Safety and pharmacokinetics of antifungal agent VT-1598 and its primary metabolite, VT-11134, in healthy adult subjects: phase 1, first-in-human, randomized, double-blind, placebo-controlled study of single-ascending oral doses of VT-1598.

VT-1598 is a novel fungal CYP51 inhibitor and 1-tetrazole-based antifungal drug candidate with improved selectivity minimizing off-target binding to and inhibition of human CYP450 enzymes. Data are presented from this first clinical study in the evaluation of the safety and pharmacokinetic (PK) of single ascending doses of 40, 80, 160, 320, and 640 mg VT-1598, comprising a 160 mg cohort in both fasting and fed states. Eight healthy adults per dose were randomized to receive either oral VT-1598 or placebo (3:1). Over the dose range, exposures were with relatively high variation. The maximum plasma concentrations (Cmax) for VT-1598 were 31.00-279.4 ng/ml and for its primary metabolite, VT-11134, were 27.80-108.8 ng/ml. The plasma area under the concentration-time curve to the last measurable concentration (AUC0-last) for VT-1598 were 116.1-4507 ng*h/ml, and for VT-11134 were 1140-7156 ng*h/ml. The dose proportionality was inconclusive based on the results of the power model. The peak concentration time (Tmax) was 4-5 h for VT-1598 and for VT-11134. Half-life was 103-126 h for VT-11134. After food intake, Cmax of VT-1598 increased by 44% (geometric mean ratio (GMR), 1.44; 90%CI [0.691, 2.19]) and AUC0-last by 126% (GMR, 2.26; 90%CI [1.09, 3.44]), while exposure of VT-11134 was decreased 23% for Cmax (GMR, 0.77; 90%CI [0.239, 1.31]) and unchanged for AUC0-last (GMR, 1.02; 90%CI [0.701, 1.33]). Neither VT-1598 nor VT-11134 were detected in urine. No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development.

VT-1598 is a tetrazole antifungal with improved selectivity and demonstrated a high survival rate when murine infected with invasive aspergillosis, coccidiodomycosis, cryptococcosis, and candidiasis. We report a first-in-human study to evaluate safety and pharmacokinetics after an oral dose of VT-1598.

Is there evidence for the asymmetrical transfer of strength to an untrained limb?

PURPOSE: The literature predominantly addresses cross-education of strength in the dominant limb rather than the non-dominant limb, guided by the hypothesis of an asymmetrical transfer of strength from unilateral training protocols. The purpose of the study was to review the literature and determine how much evidence was available to support this claim. A meta-analysis was performed to estimate the magnitude of this hypothesized asymmetrical transfer of strength. METHODS: A literature search of all possible records was implemented using Cochrane Library, PubMed, and Scopus from February 2022 to May 2022. Comparison of randomized controlled trials was computed. The change scores and standard deviations of those change scores were extracted for each group. Only three studies met the criteria, from which a total of five effect sizes were extracted and further analyzed. RESULTS: The overall effect of resistance training of the dominant limb on strength transfer to the non-dominant limb relative to the effects of resistance training the non-dominant limb on strength transfer to the dominant (non-training) limb was 0.46 (SE 0.42). The analysis from this study resulted in minimal support for the asymmetry hypothesis. Given the small number of studies available, we provide the effect but note that the estimate is unlikely to be stable. CONCLUSION: Although it is repeatedly stated that there is an asymmetrical transfer of strength, our results find little support for that claim. This is not to say that it does not exist, but additional research implementing a control group and a direct comparison between limbs is needed to better understand this question.

Blood flow restriction augments exercise-induced pressure pain thresholds over repetition and effort matched conditions.

We sought to determine the effects of blood flow restriction (BFR) on exercise-induced hypoalgesia, specifically using low-load (LL) resistance exercise (30% 1RM) protocols that accounted for each individual's local muscular endurance capabilities. Forty-four participants completed four conditions: (1) 70% of maximal BFR repetitions with blood flow restriction (LL+BFR exercise); (2) 70% maximal BFR repetitions without LL+BFR (LL exercise); (3) 70% maximal free flow repetitions (LL+EFFORT exercise); (4) time-matched, non-exercise control (CON). Pressure pain threshold (PPT) was measured before and after exercise. Ischaemic pain threshold and tolerance was assessed only at post. The change in upper body PPT was greater for LL+BFR exercise compared to LL exercise [difference of 0.15 (0.35) kg/cm2], LL+EFFORT exercise [difference of 0.23 (0.45) kg/cm2], and the CON condition. The change in lower body PPT was greater for LL+BFR exercise compared to LL exercise [difference of 0.40 (0.55) kg/cm2], LL+EFFORT exercise [difference of 0.36 (0.62) kg/cm2], and the CON condition. Ischaemic pain thresholds and tolerances did not change. Submaximal exercise with BFR resulted in systemic increases in PPT but had no influence on ischaemic pain sensitivity. This effect is likely unique to BFR as we did not see changes in the effort matched free flow condition.

Blood flow restriction pressure for narrow cuffs (5 cm) cannot be estimated with precision.

Blood flow restriction pressures are set relative to the lowest pressure needed to occlude blood flow with that specific cuff. Due to pressure limitations of some devices, it is often not possible to occlude blood flow in all subjects and apply a known relative pressure in the lower body with a 5 cm wide cuff.Objective. To use a device capable of generating high pressures (up to 907 mmHg) to create and validate an estimation equation for the 5 cm cuff in the lower body using a 12 cm cuff.Approach. 170 participants had their arterial occlusion pressure (AOP) with a 5 cm and 12 cm cuff and their thigh circumference measured in their right leg. The sample was randomly allocated to a prediction group (66%) and validation group (33%). Thigh circumference and 12 cm AOP were used as predictors. A Bland-Altman plot was constructed to assess agreement between measured and predicted values.Main results. The mean difference (95% confidence interval) between the observed (336.8 mmHg) and the predicted (343.9 mmHg) 5 cm AOP was 7.1 (-11.9, 26.1) mmHg. The 95% limits of agreement were -133.6 to 147.8 mmHg. There was a negative relationship between the difference and the average of predicted and measured 5 cm AOP (B= -0.317,p= 0.000043).Significance. Although this was the first study to quantify AOP over 600 mmHg with a 5 cm cuff, our equation is not valid across all levels of pressure. If possible, larger cuff widths should be employed in the lower body.

Blood flow restriction augments the cross-education effect of isometric handgrip training.

INTRODUCTION: The application of blood flow restriction (BFR) to low-intensity exercise may be able to increase strength not only in the trained limb but also in the homologous untrained limb. Whether this effect is repeatable and how that change compares to that observed with higher intensity exercise is unknown. PURPOSE: Examine whether low-intensity training with BFR enhances the cross-education of strength compared to exercise without BFR and maximal efforts. METHODS: A total of 179 participants completed the 6-week study, with 135 individuals performing isometric handgrip training over 18 sessions. Participants were randomly assigned to one of four groups: 1) low-intensity (4 × 2 min of 30% MVC; LI, n = 47), 2) low-intensity with blood flow restriction (LI + 50% arterial occlusion pressure; LI-BFR, n = 41), 3) maximal effort (4 × 5 s of 100% MVC; MAX, n = 47), and 4) non-exercise control (CON, n = 44). RESULTS: LI-BFR was the only group that observed a cross-education in strength (CON: 0.64 SD 2.9 kg, LI: 0.95 SD 3.6 kg, BFR-LI: 2.7 SD 3.3 kg, MAX: 0.80 SD 3.1 kg). In the trained hand, MAX observed the greatest change in strength (4.8 SD 3.3 kg) followed by LI-BFR (2.8 SD 4.0 kg). LI was not different from CON. Muscle thickness did not change in the untrained arm, but ulna muscle thickness was increased within the trained arm of the LI-BFR group (0.06 SD 0.11 cm). CONCLUSION: Incorporating BFR into low-intensity isometric training led to a cross-education effect on strength that was greater than all other groups (including high-intensity training).

The Impact of Different Ischemic Preconditioning Pressures on Pain Sensitivity and Resistance Exercise Performance.

ABSTRACT: Kataoka, R, Song, JS, Yamada, Y, Hammert, WB, Seffrin, A, Spitz, RW, Wong, V, Kang, A, and Loenneke, JP. The impact of different ischemic preconditioning pressures on pain sensitivity and resistance exercise performance. J Strength Cond Res 38(5): 864-872, 2024-To determine (a) the impact of ischemic preconditioning pressures (applied as a % of arterial occlusion pressure [AOP]) on pressure pain threshold (PPT) and resistance exercise performance and (b) whether changes in performance could be explained by changes in PPT. Subjects ( n = 39) completed 4 protocols in a randomized order: (a) ischemic preconditioning (IPC) at 110% AOP (IPC 110%), (b) IPC at 150% AOP (IPC 150%), (c) IPC at 10% AOP (Sham), and (d) time-matched control (CON). Each protocol included 4 cycles of 5 minutes of occlusion followed by 5 minutes of reperfusion. Pressure pain threshold was taken before and after. Discomfort ratings were given at the end of each cycle. Every visit finished with 2 sets of 75-second maximal isokinetic unilateral elbow flexion or extension. Overall, IPC 110% and IPC 150% resulted in similar increases in PPT relative to CON [110%: difference of 0.36 (0.18, 0.54) kg·m -2 ; 150%: difference of 0.377 (0.15, 0.59) kg·m -2 ] and Sham. Both resulted in greater discomfort than Sham and CON, with IPC 150% inducing greater discomfort than IPC 110% (BF 10 : 14.74). There were no differences between the conditions for total work (BF 10 : 0.23), peak torque (BF 10 : 0.035), or average power (BF 10 : 0.159). We did not find evidence that PPT mediated performance. We did not detect changes in performance with 2 different relative pressures greater than AOP. Our mean applied pressures were lower than those used previously. There might be a minimal level of pressure (e.g., >150% of AOP) that is required to induce ergogenic effects of ischemic preconditioning.

The Plateau in Muscle Growth with Resistance Training: An Exploration of Possible Mechanisms.

It is hypothesized that there is likely a finite ability for muscular adaptation. While it is difficult to distinguish between a true plateau following a long-term training period and short-term stalling in muscle growth, a plateau in muscle growth has been attributed to reaching a genetic potential, with limited discussion on what might physiologically contribute to this muscle growth plateau. The present paper explores potential physiological factors that may drive the decline in muscle growth after prolonged resistance training. Overall, with chronic training, the anabolic signaling pathways may become more refractory to loading. While measures of anabolic markers may have some predictive capabilities regarding muscle growth adaptation, they do not always demonstrate a clear connection. Catabolic processes may also constrain the ability to achieve further muscle growth, which is influenced by energy balance. Although speculative, muscle cells may also possess cell scaling mechanisms that sense and regulate their own size, along with molecular brakes that hinder growth rate over time. When considering muscle growth over the lifespan, there comes a point when the anabolic response is attenuated by aging, regardless of whether or not individuals approach their muscle growth potential. Our goal is that the current review opens avenues for future experimental studies to further elucidate potential mechanisms to explain why muscle growth may plateau.

Can we improve exercise-induced hypoalgesia with exercise training? An overview and suggestions for future studies.

Exercise-induced hypoalgesia refers to a reduction in pain sensitivity following a single bout of exercise, which has been shown to be diminished or impaired with aging and chronic pain. Exercise training (repeated bouts of exercise over time) is often recommended as a non-pharmacological treatment for chronic pain and age-related functional declines. However, whether exercise training can augment the exercise-induced hypoalgesia has not been well studied. The purpose of this paper is to 1) provide an overview of the existing literature investigating the effect of exercise training on the magnitude of exercise-induced hypoalgesia, and 2) discuss potential underlying mechanisms as well as considerations for future research. Given the paucity of randomized controlled trials in this area, the effects of exercise training on exercise-induced hypoalgesia are still unclear. Several potential mechanisms have been proposed to explain the impaired exercise-induced hypoalgesia in chronic pain and older individuals (e.g., endogenous opioid, cardiovascular, and immune system). Exercise training appears to induce physiological changes in those systems, however, further investigations are necessary to test whether this will lead to improved exercise-induced hypoalgesia. Future research should consider including a time- and age-matched non-training group and utilizing the same exercise protocol for testing exercise-induced hypoalgesia across intervention groups.

Unilateral high-load resistance training influences strength changes in the contralateral arm undergoing low-load training.

OBJECTIVES: Within-subject training models have become common within the exercise literature. However, it is currently unknown if training one arm with a high load would impact muscle size and strength of the opposing arm training with a low load. DESIGN: Parallel group. METHODS: 116 participants were randomized to one of three groups that completed 6-weeks (18 sessions) of elbow flexion exercise. Group 1 trained their dominant arm only, beginning with a one-repetition maximum test (≤5 attempts), followed by four sets of exercise using a weight equivalent to 8-12 repetition maximum. Group 2 completed the same training as Group 1 in their dominant arm, while the non-dominant arm completed four sets of low-load exercise (30-40 repetition maximum). Group 3 trained their non-dominant arm only, performing the same low-load exercise as Group 2. Participants were compared for changes in muscle thickness and elbow flexion one-repetition maximum. RESULTS: The greatest changes in non-dominant strength were present in Groups 1 (Δ 1.5 kg; untrained arm) and 2 (Δ1.1 kg; low-load arm with high load on opposite arm), compared to Group 3 (Δ 0.3 kg; low-load only). Only the arms being directly trained observed changes in muscle thickness (≈Δ 0.25 cm depending on site). CONCLUSIONS: Within-subject training models are potentially problematic when investigating changes in strength (though not muscle growth). This is based on the finding that the untrained limb of Group 1 saw similar changes in strength as the non-dominant limb of Group 2 which were both greater than the low-load training limb of Group 3.

Improved interference control after exercise with blood flow restriction and cooling is associated with but not mediated by increased lactate.

BACKGROUND: To evaluate the effects of recumbent sprint interval exercise with and without blood flow restriction and body cooling on interference control and whether the changes in interference control can be explained by the changes in blood lactate. METHODS: 85 participants (22 SD 3 years old) completed 1 familiarization visit and then 5 experimental visits in a randomized order: exercise only (Ex), exercise with blood flow restriction (ExB), exercise with cooling (ExC), and exercise with blood flow restriction and cooling (ExBC), and non-exercise control (Con). Measurements of blood lactate and the Stroop Color Word Test were performed before and after exercise. Each bout began with a 15-minute low-moderate intensity warm-up, followed by five 20-second "all out" sprints separated by 40 s of active recovery. Bayes Factors (BF10) quantified evidence for or against the null hypothesis. Within-subject mediation analysis quantified the indirect effect of changes in blood lactate (mediator) on the change in interference control (each exercise condition vs. Con). RESULTS: Bayesian pairwise comparisons found that only ExC [σ: -0.37 (-0.59, -0.15)] and ExBC [σ: -0.3 (-0.53, -0.09)] produced changes in incongruent reaction time different from that of Con. There was also evidence that all exercise conditions increased blood lactate (BF10 = 8.65e+29 - 1.9e+32) and improved congruent reaction time (BF10 = 4.01 - 15.371) compared to that of Con. There was no evidence to show that changes in lactate mediated the change in incongruent reaction time. CONCLUSIONS: Both exercise with body cooling and when body cooling was combined with blood flow restriction presented favorable changes in incongruent reaction time (a marker of interference control), which might not be explained by the changes in systemic blood lactate concentration.

Lack of expression of miR-29a/b1 impairs bladder function in male mice.

Lower urinary tract symptoms (LUTS) refer to various urological diseases, and incomplete bladder emptying is common among affected patients. The etiology of LUTS is largely unknown, and investigations of LUTS suggest that bladder fibrosis contributes to pathogenesis of LUTS. MicroRNAs (miRNAs) are short (∼22 nucleotides), non-coding RNAs that repress target gene expression by a combination of mRNA degradation and translation inhibition. The miR-29 family is best known for its anti-fibrotic role in various organs. miR-29 was decreased in bladders of patients with outlet obstruction and a rat model of bladder outlet obstruction, suggesting that miR-29 may contribute to impaired bladder function subsequent to tissue fibrosis. We characterized bladder function in male mice lacking expression of Mir29a and Mir29b-1 (miR-29a/b1). Lack of miR-29a/b1 resulted in severe urinary retention, increased voiding duration and reduced flow rate, and these mice failed to void or voided irregularly during anesthetized cytometry. Collagens and elastin were increased in bladders of mice lacking miR-29a/b1. These findings reveal an important role for miR-29 in bladder homeostasis and suggest the therapeutic potential of miR-29 to improve symptoms in patients with LUTS.

Effect of Increased Pressure Pain Threshold on Resistance Exercise Performance With Blood Flow Restriction.

ABSTRACT: Kataoka, R, Song, JS, Bell, ZW, Wong, V, Spitz, RW, Yamada, Y, and Loenneke, JP. Effect of increased pressure pain threshold on resistance exercise performance with blood flow restriction. J Strength Cond Res 37(6): 1204-1210, 2023-This study aimed to examine whether increasing pressure pain threshold (PPT) through isometric handgrip exercise (HG) affects the number of repetitions completed and discomfort with knee extension exercise (KE) with blood flow restriction (BFR), and examine whether performing additional exercise leads to a further increase in PPT. Forty-one participants completed 2 trials: rest followed by low-load KE with BFR at 80% of resting arterial occlusion pressure (Rest + KE BFR) and low-intensity (30% of maximal strength) HG exercise followed by KE with BFR (HG + KE BFR). Pressure pain threshold was measured before and after exercise at the forearm and tibialis anterior. Results are presented as median difference (95% credible interval). Pressure pain threshold increased at the forearm (Bayes factor [BF 10 ]: 5.2 × 10 7 ) and tibialis anterior (BF 10 : 1.5 × 10 6 ) after HG exercise. However, this did not lead to greater repetitions being completed with BFR exercise (0.2 [-0.1, 0.6] repetitions, BF 10 : 0.07). Pressure pain threshold after BFR exercise was not augmented over that observed with HG exercise (0.02 [-0.15, 0.2] kg·cm -2 , BF 10 : 0.175) at the forearm. More data are needed in the lower body to determine which model best fits the data (BF 10 : 0.84). Discomfort with BFR exercise was not different between conditions (1.0 [-2.3, 4.4] arbitrary units, BF 10 : 0.10). The pain-reducing effect of prior exercise did not change the repetitions completed with BFR exercise, suggesting that the change in PPT may not have been great enough to alter performance. Performing additional exercise did not elicit further increases in PPT nor was perceived discomfort to BFR exercise altered by changes in PPT.

Does muscle growth mediate changes in a nonspecific strength task?

The purpose of this study was to determine if muscle growth mediates increases in a strength task which was not directly trained. One hundred fifty-one participants were randomized into control, one-repetition maximum training (1RM-TRAIN), or traditional training (TRAD-TRAIN). Training groups performed isotonic elbow flexion 3x/week for 6 weeks. Anterior muscle thickness at 50%, 60% and 70% upper arm length, and maximal isokinetic torque at 60°/sec were assessed pre- and post-training. Change-score mediation models (adjusted for sex, pre-muscle thickness, and pre-strength) were constructed for each muscle thickness site. The effects of each training group were evaluated relative to the control. Data is presented as coefficient (95% CI). There were no significant relative direct effects on nonspecific strength for either training group outside of the 60% model (1.7 [0.13, 3.27] Nm). The relative effect of 1RM-TRAIN on muscle thickness was greater in 60% (0.09 [0.01, 0.17] cm) and 70% (0.09 [0.00, 0.17] cm) models; while TRAD-TRAIN was greater in all three: (50% = 0.24 [0.15, 0.32]; 60% = 0.24 [0.16, 0.33]; 70% = 0.22 [0.14, 0.31] cm). The effect of muscle thickness on nonspecific strength was only significant for the 60% (-3.06 [-5.7, -0.35] Nm) model. The relative indirect effect on nonspecific strength was not significant for the 1RM-TRAIN or TRAD-TRAIN. Similar to previous findings on specific strength, we did not find evidence for a mediating effect of muscle growth on training induced increases in nonspecific strength. The importance of muscle growth for changes in nonspecifically trained strength may need to be reconsidered.

Sex segregation in strength sports: Do equal-sized muscles express the same levels of strength between sexes?

OBJECTIVES: Concerns have been raised against the current two-sex binary category in sports competitions. The thesis states that if males and females were separated based on muscle size, it would negate the strength advantage between the sexes. We tested the possible sex differences in various strength outcomes when pair-matched for muscle thickness. METHODS: A total of 16 different data sets (n = 963) were assessed to pair-match females with males who had a muscle thickness value within 2%. We further compared the competition performances of the smallest male weight class within the International Powerlifting Federation (IPF) to different weight classes in females. RESULTS: Overall, 76%-88% of the strength assessments were greater in males than females with pair-matched muscle thickness, regardless of contraction types (i.e., isotonic, isometric, isokinetic). Additionally, males in the lightest weight division in the IPF largely outperformed females in heavier weight divisions. CONCLUSIONS: Our results would suggest that segregation based on muscle mass or surrogates of muscle mass (e.g., lean body mass) might not be an appropriate classification to create fair competition within strength sports. This is not to refute the concept of the desegregation of the two-sex binary category but to present data that raises important concerns about the potential sex-based differences in strength performance.

Potential considerations with estimating blood flow restriction pressure in the lower body using a narrower cuff.

Blood flow restriction pressures are typically set as a percentage of the arterial occlusion pressure. For those who do not have the ability to measure the arterial occlusion pressure, estimation equations are available. However, notable considerations are needed when estimating pressure with a narrow cuff (5 cm) in the lower body. A previously published equation in this journal was developed but was created only using 55% of the sample because the arterial occlusion of the others could not be obtained within the manufacturer's pressure limit. The purpose of this article was twofold: (1) to investigate how previous studies have implemented the equation and (2) to highlight potential concerns of using this equation. Two databases were used to locate articles that used the equation from Loenneke et al. (2015). We found that this equation had been cited 10 times to estimate arterial occlusion pressure with some notable concerns. Some did not use a 5 cm wide cuff, while others used it for participants who had arterial occlusion pressures exceeding 300 mmHg. To highlight the latter, we also applied the Loenneke et al. (2015) lower body equation to participants with arterial occlusion pressures known to exceed 300 mmHg to demonstrate potential concerns. This retrospective analysis found that 52% of the sample with known pressures over 300 mmHg (40 out of 77) would be estimated below 300 mmHg. This paper highlighted important considerations for those trying to estimate arterial occlusion pressure in the lower body with a narrow cuff (5 cm).

Quantifying the Generality of Strength Adaptation: A Meta-Analysis.

BACKGROUND: Isotonic exercise is the most common mode of strength training. Isotonic strength is often measured in the movement that was exercised, but isometric and isokinetic movements are also commonly used to quantify changes in muscular strength. Previous research suggests that increasing strength in one movement may not lead to an increase in strength in a different movement. Quantifying the increase in strength in a movement not trained may be important for understanding strength training adaptations and making recommendations for resistance exercise and rehabilitation programs. OBJECTIVE: To quantify changes in non-specific strength relative to a control. DESIGN: A systematic review and random effects meta-analysis was conducted investigating the effects of isotonic strength training on isotonic and isokinetic/isometric strength. SEARCH AND INCLUSION: This systematic review was conducted in Google scholar, PubMed, Academic Search Premier, and MENDELEY. To be included in this review paper the article needed to meet the following criteria: (1) report sufficient data for our variables of interest (i.e., changes in isotonic strength and changes in isokinetic or isometric strength); (2) include a time-matched non-exercise control; (3) be written in English; (4) include healthy human participants over the age of 18 years; (5) the participants had to train and test isotonically; (6) the participants had to be tested isokinetically or isometrically on a device different from that they trained on; (7) the non-specific strength task had to test a muscle involved in the training (i.e., could not have trained chest press and test handgrip strength); and (8) the control group and the experimental group had to perform the same number of strength tests. RESULTS: We completed two separate searches. In the original search a total of 880 papers were screened and nine papers met the inclusion criteria. In the secondary search a total of 2594 papers were screened and three additional papers were added (total of 12 studies). The overall effect of resistance training on changes in strength within a movement that was not directly trained was 0.8 (Cohen's d) with a standard error of 0.286. This overall effect was significant (t = 2.821, p = 0.01) and the 95% confidence interval (CI) is 0.22-1.4. The overall effect of resistance training on strength changes within a movement that was directly trained was 1.84 (Cohen's d) with a standard error of 0.296. This overall effect was significant (t = 6.221, p < 0.001) and the 95% CI is 1.23-2.4. CONCLUSION: The results of our meta-analysis suggest that strength increases in both the specific and non-specific strength tests. However, the smaller effect size associated with non-specific strength suggests that it will be difficult for a single study to meaningfully investigate the transfer of strength training adaptions.

The Hypoalgesic Effect of Low-Load Exercise to Failure Is Not Augmented by Blood Flow Restriction.

Purpose: To 1) examine whether blood flow restriction would provide an additional exercise-induced hypoalgesic response at an upper and lower limb when it is incorporated with low-load resistance exercise until failure, and 2) examine if increases in blood pressure and discomfort, with blood flow restricted exercise, would mediate the exercise-induced hypoalgesia over exercise without blood flow restriction. Methods: Forty healthy young participants completed two trials: four sets of unilateral knee extension exercise to failure at 30% of one-repetition maximum, with and without blood flow restriction. Pressure pain thresholds were assessed before (twice) and 5-min post exercise at an upper and lower limb. Blood pressure and discomfort ratings were recorded to examine mediating effects on exercise-induced hypoalgesia with blood flow restricted exercise. Results: Pressure pain threshold increased following both exercise conditions compared to a control, without any differences between exercise conditions at the upper (exercise conditions vs. control: ~0.37 kg/cm2) and lower (exercise conditions vs. control: ~0.60 kg/cm2) limb. The total number of repetitions was lower for exercise with blood flow restriction compared to exercise alone [median difference (95% credible interval) of -27.0 (-29.8, -24.4) repetitions]. There were no mediating effects of changes in blood pressure, nor changes in discomfort, for the changes in pressure pain threshold at either the upper or lower limb. Conclusion: The addition of blood flow restriction to low-load exercise induces a similar hypoalgesic response to that of non-blood flow restricted exercise, with a fewer number of repetitions.

Individuals with hypertension have lower plasma volume regardless of weight status.

Increased plasma volume is often reported as a cause or symptom of hypertension in individuals with obesity. However, these individuals are often compared to normal weight normotensive individuals. Since higher plasma volumes have been reported in larger individuals, it is possible that plasma volume is actually lower in obese hypertensive individuals compared to normotensive obese individuals. This may be important for better understanding the clinical manifestation of hypertension between weight categories. National Health and Nutritional Examination Survey (cycles 1999-2018) data were used to examine the relationship between plasma (derived from the Straus formula), blood pressure (measured with an automated device) and body mass index. We observed an inverse relationship between estimated plasma volume and systolic (B = -1.68 (95% CI: -2.06, -1.30) mmHg), p < 0.0001), diastolic (B = -3.35 (95% CI: -3.61, -3.08) mmHg) p < 0.0001), and mean arterial pressure (B = -2.79 (95% CI: -3.05, -2.53) mmHg) p < 0.0001). The relationship between estimated plasma volume and diastolic blood pressure (interaction term: B = -0.069 (-0.10, -0.03), p < 0.0001) did depend on BMI. The "normal weight" group had the lowest slope and this slope was significantly different from the "obese" (B = -1.47 (95% CI: -1.88, -1.07)) and "overweight" (B = -1.11 (-1.55, -0.67)) groups. Plasma volume is lower in hypertensive individuals regardless of weight status, but this relationship is more pronounced among obese individuals.

Can Individuals Be Taught to Sense the Degree of Vascular Occlusion? A Comparison of Methods and Implications for Practical Blood Flow Restriction.

ABSTRACT: Bell, ZW, Spitz, RW, Wong, V, Yamada, Y, Song, JS, Abe, T, and Loenneke, JP. Can individuals be taught to sense the degree of vascular occlusion? A comparison of methods and implications for practical blood flow restriction. J Strength Cond Res 36(12): 3359-3365, 2022-The study objective was to determine whether subjects could be conditioned to a relative blood flow restriction pressure in the lower body and compare 2 separate conditioning methods (unconstrained vs. constrained). Thirty-five subjects completed 4 visits, involving measurements for arterial occlusion and pressure estimations at 5 minutes and 24 hours after conditioning. The constrained method involved applying 40% of measured arterial occlusion 11 times, along with 10% above and below this pressure. The unconstrained method was time-matched, involving a series of inflations to 40% arterial occlusion for 12 seconds and then deflated for 22 seconds. Data are presented as mean differences (95% credible interval) unless otherwise noted. The absolute error between conditioning methods was found to be similar at 5 minutes (-1.1 [-5.9, 3.7] mm Hg) and 24 hours (-2.4 [-7, 2.2] mm Hg) after conditioning. The constant error differed between methods at 5 minutes [-8.2 (-14.4, -1.9) mm Hg] but was similar at 24 hours (-2.5 [-8.5, 3.6] mm Hg; H0: 0.680; H1: 0.068; and H2: 0.252) after conditioning. The bias and 95% limits of agreement for the unconstrained method were -3.9 (-33.8, 25.9) mm Hg at 5 minutes and -2.9 (-32, 26.1) mm Hg at 24 hours. The agreement for the constrained method was 4.2 (-28, 36.5) mm Hg at 5 minutes and -0.54 (-37.3, 36.2) mm Hg at 24 hours. Conditioning methods produced similar levels of absolute error, indicating that either method may offer a viable means of pressure application. Most estimates were between 20 and 60% of arterial occlusion pressure. Additional conditioning sessions may be needed to narrow this range at the individual level.

Training-induced hypoalgesia and its potential underlying mechanisms.

It is well-established that a single bout of exercise can reduce pain sensitivity (i.e., exercise-induced hypoalgesia) in healthy individuals. However, exercise-induced hypoalgesia is often impaired in individuals with chronic pain. This might suggest that repeated bouts of exercise (i.e., exercise training) are needed in order to induce a reduction in pain sensitivity (i.e., training-induced hypoalgesia) among individuals with chronic pain, given that a single bout of exercise seems to be insufficient to alter pain. However, the effect of repeated bouts of exercise on pain sensitivity and its underlying mechanisms remain poorly understood. Therefore, the purpose of this review was to provide an overview of the existing literature on training-induced hypoalgesia, as well as discuss potential mechanisms of training-induced hypoalgesia and offer considerations for future research. Existing literature suggests that training interventions may induce hypoalgesic adaptations potentially driven by central nervous system and immune system factors. However, the limited number of randomized controlled trials available, along with the lack of understanding of underlying mechanisms, provides a rationale for future research.