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The common filenames for the program's installer are Supple - Episode 2.exe, Supple Episode 2.exe, supple.exe, SuppleEpisode2-WT.exe or SuppleEpisode2.exe etc. Supple - Episode 2 can be installed on Windows XP/Vista/7/8 environment, 32-bit version. The most popular versions of the Supple - Episode 2 32.0 and 3.2.
Preview versions of the new 12/23/2022 editions of Form I-485 and form instructions, including the Form I-485 supplements, were published on Regulations.gov on Sept. 9, 2022. Preview versions of the new Form I-485 and form instructions, including Form I-485 supplements, were also published on uscis.gov on Nov. 23, 2022.
To date, 12 other studies have investigated the effects of creatine supplementation (i.e. doses ranging from 3-25 g/day for 6 days to 12 weeks) on testosterone. Two studies reported small, physiologically insignificant increases in total testosterone after six and seven days of supplementation [65, 66], while the remaining ten studies reported no change in testosterone concentrations. In five of these studies [67,68,69,70,71], free testosterone, which the body uses to produce DHT, was also measured and no increases were found.
From a clinical perspective, creatine supplementation has been found to potentially offer health benefits with minimal adverse effects in younger populations. Hayashi et al. [81] found improvements in pediatric patients with systemic lupus erythematosus and reported no adverse changes in laboratory parameters of hematology, kidney function, liver function or inflammatory markers after 12 weeks of creatine supplementation. Tarnopolsky et al. [82] reported significant improvements in fat-free mass and hand grip strength in 30 pediatric patients with Duchenne muscular dystrophy following 4 months of creatine supplementation. Importantly, the creatine supplementation protocol appeared to be well tolerated and did not adversely affect laboratory markers of kidney function, oxidative stress, and bone health [81,82,83]. In addition, Sakellaris et al. [83] reported significant improvements in traumatic brain injury-related outcomes in children and adolescents who received oral creatine supplementation (0.4 g/kg/day) for 6 months. These neurological benefits may have potential applications for young athletes participating in collision sports, which pose underlying risks of concussions or sub-concussive impacts. Further, several of these clinical trials implemented strict clinical surveillance measures, including continual monitoring of laboratory markers of kidney health, inflammation, and liver function; none of which were negatively impacted by the respective creatine supplementation interventions. These findings support the hypothesis of creatine supplementation likely being safe for children and adolescents. However, perhaps the strongest supporting evidence for the safety of creatine is the recent classification of creatine as generally recognized as safe (GRAS) by the United States Food and Drug Administration (FDA) in late 2020 ( ). Ultimately, this classification indicates that the currently available scientific data pertaining to the safety of creatine, is sufficient and has been agreed upon by a consensus of qualified experts, thereby determining creatine to be safe under the conditions of its intended use ( ). Even though infants and young children are excluded from GRAS, this would still apply to older children and adolescent populations.
The theory that creatine supplementation increases fat mass is a concern amongst exercising individuals, possibly because some experience a gain in body mass from creatine supplementation. However, randomized controlled trials (one week to two years in duration) do not validate this claim. Acute creatine supplementation (7 days) had no effect on fat mass in young and older adults; however, fat-free mass was increased [86, 87]. Furthermore, three weeks of creatine supplementation had no effect on body composition in swimmers [88]. The addition of creatine to high-intensity interval training had no effect on body composition in recreationally active females [89]. In addition, the effects of creatine supplementation during resistance training overreaching had no effect on fat mass [70]. Moreover, in a group of healthy recreational male bodybuilders, 5 g/day of creatine consumed either pre- or post-training had no effect on fat mass [90]. In other short-terms studies lasting 6-8 weeks, there were no changes in fat mass from creatine supplementation. Becque et al. [91] found no changes in fat mass after six weeks of supplementation plus resistance training. In another 6-week investigation, no significant differences in fat mass or percentage body fat were observed after creatine supplementation [42]. Furthermore, creatine supplementation during an 8-week rugby union football season also had no effect on fat mass [92].
There is a small body of research that has investigated the effects of creatine supplementation in younger females. For example, Vandenberghe et al. [176] showed that creatine supplementation (20 g/day for 4 days followed by 5 g/day thereafter) during 10 weeks of resistance training significantly increased intramuscular concentrations, muscle mass and strength compared to placebo in females (19-22 yrs). In elite female soccer players (22 ± 5 yrs), creatine supplementation (20 g/day for 6 days) improved sprint and agility performance compared to placebo [177]. Hamilton et al. [178] showed that creatine supplementation (25 g for 7 days) augmented upper-body exercise capacity in strength-trained females (21-33 yrs) compared to placebo (19-29 yrs). Furthermore, in college-aged females (20 yrs), creatine supplementation (0.5 g/kg of fat-free mass for 5 days) improved knee extension muscle performance compared to placebo [179]. In contrast, not all data show improved performance in females [89, 160, 161]. Additionally, Smith-Ryan et al. [180] reported no significant effects of creatine loading on neuromuscular properties of fatigue in young adult females. It is important to evaluate the benefit to risk ratio; as noted elsewhere in this document, there are minimal risks associated with creatine supplementation, particularly when it is evaluated against the potential benefits in females.
Accumulating research over the past decade in postmenopausal females demonstrates that creatine supplementation during a resistance training program can improve muscle mass, upper- and lower-body strength, and tasks of functionality (30-s chair stand, lying prone-to-stand test, arm curl test) (for detailed review see Candow et al. [9]). Creatine supplementation appears to be a viable option for post-menopausal females to improve muscle quality and performance. In addition to its beneficial effects on aging muscle, creatine supplementation may also have favorable effects on bone in postmenopausal females, if combined with resistance training. For example, postmenopausal females who supplemented daily with 0.1 g/kg/day of creatine during 52-weeks of supervised whole-body resistance training experienced an attenuation in the rate of bone mineral loss at the femoral neck (hip), compared to females on placebo during training [122]. Furthermore, 5 g/day of creatine supplementation during 12 weeks of resistance training in postmenopausal females resulted in a significant increase in muscle mass and upper- and lower-body strength, compared to placebo [181]. However, even without the stimulus of resistance training, there is some evidence that creatine supplementation can still be beneficial. For example, in aging females (n=10; 67 ± 6 yrs), acute creatine supplementation (0.3 g/kg/day for 7 days) significantly improved lower-extremity physical performance (sit-to-stand test) [110], and fat-free mass and upper- and lower-body strength compared to placebo [86].
Hematologic complete remission (hCR) was assessed according to criteria described by the International Working Group.17 Molecular complete remission (mCR) required the absence of detectable PML-RARA transcripts. Relapse was defined as either: (1) the reappearance of abnormal blast cells and/or promyelocytes or the development of extramedullary disease (hematologic relapse) or (2) reversion to PML-RARA positivity confirmed on serial samples after previously documented negativity (molecular relapse), whichever occurred first. The primary end point of the study, freedom from relapse (FFR), was calculated as the time from documented hCR to hematologic or molecular relapse. Secondary end points were measured as follows: overall survival (OS), time from commencement of ATRA therapy to death from any cause; DFS, time from documented hCR to the earliest of relapse or death; and failure-free survival (FFS), time from commencement of ATRA therapy to the earliest of treatment failure, relapse, or death, where treatment failure included failure to achieve mCR by the end of consolidation or withdrawal from protocol therapy because of patient refusal to continue or excessive toxicity. Early death was defined as death during induction (ie, within 36 days from the commencement of ATRA therapy). Adverse events (AEs) were reported using the Common Terminology Criteria for Adverse Events Version 3.0 (National Cancer Institute). 2b1af7f3a8
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