Dose Response of Acute ATP Supplementation on Strength Training Performance

Background: Chronic oral ATP supplementation benefits cardiovascular health, muscular performance, body composition, and recovery while attenuating muscle breakdown and fatigue. A single 400 mg dose of oral ATP supplementation improved lower body resistance training performance and energy expenditure in recreational resistance trained males, however, the minimal effective dose is currently unknown.Materials and Methods: Twenty recreationally trained men (age 28.6 ± 1.0 years, body mass 81.2 ± 2.0 kg, height 175.2 ± 1.4 cm, 1RM 141.5 ± 5.0 kg) consumed a single dose of either 400 mg, 200 mg, or 100 mg ATP (PEAK ATP®, TSI USA LLC, Missoula, MT, USA) or a placebo in a randomized, placebo-controlled crossover design, separated by a one week wash out between treatments. After warm-up, participants performed 4 sets of half-squats using free-weights until movement failure separated by 2 mins of rest between sets.Results: In comparison to placebo, 400 mg ATP significantly increased the number of set 1 repetitions (+13%, p = 0.04), and numerically increased total repetitions (+7%, p = 0.19) and total weight lifted (+6%, p = 0.22). 200 mg ATP numerically increased set 1 repetitions (+4% p = 0.47), while 100 mg ATP showed no improvements over placebo. 100 mg ATP (−4%, p < 0.05) and 400 mg ATP (−4%, p = 0.11) decreased the perceived rate of exertion compared to placebo.Conclusions: In this study, the effective minimal dose of acute oral ATP supplementation during resistance exercise to increase performance was determined to be 400 mg, while as little as 100 mg showed improvements in perceived exertion.

Identifying the Minimal Effective Dose of Dexmedetomidine Infusion for Post-Operative Pain Control in Laparoscopic Cholecystectomy Patients

Objective: To compare the frequency of need of rescue analgesia and time of first rescue analgesia) of two different doses 0.2 μg/kg/h and 0.4 μg/kg/h of IV dexmedetomidine in patients undergoing laparoscopic cholecystectomy (LC). Material and Methods: A total number of 68 patients planned for LC under general anesthesia were included from January-2020 to January-2021. The patients were randomly divided into two groups; group D1 patients received dexmedetomidine 0.2 μg/kg/h i.v and group D2: received dexmedetomidine0.4 μg/kg/h i.v. After shifting the patient in recovery unit, the need of rescue analgesia and time of first rescue analgesia was noted for each patient. Results: Mean age of patients was 42.64±13.54 years. There were 47 (69.12%) females and 21 (30.88%) male patients. Rescue analgesia was needed by 16 patients (47.1 %) in group D1 and 07 patients (20.6 %) in group D2. The time of first rescue analgesia was 167.50±11.64 minutes in groups D1 and 263.44±19.03 minutes in group D2 (p-value of <0.001). Conclusion: Dexmedetomidine in an infusion dosage of 0.4 µg/kg/hour is helpful in providing adequate postoperative analgesia. Keywords: Rescue analgesia, dexmedetomidine, laparoscopic cholecystectomy.

P087 Polyarteritis nodosa: a case report

Background Polyarteritis nodosa is a necrotizing vasculitis of small and medium caliber arteries. Rarely described in children, its pathophysiology is complex and remains poorly elucidated. Two main forms were described in the literature: cutaneous and visceral. Material and results We report the cases of two boys, aged of 7 and 11 years old. They had a history of recurrent sore throat with a recurrent aphthosis in the 11-year-old child. Both boys presented with polyarthralgias, myalgias, polymorphous skin lesions made of livedo reticularis with subcutaneous nodosa on the lower limbs in the first child and distal necrosis of the toes with oedema of the lower limbs in the second. Patients suffered also of cough evolving in a context of alteration of the general state made of fever and asthenia. A biological inflammatory syndrome was present in both children and the skin histology confirmed periarteritis nodosa. The evolution was marked by the disappearance of arthralgias and myalgias after a corticosteroid-based treatment with progressive dose reduction until minimal effective dose. Conclusion The diagnosis of Polyarteritis nodosa should be made in any child presenting with the following signs: fever, altered general condition, myalgias, arthralgias and skin manifestations. The prognosis is usually benign but long-term surveillance is necessary.

Minimal Effective Dose of Ropivacaine Under Spinal Anesthesia for Cesarean Section After Failed Vaginal Delivery by Epidural Labor Analgesia

Background: The studies associated with EC50 of ropivacaine for spinal anesthesia are few worldwide during failed vaginal trial by epidural labor analgesia transfer to cesarean section. We preliminarily explore it to determine the minimum local analgesic dose (MLAD) of ropivacaine for spinal anesthesia during failed vaginal trial by epidural labor analgesia transfer to cesarean section(CS) and survey its adverse effect. Trial design: a sequential experimentMethods: The analgesia quality was defined as effective if VAS ( Visual Analogue Scale) score was less than 3 from 15 min after spinal anesthesia to the end of CS. The Brownlee up-and-down sequential allocation was used to estimate the MLAD of subarachnoid ropivacaine and its 95% confidence intervals during failed vaginal trial by epidural labor analgesia transfer to CS. Results: There were significant changes for the time to reach maximum sensory block, the time to reach maximum motor block and the duration from spinal anesthesia to starting operation and hypotension occurence (p＜0.05, p＜0.0001, respectively) between the effective group and ineffective group. Bradyarrhythmia, nausea, vomiting and chills were no significant changes between these two groups. The EC50 dose of f subarachnoid ropivacaine for failed vaginal trial conversion to CS by epidural labor analgesia was 8.2985 mg , and 95% CI( Confidence Interval) was 8.07947mg~8.52348mg.Conclusion: The MLAD of ropivacaine was 8.2985 mg ( 95% CI: 8.0795mg~ 8.5235mg) for spinal anesthesia for failed vaginal trial by epidural labor analgesia conversion to CS. It was indicated that 8.2985 mg ropivacaine by subarachnoid block for failed vaginal trial transfer to CS can provide satisfactory and safe analgesia to parturients with low incidence rate of side effects.Clinical Trial Registration: This clinical study has been registered at www.chictr.org.cn(ChiCTR1900027527).

Regional Delivery of Anti-PD-1 Agent for Colorectal Liver Metastases Improves Therapeutic Index and Anti-Tumor Activity

Metastatic liver tumors have presented challenges with the use of checkpoint inhibitors (CPIs), with only limited success. We hypothesize that regional delivery (RD) of CPIs can improve activity in the liver and minimize systemic exposure, thereby reducing immune-related adverse events (irAE). Using a murine model of colorectal cancer liver metastases (LM), we confirmed high levels of PD-L1 expression on the tumor cells and liver myeloid-derived suppressor cells (L-MDSC). In vivo, we detected improved LM response at 3 mg/kg on PTD7 via portal vein (PV) regional delivery as compared to 3 mg/kg via tail vein (TV) systemic delivery (p = 0.04). The minimal effective dose at PTD7 was 5 mg/kg (p = 0.01) via TV and 0.3 mg/kg (p = 0.02) via PV. We detected 6.7-fold lower circulating CPI antibody levels in the serum using the 0.3 mg/kg PV treatment compared to the 5 mg/kg TV cohort (p < 0.001) without increased liver toxicity. Additionally, 3 mg/kg PV treatment resulted in increased tumor cell apoptotic signaling compared to 5 mg/kg TV (p < 0.05). Therefore, RD of an anti-PD-1 CPI therapy for CRCLM may improve the therapeutic index by reducing the total dose required and limiting the systemic exposure. These advantages could expand CPI indications for liver tumors.

Long-term time-course of strength adaptation to minimal dose resistance training: Retrospective longitudinal growth modelling of a large cohort through training records

Objective: Public health guidelines for resistance training typically emphasize a minimal effective dose approach. The intention for such guidelines is that individuals engage in these behaviors over the long-term. However, relatively few studies have examined the longitudinal time-course of strength adaptations to resistance training and those which have typically utilize small samples and/or athletic populations. Further, no studies have employed approaches to incorporate participant level random factors into modelling. Thus, the aim of this study was to examine the time-course of strength development resulting from continued participation in minimal dose resistance training in a large sample through retrospective training records. Methods: Data was available for analysis from 14,690 participants who had undergone minimal dose resistance training (1x/week, single sets to momentary failure of six exercises) with records ranging up to 352 weeks (~6.8 years) in length. Linear-log growth models examining the development of strength over time were fit allowing random intercepts and slopes by participant. In addition, the interaction of sex and age were examined as fixed effects. Results: All models demonstrated a robust linear-log relationship which on the untransformed time scale clearly demonstrated the presence of a plateau in strength development around ~1 year into training after which strength was essentially maintained with minimal growth. Sex and age had minimal interaction effects. Conclusions: Substantial strength gains are possible with the use of a minimal dose resistance training approach. Though, these begin to plateau after ~1 year of training with little impact from sex or age on the emergence of this plateau. It is unclear if this plateau can be overcome through alternative approaches. Considering this, our results support public health recommendations for minimal dose resistance training to induce and maintain strength adaptations in adults.

S62798, a TAFIa inhibitor, accelerates endogenous thrombolysis in a murine model of pulmonary thromboembolism

Pulmonary embolism (PE) is the third leading cause of cardiovascular death in western countries. The enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. In patients, venous thrombosis and thromboembolism risks are associated with increased plasma levels of TAFI (Thrombin Activatable Fibrinolysis Inhibitor) antigen as well as the active form TAFIa. S62798 is a competitive, selective and potent human TAFIa inhibitor (IC50±SD=11.2±0.4nM). It is however less potent on mouse TAFIa (IC50±SD=270±39nM). Here, we tested the ability of S62798 to enhance endogenous fibrinolysis in a mouse model of pulmonary thromboembolism. Human Tissue Factor (TF) was injected in C57Bl6 male mice. Ten minutes later, mice (n=4 to 14 per group) were treated (IV) with S62798 (from 0.01 to 100mg/kg) or vehicle (0.9% NaCl). Ten or twenty minutes (min) later, mice were anesthetized and lungs were collected, homogenized and pulmonary fibrin was quantified by ELISA. Results are expressed as ratio of geometric mean of pulmonary fibrin (μg/mL): tested treatment/ vehicle [95% confidence interval (CI)]. Ten minutes after S62798 treatment, pulmonary fibrin deposition was dose-dependently decreased with a Minimal Effective Dose of 0.04mg/kg [90% prediction interval 0.037 - 0.051] and an ED50 of 0.03mg/kg [95% CI: 0.01; 0.06]. Mice were then treated with 0.1mg/kg S62798 or vehicle (10 min after TF induction) and fibrin deposition in lungs was quantified 10 and 20 minutes post S62798 treatment. The level of pulmonary fibrin deposition was significantly decreased (p&lt;0.0001) compared to vehicle group (ratio 0.31 [0.21; 0.45] at 10 min; 0.35 [0.24; 0.51] at 20 min). Finally, the effect of S62798 (1mg/kg) in combination with heparin was evaluated (n=10/group). When administered 10 min before TF injection, heparin (2000IU/kg) significantly (p&lt;0.0001) decreased pulmonary fibrin level (20 min post TF: ratio 0.03 [0.01; 0.05]). When treatment was done in a curative setting (10 min post TF), heparin alone had no effect (p=0.85) on fibrin deposition (ratio 0.96 [0.65; 1.43]) whereas a similar significant (p&lt;0.0001) decreased pulmonary fibrin deposition was observed in response to S62798 alone or associated with heparin (ratio 0.27 [0.18; 0.40] (S62798 alone) and 0.29 [0.20; 0.43] (S62798+heparin)). In this model, curative S62798 treatment, alone or associated to heparin, accelerated clot degradation by potentiating endogenous fibrinolysis and thus decreased pulmonary fibrin deposition. Due to its capacity to enhance endogenous fibrinolysis, S62798, which has completed phase I studies, is expected to be a therapeutic option for intermediate high risk PE patients on top of anticoagulants. With early recanalization, S62798 should rapidly reduce pulmonary artery pressure and resistance, with concomitant improvement in right ventricular function, preserving cardiac function, and reducing acute PE-related morbidity and mortality in these patients. Funding Acknowledgement Type of funding source: None

Relationship Between the Dose Administered, Target Tissue Dose, and Toxicity Level After Acute Oral Exposure to Bifenthrin and Tefluthrin in Young Adult Rats

Most pyrethroid insecticides (PYRs) share a similar primary target site in mammals. However, the potency estimates of the lethal and sublethal effects of these compounds differ up to 103-fold. The aim of this study was to evaluate the relationship between the dose administered, the target tissue dose, and the effect of 2 highly toxic PYRs, tefluthrin (TEF; 0.1–9 mg/kg) and bifenthrin (BIF; 0.5–12 mg/kg), by using the oral route, a corn oil vehicle (1 ml/kg) and subcutaneous temperature (Tsc) monitoring assays in adult rats. The Tsc was determined at 30-min intervals for 5 h (TEF) or 4.5 h (BIF) after dosing. Rats were sacrificed at 6 h after dosing, and BIF and TEF concentrations were determined in blood (Bd), liver (Lv), and cerebellum (Cb) by using a GC-ECD system. The minimal effective dose of BIF (3 mg/kg) affecting Tsc was similar to that found in prior studies using other testing paradigms. Regarding TEF, a very steep relationship between the dose administered and toxicity was observed, with a near-threshold to low-effective range for Tsc at 0.1–6 mg/kg, and a near lethal syndrome at ≥ 7.5 mg/kg. At 6–7.5 mg/kg TEF, the Cb/Bd and Cb/Lv concentration ratios were both > 1. Conversely, for BIF, the Cb concentration was barely over the Bd concentration and the Cb/Lv concentration ratio remained < 1. Our results and previous findings call for more comprehensive consideration to establish the relevance of the distribution into target tissues and the tissue dosimetry for health risks through the exposure to PYRs in humans.

The Impact of Hormonal Replacement Treatment in Postmenopausal Women with Uterine Fibroids: A State-of-the-Art Review of the Literature

Background and Objectives: Hormonal replacement therapy (HRT) is effective in treating many debilitating symptoms of menopause. However, its use in women with uterine fibroids is widely debated, based on the susceptibility of these tumors to sexual steroids. This review aims to ascertain the effects of HRT on leiomyomas development and growth in postmenopausal women. Materials and Methods: Electronic databases (i.e., MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, Sciencedirect, the Cochrane Library at the CENTRAL Register of Controlled Trials, Scielo) were searched from January 1990 until May 2019. All English-written studies evaluating the impact of various HRT regimens on uterine leiomyomas were selected. Results: Seventeen papers, considering a total of 1122 participants, were included. Fifteen of these were prospective trials, of which nine were randomized controlled trials. The remaining two works were a retrospective observational trial and a retrospective case series respectively. Five studies evaluated the effects of tibolone, also comparing it with various estrogen/progestin combinations, while two were about raloxifene. Thirteen studies compared different combinations of estrogens/progestins, the most common being transdermal estrogens (used in nine studies) and medroxyprogesterone acetate at different doses (used in 10 studies). Conclusions: For women with uterine fibroids, the choice of the most appropriate HRT regimen is crucial to avoid leiomyomas growth and the symptoms possibly related to it. Available data are conflicting, but suggest that uterine fibroids might be influenced by HRT, without representing an absolute contraindication to hormonal replacement therapy. Women with uterine fibroids subjected to HRT should be periodically examined and hormonal treatment should be discontinued if leiomyomas appear to increase in size. Moreover, the minimal effective dose of progestin should be employed.