Interval Research Articles

Exercise Training Independent of Intensity Lowers Plasma Bile Acids in Prediabetes.

People with obesity have high circulating bile acids (BA). Although aerobic fitness favors low circulating BA, the effect of training intensity before clinically meaningful weight loss on BA is unclear. This study aimed to test the hypothesis that 2 wk of interval (INT) versus continuous (CONT) exercise would lower plasma BA in relation to insulin sensitivity. Twenty-three older adults with prediabetes (ADA criteria) were randomized to 12 work-matched bouts of INT ( n = 11, 60.3 ± 2.4 yr, 32.1 ± 1.2 kg·m -2 ) at 3 min at 50% HR peak and 3 min at 90% HR peak or CONT ( n = 12, 60.8 ± 2.4 yr, 34.0 ± 1.7 kg·m -2 ) at 70% HR peak cycling training for 60 min·d -1 over 2 wk. A 180-min 75-g oral glucose tolerance test (OGTT) was performed to assess glucose tolerance (tAUC), insulin sensitivity (Siis), and metabolic flexibility (RER postprandial -RER fast ; indirect calorimetry). BA ( n = 8 conjugated and 7 unconjugated) were analyzed at 0, 30, and 60 min of the OGTT. Anthropometrics and fitness (V̇O 2peak ) were also assessed. INT and CONT comparably reduced body mass index (BMI; P < 0.001) and fasting RER ( P < 0.001) but raised insulin sensitivity ( P = 0.03). INT increased V̇O 2peak as compared with CONT ( P = 0.01). Exercise decreased the unconjugated BA chenodeoxycholic acid iAUC 60min ( P < 0.001), deoxycholic acid iAUC 60min ( P < 0.001), lithocholic acid iAUC 60min ( P < 0.001), and glycodeoxycholic acid (GCDCA) iAUC 60min ( P < 0.001). Comparable reductions were also seen in the conjugated BA hyodeoxycholic acid iAUC 60min ( P = 0.01) and taurolithocholic acid iAUC 60min ( P = 0.007). Increased V̇O 2peak was associated with lowered UDCA 0min ( r = -0.56, P = 0.02) and cholic acid iAUC 60min ( r = -0.60, P = 0.005), whereas reduced BMI was related to higher GDCA 0min ( r = 0.60, P = 0.005) and GCDCA 0min ( r = 0.53, P = 0.01). Improved insulin sensitivity correlated with lower GCDCA iAUC 60min ( r = -0.45, P = 0.03) and GDCA iAUC 60min ( r = -0.48, P = 0.02), whereas increased metabolic flexibility was related to deoxycholic acid iAUC 60min ( r = 0.64, P = 0.004) and GCDCA iAUC 60min ( r = 0.43, P = 0.05). Short-term training lowers some BA in relation to insulin sensitivity independent of intensity.

One-day versus two-day mifepristone–misoprostol interval prior to initiation of misoprostol during late second trimester medication abortion: A cohort study

ObjectivesTo compare one-day versus two-day mifepristone–misoprostol interval in late second trimester medication abortion. Study designThis retrospective cohort study was conducted at St. Paul’s Hospital Millennium Medical College, in Ethiopia. Data were collected retrospectively and analysed with SPSS 23 using simple descriptive analysis, t-test, Chi-squared test, and regression analysis, as appropriate. P-value < 0.05 and adjusted odds ratio (AOR) with 95% CI were used to present results significance. ResultsA total of 282 women who had medication abortion in the late second trimester (167 with one-day and 115 with two-day mifepristone-misoprostol intervals) at 20–28 weeks of gestation were analysed. Both median and mean induction to expulsion interval (I-E) were much higher in the one-day mifepristone-misoprostol (mife-miso) interval than in the two-day mife-miso interval group. The median (and mean) I-E in the one-day interval group was 24 hours (21.9+/−6.6 hours) compared to 12 hours (14.6+/−8.8 hours) in the two-day mife-miso interval group (p-value < 0.001). Expulsion rate within 12 hours of starting misoprostol was significantly higher in the two-day cohort than in the one-day cohort (73% vs 25.6%, p-value < 0.001, aOR = 19.08 95%, CI = 5.1–70.7). ConclusionsFor second trimester medication abortion at later gestation, a two-day mifepristone-to-misoprostol interval significantly reduces induction to expulsion time compared to a one-day interval. ImplicationsCompared to one-day interval, administration of mifepristone two days prior to misoprostol initiation has a shorter interval of induction to expulsion and a higher rate of abortion completion within 12 hours of initiation of misoprostol during late second trimester medication abortion.

Aerobic adaptations following two iso-effort training programs: an intense continuous and a high-intensity interval.

The intensity of the training stimulus and the effort exerted (regarded as an index of internal load) to complete an exercise session are driving forces for physiological processes and long-term training adaptations. This study compared the aerobic adaptations following two iso-effort, ratings of perceived exertion (RPE)-based training programs, an intense continuous (CON) and a high-intensity interval (INT). Young adults were assigned to a CON (n=11) or an INT (n=13) training group to perform 14 training sessions within 6 weeks. The INT group performed running bouts (9.3±4.4 repetitions) at 90% of peak treadmill velocity (PTV) with bout duration equal to 1/4 of time to exhaustion at this speed (134.2±27.9 s). The CONT group ran (1185.0±487.6 s) at a speed corresponding to -2.5% of critical velocity (CV; 80.1%±3.0% of PTV). Training-sessions were executed until RPE attained 17 on the Borg scale. VO2max, PTV, CV, lactate threshold velocity (vLT), and running economy were assessed pre-, mid-, and post-training. Both CONT and INT methods increased (p<0.05) VO2max (INT: 57.7±8.1-61.41±9.2; CONT: 58.1±7.5-61.1±6.3 mL kg-1 min-1), PTV (INT: 14.6±1.8-15.7±2.1; CONT: 15.0±1.7-15.7±1.8 km h-1), CV (INT: 11.8±1.4-12.8±1.8; CONT: 12.2±1.6-12.9±1.7 km h-1), and vLT (INT: 9.77±1.1-10.8±1.4; CONT: 10.4±1.4-11.0±1.8 km h-1) with no differences (p>0.05) between them; running economy remained unchanged. The continuous training method, when matched for effort and executed at relatively high intensity at the upper boundaries of the heavy-intensity domain (∼80% of PTV), confers comparable aerobic adaptations to those attained after a high-intensity interval protocol following a short-term training period.

Human skeletal muscle mitochondrial responses to single-leg intermittent or continuous cycle exercise training matched for absolute intensity and total work.

There is renewed interest in the potential for interval (INT) training to increase skeletal muscle mitochondrial content including whether the response differs from continuous (CONT) training. Comparisons of INT and CONT exercise are impacted by the manner in which protocols are "matched", particularly with respect to exercise intensity, as well as inter-individual differences in training responses. We employed single-leg cycling to facilitate a within-participant design and test the hypothesis that short-term INT training would elicit a greater increase in mitochondrial content than work- and intensity-matched CONT training. Ten young healthy adults (five males and five females) completed 12 training sessions over 4 weeks with each leg. Legs were randomly assigned to complete either 30 min of CONT exercise at a challenging sustainable workload (~50% single-leg peak power output; Wpeak) or INT exercise that involved 10 × 3-min bouts at the same absolute workload. INT bouts were interspersed with 1min of recovery at 10% Wpeak and each CONT session ended with 10min at 10% Wpeak. Absolute and mean intensity, total training time, and volume were thus matched between legs but the pattern of exercise differed. Contrary to our hypothesis, biomarkers of mitochondrial content including citrate synthase maximal activity, mitochondrial protein content and subsarcolemmal mitochondrial volume increased after CONT (p < 0.05) but not INT training. Both training modes increased single-leg Wpeak (p < 0.01) and time to exhaustion at 70% of single-leg Wpeak (p < 0.01). In a work- and intensity-matched comparison, short-term CONT training increased skeletal muscle mitochondrial content whereas INT training did not.

Indicators of the effectiveness of the competitive activity of boxers, taking into account different manners of fighting

Boxing is one of the famous and spectacular sports in our country and abroad. The progress of sports is determined on the basis of objective knowledge about the structure of competitive activities and the preparation of athletes, taking into account the general laws of the formation of sports skills and the individual capabilities of single-player athletes. In competitive activities, the positive and negative sides of boxers' skill are reflected, and therefore the features of modern boxing. However, it is not so easy to detect them due to the complexity of the matches during the competition, i.e. the competitive activity itself, which consists of a large number of the most diverse aspects of the process and, accordingly, ways of studying them. In the theory and methodology of boxing, we did not find a clear concept of studying the patterns of the development of competitive activity. We performed a selection of technical and tactical indicators of sports activity, which are determined primarily by the total number of blows and were used during the fight: the coefficient of effectiveness of blows (KEU) - the ratio of the number of blows that reached the goal to the total number of blows inflicted during the fight; defense reliability coefficient (DRC) - the ratio of the number of effective blows to the total number of blows inflicted during the fight; density of technical actions (SHTD) - the ratio of the number of hits that reached the goal to the duration of the match (in minutes); attack interval (IA) - the ratio of the duration of the fight (in seconds) to the total number of blows inflicted during the fight. The results of various experimental and theoretical studies in this direction are difficult to systematize in connection with the various goals, tasks and methods of these studies, which reduces the value of the obtained scientific data. The rules of boxing competitions, including the fight formula, were often changed during the period under consideration. The return to the previous 3×3 system again changed the requirements for the standards of organizing competitive activities of athletes in amateur boxing. As it was shown above, when the battle formula is changed, the parameters of the competitive activity also undergo changes, for example, the battle density indicator increases. In this regard, in the training process, it is necessary to take into account the rules by which the future fight is planned. This will make it possible to transform sports loads in a timely manner, taking into account the revealed patterns of changes in competitive activity indicators.

The effect of prolonged interval and continuous exercise in the heat on circulatory markers of intestinal barrier integrity.

The purpose of this study was to determine the effect of prolonged high-intensity interval (INT) and moderate-intensity continuous (CONT) treadmill exercise in the heat on markers of enterocyte injury and bacterial endotoxin translocation. Nine males completed 2 h of work-matched exercise in the heat (40°C and 15% RH) as either INT (2min at 80% VO2max and 3min at 30% VO2max) or CONT (~ 50% of VO2max). Blood samples collected pre- and post-exercise were assayed for intestinal fatty acid-binding protein (I-FABP), claudin-3 (CLDN-3), and lipopolysaccharide-binding protein (LBP). I-FABP was significantly increased from pre- to post-exercise in CONT (913.96 ± 625.13 to 1477.26 ± 760.99pg•mL-1; p = 0.014, d = 0.766) and INT (714.59 ± 470.27 to 1547.93 ± 760.99pg•mL-1; p = 0.001, d = 1.160). Pre- to post-exercise changes in I-FABP were not different between CONT and INT (p = 0.088, d = 0.414). LBP was significantly increased from pre- to post-exercise in INT (15.94 ± 2.90 to 17.35 ± 3.26μg•mL-1; p = 0.028, d = 0.459) but not CONT (18.11 ± 5.35 to 16.93 ± 5.39μg•mL-1; p = 0.070, d = 0.226), and pre- to post-exercise changes in LBP were higher in the INT compared to CONT (p < 0.001, d = 1.160). No significant changes were detected from pre- to post-exercise for CLDN-3 in CONT (14.90 ± 2.21 to 15.30 ± 3.07μg•mL-1) or INT (15.55 ± 1.63 to 16.41 ± 2.11μg•mL-1) (p > 0.05). We conclude that prolonged exercise in the heat induces enterocyte injury, but interval (or intermittent) exercise may cause greater bacterial endotoxin translocation which may increase the risk for local and systemic inflammation.

Effects Of Specific Exercise Training During 120 Days Isolation On Physiological Kinetics And Inhibitory Control

PURPOSE: Long-term isolation is known for the detrimental effects of inactivity and decreased external stimuli on physical and cognitive systems, which is relevant for space travel in microgravity but also for pandemic-related isolation periods. Exercise countermeasures are investigated in terrestrial analog settings concerning feasibility, time efficiency, and overall beneficial effects on cardiorespiratory and cognitive fitness (i.e., positive exercise-cognition interaction). In terrestrial settings, interval (INT) and continuous (CON) treadmill exercise showed positive effects on heart rate (HR) and oxygen uptake (V̇O2) capacities and kinetics, but research for space application is still pending. We expected (I) negative effects of isolation on cognitive performance and (II) physical fitness improvements, especially from INT. METHODS: Six participants (34 ± 6 years, 3 females) spent 120 days in isolation on a simulated journey to the moon (SIRIUS-19). 8 weeks of CON, followed by 8 weeks of INT aerobic exercise on a treadmill were conducted in a crossover design. Cardiorespiratory capacities, kinetics (HR, V̇O2), and cognitive performance (Flanker task measuring inhibitory control) were assessed with an exercise protocol, including pseudo-random binary sequences (PRBS), constant work-rate phases (Rest, 3, 6, 9 km h-1, recovery), and incremental exercise for Pre, Post, and five times during isolation (ANOVA: time x phase). RESULTS: Peak values for HR (P = 0.025), V̇O2 (P = 0.012), and respiratory exchange ratio (P = 0.001) had significant time effects with lower values during isolation. Kinetics of HR and V̇O2 improved during the mission with slightly better effects for INT (both p < 0.05). Inhibitory control was not altered by 120 days of isolation. CONCLUSIONS: This study proved the successful implementation of cognitive testing within our endurance exercise test. Positive effects for INT and CON aerobic exercise were confirmed for HR, but not for V̇O2 kinetics during isolation periods. We assume the lack of general physical activity is merely compensated for by the applied exercise countermeasure, at least in 1G contexts. Currently, additional exercise modalities (i.e., strength training, passive treadmill exercise) are investigated during a consecutive 240-day mission (SIRIUS-21).

Effects of aerobic exercise in confinement on cardiorespiratory kinetics and cognitive functions – Results from the 4-month SIRIUS-19 isolation project

IntroductionConfinement during sojourns in microgravity affects cardiorespiratory fitness, cognitive parameters, and their interaction with influences on mission success, fitness, and overall well-being. The aim of the experiment was to test the efficacy of two endurance exercise countermeasures to maintain aerobic fitness, indicated by cardiorespiratory kinetics, and cognitive performance during 120 days of confinement. MethodsSix participants (34 ± 6 years, 3 females) spent 120 days in confinement, conducting eight weeks of either continuous (CON) or interval (INT) aerobic treadmill exercise in a crossover design. Heart rate (HR) and oxygen uptake (V˙O2) were assessed with an exercise test protocol, including pseudo-random work rate (WR) changes to determine the respective kinetics before the start of confinement (pre), five times during confinement (mission day (MD) 9(±1), 29(±1), 57(±1), 87(±1), and 117(±1)), and after the termination of the mission phase (post). Additionally, constant WR phases and incremental exercise were part of the protocol. During the constant phases of the exercise protocol, cognitive performance was assessed. ResultsHR kinetics accelerated, and mean HR values during the work rate protocol decreased as the mission progressed (p < 0.05). CON and INT exercise both seemed to speed HR kinetics during the mission, with slightly better effects for INT. Inhibitory control was not altered by 120 days of confinement. ConclusionDetrimental effects on cardiorespiratory fitness and cognitive performance from the lack of general physical activity during confinement were compensated by the applied exercise countermeasure, with no clear advantage for CON or INT exercise.

Adaptive benchmarking design for additive manufacturing processes

Standards enabling the objective tolerancing and evaluation of dimensional and geometrical performances of additive manufacturing (AM) printers are still missing. The design, printing and measurements of geometrical benchmark test artefacts (GBTA) is the current solution proposed in literature. However, the current GBTA with fixed dimensions cannot cover most of the available printing area of printers with large building platform dimensions. This article proposes to solve this problem by developing an adaptive GBTA design whose main dimensions can be adapted to any common 3D printer. Moreover, an innovative design is implemented to decrease the risk of warping. The adaptive GBTA will then be used to characterise the performances of two different architecture material extrusion printers (Ultimaker 2+ and Pollen AM Series MC). Dimensional and geometrical accuracy, as well as top surface topography, were evaluated. The Ultimaker printer could reproduce features with maximum deviations below the tolerance interval (IT) 13 of the ISO 286-1, while the Pollen machine achieved a higher IT of 15 or 16. The highest geometrical deviations were observed for the coaxiality of cylinders oriented along the build direction (Ultimaker: 0.250 mm and Pollen: 0.497 mm). Top surface topography exhibited higher Ra values for Pollen (13.7 µm) than for Ultimaker 2+ (4.9 µm). The performances of the Pollen printer were lower than the Ultimaker machine in terms of surface topography, dimensional and geometrical accuracy. The proposed adaptive GBTA design covers most of the printing areas exhibited by Pollen and Ultimaker printers and offers flexibility to test other printers even with larger or smaller dimensions.

The oncological outcome of the patients with ovarian clear cell cancer: Platinum-based adjuvant chemotherapy is not suitable

Background/Aim: Ovarian clear cell cancer (OCCC) is one of the rare histological subtypes of epithelial ovarian cancer with different tumoral biology and prognosis. This study aimed to evaluate the clinical and pathological data of OCCC and define the prognostic factors. Methods: Sixty-three patients with OCCC were included in this retrospective cross-sectional study. Patients with mixed-type clear cell carcinoma were excluded. Response to chemotherapy was assessed according to the WHO criteria. The survival analysis was performed using the Kaplan-Meier method and survival curves were compared with the log-rank test. Cox proportional hazards model was used in the multivariate analysis. Results: The mean age of patients was 54.6 (10.7) years. Twenty-three (36.5%) patients were stage III&IV. Systematic lymphadenectomy was performed in 55 (87.3%) patients and 13 (23.6%) had lymph node metastasis. Maximal cytoreduction was performed in 57 (90.5%) patients, optimal cytoreduction, in 1 (1.6%) patient, and suboptimal cytoreduction was performed in 2 (3.2%) patients via primary cytoreductive surgery. The complete clinical response rate following adjuvant treatment was 61.1% in stages III&IV. Five-year failure-free survival was 63% in the entire cohort. According to the multivariate analysis, the stage was an independent risk factor for treatment failure. The probability of recurrence increased 24 times in stages III and IV (95% Confidence interval: 5.561-104.421; P<0.001). Conclusion: The stage of the disease is a prognostic factor for OCCC. The response to platinum-based chemotherapy in OCCC is very low.

Continuation of Copper T in Immediate Postplacental, Immediate Postabortal and Interval Period of Insertion.

Copper containing IUCDs are one of most effective mode of contraception for birth spacing. We conducted this prospective observational study to suggest a possible better period of insertion of IUCDs with cost-saving benefits. All married women in the reproductive age group desirous of Copper-T 375 IUD insertion in either immediate postplacental (PP), immediate postabortal (PA) or interval (INT) period were recruited. The women were asked to return for scheduled follow-up visits at 6weeks, 6months and 12months. They were advised to visit family planning clinic any time if they experienced pelvic pain, discharge per vaginum, unusual bleeding or missed periods. At each visit, women were interviewed for any side effects they have experienced and were asked to elaborate. Pelvic pain was assessed from visual analogue scale. Continuation rate was measured at the end of one year. Women in INT group (90.14%) had the highest continuation rate followed by PP (83.18%) and PA (80%) groups. Women in PP (AOR = 3.37, 95% CI 1.17-9.72) and PA (AOR = 4.53, 95% CI 1.33-14.04) groups had higher odds of discontinuation compared to INT group after adjusting for age, parity, working and education status. There was a significant difference between the groups when cumulative expulsion was considered (p = 0.045), but none when cumulative removal (p = 0.107) was taken into account. The continuation rate remained high in women who had insertion in the interval period compared to immediate postplacental and postabortal periods.

Greater decrements in neuromuscular function following interval compared to continuous eccentric cycling

Our aim was to determine the demands and consequences of a single session of continuous (CONT) or interval (INT) eccentric cycling. Fourteen healthy males performed ‘work-matched’ CONT and INT eccentric cycling in a cross over design. Measures of maximal voluntary contraction (MVC), resting twitch force, voluntary activation (VA), muscle soreness and creatine kinase (CK) were taken at baseline, immediately post, and 24, 48 and 72 h post the first exercise bout. The second bout was used to characterise within session demands. Decreases in MVC (INT 19%, CONT 13%), twitch force (INT 31%, CONT 18%), and VA (INT 10%, CONT 6%) were observed immediately post session (p < 0.05). Reductions in twitch force were greater after INT (p < 0.05) and lasted 48 h. Muscle soreness was greater following INT, versus CONT (p < 0.05), although no differences in CK were observed. Metabolic demands (% of V̇O2peak and [BLa]) were greater during INT vs. CONT (32 ± 6% 28 ± 6%; p < 0.001), [BLa] (1.0 ± 0.4 vs. 0.8 ± 0.2 mmol·L−1; p < 0.001) and RPE (12 ± 1 vs. 11 ± 1; p < 0.001), respectively. Total time under tension was 48% greater in CONT compared to INT (p < 0.001), whereas average torque (during exercise) was 40% greater during INT compared to CONT (p < 0.001). Interval eccentric cycling exacerbates muscle soreness, decrements in muscle function and lengthens recovery compared to a work matched continuous bout, which is attributable to increased force rather than time under tension.

Incidence of recently acquired hepatitis C virus infection among HIV-infected patients in southern Spain.

Spain is close to HCV microelimination, so rates of recently acquired HCV infection (RAHC) should decrease. Nowadays, men who have sex with men (MSM) carry the highest risk of HCV acquisition. Our aim was to estimate the incidence of and the factors associated with RAHC, together with reinfection rates, among patients sexually infected by HIV. Primary RAHC infection was diagnosed when anti-HCV antibody seroconversion was documented. In anti-HCV positive patients, initially without HCV viraemia, a diagnosis of reinfection was established if plasma HCV RNA was detected. All 350 patients tested negative for anti-HCV at baseline and had at least one follow-up visit. Among them, there were 16 RAHC cases from 2016 to 2019. RAHC incidence rates [IR (95% confidence interval, CI)] per 100 person-years were 3.77 (0.5-12.9) in 2016, 1.85 (0.6-4.3) in 2017, 1.49 (0.4-3.8) in 2018 and 1.98 (0.6-4.5) in 2019. Only previous sexually transmitted infections [incidence rate ratio (IRR) = 18.23, 95% CI: 1.93-172.1; P=0.011], male sex (IRR = 8.33, 95% CI: 1.38-54.15; P=0.026) and sharing chem-sex drugs (IRR: 4.93, 95% CI: 1.17-20.76; P=0.030), were independently associated with RAHC. Four out of 42 (9.5%) patients became reinfected. The incidence of RAHC among HIV-infected patients showed a decrease after 2016, although a lower but steady incidence of residual cases still remains. HCV reinfections showed a similar pattern. New infections were associated with sharing chem-sex drugs among MSM.

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme.

Background and AimsTofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes.MethodsThree cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event].ResultsIn the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23–7.00] for placebo and 1.35 [0.16–4.87] and 0.64 [0.02–3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02–5.42], 2.05 [0.42–6.00], and 6.64 [3.19–12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24–2.27], 3.48 [2.79–4.30], and 0.15 [0.04–0.38], respectively. No SIs resulted in death.ConclusionsDuring induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

S0703 Tofacitinib for the Treatment of Ulcerative Colitis: Up to 6.8 Years of Safety Data From Global Clinical Trials

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Efficacy and safety of tofacitinib were evaluated in randomized, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, and in an ongoing, open-label, long-term extension (OLE) study (NCT01470612) (1–3). We report updated tofacitinib safety analyses from the tofacitinib UC clinical program, with exposure up to 6.8 years. METHODS: Two cohorts were analyzed: P3 Maintenance (N = 592; patients [pts] receiving placebo, tofacitinib 5 or 10 mg twice daily [BID]) and Overall (N = 1,157; pts receiving tofacitinib 5 or 10 mg BID in P2/P3/OLE studies; data as of May 2019, database not locked). Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for adverse events (AEs) of special interest. Opportunistic infections (OIs), malignancies, major adverse cardiovascular events (MACE), and gastrointestinal (GI) perforations were reviewed by independent adjudication committees. RESULTS: Demographics, clinical characteristics, and safety data are shown in the table. In the Overall Cohort, 1,157 pts received ≥ 1 dose of tofacitinib 5 or 10 mg BID; most pts (N = 959, 83%) received an average dose of 10 mg BID. Median treatment duration was 623 (range 1–2,494) days (2,581.3 PY of exposure). IRs (95% confidence interval) for AEs of special interest were: deaths, 0.19 (0.06, 0.44); serious infections, 1.70 (1.24, 2.27); herpes zoster (non-serious and serious), 3.48 (2.79, 4.30); OIs, 1.07 (0.71, 1.55); malignancies (excl. non-melanoma skin cancer [NMSC]), 0.75 (0.46, 1.16); NMSC, 0.73 (0.44, 1.13); MACE, 0.26 (0.11, 0.54); deep vein thrombosis, 0.04 (0.00, 0.21); pulmonary embolism, 0.15 (0.04, 0.38); GI perforations, 0.11 (0.02, 0.33). Results in the Overall Cohort as per the previous Nov 2017 data cut are presented for context (4). CONCLUSION: The safety profile of tofacitinib in pts with UC was manageable and consistent with that of other UC therapies incl. biologics. Overall, IRs for AEs of interest have generally remained stable in the tofacitinib UC clinical program over an extended period of time (up to 6.8 years).Table 1

The association between removing and reintroducing man-made jumps in terrain parks and severe alpine skiing and snowboarding injuries

ObjectivesTo explore the effect of removing and reintroducing man-made jumps in terrain parks (TPs), on the proportion of severe injuries among alpine skiers and snowboarders in Québec, Canada. DesignQuasi-experimental study. MethodsInjuries were identified via injury report forms completed by ski patrollers during seasons 2000–2001 to 2016–2017 in Québec ski areas. Severe injuries were defined based on the type of injury or ambulance evacuation. Logistic regression analysis was used to provide adjusted odds ratios (AOR) for the comparison of the time periods before jump removal (PRE) and after jump reintroduction (POST) with the jump removal interval (INT). ResultsCompared with INT, the proportion of severe injuries in PRE was not significantly different (AOR: 1.05; 95% CI: 0.85–1.30), but was higher in POST (AOR: 1.76; 95% CI: 1.24–2.51) for ski areas with jump removal. In ski areas without jump removal, there was no change in PRE (AOR: 0.96; 95% CI: 0.87–1.07) and increased odds of severe injuries in POST (AOR: 1.20; 95% CI: 1.07–1.35). A supplementary analysis suggested that removing jumps from TPs has contributed significantly to a reduction in the proportion of severe injuries. This protective effect appears to decline over time. ConclusionsThese results do not suggest that removing jumps from TPs as an effective long-term injury prevention strategy in skiing and snowboarding. Collecting data on exposure could improve our understanding of how removing, introducing or reintroducing man-made jumps in TPs is associated with the risk of minor and severe injuries in TPs and on regular trails.

Physiological Responses To Intermittent Blood Flow Restriction During Cycling Exercise

Aerobic exercise with the addition of blood flow restriction (BFR) has the potential to elicit physiological adaptations. However, the acute physiological and perceptual responses during aerobic exercise with intermittent BFR remains unclear. PURPOSE: The purpose of this investigation was to examine the physiological and perceptual responses to intermittent BFR compared to low- (LIIE) and high-intensity interval exercise (HIIE). METHODS: Participants randomly performed 3 interval (INT) exercise protocols: BFR, LIIE and HIIE. BFR and LIIE consisted of 10 INTs of 2-min of work at 70% of ventilatory threshold (VT) and 1-min of recovery (20 W). During BFR, the cuffs were inflated to 80% of limb occlusion pressure (154 ± 17 mmHg) during each work INT and deflated during recovery INTs. HIIE consisted of 5 INTs at 140% of VT and 1-min of recovery (20 W). Pulmonary VO2 and respiratory exchange ratio (RER) were recorded and tissue oxygen saturation (StO2) was assessed by near-infrared spectroscopy. The level of perceived exertion (RPE) was assessed at the end of each INT. INTs 2, 4, 6, 8, and 10 during BFR and LIIE were used for comparison with INTs 1-5 during HIIE. The last 30 seconds of each INT were used for analysis. StO2 during each condition is expressed as change from baseline cycling (20W) (arbitrary units; AU). Two-way (INT x trial) ANOVAs analyzed differences. Significance was established if p<0.05. RESULTS: There was a main effect of trial for VO2 and RER. VO2 was greater in HIIE (INT 5 = 2.12 ± 0.56 L*min-1) than BFR (INT 10 = 1.41 ± 0.21 L*min-1) and LIIE (INT 10 = 1.28 ± 0.27 L*min-1). RER was lower in LIIE (INT 10 = 0.93 ± 0.01) compared to BFR (INT 10 = 0.94 ± 0.06) and HIIE (INT 5 = 0.99 ± 0.03). At all points, HR was lower in LIIE (INT 10 = 110 ± 10 bpm) than BFR (INT 10 = 155 ± 24 bpm) and HIIE (INT 5 = 154 ± 14 bpm). There were no differences in HR between BFR and HIIE. Delta StO2 was greater during BFR (INT 10 = -37.5 ± 15.6 AU) and HIIE (INT 5 = -34.2 ± 6.5 AU) compared to LIIE (INT 10 = -14.6 ± 8.67 AU). During all points, RPE was greater in BFR (INT 10 = 15.0 ± 2.4) and HIIE (INT 5 = 14.3 ± 1.3) compared to LIIE (INT 10 = 9.3 ± 0.4). CONCLUSIONS: This study suggests that cycling with the addition of intermittent BFR at an intensity equivalent to 70% of VT may provide similar cardiovascular and local physiological stress to traditional HIIE, albeit at a lower work rate.

Effect Of Aerobic Exercise With Blood Flow Restriction On Substrate Utilization And Energy Expenditure

Blood flow restriction (BFR) added to aerobic exercise has the potential to elicit physiological adaptations. However, the acute effects of BFR on substrate utilization and energy expenditure (EE) remains unclear. PURPOSE: The purpose of this study was to examine the effects of intermittent BFR compared to low- (LIIE) and high-intensity interval exercise (HIIE) on EE and substrate utilization during exercise and recovery. METHODS: Participants randomly performed 3 interval (INT) exercise protocols: BFR, LIIE and HIIE. BFR and LIIE consisted of 10 INTs of 2-min of work at 70% of ventilatory threshold (VT) and 1-min of recovery (20 watts; W). During BFR, the cuffs were inflated to 80% of limb occlusion pressure (154 ± 17 mmHg) during each work INT and deflated during each recovery INT. HIIE consisted of 5 INTs at 140% of VT and 1-min of recovery (20 W). Breath by breath pulmonary oxygen uptake (VO2) and carbon dioxide production (VCO2) were recorded during a 15-min seated rest, exercise, and a 180-min seated recovery. Excess post exercise oxygen consumption (EPOC) magnitude was calculated as area under the curve from netVO2 (VO2 - VO2 at rest) during the first 90 minutes post-exercise. EE was calculated from VO2 during exercise and recovery. Fat oxidation (FatOx) and carbohydrate oxidation (CarbOx) rates were calculated from VO2 and VCO2 at rest, 1, 2 and 3 hrs post-exercise. Enjoyment was assessed post-exercise using the physical activity enjoyment scale (PACES). RESULTS: EPOC magnitude was similar among trials (LIIE = 4.87 ± 2.60 L*min-1, BFR = 6.59 ± 2.33 L*min-1, HIIE= 6.56 ± 2.01 L*min-1; p = 0.06). Total EE was different between BFR (321.6 ± 30.1 kcals), HIIE (254.5 ± 33.5 kcals), and LIIE (287.1 ± 25.5 kcals) (p<0.05). FatOx in BFR (1hr = 0.14 ± 0.01 g*min-1, 3hr = 0.11 ± 0.01 g*min-1) was greater than LIIE (1hr = 0.08 ± 0.02 g*min-1, 3hr = 0.9 ± 0.02 g*min-1), but not different from HIIE (1hr = 0.12 ± 0.02 g*min-1, 3hr = 0.09 ± 0.01 g*min-1) (main effect of trial; p<0.05). CarbOx during BFR (3hr = 0.16 ± 0.03 g*min-1) was less than LIIE (3hr = 0.19 ± 0.03 g*min-1) and HIIE (3hr = 0.23 ± 0.05 g*min-1) (main effect of trial). There were no differences in PACES scores. CONCLUSIONS: This study suggests that the addition of intermittent BFR to LIIE may result in greater EE but similar substrate utilization and enjoyment as HIIE, albeit at a lower work rate.

Impact of Short-Term Continuous and Interval Exercise Training on Endothelial Function and Glucose Metabolism in Prediabetes.

Introduction The impact of interval (INT) vs. continuous (CONT) exercise training on endothelial function in relation to glucose metabolism prior to clinically meaningful weight loss is unknown in adults with prediabetes. Methods Twenty-six subjects with prediabetes (60 ± 1 y; 33 ± 1 kg/m2; 2-hr-PG OGTT: 145 ± 7 mg/dl) were randomized to 60 min of CONT (n = 12; 70% of HRpeak) or work-matched INT exercise training (n = 14; alternating 3 min at 90 and 50% HRpeak) for 2 weeks. Aerobic fitness (VO2peak) and body composition (bioelectrical impedance) were assessed before and after training. Flow-mediated dilation (FMD) was measured during a 2 h 75 g OGTT (0, 60, and 120 min) to assess endothelial function. Postprandial FMD was calculated as incremental area under the curve (iAUC). Glucose tolerance and insulin were also calculated by iAUC. Fasting plasma VCAM, ICAM, and hs-CRP were also assessed as indicators of vascular/systemic inflammation. Results Both interventions increased VO2peak (P = 0.002) but had no effect on body fat (P = 0.20). Although both treatments improved glucose tolerance (P = 0.06) and insulin iAUC (P = 0.02), VCAM increased (P = 0.01). There was no effect of either treatment on ICAM, hs-CRP, or fasting as well as postprandial FMD. However, 57% of people improved fasting and iAUC FMD following CONT compared with only 42% after INT exercise (each: P = 0.04). Elevated VCAM was linked to blunted fasting FMD after training (r = −0.38, P = 0.05). But, there was no correlation between fasting FMD or postprandial FMD with glucose tolerance (r = 0.17, P = 0.39 and r = 0.02, P = 0.90, respectively) or insulin iAUC following training (r = 0.34, P = 0.08 and r = 0.04, P = 0.83, respectively). Conclusion Endothelial function is not improved consistently after short-term training, despite improvements in glucose and insulin responses to the OGTT in obese adults with prediabetes.

The Effects of Interval and Continuous Training on the Oxygen Cost of Running in Recreational Runners: A Systematic Review and Meta-analysis.

Oxygen cost of running is largely influenced by endurance training strategies, including interval and continuous training. However, which training method better reduces the oxygen cost remains unknown. This study aimed to systematically review the scientific literature and performs a meta-analysis to address the effects of different endurance training modalities on the oxygen cost of running. A literature search on 3 databases (MEDLINE, SPORTDiscus and Web of Science) was conducted on February 28, 2019. After analysing 8028 resultant articles, studies were included if they met the following inclusion criteria: (a) studies were randomised controlled trials, (b) studies included trained runners without previous injuries (c) interventions lasted at least 6weeks, with participants allocated to Interval (INT) or Continuous (CON) groups, and (d) oxygen cost was assessed pre- and post-training intervention. Six studies (seven trials) met the inclusion criteria and were included in the meta-analysis. This resulted in 295 participants (n = 200 INT; n = 95 CON training method). Standardised mean difference with 95% confidence intervals (CI) between INT and CON conditions and effect sizes were calculated. To assess the potential effects of moderator variables (such as, age, VO2max of participants, number of weeks of intervention) on main outcome (oxygen cost of running), subgroup analyses were performed. Comparing changes from pre- to post-intervention, oxygen cost improved to a greater extent in CON when compared to INT interventions (0.28 [95% CI 0.01, 0.54], Z = 2.05, p = 0.04, I2 = 30%). Oxygen cost improvements were larger in participants with higher VO2max (≥ 52.3mlkg-1min-1) (0.39 [95% CI 0.06, 0.72], Z = 2.34, p = 0.02), andin programs greater or equal to 8weeks (0.35 [95% CI 0.03, 0.67], Z = 2.13, p = 0.03). When the total volume per week of INT was ≥ 23.2min, there was a significant improvement favorable to CON (0.34 [95% CI 0.01, 0.61], Z = 2.02, p = 0.04). Continuous training seems, overall, a better strategy than interval training to reduce the oxygen cost in recreational endurance runners. However, oxygen cost reductions are influenced by several variables including the duration of the program, runners' aerobic capacity, the intervals duration and the volume of interval training per week. Practitioners and coaches should construct training programs that include both endurance training methods shown to be effective in reducing the oxygen cost of running.