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The search and selection criteria were restricted to English language articles and limited to humans. No publication year restriction was considered. Reference lists of relevant articles and reviews were manually searched for additional reports. The results for the meta-analysis and systematic review were retrieved from the same search strategy.

Inclusion and Exclusion Criteria Studies were assessed according to the following criteria: population characteristics, intervention, and reported outcome. Different inclusion criteria were used for each primary aim. The age cut-off was set to obtain a study population as representative as possible of the average patient receiving ISI as adjuvant treatment for esophageal stenosis. Studies reporting an aggregate age of the patients were included when the mean age was under 2 years and the age range between 0 and 5 years.

In the systematic literature search concerning the effectiveness of ISI in esophageal strictures, studies evaluating ISI in all children with a history of EA repair were included. Studies focusing on different types of steroid administration IV, oral, topical were manually excluded. Conference abstracts, editorials, letters, short surveys, studies reporting non-original data systematic reviews, meta-analysis, narrative reviews and unavailable full-text articles were excluded.

Absence of discrete patient-data was an additional exclusion criterion. Disagreements about study selection were resolved by discussion. AH and RP screened full-texts of the selected studies against the inclusion and exclusion criteria. During all stages of study selection, any uncertainties or discrepancies were discussed until consensus was achieved. If consensus was not reached, disagreements were resolved by discussing them with a senior researcher JV.

Methodological Quality The included studies were reviewed independently by AH and RP on methodological quality according to the Joanna Briggs institute JBI critical appraisal tool for case reports, case series, cohort studies, and quasi-experimental studies; depending on the type of study 29 — The obtained scores could not be linked to a standardized judgement tool.

For case reports the total range varied between 0 and 8. Within the research team it was concluded that six to eight points were regarded as high quality; 4—5 points moderate quality; and 1—3 points low quality. For case series, with total range between 0—10, 8—10 was defined as high quality; 5—7 moderate quality, and 1—6 low quality.

Subsequently, quasi-experimental studies, with total range between 0—9, were divided into the following groups: 7—9 high quality, 4—6 moderate quality, and 1—3 low quality. Finally, for cohort studies with a total range between 0—11 was concluded that 9—11 would be high quality; 5—8 moderate quality and 1—4 low quality. The critical appraisals by AH and RP were crosschecked; any differences were discussed until consensus was achieved. If consensus was not reached, disagreements were resolved by discussing these issues with JV.

Data Extraction The following variables were extracted and entered into a standard data extraction form: author, publication year, country treating hospital, study type, number of included patients, patient's age at time of the injections, intervention description, type of steroid used, dosage, number of injections, time interval between injections, co-medication, length of follow-up, local side effects, systemic side effects, need for treatment of side effects, and whether the adrenocorticotropic hormone ACTH or cortisol levels had been measured.

Moreover, regarding the evaluation of the effectiveness, the following information was gathered: type of EA according to Gross 32 , stricture length, symptoms, mean number of dilatations prior to and post injection, type of dilatation technique used, need and time for further dilatation, side effects, and possible complications. Synthesis Triamcinolone is the most commonly used steroid in the treatment of esophageal strictures. Hence, all steroid dosages were converted to triamcinolone-dose equivalents for the comparison of the administered steroid dosages.

Both documents state that single injections at multiple sites up to a total amount of 80 mg have been administered without severe side effects. When multiple injections were given, the dosage of the first injection was used to group the patients. In addition, when assessing the dosage, some of the included studies did not show the total amount of received corticosteroid, yet only the amount of milligrams per kilogram body weight administered.

Statistical analysis was performed with SPSS Aggregated continuous baseline variables were calculated as means or medians of extracted variables from the included studies. Categorical and continuous variables were summarized as numbers with percentages. Using a generalized linear mixed model, pooled proportions of outcomes were calculated.

The Knapp-Hartung adjustment was applied. A prediction interval was given, which indicates the interval in which a single future observation will fall, given what has been observed. In order to perform such analysis, studies not stating the mean number of injections or the steroid dosage, were not included. In order to assess potential publication bias, a funnel plot was created. A subgroup of studies mentioning systemic complications was evaluated for age, dosage, number of injections, co-medication, and the need for treatment.

The same outcome parameters were evaluated for subgroups involving studies referring to ISI-related endocrine complications and studies measuring cortisol and ACTH blood levels. Results The systematic search strategy yielded 8, articles, of which were further assessed for eligibility. After full-text screening, 53 articles were selected for inclusion. Reference screening of the included studies yielded three additional studies suitable for inclusion. One study, discussing ISI for anastomotic esophageal strictures, was not retrieved from the search strategy, yet included in the systematic review since it complied with all inclusion criteria 34 Figure 1.

Fifty-five studies, amounting to 3, patients who underwent one or several ISI were included for the general safety assessment 12 , 34 — Five studies were included for the effectiveness assessment of ISI in the treatment of esophageal strictures, comprising esophageal atresia patients 12 , 34 , 47 , 88 , Clinical indications for the ISI varied between patients, with cutaneous hemangioma being the most common with a total of 3, patients.

Characteristics of the included studies are shown in Table 1. Characteristics of included studies. Study Types and Quality Assessment A total of sixteen case reports, 28 case series of which seventeen retrospective , twelve quasi-experimental studies and one cohort study were selected for final inclusion. The quality assessment for case reports provided two high quality, eleven moderate quality and three low quality studies.

Eleven high quality, thirteen moderate quality and four low quality case series were assessed. With regard to quasi-experimental studies, seven studies were of high quality, two of moderate quality and three of low quality. The included cohort study was classified as high quality. A summary of the quality assessments for the included studies and their reported outcomes can be found in the Supplementary Material. A funnel plot was used in order to assess potential publication bias Figure 2.

The x-axis displays the observed incidence of any complication for each of the included studies, normalized by log-transformation in order to be comparable across studies. The y-axis displays the standard error. The outcome considered was the occurrence of any complication, regardless of dosage. There is clear asymmetry, which could indicate potential publication bias, as studies mainly seem to be missing areas of low statistical significance.

Funnel plot for assessment of potential publication bias 12 , 34 — Forty-nine studies provided information on the mean number of injections, resulting in 2. The type of steroid injected, mean number of injections and time interval between injections greatly varied among the included studies. Details can be found in the Supplementary Material. Adverse events following ISI were evaluated.

The overall rate for side effects, based on 48 studies and 3, patients, was 7. Six studies mentioned the need for additional treatment local or systemic for adverse events 38 , 40 , 45 , 52 , 54 , The aggregated mean and median follow-up lengths were Systemic vs. Local Side Effects The pooled rates of local and systemic side effects were determined. A total of side effects were seen, consisting of systemic and local effects.

Further complication analysis, comparing the high and low dose groups, was not performed as the data retrieved in this systematic review did not allow further statistical analysis. Pooled proportions for systemic A and local B complications 12 , 34 — Total, total number of injections. Systemic Complications Eighteen studies reported systemic complications, of which sixteen referred to endocrinological side effects see Figure 4 34 , 36 — 40 , 43 , 45 , 46 , 52 , 53 , 55 , 58 — 61 , 81 , 82 , 84 , A total of systemic complications were described in 3, patients at risk, with being related to adrenal insufficiency, Cushingoid syndrome or growth retardation.

Among patients experiencing systemic complications, the indications for treatment were mostly periorbital or cutaneous hemangiomas, with only one study using ISI for the management of esophageal strictures.

Summary of the systemic complications. N, number of patients; n, number of complications. The assessment of complications varied between studies. Forty-four studies only provided general clinical information, five studies evaluated patients' growth curves and six studies performed blood test analysis before and after the injection to rule out the development of adrenal insufficiency. Among the six studies assessing cortisol and ACTH levels patients , four found adrenal suppression following ISI patients , mainly associated to weight loss or growth retardation 43 , 45 , 46 , 53 , 59 , One study reported the development of Cushingoid syndrome in seven patients Only two out of patients received replacement therapy being oral hydrocortisone.

All patients underwent strict clinical and laboratory follow-up. In all cases, height and weight percentiles returned to pre-treatment levels after pituitary-adrenal axis recovery. The time needed for hypothalamic-pituitary axis HPA recovery after ISI ranged between 4 and 65 weeks in the included studies. One study assessed HPA functioning in only one patient, who was re-admitted 3 weeks after the ISI due to a bronchopneumonia.

Effectiveness of ISI The mean age of the patients included in the effectiveness analysis was Only one study specified the type of esophageal atresia, with five patients being affected by type C and one patient by type D The indication for dilatation plus ISI was dysphagia in three studies 12 , 34 , 89 and failure to thrive in one study One study did not explicitly mention the reason for dilatation All patients received one or multiple injections of 40 mg of triamcinolone acetonide or less range 8—40 mg.

The injections were performed within four quadrants at the level of the esophageal stricture in all studies. In two studies, more than one injection was scheduled independently from the patients' symptoms 12 , 89 , while in the remaining studies the number of injections was individualized. The mean number of injections per patient was 2.

In all studies ISI were performed directly before an endoscopic dilatation, carried out either with balloon or bougie. There was a minimum interval of 1 week between one ISI and the following one Referring to side effects, only one patient 0. No local side effects were defined.

The follow-up length was mentioned in two studies, respectively, being Four studies stated the number of ISI required or planned and the number of dilatations needed for each patient before and after the first injection, as shown in Table 2 12 , 47 , 88 , The mean and median number of dilatations needed before ISI were 5. After ISI the mean and median number of further dilatations required were, respectively, 1. Overall, a mean of 7.

Summary of dilatations and ISI per patient. One study was not included in the analysis due to the lack of data referring to the number of dilatations prior to ISI This study does show a significant difference in the esophageal diameter between patients receiving dilatation plus ISI and those receiving dilatations only, with the former group achieving a bigger diameter after treatment. Nevertheless, this difference was not sustained after three injections.

Discussion Summary of Main Results This systematic review aimed to determine the safety of ISI in young children and their effectiveness in anastomotic strictures after EA repair. The studies included in this systematic review and meta-analysis widely varied in terms of study design, population, and outcome.

Different therapeutic approaches were used, with no standardized protocols neither for different treatment indications nor within the same disease group. As a consequence, a wide range of dosages and mean number of injections have been reported. The literature review shows that the reported side effects following ISI are mostly local and do not require additional treatment.

To date, several papers have described the potential use of circulating miRNAs as specific biomarkers in the anti-doping field. For example, the use of continuous erythropoietin receptor activator induces higher plasma levels of miR the plasma dosage of this miRNA could be used for the detection of erythropoiesis-stimulating agents Zhou et al. Another study described a relationship between the expression of 4 miRNAs and the use of recombinant human GH Keane et al.

Moreover, the study of Leuenberger et al. The use of circulating miRNAs to detect performance-enhancing agents could be incorporated into the adaptive model of the ABP, considering their high stability in blood and unmodified characteristics when exposed to the environmental factors Ponzetto et al. Furthermore, the possibility to detect miRNAs not only in serum and plasma but also in urine, saliva and other body fluids Gilad et al.

Organ damage and miRNA expression profiles investigated in the literature. Cardiovascular System and Heart The adverse effects on the heart and cardiovascular system caused by AAS abuse have been frequently investigated: harmful changes in the risk factors for cardiovascular pathology are frequently described, such as the decrease in plasma HDL cholesterol levels Payne et al.

Moreover, perhaps through a direct cardiotoxic action, which results in cardiomegaly and cardiovascular failure, AASs are often involved in the sudden cardiac death of young consumers Frati et al. MiRNAs exert their action though signaling and transcriptional pathways affecting cardiac development, function, and disease.

With the aim of identifying miRNAs related to dysfunctions, several heart diseases Ischemia, Hypertrophy, cardiac fibrosis, and Arrhythmia have been investigated. MyomiRs miRa, miRb and miR play a pivot role in the control of myosin heavy chain isoform expression Van Rooij et al. Moreover, miR-1 and miR increased the risk of arrhythmia in the ischemic heart Huang et al. Several studies reported elevated plasma levels of miR-1, miR, miRa, and miR, after acute myocardial infarction, suggesting a role as valuable prognostic biomarkers Hata, ; Joladarashi et al.

Musculoskeletal Apparatus Skeletal muscle represents the example of the tissue subjected to environmental impulses nutrients and exercise and, about that, AAS use is frequently combined with resistance training. This practice is linked to a higher risk of tendon injury Seynnes et al. Several studies using northern blot analyses reported that the myomiR family miR-1, miRa, miRb, miR, miRa, miRb, and miR is strictly striated-muscle specific Sempere et al.

Muscle fibers are typically distinguished in type I slow and type II fast fibers. Considering that AASs are strictly related to muscular hypertrophy, a direct relationship to these miRNA levels expressed in plasma and drug abuse could be hypothesized. It is interesting that after training the mature levels of miR-1, miR and miR decrease both at the tissue level and the plasma level Kirby et al. Furthermore, miR plasma levels were reported to be up-regulated in aged human skeletal muscle Kim et al.

At the light of these findings, a direct relationship between miRNA plasma levels and type of sport practiced could be considered, given that frequently AAS use is associated with these activities. Reproductive Systems AASs are related to various side effects in males hypofertility and gynecomastia and in females virilization and hirsutism, acne, irregular menses, lower-pitched voice, and male-pattern baldness, increased body hair and sex drive Evans, a ; Parkinson and Evans, ; Zahnow et al.

In males, moreover, there are multiple effects on the neuroendocrine system such as hypogonadism especially following abrupt discontinuation of the drug , impotence, suppression of spermatogenesis and inhibition of the hypothalamic—pituitary— testicular axis Dickerman et al. Infact, androgens play a pivotal role in development and maintenance of the male reproductive system; the exogenous administration of androgens leads to a reduction in endogenous production, causing testicular atrophy, androgen deficiency, and infertility Fronczak et al.

Moreover, AAS abuse promotes prostatic hypertrophy and increases the risk of prostate cancer El Osta et al. Aberrant expression of numerous miRNAs was reported related to different reproductive system diseases. For example, the expression profile of miR was found to be altered in prostate imbalance Bucay et al. Another study described a pivotal role for miR and miR in prostate cancer regulation Zhang et al. Afshar et al.

Notwithstanding the numerous studies, to date it is very difficult to establish which are the miRNAs that could be considered as important molecular biomarkers for these diseases Bertoli et al. The principal adverse effects derived from AAS use on the female reproductive system are related to the subtle equilibrium of the female hypothalamus-pituitary-gonadal axis, which becomes twisted consequently to increases in concentration of circulating testosterone and reduction in estrogen activity.

In particular, the diminishing in estrogen and progesterone levels results in: i inhibition of follicle formation; ii ovulation, iii irregular menstrual cycle, iv amenorrhea absence of the menstrual cycle. As stated before, circulating miRNAs are considered as possible biomarkers for the identification of different pathological conditions. It is very interesting that miR, miR, and miR showed higher levels in ovarian cancer compared to normal ovary state, suggesting an important role as molecular biomarkers Donadeu et al.

Central Nervous System The side effects linked to AAS use on the central nervous system CNS are prevalently linked with the behavioral sphere such as impulsive behavior, aggression, anxiety, hypomania, and occasionally, depressive disorders Henderson et al.

Moreover, miRNAs are expressed highly in neurons, and neuronal miRNA pathways can create an extremely powerful mechanism to dynamically adjust the protein content of neuronal compartments. However, miRNAs are hypothesized to play a specialized role in cellular responses to stress Hunsberger et al. Moreover, two of the best-studied miRNAs related to cognitive impairment roles are miR and miR An up-regulation of miR was associated with an improvement in learning and memory, while miR plays an important role in neurogenesis: these two miRNAs could be used as molecular biomarkers for brain functionally and pharmacological therapies Shi, ; Nadim et al.

A controversial role is played by miR several reports in the literature describe a different behavior according to different biological conditions, resulting in some instances of up-regulation whereas, in some, it is down-regulated Adlakha and Saini, After liver injury, studies have documented the presence of miRNAs in the circulation. Liver damage caused by chemical toxins and diet can produce a release of various miRNAs inside exosomes, microvescicles, HDL, apoptotic bodies and proteins, in the same way as other disturbances such as alcohol, acetaminophen, viral, or bacterial infection, etc… Szabo and Bala, MiR, miR, miR, miR, miR, and miR, instead, are involved in lipid metabolism too: their serum levels are significantly higher in patients with non-alcoholic fatty liver disease compared to controls Takahashi et al.

Moreover, a large number of miRNAs have been related to inflammatory responses let-7, miR As previously described, serum levels of miR, miR, and miR, seem to be related to HCV infection, and they were evaluated as markers of inflammation Szabo and Bala, ; Takahashi et al. Many studies on miRNAs involved in liver injury caused by drug assumption were evaluated: in serum samples miR, miRb, miRa, miR, and miR, were up-regulated Bafunno et al.

Higher level of miR into the bloodstream were documented after hepatocyte death: the plasma levels of this miRNA are upregulated in alcoholic and non-alcholic liver diseases, and virus related consequences chronic HBV and HCV Takahashi et al. As previously described, miR is involved in several side effects related to AAS abuse: for this reason, it could be considered as an important molecular biomarker Zheng et al.

In some cases, anabolic abuse has been related to the nephrotic syndrome and focal segmental glomerulosclerosis Herlitz et al. As previously reported miRa upregulated and miR downregulated are related to focal segmental glomerulosclerosis; moreover, among several miRNAs analyzed in renal fibrosis, miR upregulated and miR downregulated expression were found altered Badal and Danesh, Other studies described a large number of miRNAs miR, miR, miRa, miRb, miR, miR with an increased expression profile in human nephrosclerosis biopsies Wei et al.

Several studies described an altered miRNA expression profile in urinary exosomes in diabetic nephropathy patients miRa and miR upregulated, while miR and miR under-regulated Li et al. Skin Acne vulgaris and folliculitis are frequently described in AAS users: these symptoms are related to hypertrophy of the sebaceous glands.

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In looking at the my FX book demo account it looks like the system is very broker dependent. The software takes extremely small and short trades. During this period the average pips gained in a trade was around 1. Which means if you have any spread whatsoever with your brokerage it will be very difficult for you to make money using this software.

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Which means if you have any spread whatsoever with your brokerage it will be very difficult for you to make money using this software. The Forex steroid software is clearly spread dependent. I would like to see the developers of the system run their software and alive account before I get involved.

There are many systems that work very well on demo accounts and live accounts but I generally like to see someone else run and EA on alive account before I do it myself. If you are new to Forex robot nation please feel free to click contact at the top of the page and send me a personal email if you ever need any help with your Forex trading.

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