Experiencing discrimination can have detrimental effects on psychological well-being. For older adults in the U.S., discrimination on the basis of country of origin may be a particularly alienating experience. A positive social environment, however, has been shown to buffer associations between discrimination and poorer psychological well-being. However, this hypothesis has not been tested in a sample of older Americans who perceive discrimination because of country of origin. As the United States continues to diversify and politically polarize, understanding older adults’ experiences with discrimination and identifying potential buffers to these negative effects is increasingly important. We analyze 942 older Americans (aged 50+) from the Psychosocial Module of the most recent wave of the Health and Retirement Study . Specifically, we analyze associations between perceived discrimination on the basis of country of origin and three psychological well-being outcomes: loneliness, anxiety, and life satisfaction. We further test if the social environment buffers negative effects by examining interactions between discrimination and social support as well as discrimination and neighborhood environment. Our results reveal clear and consistent associations between older adults’ perceived discrimination and increased loneliness and decreased life satisfaction. These negative associations, however, appear to be buffered by social support and positive neighborhood environment, respectively. The potential buffering effect of positive social environments on psychological well-being is particularly pronounced for older adults under the age of 65. We discuss these findings in light of the prevalence of discrimination in the U.S. and consider potential mechanisms for improving the social environment of older adults.


Umbilical cord infection contributes significantly to neonatal mortality rate in sub-Saharan Africa. Studies have shown low knowledge of chlorhexidine (CHX) gel for umbilical cord management amongst mothers in low-resource settings, including Nigeria.The objective of this study was to assess the effectiveness of a supportive-educative nursing intervention programme on knowledge of CHX gel amongst mothers in Cross River State, Nigeria.p < 0.05.A quasi-experimental study design was used, and study participants comprised 168 expectant mothers, who were purposely selected and assigned to randomised control and intervention groups. The instrument for data collection was a researcher-developed structured questionnaire. The data were analysed using Statistical Package for Social Sciences version 23 for descriptive and inferential statistics at significant level was set at t 77 = 24.394; p < 0.05). The result showed no significant difference between mothers’ demographic variables and knowledge of CHX gel.The result showed that at post-test the knowledge score of mothers on CHX gel improved significantly in the intervention group (A supportive-educative nursing intervention programme could effectively improve knowledge of CHX gel for umbilical cord management amongst mothers. This underscores the need to improve mothers’ knowledge of CHX gel by healthcare personnel. The bacteriostatic and bactericidal actions of CHX gel quickly destroy the cell walls of microbes and interfere with osmosis, thereby causing cell death.5 Various studies have identified factors that influence compliance. Evidence shows that there have been challenges adjusting to WHO guidelines on cord care in community settings as a result of poor socio-economic and sociocultural factors that are deeply rooted in complex traditional practices.13 These traditional complexities further limit women’s knowledge of standard cord care practices. Most women significantly rely on the mentorship of their grandmothers, mothers and other family members or relatives for care during pregnancy and after delivery (care of neonates).3Achievement of compliance to the standard cord practice is far from optimal, which accounts for 40% of all deaths in children younger than 5 years annually.13 The level of neonatal infection is of growing concern. The high neonatal mortality rate may indicate a lack of knowledge, informing a need for focused education regarding CHX gel for cord management. Dhingra et al.14 reported that education of mothers on CHX at the community level showed appreciable knowledge and increased acceptance of CHX amongst mothers. Although a few studies have identified parity and lower educational status of women as major predictors of poor knowledge of CHX gel,7 empirical evidence on the effect of educational intervention on knowledge amongst mothers is limited in Cross River State. Thus, the purpose of this study was to determine if a supportive-educative nursing intervention programme would improve knowledge of CHX gel for cord management amongst mothers in Cross River State.Studies suggest that home birth and application of harmful substances are common in low-income countries with elevated risk for cord infection.9 The second stage involved the random selection  of two functional PHCs (those with delivery facilities) from each of the seven local government areas in the senatorial district, giving a total of 14 PHCs. There were a total of 19 functional primary health facilities at the time of the study. In the third stage, cluster randomisation was employed in the selection of health centres for the intervention and control groups using simple balloting (coin toss). This was done to avoid or minimise the rate of contamination and bias as done in similar studies, although the outcome is usually measured at individual level. From this exercise, seven PHCs were selected as the intervention group , whilst the other seven PHCs served as the control group .A quasi-experimental before and after study design was adopted for the study. A multistage sampling technique was employed to recruit 168 expectant mothers in their third trimester attending prenatal care from selected primary health centres (PHCs) in Cross River State. The selection was conducted in four stages. The first stage was at the state level; Cross River State has three senatorial districts – North, Central and Southern senatorial districts. Out of these three, Southern Senatorial District was purposely selected because of its high neonatal mortality (45.2%) related to umbilical cord infection.9 Twelve participants were selected from each of the facilities. The study was conducted at selected facilities considered for the study.Lastly, the fourth stage involved the selection of participants into the study using a purposive sampling technique with inclusion criteria and informed consent, as has been employed by some authors to conduct related studies.Cluster randomisation was employed in the selection of PHCs for the intervention and control groups using simple balloting (coin toss). Participants were observed before and after implementation of an intervention. The inclusion criteria included expectant mothers in the third trimester, who gave consent, were willing to deliver the baby within the study area and whose baby was born with no congenital abnormalities.The study was conducted in three phases, the pretest, intervention and post-test phases. Ethical approval to conduct the study was given by the Cross River State Ethics Research Committee, Ministry of Health. Six research assistants were trained by the principal investigator on data collection techniques. Written consent was also obtained from the participants and parents of babies who were used for the study.The researcher explained the study to the participants. The participants in both the intervention and control groups had the routine prenatal health talk in the clinic and thereafter were assessed to get the baseline data (pretest) using a researcher–developed structured questionnaire, which was validated by three experts in child health. It was a three-part self-administered questionnaire requesting information on demographics and knowledge of CHX gel amongst mothers. The questionnaire was designed by the researcher and pretested amongst 20 expectant mothers who were not in the study to ascertain its reliability and validity. A computed Cronbach’s alpha coefficient of 0.79 was reported for the questionnaire.5 There was an exchange of mobile phone numbers with the participants. Each of the participants received a home visit before delivery to offer support and encouragement. The delivery dates were retrieved from the prenatal records with the help of the nurse manager.Other research instruments included the intervention tool CHX gel, an educational plan, posters, a pamphlet and guidelines for home visits. The CHX gel educational plan was developed by the researcher with reference to WHO clinical guidelines on CHX gel. The educational package was divided into two sessions, which were mainly for the intervention, each lasting for 60 min.This was conducted in two sessions.This session involved the introduction of CHX gel to the participants during the prenatal visits. Information was given on the usefulness of CHX gel in umbilical cord care. The participants were also educated on when to commence CHX gel, method of application, frequency and duration of application. Posters and samples of CHX gel were used during the sessions. There was also question and answer session.This session was specifically conducted to demonstrate how to apply CHX gel shortly after severing the umbilical cord. Application of the gel was done after thorough washing of hands. Doll models were used in the demonstration. Each of the mothers took a turn to demonstrate. The duration for application of CHX gel should be 7–10 days. Pamphlets were given to the participants. The session was held at the selected health facilities considered for the study.This phase took place in each participant’s house 10 days post-delivery. Each participant was visited on separate days depending on the delivery date. An assessment was conducted on their knowledge of CHX gel. Post-test data were collected using the coded questionnaire developed by the researcher for this study. The control group had no intervention, and post-test data were collected 10 days after delivery in each participant’s home based on the date of delivery. The study lasted for 12 months, May 2017 through April 2018, whilst the actual data collection lasted for 6 months.t-test was used to compare respondents’ assessment scores on their knowledge of CHX gel at the pretest and post-test stages for both the intervention and control groups. The significance level was set at p < 0.05.The study adopted both descriptive and inferential statistics in the analysis of the data generated from the study. Descriptive statistics, which included mean scores, percentages and frequency tables, were used to summarise the participants’ demographic variables as well as their knowledge of CHX gel. The study also employed Chi-square test to establish if there was a significant association between the participants’ demographic variables and their assessed knowledge of CHX gel at the pretest phase. Lastly, in order to establish a supportive-educative nursing intervention programme on knowledge of CHX gel, a paired-sample The Institution Review Board at the Cross River State Ethics Research Committee, Ministry of Health, approved the study protocol. All study participants signed a consent form prior to participation.A summary of the control group respondents’ knowledge is presented in A summary of respondents’ knowledge in the intervention group is presented in p < 0.05. This implies that the supportive-educative nursing intervention programme was effective to upgrade the knowledge of mothers.16 This principally implies that access to correct and factual information on CHX gel could significantly influence standard and safe cord care practices. This is evident in a study conducted in Ibadan, Nigeria, where women who had access to umbilical cord care (UCC) information exhibited good practices compared with their counterparts with limit access to information on UCC.15The quality of care that newborns receive in the minutes after birth has a lot of influence on its survival and development. Chlorhexidine gel has been recommended by the WHO for cord management in low- and middle-income countries. However, it has been observed that there is substantial lack of empirical evidence concerning knowledge about CHX gel amongst expectant mothers in Cross River State, Nigeria. To address this gap, the researchers developed and evaluated a supportive-educative nursing intervention programme on knowledge of CHX gel amongst mothers. The effect of the supportive-educative nursing intervention programme was evaluated by comparing the mean knowledge scores between the intervention and control groups before and after the intervention. The findings, as observed in 17 It was observed that there was a significant difference in the mean knowledge scores between the intervention and control groups. The supportive-educative nursing intervention programme was effective at upgrading the knowledge of mothers. This indicates that giving sufficient information regarding CHX gel usage for cord management to mothers will improve their knowledge and overall neonatal care.The study further showed that there was a significant difference in knowledge scores at post-test between the intervention and control groups. This was in accordance with a study that reported a very good level of knowledge and a high mean post-test knowledge score among postnatal women after an intervention.18 This was expected, given that this was a community-based study where their behaviour was principally influenced by cultural practices and norms. Moreover, the demographic variables of the participants between the intervention and control groups were within the same range.The study also showed in This study showed that a well-tailored supportive - educative nursing intervention programme is significantly effective in improving expectant mothers’ knowledge of CHX gel for umbilical cord management. This can be internalised during prenatal visits. Further research should be conducted to identify possible predictors of cord care practices amongst expectant mothers.


Origami, the Japanese art of paper folding, has taken on new meaning for the fields of chemistry and biology. DNA origami describes the folding of DNA strands to form nanoscale structures. The ability to design and form complex structures at a nanoscale level has fuelled new ambitions of nanostructure applications in life science. These predefined shapes become base structures for the development of a higher and complex functional structure. In a recent paper, Stömmer et al., demonstrated the ability to design a macromolecular level transportation network that allows the movement of molecules at sub-molecular levels using DNA. A multi-layer DNA origami was used to build micrometer-long hollow tunnels akin to railway tunnels. An accompanying DNA piston travelled through the tunnels with constant motion. The system also accommodated the application of electric fields to fuel the motion of the pistons along the filaments simulating a nanoscale electric railway system. This could revolutionize the way molecular drug delivery systems can be perceived in the future. The double helix DNA structure allows DNA origami designers to develop complex constructs using strands of DNA. The developments in DNA origami technology have seen DNA nanostructures being used initially for the construction of 1-dimensional structures to now more complex, higher order structures. These nanostructures have been applied to many applications including studying enzyme-substrate interactions, molecular motor actions, drug delivery, fluorescence and nanorobotics.Stömmer et al. described the design of a hollow filament structure using multi-layer DNA origami to propel a molecular piston1. The authors applied a DNA-based, programmable self-assembly system that replicates the intrinsic properties of molecular transporters in nature. This system includes multiple-micrometer-long travel ranges with μm/s displacement speeds and is an evolution of other known artificial molecular devices and machines like pivots, hinges, crank sliders, pliers and rotors. The authors observed the piston motions within the filaments using single-molecule fluorescence microscopy and performed a dynamics simulation to determine the free energy surface that fuels the movement of the pistons. They reported that the diffusive and displacement ranges of this new system were within the ranges of natural molecular motors but with five orders of magnitude of improvement over existing artificial random walker designs. The system also showed adaptability in different environments and stimuli, and the work also showcased the possibility of applying electric fields to fuel the linear motion of the DNA piston over a long range along molecular tracks at high speeds.Recently, The published system is a marked improvement over traditional propulsion mechanisms used in DNA origami structures. The authors were able to stretch the boundaries of distance and speed with this new design thus broadening the realm of possible applications of this technology.


Case Report. Herein, we report replantation of two avulsed teeth. Our patient was an 11-year-old boy with two avulsed maxillary central incisors due to a bicycle fall 2 months earlier. The patient was referred to us after rigid splinting of his teeth by a surgeon. Long-term calcium hydroxide (CH) therapy was performed for the patient, and after healing of periodontal ligament (PDL), apexification was performed for both teeth followed by root canal therapy. During the 2-year follow-up, both teeth were functional and had no radiographic or clinical evidence of resorption or ankylosis.  Avulsion is among the most severe types of dental trauma, which often occurs at young ages and can compromise the long-term prognosis of the traumatized tooth.  The reported case highlights the favorably high tissue healing potential following severe dental trauma, given that appropriate treatment is performed. Correct endodontic management can guarantee the long-term prognosis of teeth following severe dental trauma. Severe dental traumas often cause complex dental fractures or injuries and can simultaneously involve the dental hard tissue, periodontium, and dental pulp. The currently used classification for dental traumas differentiates between the fracture injuries and tooth displacement/luxation. Concussion and subluxation are the most common displacement traumas while avulsion has a lower prevalence and accounts for 7% to 23% of dislocation traumas. Horizontal root fracture of permanent teeth is an uncommon incidence, with a prevalence rate of 0.5% to 0.7% . The preThe time interval between the avulsion and replantation of the tooth, as well as the storage medium in which the tooth is stored during this time period, are critical factors determining the periodontal prognosis of the avulsed tooth. Periodontal injuries due to dehydration or immersion in a nonphysiological solution would cause inflammatory or replacement/substitutive root resorption, which would highly jeopardize the success of subsequent treatments. If endodontic treatment is not performed or is performed after a delay, the root canal system becomes infected. The infection can reach the injured cementum through the dentinal tubules and cause infection-related root resorption . In caseTreatment of horizontal root fracture is often limited to repositioning of the coronal segment and semirigid splinting for 2 to 4 weeks to provide function and comfort for the patient. Dental pulp often remains viable in 80% of the cases. In case of occurrence of the signs and symptoms of pulpitis, root canal treatment of the coronal segment is performed. In most cases, the apical segment remains vital and apical closure occurs in some cases .This case report describes the management and 2-year follow-up of an 11-year-old boy with external root resorption of his avulsed maxillary left central incisor and horizontal root fracture and inflammatory root resorption of his avulsed maxillary right central incisor.Our patient was an 11-year-old boy with a history of bicycle fall 2 months earlier, with the resultant dental trauma. He was taken to a hospital immediately after the accident, and his avulsed maxillary central incisors were replanted with a rigid splint (arch bar) by a surgeon after storage in milk for about an hour. The splints were removed by the surgeon after 1 month and the patient was referred to the Endodontics Department of the School of Dentistry.Two months after the accident, the patient was referred to us for the first time. The patient was systemically healthy, and his facial soft tissue and gingiva were normal. Clinical and periapical radiographic examinations revealed horizontal root fracture in tooth #8 and external root resorption in teeth #8 and #9 . CBCT waThe temporary restoration was removed; the root canals were rinsed with sodium hypochlorite, and filled with CH with powdery consistency. The teeth were followed-up monthly to accomplish the root canal treatment in case of observing a sound and intact periodontal ligament (PDL) and complete resolution of inflammatory root resorption .The process of root resorption had been stopped, and a sound PDL was observed on the radiographs. Considering the poor patient cooperation, we decided to accomplish the endodontic treatment of the teeth within two sessions. Since the apices were open (larger than a #60 K-file), a 4 mm MTA plug was applied at the root end, and then the coronal part of the canal was filled by a warm vertical condensation technique. Fast-setting MTA Angelus  was used for filling the apical part of the root canal. In tooth #9, the apical 4 mm of the apex was instrumented with hand K-files after elimination of CH, rinsed with sodium hypochlorite and saline, dried with paper points, and filled with MTA Angelus. Next, the coronal part of the canal was filled with gutta-percha and AH-26 sealer using a warm vertical condensation technique .In tooth #8, the apical 4 mm of the canal was instrumented with hand K-files after elimination of CH, rinsed with sodium hypochlorite and saline, dried with paper points, and filled with MTA Angelus. The coronal part of the canal was then filled with gutta-percha and AH-26 sealer using a warm vertical condensation technique. The patient was then referred to the Operative Dentistry Department for restoration of both teeth .At the 1-year follow-up, tooth #9 showed discoloration (due to the bismuth oxide present in MTA Angelus) . Thus, wOne week later, the patient presented for continuation of bleaching treatment. Since the tooth color had been corrected, temporary restoration and sodium perborate were removed and the patient was referred to the Operative Dentistry Department for permanent restoration of the tooth.The patient was completely satisfied with the function and esthetic appearance of his teeth. Both teeth were completely functional and had normal mobility. Radiographically, no periapical lesion was seen, and the inflammatory root resorption of both teeth had been completely resolved .Avulsion is a serious trauma to the dental pulp and PDL. Following avulsion and replantation, the tooth is at risk of infection and root resorption, which may compromise the prognosis of treatment and decrease the survival rate. Radiographic detection of root resorption and ankylosis is difficult shortly after replantation. Also, it is noteworthy that the risk of root resorption increases with time , 8. MoreThe prevalence of dental trauma to permanent teeth is 25% to 33% , and croIn our patient, avulsed maxillary central incisors underwent rigid splinting by a surgeon after 1 h of storage in milk. Milk is a good storage medium considering its osmolarity and adequate pH and can preserve the PDL cells viable for up to 6 h . ReplantCurrent recommended clinical management of avulsed teeth includes intracanal CH placement initiated within 7–10 days after avulsion for a tooth with a closed apex to help prevent resorption. If endodontic treatment is started after this time period or after a resorptive root lesion is detected on a radiograph, CH is placed for an extended amount of time .In our patient, since more than 2 weeks had passed since the avulsion, and the teeth showed external root resorption, long-term CH therapy was considered to stop the root resorption and then accomplish the root canal treatment. Radiographs were obtained on a monthly basis to assess the hard tissue formation and washout of CH, and also to accomplish endodontic treatment as soon as the root resorption stopped. Long-term treatment with CH may weaken the roots and make them susceptible to fracture. However, this effect was minimal in our case since CH was only used for 3 months .Damage to the external root surface along with intracanal infection can cause inflammatory root resorption. Bacterial toxins originating from the root canal can reach the PDL through dentinal tubules and aggravate the external root resorption. Appropriate endodontic treatment can prevent the progression of resorption , 16.The prognosis of horizontal root fracture depends on the site of fracture; the apical segment often survives while the coronal segment is necrotized in 25% of the cases. Also, fractures below the alveolar crest, as in our case , often have good prognosis [Apexification and revascularization have been considered effective treatment procedures for nonvital immature teeth. Apexification involves disinfection of the root canal, promoting an apical hard tissue barrier and obturating the empty canal space with root filling material. On the other hand, revascularization is aimed at promoting continued root development, the replacement of lost tissue, and function with stem cell-mediated growth of reparative tissue .Endodontic treatment of immature teeth with horizontal root fracture is difficult due to the absence of an apical stop. In such teeth, one-session apexification with MTA can serve as an alternative to the traditional apexification with CH, and has shown promising results . MTA canA rigid splint does not permit any physiological mobility of the tooth and thereby creates the conditions for complications in the sense of ankylosis or external resorption.In the case of a semirigid splint, the physiological functional mobility of the traumatized tooth is possible, which is more favorable for the healing of PDL . SemirigSplinting can be performed to immobilize the traumatized teeth whenever required. The prevalence of ankylosis after replantation of an avulsed tooth and rigid splinting is 57%-80%. Ankylosis in adults can be well managed by prosthetic and dental implant treatments. Rigid splinting is often contraindicated except for some certain cases of bone fracture, which can cause the death of PDL cells due to their compression, and can lead to subsequent root resorption. In our present case, due to the use of a rigid splint for 1 month, signs of inflammatory root resorption were noted at different parts of the root .The follow-up radiographs of our case indicated healing of the PDL, and no further root resorption was noted. Several international surveys demonstrated the inadequate knowledge of dentists about emergency management of TDIs. As TDIs include other injuries and both GDPs and specialists in various dental disciplines can encounter such injuries in their practice, they must have sufficient knowledge on the emergency management of TDIs in general . The cur


The scientific literature of recent years contains a lot of data about using multipotent stromal cells (MSCs) for urinary incontinence correction. Despite this, the ideal treatment method for urinary incontinence has not yet been created. The cell therapy results in patients and experimental animals with incontinence have shown promising results, but the procedures require further optimization, and more research is needed to focus on the clinical phase. The MSC use appears to be a feasible, safe, and effective method of treatment for patients with urinary incontinence. However, the best mode for application of cell technology is still under study. Most clinical investigations have been performed on only a few patients and during rather short follow-up periods, which, together with an incomplete knowledge of the mechanisms of MSC action, does not make it possible for their widespread implementation. The technical details regarding the MSC application remain to be identified in more rigorous preclinical and clinical trials. Pelvic organ prolapse and stress urinary incontinence are reported in 40–50% of postmenopausal women, affecting 200 million people worldwide. Stress urinary incontinence is more common in women after vaginal delivery than in patients who have undergone a caesarean section, this suggesting a lack of complete tissue repair after vaginal delivery. Standard therapies often provide symptomatic relief, but do not target against the underlying etiology, and exhibit tremendous patient-to-patient variability of results, limited success, and procedure-related complications. More clinical trials of new treatment methods involving the required number of patients and with evaluation the long-term results of therapeutic methods for the incontinence correction should be encouraged ,4,5,6,7.When studying the pathogenesis of stress urinary incontinence in women, it is necessary to pay attention to age-related changes of the female urethra. The minimum and maximum indicators of the length, width, area or volume of organs and structures in the lower urinary tract can normally vary up to 2–3 times. With age, in healthy women the absolute and relative length of the urethra, the urethrovesical angle, and the inclination of the urethra do not change. Both smooth and striated muscle tissues, which are part of various departments of the female urethra, undergo atrophy during the aging process. Smooth muscle tissue is less variable with age, but striated muscle symplasts are sometimes completely absent in urethral biopsies from elderly patients. With age, the vascularization and density of the innervation decrease in the urethral structures, but the content of connective tissue in the external urethral sphincter increases. Urinary tract mobility at young women is more pronounced than at older women .Over the past two decades, tissue engineering and regenerative medicine have made significant advances. Although the term “regenerative medicine” covers most areas of medicine, in fact urology is one of the most progressive. A lot of urological innovations and inventions have been studied over the past decades. Given the quality-of-life problems associated with urinary incontinence, there is a strong incentive for the development and implementation of new technologies. In addition, there is potential for further significant progress in regenerative medicine approaches using biomaterials, multipotent stromal cells (MSCs), or combinations thereof. All this is based on the need to replenish anatomical or physiological tissue deficiencies, reduce morbidity, and improve the long-term effectiveness of treatment. The ideal material for these purposes must meet the following criteria: provide mechanical and structural support; be biocompatible and maintain consistency with surrounding tissues; be “suitable for purpose” to meet specific application needs ranging from static support to transmission of biologically active cell signals .Along with MSC therapy, the rapidly expanding field of tissue engineering has a promising future in urology clinics. The renal tissue functional biounit has been developed using cellular technologies. Urinary excretion has been successfully demonstrated by embryonic kidneys generated from MSCs. It has been shown that artificial embryonic cells derived from pluripotent mouse stromal cells give rise to living offspring. Cell therapy represents an attractive alternative for the treatment of stress urinary incontinence: Myoblast and fibroblast therapy has been used safely and effectively. In addition, stress urinary incontinence has been successfully treated clinically with MSCs derived from muscle tissue. Skeletal muscle-derived MSCs differentiated into smooth muscle cells when implanted into the corpora cavernosa in experimental models. Various types of MSCs have been investigated for use in the repair of the external sphincter and striated muscle tissue of the urethra. The use of MSCs appears to be a feasible and safe method with promising results for treatment of patients with incontinence ,10,11,12MSCs have the ability for self-renewal and differentiation into a number of cell types and promote the release of chemokines and the migration of cells necessary for tissue regeneration. Mesenchymal MSCs are progenitor cells with an increased ability to proliferate and differentiate and these cells are less tumorigenic than MSCs from adult tissues .In connection with the above, the aim of the investigation was to make a narrative overview of the literature regarding experimental and clinical data with using cell technologies, especially MSCs, to improve the treatment of stress urinary incontinence and to facilitate the search of guidance for further research.Cellular therapy shall have the potential to offer future solutions for both the initial placement of a slings and the procedure failure treatment. Preclinical studies show that MSCs can enhance the repair of damaged tissue, either through direct integration and replacement of damaged tissue (differentiation), or through secreted factors that influence the recipient’s response mechanisms (paracrine effect) . SpragueThe type I collagen content during stress urinary incontinence in women is significantly reduced in the periurethral tissues at the level of the vagina and in its fibroblasts. Exosomes increased the expression of the col1a1 gene in these cells, the expression levels of TIMP-1  and TIMP-3 were upregulated in them with significant downregulation of MMP-1  and the level of MMP-2 expression. That is, the use of MSC exosomes increases the type I collagen content by increasing its synthesis and decreasing degradation by fibroblasts .Thus, experimental studies have demonstrated that MSCs increase the content of collagen in the periurethral tissues and persist for a long time in conditions of static stress on several materials used for the manufacture of slings. This may be of relevance for future treatment modalities of stress urinary incontinence including the use of cellular technologies.The scientific literature of recent years contains a large amount of data devoted to the study of mesh structures and the possibilities of their modification using MSCs for implantation into patients for correcting tissue defects and pelvic organ prolapse. Based on the literary analysis, Maiborodin et al.  studied Injection therapy with formulations including MSCs has been developed as a minimally invasive alternative to the surgical treatment of stress incontinence. MSC treatment is believed to promote functional regeneration of the urethral sphincter in patients with suspected internal sphincter system insufficiency. Evidently autologous fat and muscle tissues appear to be the most suitable source of MSCs for urological applications .Current published literature presents safety and efficacy data regarding adult autologous muscle-derived cell injection for urinary sphincter regeneration in 80 patients at 12-month follow-up. In these studies, no long-term adverse events were reported and patients undergoing cellular injection at higher doses revealed at least 50% reduction in stress leaks and pad weight at 12-month follow-up. All dose groups demonstrated statistically significant improvement in patient-reported incontinence-specific quality-of-life scores at 12-month follow-up. Most likely, injection of muscle-derived cells across a range of dosages are safe. Efficacy data suggest a dose–response with more patients responsive to the higher doses of these cells .Pathology (insufficiency) of the ligamentous apparatus of the urethra is most often the main cause in the development of the stress urinary incontinence in women. The transplantation of autologous MSCs derived from adipose tissue into the periurethral region is a new treatment method for stress urinary incontinence. Ten women with symptoms of stress incontinence were injected with MSCs via a transurethral and transvaginal approach under urethroscopy observation. Urinary incontinence decreased significantly during the first 2, 6, and 24 weeks after injection therapy. Autologous MSC periurethral injection represents a safe but short-term effective treatment for stress urinary incontinence. However, further studies with a longer follow-up period shall be needed to confirm long-term effectiveness . AccordiThe results of a small uncontrolled single center clinical study showed effectiveness of injection of MSCs into the region of urethral sphincters for the stress urinary incontinence correction. These results should be confirmed in larger cohort and controlled studies with longer follow-up that also evaluates applicability and safety.The regenerative potential of MSCs derived from the human dental pulp was evaluated in an animal model of stress urinary incontinence. To simulate stress urinary incontinence the n. pudendus were cut in female rats, and then MSCs previously differentiated in the myogenic direction were injected into the striated muscle tissue of the urethra. MSCs bound to cells of myogenic lines in vitro, and 4 weeks after injection they contacted with the cells of muscle tissues in vivo. MSCs promoted vascularization and significant recovery of continence, and the sphincter volume was almost restored. Moreover, MSCs were found in the damaged nerve, suggesting a role in nerve repair .6 MSCs 1 h, 7 days, and 14 days after vaginal distension and crushing n. pudendus in rats improved the integrity of the urethra, restoring the composition of its connective tissue and neuromuscular structures. MSC treatment improved elastogenesis, prevented dysfunction of the external urethral sphincter, and restored the n. pudendus morphology [A single injection of MSCs partially restores urethral function in an incontinence model. Single as well as repeated doses of 2 × 10Muscle MSCs expressing green fluorescent protein (GFP) were injected into the tail vein of rats 3 days after vaginal overstretching. In samples of the damaged urethra, MSCs were detected only 2 h after injection, but they did not integrate into the tissues. Along with this, MSCs enhance the expression of genes associated with cell proliferation, neural growth factor and extracellular matrix, as well as the expression of smooth and striated muscle proteins in the injured urethra .The muscle and adipose tissue MSC effect on the stress urinary incontinence treatment was investigated experimentally. These cells were isolated from rats and labeled by transfection of an enhanced GFP-gene. Rats received an injection of cells into the bladder neck and transurethral into the sphincter region. Through 0, 15, 30, and 60 days after cell injection the urodynamic test showed that both types of MSCs improved urinary function in rats with internal sphincter deficiency, but the effect of MSC from muscle tissue was more pronounced. According to data of histological analysis in rats treated with MSCs, the content of myosin and α-actin of smooth muscle cells was significantly higher than in the control group after the Hanks solution injection .It was not ruled out that the transplantation of mesenchymal MSCs leads to neovascularization and restoration of muscle cells in animal models of incontinence via the paracrine process  or throuIt has been investigated whether local administration of exosomes derived from human adipose tissue MSCs contributes to the correction of experimental stress urinary incontinence in rats. Incontinence was modeled by cutting n. pudendus and vaginal distension. MSCs or exosomes on a Cell Counting Kit-8 matrix were inserted into the peripheral urethra. MSC exosomes can dose-dependently enhance the growth of cultured skeletal muscle and Schwann cell lines. Proteomic analysis has shown that these exosomes contain varied proteins of different signaling pathways: PI3K-Akt, Jak-STAT, and Wnt, which are associated with the regeneration and proliferation of striated muscles and nerves. After exosome injection, rats had a higher bladder capacity and urinary onset pressure, more striated muscle symplasts and peripheral nerve fibers in the urethra than untreated animals. Both urethral function and histological results in rats in the exosome-injected group were slightly better than in the MSC-injected group .Urine-derived MSCs may promote myogenesis after injury of the urethral sphincter muscle (hyperextension of the rat vagina). Following the injection of exosomes from these MSCs the urodynamic parameters of the damaged sphincter have also been improved significantly, and the damaged muscle tissue was restored. The activation, proliferation, and differentiation of own MSC have been proven .Laboratory studies and small sized clinical series suggest applicability of MSCs for the correction of the stress urinary incontinence. However, when summarizing these results, there are often doubts about the adequacy of the impact in modeling experimental pathology. In clinical conditions, the stress urinary incontinence in women is very often diagnosed after vaginal childbirth, which is accompanied by hormonal influences with corresponding changes in the birth canal and surrounding tissues; an initial  change in the periurethral tissues, including their ligamentous apparatus, is also possible, whereas in experimental modeling, healthy tissues are injured without taking into account their initial state and the general hormonal changes in the body. In addition, it is necessary to note the heterogeneity of recommendations for choosing the best source of MSCs. The data that the cell therapy effectiveness in patients with stress urinary incontinence is lower than expected have emerged recently ,25,26,276. The urethra samples were obtained at 28 or 84 days after cell transplantation. The transplanted cells were identified in all urethras on day 28, regardless of the type. The most pronounced fluorescence was noted in the co-transplant group. A distinct decrease in the luminescence intensity was observed between 28 and 84 days after all types of transplantation. Both MSCs and muscle cells have promoted striated muscle formation when co-transplanted directly into the external urethral sphincter. These events were rare in the MSC-only group. If cells were injected into the submucosa, they remained undifferentiated, usually in the form of clearly distinguishable repositories. The results showed that co-transplantation of MSCs and muscle cells is more likely to improve urethral closure than transplantation of each cell type separately [The results of joint transplantation of muscle-derived cells and mesenchymal MSCs into the urethra have been evaluated. The experiment was carried out on old goats that gave birth many times. The average number of cells with a luminescent label injected per animal was 29.6 ± 4.3 × 10The distribution of autologous cells was established during transurethral (under endoscopic control) and periurethral administration to female goats. There have been episodes of leakage of cell suspension in 19% of transurethral injections after needle withdrawal. A repository in the urethral wall was found in all animals 28 days after transplantation. The average percentage of these depots in relation to all injections performed was 68.7% and 67.0% for the groups after periurethral and transurethral injection, respectively. The repository frequency identified in the external urethral sphincter was 18.8% and 17.1%, respectively. Leakage of cell suspension, insufficient accuracy of injection of cells into the external urethral sphincter, and long-term deposition of these cells may contribute to insufficient effectiveness of cell therapy in patients with incontinence .MSC therapy for stress incontinence, common in women with type 2 diabetes and obesity, has also shown low efficacy. It was found that epigenetic changes caused by prolonged exposure to a dyslipidemic environment led to abnormal global transcriptional traits of genes and microRNAs and disrupt the reparative capacity of MSCs in muscle tissue .Literature about efficacy of using MSCs for the correction of stress urinary incontinence reports different results. We speculate that technical variations are largely responsible for the failures and low efficiency of cell therapy, first of all, the speed and method of introducing the cell suspension.The cell therapy results in patients and experimental animals with incontinence have shown promising results, but the procedures require further optimization, and more research is needed to focus on the clinical phase. The MSC use appears to be a feasible, safe, and effective method of treatment for patients with urinary incontinence. However, the best mode for application of cell technology is still under study. Most clinical investigations have been performed on only a few patients and during rather short follow-up periods, which, together with an incomplete knowledge of the mechanisms of MSC action, does not make it possible for their widespread implementation. The technical details regarding the MSC application remain to be identified in more rigorous preclinical and clinical trials.


The principal biological function of bacterial and archaeal CRISPR systems is RNA-guided adaptive immunity against viruses and other mobile genetic elements (MGEs). These systems show remarkable evolutionary plasticity and functional versatility at multiple levels, including both the defense mechanisms that lead to direct, specific elimination of the target DNA or RNA and those that cause programmed cell death (PCD) or induction of dormancy. This flexibility is also evident in the recruitment of CRISPR systems for nondefense functions. Defective CRISPR systems or individual CRISPR components have been recruited by transposons for RNA-guided transposition, by plasmids for interplasmid competition, and by viruses for antidefense and interviral conflicts. Additionally, multiple highly derived CRISPR variants of yet unknown functions have been discovered. A major route of innovation in CRISPR evolution is the repurposing of diverged repeat variants encoded outside CRISPR arrays for various structural and regulatory functions. The evolutionary plasticity and functional versatility of CRISPR systems are striking manifestations of the ubiquitous interplay between defense and “normal” cellular functions. The CRISPR systems show remarkable functional versatility beyond their principal function as an adaptive immune mechanism. This Essay discusses how derived CRISPR systems have been recruited by transposons on multiple occasions and mediate RNA-guided transposition; derived CRISPR RNAs are frequently recruited for regulatory functions. The CRISPR systems are known primarily as a new generation of genome editing tools that possess unprecedented specificity and efficiency thanks to the use of guide RNAs to recognize unique sequences in the genome –3. This adaptation, the process of acquisition of pieces of foreign DNA (protospacers) that become spacers inserted between repeats in CRISPR arrays and are subsequently employed to produce guide RNAs that specifically target the cognate foreign nucleic acid;expression and maturation of the CRISPR (cr) RNAs, whereby the long transcript of the CRISPR array, the pre-crRNA, is processed to yield functional, mature crRNA; andinterference, whereby crRNAs are exploited as guides to recognize the target DNA or RNA that is then, typically, cleaved by the nuclease moiety of the CRISPR effector complex.Each of these stages in the CRISPR immune function is mediated by a distinct set of Cas (CRISPR associated) proteins that comprise functional modules of the CRISPR systems ,9. Characas operons have been discovered that are often not linked to CRISPR arrays . In. In20]. All the CRISPR-like systems discussed here are limited in their spread to a particular group of prokaryotes or MGE, which supports the view that these are derived CRISPR forms. There is little doubt that, with further advance of genomics and metagenomics, many additional specialized CRISPR derivatives will be discovered.trans-acting crRNAs (tracrRNAs) that are required for interference in type II and some subtypes of type V systems [In the final section of this essay, we discuss a different type of exaptation of CRISPR system components, namely repurposing of the crRNAs or just the repeats, often for additional functions within CRISPR systems . The bes systems –77. The  systems . The tra systems .Streptococcus species has remarkably been recently shown to regulate the expression of the II-A cas operon [A distinct, long form of tracrRNA (L-tracrRNA) present in many s operon . Similars operon . Thus, iFrancisella novicida. Here, Cas9, in a complex with tracrRNA and scaRNA, which is another small RNA encoded in the vicinity of the CRISPR locus, represses the expression of bacterial lipoprotein genes, which is required for bacterial virulence [Similar repurposing of an ectopic copy of a repeat and of Cas9 has been studied in detail in the pathogenic bacterium irulence ,79. The irulence . The shoirulence . Comparairulence .Haloarcula hispanica and predicted to operate also in related species [creT promoter, to which it binds as a complex with Cascade, and represses the toxin expression  unleashes the toxin.A distinct, even more surprising form of exaptation of a repeat has been discovered in the archaeon  species . The subpression . This elA different type of repeat exaptation was discovered in the V-K and I-F CASTs (see the previous section). For RNA-guided transposition, both these systems employ a “delocalized crRNA” that is encoded near the transposon end, separately from the CAST CRISPR array ,81. The The cases of repeat exaptation discussed above are biologically diverse but all seem to follow the same evolutionary scenario. This series of events involves ectopic duplication of a repeat followed by partial sequence divergence. The crRNA-like transcript containing such a derived repeat forms a complex with a CRISPR effector, targeting it to a sequence recognized by the spacer-like portion of the CRISPR-like RNA. Importantly, these derived repeats located outside CRISPR arrays are not easy to detect in genome analysis as illustrated by the delocalized crRNA and by scaRNA, which were not detected in the initial analyses of the CASTs and type II loci, respectively. Along similar lines, regulatory functions of noncanonical CRISPR RNAs typically rely on partial complementary of the spacer-like sequence and the target, which can serve a toggle between target cleavage and expression regulation . We do nThe final case we discuss further exemplifies the “guns for hire” phenomenon. A search for CRISPR components encoded in MGE led to the unexpected identification of CRISPR miniarrays (typically, 2 repeats flanking a spacer; The extensive study of CRISPR systems over the last decade or so has revealed remarkable diversity and functional plasticity that are manifested both in the variety of immunity mechanisms and in the exaptation of CRISPR systems and their components for functions different from adaptive immunity or even from any form of defense. At a higher level of generalization, evolution of CRISPR systems seems to have involved 2 phases that occurred convergently in the 2 classes and in some of the types and subtypes . The fir


Background: Survivors with spinal cord injury (SCI) have neuromuscular deficits such as muscle atrophy that lead to functional impairments. This study utilized myotonometry and electrical impedance myography (EIM) to quantitatively evaluate the changes in muscle mechanical properties and compositions after SCI.Methods: This study adopted a cross-sectional design. Eighteen SCI patients and 18 healthy individuals were recruited. The outcome measures were: (1) The myotonometer measured muscle mechanical parameters of oscillation frequency (freq), dynamic stiffness, logarithmic decrement (decr), mechanical stress relaxation time, and indication of creep. (2) The electrical impedance myography measured parameters of resistance (R), reactance (X), and phase angle (θ). (3) muscle strength (maxForce); (4) clinical scales of Manual Muscle Testing (MMT) and modified Ashworth scale (MAS). All outcome measures were compared between the bicep brachii muscle of the weaker side of the SCI group and the non-dominate side of the healthy group. Correlation analysis was performed at quantitative data and clinical scales.Results: Freq, stiffness, and maxForce of the SCI group were significantly lower (p < 0.01) than those of the healthy control. The relaxation time and creep were significantly higher in the SCI group than in the control group. Significant differences of R and Xc were observed between the two groups. Significant correlation was observed between freq, stiffness, and months past injury, and between Xc, creep, and relaxation time.Conclusions: Reduced muscle tone and stiffness might relate to muscle atrophy, and higher relax time and creep may be caused by poor contractile ability. The changes in EIM parameters could indirectly reflect the muscle cell size, and fatty and connective tissue alterations. These findings support the feasibility of myotonometer and EIM to quantify muscle mechanical and intrinsic properties in patients with SCI. The results could facilitate the understanding of neuromuscular changes that are related to functional impairments. Spinal cord injury (SCI) refers to the damage of the structure or function of the spinal cord that results in a different extent of motor, sensory, and autonomic dysfunction below the injured level . SCI-relMuscle atrophy is related to the damage of the motor neuron, which contributes to the inactivity of the affected skeletal muscles, leading to changes in the muscle mechanical load conditions and muscle length shortening due to sarcomere loss . Muscle Common complications of patients with SCI such as muscle wastage, muscle contracture, and muscle atrophy contribute to the alteration of muscle mechanical properties. The muscle mechanical properties of tone and stiffness are considered to be fundamental in energy-efficient muscle contraction . Upper lMuscle composition could be monitored non-invasively by electrical impedance myography (EIM). EIM applies low-intensity, high-frequency current to the localized muscle area and measures the voltage and current that pass through the tissues. Muscle health could then be evaluated from the electrophysiological conditions of muscle tissue by calculating tissue compliance and resistance . The thrTo date, the majority of the literature assessed the feasibility of the application of EIM to detect muscle composition in patients with SCI. It remains unclear if muscle composition may be related to muscle mechanical properties, and whether changes in muscle composition and muscle mechanical properties are related to clinical measurements in patients with CSCI. This study aimed to apply EIM technology and myotonometer to assess muscle function, and explored their potential relationships with clinical measurements. Findings of this study would provide further understanding of the alteration of muscle health and may form the basis of targeted rehabilitation strategies to improve functional outcome.This study adopted a cross-sectional design to compare the difference in muscle composition, muscle mechanical properties, and muscle force between patients with SCI and healthy individuals. The study also investigated the association between muscle composition, muscle mechanical properties, and muscle strength in patients with SCI. The inclusion criteria were as follows: (1) meet the diagnostic criteria of the American Spinal Cord Injury Society in 2000; (2) traumatic CSCI confirmed by magnetic resonance imaging; (3) medically stabled CSCI patients who underwent cervical spine internal fixation procedure; (4) intact motor function prior to SCI injury, without bone tuberculosis and bone malignant lesions; and (5) able to follow instructions and provide informed consent. The exclusion criteria were as follows: (1) minors; (2) fractures of other body parts other than SCI; (3) existing neurological, musculoskeletal, respiratory, and psychological disorders; and (3) patients who were unable to cooperate. Healthy participants who had no history of neuromuscular disease or other neurological disorders were recruited for the control group. The experimental procedures were conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of the Guangdong Industrial Injury Rehabilitation Hospital, Guangzhou.The electrical resistance properties that reflect the muscle composition of the bicep brachii were assessed by EIM . The center of the electrodes was identified as the middle distance between the acromion process and the medial border of the cubital fossa. B-mode ultrasound scan was conducted to confirm the location of the muscle belly and the direction of the muscle fibers of the bicep brachii. Two pairs of electrodes were linearly arranged along the muscle fiber direction, including one pair of voltage electrodes on the inner regions and an outer pair of current electrodes . Each paA handheld myotonometer  was applied to quantify the mechanical muscle properties of the bicep brachii. The patients laid in supine with upper extremities relaxed by the side. The wrist joint was kept in the neutral position, and the elbow joint was in full extension. Since muscle tissue is affected by gravity, it is recommended to place the probe perpendicularly to the skin surface . The proMuscle force was recorded by the handheld dynamometer  placed on the wrist joint. Subjects were then asked to perform maximum isometric contraction of elbow flexion and maintained the position when maximum force was applied see . During A professional physiotherapist conducted the clinical test of ASIA impairment assessment, Manual Muscle Testing (MMT), and modified Ashworth Scale (MAS). The therapist was blinded to the results of the EIM, myotonometer, and dynamometer. Anthropometric characteristics of the sample population were collected prior to the start of the study. According to the MMT results of the biceps muscles of the patient, the upper limbs were classified as the stronger side (the side with higher MMT score) and weaker side. If the MMT scores on both sides are equal, the dominant side was considered as the stronger side, and the non-dominant side was considered as the weaker side . Participants were asked to lie on the treatment bed in a relaxed supine position, with both upper limbs parallel to the body. Then the biceps were evaluated by myotonometer, EIM, and handheld dynamometer. Only the biceps muscle of the weaker side of SCI patients and the non-dominant side of healthy control were recorded.t-test was conducted for the parameters that follow a normal distribution, and Wilcoxon rank sum test was conducted for parameters that deviate from the normal hypothesis. The correlation between muscle parameters and clinical functions were assessed by either Pearson or Kendall's correlation analysis, depending on normality. For all statistical tests, a two-sided test was performed with statistical level set at P p < 0.05.Data analysis was conducted in SPSS 22 software . Descriptive statistics were calculated for all dependent variables. All parameters were tested for normality by the Chi-square goodness of fit test. Parameters that were normally distributed are reported as mean and standard deviation, whereas median and interquartile range  were reported for non-normally distributed data sets. All parameters of the weaker side of the SCI patients were paired with those of the non-dominant side of healthy controls to assess the difference in muscle characteristics. Paired Eighteen patients with SCI  were recruited in this study. The neurological injury level of the patients ranged between C4 and C6, and the American Spinal Injury Association (ASIA) impairment levels ranged between A and D. The clinical characteristics of the SCI group are presented in R = 61.32 ± 9.63, Xc = 14.99 ± 2.92) than in the control group  recorded at 50 kHz  and partly supported by the Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515011356), Guangzhou Research Collaborative Innovation Projects (No. 201907010034), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2020-JKCS-005).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The definition of myocardial infarction was updated in 2000 to include an elevation of cardiac troponin T or I (cTnT or xTnI) alongside clinical evidence of myocardial infarction. The redefinition was jointly done by the American College of Cardiology Committee and the European Society of Cardiology. Since then, cardiac troponin T and I have assumed the position as the primary biochemical markers for diagnosing myocardial infarction. The high sensitivity of cardiac troponin for myocardial necrosis influenced the decision to include cardiac troponins (cTn) in the diagnostic pathway. An elevated cTn level indicates the presence of myocardial injury. However, it does not give the underlying reason for the damage. Apart from acute myocardial infarction (AMI), a range of potential diseases feature troponin release, including heart failure, acute pulmonary embolism, end-stage renal disease, and myocarditis. However, regardless of the mechanism that triggers the release from cardiac myocytes, elevated cTnI and cTnT typically implies a poor prognosis. This review attempts to explain both the cardiac and non-cardiac causes of increased cTnT in emergency department patients. Cardiac troponin T (cTnT), cardiac troponin I isoforms (cTnI), and cardiac troponin C (cTnC) are typically expressed in the cardiac muscle tissues Figure .It is important to note that they are the most sensitive and most specific indicators for acute myocardial infarction (AMI) diagnosis -4. Not mThe techniques for determining cTnT and cTnI were developed in the late 90s , 11 and It is important to note that despite the specificity of cTnI and cTnT, one cannot classify them as ideal biomarkers for AMI diagnosis because their concentrations increase in blood serum both in ischemic necrosis of myocardial cells and also in several other pathologies that lead to damage or death of myocardial cells due to non-ischemic factors -19. It iIt should also be noted that an increase in cardiac troponin concentrate in biological fluids, mainly in the blood serum, is an indication of reversible or irreversible damage to the cardiomyocytes but fails to explain the etiopathogenesis of the damage, which may occur in several other pathological processes not linked to myocardial infarction , 14, 20.Elucidation of primary causes and mechanisms of cardiac troponin increase that is of theoretical value and practical importance . This plThis article will discuss the primary causes and the mechanisms of increased cardiac troponin T concentration in emergency department patients.Cardiac troponin release, unrelated to acute coronary syndromeSeptic Shock/Sepsis and Systemic Inflammatory Response SyndromeAccording to results from several studies, over 36% of patients treated in the emergency department for systemic inflammatory response syndrome (SIRS) or sepsis have elevated cTn. The range is more comprehensive, i.e., 36% to 85% of cases . This wiPulmonary EmbolismPulmonary embolism (PE) is a primary cause of troponin elevation. Over half of patients feel a so-called "coronary pain, " resulting in difficulties and wrong differential diagnosis , 25.A study by Giannitis and colleagues  found thAccording to a 2012 study by Kilinc et al. , elevateOn the other hand, a survey of 1367 subjects with reference troponin values revealed a lower mortality rate . Also, cardiac troponin I and troponin T had almost similar predictive values. A review of the meta-analysis results shows that high levels of cardiac troponins in the serum are associated with short-term mortality in PE patients . A review of a group of PE patients who were hemodynamically stable found that elevated serum troponin concentrations were associated with an increased risk of mortality  . And so,Acute and Chronic Heart FailureElevated cardiac troponin in heart failure strongly links with decreased left ventricular ejection fraction. Elevated cTn also correlates with the severity of heart failure (HF) and the prognosis. The aggravation of ischemic or non-ischemic heart failure is attributed to the progressive loss of myocytes caused by apoptosis and necrosis. Other factors, such as the activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system and inflammatory mediators, may also trigger an injury to the myocardium. Myocytes lost are replaced by fibrotic tissue resulting in progressive cardiac dysfunction. Elevation of cTn in heart failure patients indicates myocardial injury. In decompensated heart failure, cTn release is believed to be caused by excessive tension from the myocardium wall due to acute volume and pressure overload. Also, increased strain on the myocardial wall results in subendocardial ischemia. In patients with chronic stable heart failure, high cTnI values occurred in 15-23% of cases (> 0.1 ng/ml). In the case of cTnT, values exceeding 0.1 ng/ml have been reported in at least 10-15% of cases . No diffStrenuous ExerciseResults from several studies have reported the appearance of cTnI and cTnT after strenuous ultra-endurance exercise . But theAcute PericarditisAcute pericarditis/myocarditis is typically diagnosed in patients in the emergency department presenting with acute chest pain. While troponins may not be present in the pericardium, it was reported that cTnI was elevated in 32-49% of pericarditis cases due to the involvement of the epicardium in the process of inflammation. In patients presenting with acute myocarditis, cTnI concentrations are seen to increase in no less than 34% of patients .Coronary angiography is usually performed in patients who have pericarditis. The aim is to rule out myocardial infarction. In the absence of coronary disease, endomyocardial biopsies (EMB) are done to establish an accurate diagnosis. However, EMB shows lymphocytic and myocytolysis infiltrates in only 10 - 25% of patients with myocarditis. Increased cTnT values have a higher sensitivity than EMB and may have the capacity to confirm the clinical diagnosis of myocarditis .Chronic Renal FailureLooking at modern concepts, one may consider cardiac troponins to be products of normal myocardial metabolism , and theBecause of the presence of cardiac troponins in healthy patients, researchers are now compelled to consider what causes their release from cardiomyocytes under normal circumstances . It is aa - In reticuloendothelial system cells (intracellular cleavage by certain proteases)b - In the serum (extracellular cleavage by proteolytic enzymes). It has been established that thrombin (an enzyme of the hemostasis system) causes the troponin T molecule to cleave into two fragments.c - Glomerular filtrationGlomerular filtration, without a doubt, is the most discussed and possibly the primary mechanism by which cardiac troponin is eliminated with regards to clinical significance. Some researchers have reported that the involvement of the kidneys in the elimination of cardiac troponin is highly doubtful and controversial, owing to the fact that cardiac troponin molecules were not detected in the urine of the majority of the patients . RegardlBased on this review, it can be concluded that several factors can contribute to the elevation of cardiac troponin concentration. The pathological conditions  and the physiological conditions (strength training) are very common causes of high cardiac troponin concentration. It is also important to note that modern sensitive techniques for the determination of cardiac troponin detect troponin molecules at a higher frequency and in a larger number of individuals at the same time. It is worth mentioning that, for the sake of increasing a key criterion of lab diagnostics, the developers gave up another key criterion for diagnostics (specificity of immunoassays). Clinicians should consider this circumstance when interpreting laboratory results of patients admitted with possible acute myocardial infarction. Otherwise, the chances of misdiagnosis in the blood serum after these are numerous and differ from the mechanism of increased cardiac troponins in acute MI. Taking note of the mechanisms of high-sensitivity cardiac troponin concentration elevation will improve the differential diagnosis of acute myocardial infarction from the conditions listed above and also introduce additional diagnostic techniques. For instance, one can determine high-sensitivity troponins in serum after pharmacological or physical exercise, thus troponins can serve as markers of latent ischemic disease.


Bladder cancer (BCa) is the most common malignancy of the urinary tract and one of the most prevalent cancers worldwide. While the clinical approach to BCa has remained largely unchanged for many years, recent discoveries have paved the way to a new era of diagnosis and management of the disease. BCa-specific mortality started to decrease in the regions with a wide range of activities leading to greater social awareness of the risk factors and the decline in carcinogenic exposure. The urologic community refines the role of transurethral surgery towards more rigorous and high-quality techniques. New agents have been approved for patients with BCG failure who faced radical cystectomy so far. Although radical removal of the bladder is the gold standard for muscle invasive cancer management, the extent and clinical value of lymphadenectomy is currently heavily challenged in randomized trials. Furthermore, alternatives to perioperative chemotherapy have arisen to increase the likelihood of complete treatment delivery and successful oncological outcomes. Finally, improvements in molecular biology and our understanding of tumorigenesis open the era of personalized medicine in bladder cancer. In the present review, the status and future directions in bladder cancer epidemiology, diagnosis and management are thoroughly discussed. Bladder cancer (BCa) remains the most common malignancy of the urinary tract. In 2018, BCa was diagnosed in 549,393 patients and 199,922 succumbed to the disease worldwide [The most significant symptom of BCa is either microscopic or gross hematuria. If the bladder tumor is identified, in 75% of cases, urothelial bladder cancer (UBC) confined to the mucosa (NMIBCa—non-muscle invasive disease) is diagnosed . In the A nonsystematic review of the PubMed database to identify articles focused on current challenges and future directions published in recent years in the English language was conducted. The following phrases were used during the search: urothelial cancer or bladder cancer, combined with several groups of keywords relevant to the discussed sections. These included: biology, etiology, epidemiology, management, and outcomes. Clinical series, review articles and editorials were identified, and all abstracts were reviewed but only the most significant papers were completely analyzed and used as references. According to WHO reports, the incidence of BCa varies significantly among different geographical regions, such that age-standardized rates are almost three times greater in more developed areas than in less prosperous countries 9.5 vs. 3.3). The variety is among others suggested to result from disparities in tobacco smoking, obesity, alcohol consumption and overuse of red meat. Although the BCa risk is multifactorial, cigarette smoking remains the most prevalent risk factor. It has been estimated to be responsible for half of all BCa cases  vs. 3.3.. AccordiThere is no widely accepted BCa screening program. This is probably due to the low incidence of aggressive disease and lack of an optimal screening tool. Screening has been suggested, however, to be efficacious in highly selected populations. Those known to have aristolochic acid nephropathy were subjected to biannual cystoscopies for 10 years, and in half of them, BCa was diagnosed. After a median of 94 months follow-up, nobody died of the disease [Occupational exposures have long been associated with bladder cancer risk. While professions at the greatest risk include industrial areas processing paint, rubber, petroleum products and dye workers, the greatest risk of BCa specific mortality is observed in electrical and chemical process workers ,11. Of aTransurethral resection of the bladder tumor (TURBT) is the mainstay therapy for non-muscle invasive disease. This surgery is performed with resectoscope that is used to cut the lesion into pieces subsequently directed for pathology. TURBT has been heavily criticized due to its piecemeal technology that may lead to tumor cells implantation within healthy bladder mucosa. Single post-TURBT chemotherapy instillations were found to decrease the recurrence risk in NMIBCa cases, explicitly seen in primary, single lesions . TherefoNMIBCa has been observed by many investigators to recur and progress. Five-year probability of recurrence and progression mounts to 78% and 45%, respectively . SeveralBacillus Calmette-Guerin (BCG) immunotherapy is the only one conservative measure that has been proved and used for decades to prevent progression in high-risk NMIBCa. Although shown to be efficient, the optimal schedule, timing, dosing, strains, and the definition of failure remained under protracted dispute over the years. In EORTC-GU trial (EORTC 30962), the optimal dose of BCG has been tested . When coIn 2018, FDA has summarized the evidence and proposed the definition of BCG unresponsive disease. It is to be diagnosed only if either five of six doses of an induction course followed by at least two of three doses of maintenance therapy or two of six doses of a second induction course . This haSeveral unfavorable predictive factors for disease progression in T1G3 BCa patients treated with BCG have been recognized so far. Besides well-established tumor-dependent factors such as concomitant CIS and tumor size, lymphovascular invasion (LVI)  and somep < 0.001) and obesity  were significantly correlated with an increased risk of progression in BCG-treated T1G3 BCa patients [Moreover, an association between BCG refractoriness and metabolic disorders has been recently postulated . Insulinpatients . Similarpatients .Radical cystectomy is the mainstay therapy for patients who progressed despite the BCG treatment. For those who deny removal of the bladder or cannot be subjected to the surgery for number of reasons, there is an urgent need for a conservative alternative to intravesical immunotherapy that would salvage the patients who progress after BCG. So far, two novel agents have been shown to be successful and FDA approved in the management of BCG failure: pembrolizumab and nadofaragene. A number of trials are under way and new drugs will hopefully arrive soon .If left without treatment, the majority of patients with MIBCa succumb to the disease within two years of diagnosis . TherefoSeveral authors have attempted to link the tumor molecular profile with its response to chemotherapy. Alterations in one or more of the three DNA repair genes  were associated with pathologic response and better overall survival . SimilarThe therapeutic landscape for patients with advanced disease is constantly expanding with immune-checkpoint inhibitors and pan FGFR inhibitor approved by FDA in recent years. Their success in metastatic disease forces many investigators to look into their potential role in earlier stages of bladder cancer . An immuAdvances in the bladder cancer diagnosis and management have improved our understanding of the disease biology. Social awareness of risk factors together with decreased occupational exposure and a vigilant approach to the diagnosis of the disease will reduce the amount of newly diagnosed advanced cases. High-quality transurethral surgeries with more efficient and less morbid adjuvant therapies will reduce the caseload of radical cystectomies. Finally, the molecular picture of advanced disease revealed by sophisticated technology will tailor systemic therapy. To provide a favorable outcome, the treatment of bladder cancer will require constant mutual interplay among a variety of medical professions.


In silico modeling is a powerful strategy to investigate the biological events occurring at tissue, cellular and subcellular level during bone fracture healing. However, most current models do not consider the impact of the inflammatory response on the later stages of bone repair. Indeed, as initiator of the healing process, this early phase can alter the regenerative outcome: if the inflammatory response is too strongly down- or upregulated, the fracture can result in a non-union. This review covers the fundamental information on fracture healing, in silico modeling and experimental validation. It starts with a description of the biology of fracture healing, paying particular attention to the inflammatory phase and its cellular and subcellular components. We then discuss the current state-of-the-art regarding in silico models of the immune response in different tissues as well as the bone regeneration process at the later stages of fracture healing. Combining the aforementioned biological and computational state-of-the-art, continuous, discrete and hybrid modeling technologies are discussed in light of their suitability to capture adequately the multiscale course of the inflammatory phase and its overall role in the healing outcome. Both in the establishment of models as in their validation step, experimental data is required. Hence, this review provides an overview of the different in vitro and in vivo set-ups that can be used to quantify cell- and tissue-scale properties and provide necessary input for model credibility assessment. In conclusion, this review aims to provide hands-on guidance for scientists interested in building in silico models as an additional tool to investigate the critical role of the inflammatory phase in bone regeneration. Bone healing is a complex, well-coordinated process that starts autonomously when a bone fracture occurs. Bone fractures are one of the most common injuries and their incidence in Europe is expected to increase by 23% over the coming decade due to ageing, as average life expectancy rises . Owing tin vitro and in vivo experimentation, as it can provide an integrated view of the many events happening during the bone healing process and hence lead to a deeper understanding of said process. Moreover, computational models aim to reduce animal experimentation, although in vivo studies are often still required for validation purposes. Despite the importance of the inflammatory phase in bone fracture healing  and fibroblasts . Granulafication . Both osfication . As softfication . The forfication  and geneThe remodeling phase is the final stage of the bone healing process and takes years to complete. Bone remodeling involves the resorption of immature woven bone and underlying cartilage matrix by osteoclasts, replacing these tissues with lamellar bone, as well as the decay of osteoblasts, undergoing apoptosis, or their maturation and embedding into the bone matrix as osteocytes. The cellular functions of osteoclasts and osteoblasts are regulated by cytokines such as receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG). While RANKL promotes cell activation, differentiation and survival, OPG inhibits cell activation and induces apoptosis ; leadingThe inflammatory response is the immediate reaction to a trauma that starts when pathogenic agents enter the body due to a wound, generating undesired living conditions for the injured organism . The infThe inflammatory response has a primary role on the overall bone healing process, and immune restricted patients are more prone to experience impaired healing . For exaThe cells involved in the inflammatory response can be divided into two groups according to their belonging to the innate or adaptive immune system . The celCells of both the innate and adaptive immune system are present in the fracture site during the inflammatory stage of bone healing . For exaThe adaptive response in fracture healing starts when T cells sense the molecular signals released from the cells of the innate immune system within the injury region. If the injury is characterized by infection from an external pathogen, specific antibodies are produced and released from B cells to accelerate the neutralization of the threat. The adaptive response in fracture healing follows a two-wave dynamics as it is observed to peak both after the fracture and later during the cartilage revascularization . ContrasBesides cells, the inflammatory response is mediated at subcellular level by molecular signals called cytokines. Cytokines are small proteins released from the inflammatory cells to regulate the inflammatory response, thus playing a role in the correct development of the early stages of bone healing. According to their ability to enhance or inhibit the inflammatory response, cytokines are typically divided into pro-inflammatory or anti-inflammatory, respectively.Pro-inflammatory cytokines, such as interleukin 1 and 6  and tumor necrosis factor alpha (TNF-α), are observed to peak their expression in the healing region within the first 24 h post-injury . At subcAnti-inflammatory cytokines, which include different interleukins such as IL-4, IL-10, IL-11 and IL-13, are released to reduce inflammation when the first wave of pro-inflammatory response is over. Anti-inflammatory cytokines downregulate the inflammatory response and prevent chronic inflammation, which would be detrimental to fracture healing .Although cells and cytokines are the major biological regulators of the inflammatory response in bone fracture healing, the micromovement in the interfragmentary region also regulates bone healing at cellular level. The early stage of bone healing is particularly sensitive to changes in mechano-stimulation, hence establishing an adequate mechanical environment at the injury site is necessary from the beginning of the inflammatory phase .Monocytes, for example, express a stronger pro-inflammatory response under shear or compressive loading . Mechanoin silico, scientists refer to the wide field of research that benefits from the use of computer modeling and simulation to investigate intricate and complex systems. This approach is becoming established in the biomedical field, as an additional resource to obtain a detailed understanding of the organism or its individual components. The flexibility provided by the computational approach favors the unveiling of aspects and insights that would be otherwise challenging to monitor experimentally. For this reason, the use of in silico clinical trials in all stages of the research and development pipeline has progressively gained more attention in the last decades  allows to quantify the parametric uncertainty in large data sets obtained from the results of the computational simulations. This is one way in which the effect of population variation can be captured in silico. To date, this approach is used by researchers to investigate the mechanisms behind neuron activation , delay (DDE), partial (PDE) or stochastic (SDE), imply a continuous overlap of generations , thus deDiscrete-time models use difference equations to study small-scale biological processes at (sub)cellular levels. Difference equations do not consider overlap between successive generations as they are solved for each time increment, involving an inherent delay to register changes . DiscretContinuous and discrete models can complement each other in hybrid models. In hybrid models, continuous- and discrete-time approaches are coupled through input/output variables to provide multiscale models describing mechano-biological processes at tissue, cellular and/or subcellular levels. The most common hybrid formulation in biomedicine couples a PDE system of reaction-diffusion equations with AB or CA models . The PDEComputational models describing the immune response, also known as computational immunology, can be broadly classified into two groups: those describing generic inflammatory responses after infection or trauma, and those simulating immune responses in specific tissues. Most approaches of the former group are continuous, whereas the latter are often simulated using discrete or hybrid models. Starting with the models describing generic inflammatory responses, in silico models of tissue-specific immune responses, the popularity of AB methods is clear  within the injury. However, to date, many studies in this field started to additionally employ AB models to acquire a different point of view on the investigation of the mechano-biological relationships driving bone fracture healing. The supporting AB models are commonly employed to simulate the dynamics of repair cells , 2021 anin silico studies of the repair and remodeling phases reported in the previous section do not include the simulation of the early stages of bone fracture healing, thus ignoring the role of the inflammatory response. Inflammation is characterized by numerous actors whose role in the overall scenario is worthy to be investigated. However, due to its complex nature, the inflammatory response to bone injury has been rarely simulated with a computer model. To the best of the authors’ knowledge, only one in silico model describing the inflammatory response in bone fracture healing has been reported in the literature. The model was first introduced by The Two years later, in silico fracture healing models should include both temporal and spatial evolution of the densities and concentrations of the different biological agents related to the inflammation phase. Moreover, many experimental studies investigate the immune response nowadays, as presented in in silico would allow a stronger validation of the future computational models investigating bone fracture healing from the initial inflammatory response to the later remodeling phase.The spatiotemporal evolution is of upmost importance to further explore the dynamics of all the involved actors during the progress of the inflammatory response, as it represents the heterogeneous distributions within the region of interest. For example, one hypothesis would be that macrophage migration to the fracture zone will initially have a bigger impact in the peripheral area and less effect in the central area, generating different spatial dynamics in the healing process. Therefore, we believe that the next generation of in vitro systems to large in vivo animal models. These results provide important information also in view of validating the predictive capacity of bone healing in silico models. Each modeling technique has its unique advantages and provides essential information about the inflammatory process  and lipopolysaccharide (LPS). Each standard activator, or their combination, is associated with a specific activation state within the M1-M2 spectrum, identified by specific markers . Once isrotocols . Co-cultrotocols . By tunirotocols  or the crotocols . Recent  T cells  or macro T cells , as wellin vitro systems enable higher control of the culture environment and cellular interaction. Recent developments of the organ-on-chip technology provide confined engineered microenvironments where biochemical and physical stimuli can be finely tuned over space and time , histology and immunohistochemistry. While their use in preclinical models of bone defects has been recently described elsewhere , the preomics. To explore cellular processes in bone biology, omics technologies characterize, among others, DNA modifications (epigenomics), RNA transcriptions (transcriptomics), protein synthesis (proteomics) and metabolic activity (metabolomics)  . Transcrolomics) . Therefoaptation .Regarding transcriptomics, RNA sequencing (RNA-seq) technologies measure whole transcriptomes, thus they simultaneously analyze the gene expression profile of thousands of genes . When apin vitro  and systems . However, while the mechano-biological activities at cellular and subcellular levels are usually challenging to investigate experimentally, the e models  to integin silico models of the inflammatory response for different organ systems have been developed within the field of computational immunology    are essein silico) characterized by organized combinations of parametric values assigned to the factors that describe the bone fracture healing process at cellular level (in silico model by using the Particle Swarm Optimization (PSO) method to achieve the optimal characterization of the mechanical properties of the tissues in a bone fracture healing scenario. The PSO algorithm evaluated combinations of parameters equally distributed in a stochastic way to find the best combination to describe the tissue mechanics  or Machine Learning approaches  to assesar level . Anotherechanics . Machineechanics .in silico models help us to understand the principles regulating the diverse events occurring at tissue, cellular and subcellular level. Certainly, the experimental validation of such in silico models is mandatory if we aim to go from bench to bedside. With this review, we aimed to highlight the potential of using multiscale in silico approaches to tackle bone healing intricacy. Based on the current state-of-the-art, we conclude that hybrid models are particularly suited to simulate adequately the multiscale course of events of the inflammatory phase and its overall role in the healing outcome. We furthermore described possible in vitro and in vivo methodologies that can be employed to experimentally calibrate the parametric description of the in silico model during its development and, afterwards, to validate the computational results and support their bench to bed transition. We believe that the next generation of in silico models of bone regeneration should account for inflammatory events to guarantee a more realistic investigation of the process, favoring its employment within a clinical context.The inflammatory response in bone fracture healing has a noteworthy complexity, but