologies, so that data were excluded from the analysis of those conditions to prevent bias for those conditions. Certain data from large studies using SCAD registries may result in bias due to the voluntary nature of the patient data collection at the registry itself. Finally, the small number of patients with SCAD recurrence after pregnancy or P-SCAD made it challenging to definitively identify significant differences in recurrence of SCAD between P-SCAD and NP-SCAD cases.Because SCAD primarily affects women often not presenting with typical symptoms of cardiovascular diseases during late pregnancy or postpartum, pregnant women and those planning pregnancy need to be carefully screened for any predisposing factors and physical complaints to facilitate timely diagnosis, using angiography along with blood tests to check Troponin levels. Counseling should be conducted using a multidisciplinary approach involving cardiology and obstetrics specialists. Moreover, primary care providers and emergency medicine physicians should be made aware of the main SCAD risk factors to facilitate more timely referrals when needed.The author has indicated that she has no conflicts of interest regarding the content of this article.


Diagnostic and prognostic assessment of patients with disorders of consciousness (DoC) presents ethical and clinical implications as they may affect the course of medical treatment and the decision to withdraw life-sustaining therapy. There has been increasing research in this field to lower misdiagnosis rates by developing standardized and consensual tools to detect consciousness. In this article, we summarize recent evidence regarding behavioral signs that are not yet included in the current clinical guidelines but could detect consciousness. The new potential behavioral signs of consciousness described here are as follows: resistance to eye opening, spontaneous eye blink rate, auditory localization, habituation of auditory startle reflex, olfactory sniffing, efficacy of swallowing/oral feeding, leg crossing, facial expressions to noxious stimulation, and subtle motor behaviors. All of these signs show promising results in discriminating patients' level of consciousness. Multimodal studies with large sample sizes in different centers are needed to further evaluate whether these behaviors reliably indicate the presence of consciousness. Future translation of these research findings into clinical practice has potential to improve the accuracy of diagnosis and prognostication for patients with DoC. Advances in medical knowledge and technologies have made it possible for many patients who had traumatic or nontraumatic severe brain injuries to survive, and, consequently, transition into or remain in what are now referred to as disorders of consciousness (DoC). Over one million people are affected by DoC each year worldwide.DoC are categorized on a spectrum of diagnostic entities, ranging from the most severe state, coma, to vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state minus (MCS − ), minimally conscious state plus (MCS + ), and emergence from MCS (eMCS). The acute period of DoC is defined as the first 28 days after the brain injury, and subacute-to-chronic (or “prolonged” DoC) as longer than 28 days.Accurate diagnosis of DoC patients is highly challenging. Indeed, over one-third of DoC patients previously diagnosed with VS/UWS by clinical consensus  had evidence of consciousness when they were later evaluated based on standardized behavioral assessments using the Coma Recovery Scale-Revised (CRS-R).Currently available standardized behavioral scales to assess patients with DoC include, among others, the Glasgow Coma Scale (GCS),The CRS-R consists of 23 items composed of six subscales assessing auditory, visual, motor, oromotor/verbal functions, communication, and arousal. Among these items, 11 indicate an MCS diagnosis (six for MCS− and five for MCS + ). From these items, visual pursuit, reproducible command-following, and automatic motor response  were found to be the first three most common signs of MCS to reemerge after brain injury.In addition to the already available items that denote MCS in the CRS-R, recent studies suggest that other behaviors may be considered as signs of consciousness in DoC patients. The objective of this article is to summarize and review these new behavioral findings: resistance to eye opening, spontaneous eye blink rate, auditory localization, habituation of auditory startle reflex, olfactory sniffing, swallowing/oral feeding, facial expressions to noxious stimulation, subtle motor behavior assessed by Motor Behavioral Tool-revised (MBT-r), and leg crossing .Resistance to eye opening, a firm closure of already closed eyelids when an examiner touches or tries to open the eyes, is evident in multiple neurological disorders.Furthermore, atypical neuroimaging findings (brain activity consistent with MCS diagnosis) were more likely to be seen in VS/UWS patients with resistance to eye opening (83%) than without (29%). Indeed, five out of six patients diagnosed with VS/UWS and with resistance to eye opening had neuroimaging results more compatible with MCS. Four showed relatively preserved PET metabolism in the frontoparietal network (similar to MCS patients), and one showed response to command during a motor imagery task assessed with fMRI, suggesting that these patients were MCS*/CMD.Several research teams have shown that eye blink rate is modulated by fatigue, vigilance, task demand, and cognitive load.In the CRS-R, spatial localization in visual and motor domains  is considered signs of MCS, whereas in the auditory subscale this is not the case, and localization to auditory stimulus is considered a reflex. In the CRS-R, auditory localization is evaluated by presenting auditory stimuli  behind the patient, out of view, for 5 seconds twice on each side (right and left). When there is a clear head or eye movement toward the auditory stimuli on both trials in at least one direction within 10 seconds of stimulus presentation, the patient is considered to have auditory localization.In the auditory subscale of the CRS-R, auditory startle reflex is the lowest score item above zero (no response). To test its validity as a sign of MCS, habituation of auditory startle reflex was examined in 98 patients with prolonged DoC (TBI and non-TBI).The sense of smell in DoC patients has been scarcely studied; yet, accumulating findings suggest a link between olfactory abilities and the level of consciousness. A pilot study in 11 DoC patients (nine VS/UWS and two MCS) examined olfactory discrimination abilities based on patients' behavior.A recent study investigated olfactory sniffing in 43 patients with chronic DoC (TBI and non-TBI).A more recent study evaluated DoC patients' behavioral responses to different olfactory stimuli, with a more qualitative approach compared with the aforementioned olfactory sniffing studies.Altogether, these findings suggest that olfactory stimuli are valuable additions to the current assessment protocols and that olfactory sniff response is a powerful and easily accessible tool which can be used in the assessment, diagnosis, and prognosis of DoC patients, further decreasing misdiagnosis rates.Previous neuropathological studies suggest that a correlation may exist between the level of consciousness and swallowing function.A more recent study collected information regarding respiratory status, nutritional status, and otolaryngological swallowing examination from 92 patients with prolonged DoC (TBI and non-TBI).Pain assessment and management in DoC patients have long been an important ethical issue, since these patients cannot communicate their needs explicitly. Whether the level of responsiveness to painful stimuli could reflect the level of consciousness was investigated in a study enrolling 85 acute and prolonged DoC patients (TBI and non-TBI).Another study including 147 brain-injured patients (TBI and non-TBI) assessed behaviors related to standard ICU care procedures (nociceptive and non-nociceptive) in patients with different levels of consciousness.The Motor Behavioral Tool-revised (MBT-r)This tool was also used in a study of 140 patients (TBI and non-TBI), where the patients were grouped into DoC , non-DoC (patients who were able to interact adequately), and potential clinical CMD .Crossing legs is considered an automatic motor response in the CRS-R, one of the eleven signs that denotes MCS − . In one study, 34 patients with severe stroke who crossed their legs during their hospitalization (“crossers”) were matched with 34 severe stroke patients who did not cross their legs (“non-crossers”).In this review, we summarized recent findings regarding newly proposed behaviors denoting consciousness in patients with DoC, which could help improve the accuracy of detecting and predicting recovery of consciousness. A summary of the findings is presented inBeyond repeated assessments with CRS-R, we encourage the use of additional standardized tools in patients with DoC to test specific functions, such as the MBT-r or the SWADOC  with five patients with chronic anoxic MCS in whom the only sign of consciousness was visual fixation, no significant difference was found in cortical metabolism or cortico-cortical connectivity between the two groups.Recent studies, beyond the scope of this article, suggest that electrophysiological findings,Regarding the diagnosis of DoC patients, some of the recommendations by the 2020 European Academy of Neurology guidelineThe diagnostic assessment of DoC patients is associated with major clinical and ethical implications. Feasible solutions to improve diagnostic accuracy are urgently needed in clinical practice, which should be addressed in a multidisciplinary approach. Further formal validation studies for the proposed new behavioral signs of consciousness summarized in this article are needed for implementation in clinical practice, although we acknowledge the challenge of lacking a gold standard reference for consciousness. Currently, very few specialized centers perform an up-to-date multimodal assessment of these patients. As a result, there is a distinct gap between scientific research and clinical practice. We encourage ICU and rehabilitation healthcare workers to collaborate with translational research teams worldwide and adopt a multidisciplinary approach in their assessment of patients with DoC, which may help bridge the gap between research and clinical practice in this field.