Physiological mechanisms associated with the use of a passive heat intervention: positive implications for soccer substitutes.

PURPOSE: Soccer substitutes are exposed to periods of limited activity before entering match-play, likely negating benefits of active warm-ups. This study aimed to determine the effects of using a passive heat intervention following a pre-match, and half-time warm-up, on muscle and core temperature in soccer players during ambient (18 °C) and cold (2 °C) conditions. METHODS: On four occasions, 8 male players, completed a pre-match warm-up, followed by 45 min of rest. Following this, participants completed a half-time re-warm-up followed by an additional 45 min of rest, simulating a full match for an unplaying substitute. During periods of rest, participants wore either standardised tracksuit bottoms (CON), or heated trousers (HEAT), over typical soccer attire. RESULTS: Vastus lateralis temperature declined less in HEAT compared to CON following the 1st half in 2 °C (Δ - 4.39 ± 0.81 vs. - 6.21 ± 1.32 °C, P = 0.002) and 18 °C (Δ - 2.48 ± 0.71 vs. - 3.54 ± 0.88 °C, P = 0.003). These findings were also observed in the 2nd half for the 2 °C (Δ - 4.36 ± 1.03 vs. - 6.26 ± 1.04 °C, P = 0.002) and 18 °C (Δ - 2.85 ± 0.57 vs. - 4.06 ± 1 °C, P = 0.018) conditions. In addition, core temperature declined less in HEAT compared to CON following the 1st (Δ - 0.41 ± 0.25 vs. - 0.84 ± 0.41 °C, P = 0.037) and 2nd (Δ - 0.25 ± 0.33 vs. - 0.64 ± 0.34 °C, P = 0.028) halves of passive rest in 2 °C, with no differences in the 18 °C condition. Perceptual data confirmed that participants were more comfortable in HEAT vs. CON in 2 °C (P < 0.01). CONCLUSIONS: Following active warm-ups, heated trousers attenuate the decline in muscle temperature in ambient and cold environments.

The Relationship Between the Anaerobic Speed Reserve and Acute Responses to High-Intensity Interval Training in Female Soccer Players.

ABSTRACT: Aspin, GL, Graham, M, Franklin, J, Hicks, KM, and Taylor, JM. The relationship between the anaerobic speed reserve and acute responses to high-intensity interval training in female soccer players. J Strength Cond Res XX(X): 000-000, 2024-The anaerobic speed reserve (ASR) is a popular method of profiling soccer players, often used to individualize training prescription. This study explored the reliability of ASR profiling, and the relationship between the ASR and acute physiological responses to high-intensity interval training (HIIT). Acute physiological responses to different HIIT types were also compared. Thirteen subelite female soccer players aged 20.2 ± 4.6 years completed 6 exercise sessions. In sessions 1-2, players completed a 40-m sprint to assess maximal sprint speed (MSS) and 1600-m time-trial to estimate maximal aerobic speed (MAS), which were used to calculate ASR and assess test-retest reliability. In sessions 3-6, players completed 4 HIIT sessions (repeated-sprint training, sprint interval training, long intervals, and short intervals HIIT). Intensities for long and short intervals HIIT were individualized according to MAS. Ratings of perceived exertion (RPE), heart rate (HR), and postsession blood lactates were recorded throughout. Relationships between the ASR and acute responses to HIIT, and between HIIT session comparisons in outcome measures were assessed. Anaerobic speed reserve (coefficient of variation ± 95% confidence limits; 3.1 ± 1.5%), MAS (1.8 ± 1.3%), and MSS (0.8 ± 0.6%) indicated acceptable reliability. Moderate correlations between ASR and RPE (r = 0.33), postsession blood lactate (r = 0.34), and HR (r = 0.37) were observed during long intervals HIIT. A strong correlation was observed between ASR and RPE during SIT (r = 0.50). Sprint interval training elicited higher RPE's and postsession blood lactate's than other HIIT sessions. Anaerobic speed reserve has good reliability and may influence acute physiological responses to HIIT in female soccer players.

Acute aerobic exercise-conditioned serum reduces colon cancer cell proliferation in vitro through interleukin-6-induced regulation of DNA damage.

Epidemiological evidence shows that regular physical activity is associated with reduced risk of primary and recurrent colon cancer. However, the underlying mechanisms of action are poorly understood. We evaluated the effects of stimulating a human colon cancer cell line (LoVo) with human serum collected before and after an acute exercise bout vs nonexercise control serum on cancer cell proliferation. We also measured exercise-induced changes in serum cytokines and intracellular protein expression to explore potential biological mechanisms. Blood samples were collected from 16 men with lifestyle risk factors for colon cancer (age ≥50 years; body mass index ≥25 kg/m2 ; physically inactive) before and immediately after an acute bout of moderate-intensity aerobic interval exercise (6 × 5 minutes intervals at 60% heart rate reserve) and a nonexercise control condition. Stimulating LoVo cells with serum obtained immediately after exercise reduced cancer cell proliferation compared to control (-5.7%; P = .002). This was accompanied by a decrease in LoVo cell γ-H2AX expression (-24.6%; P = .029), indicating a reduction in DNA damage. Acute exercise also increased serum IL-6 (24.6%, P = .002). Furthermore, stimulating LoVo cells with recombinant IL-6 reduced γ-H2AX expression (ß = -22.7%; P < .001) and cell proliferation (ß = -5.3%; P < .001) in a linear dose-dependent manner, mimicking the effect of exercise. These findings suggest that the systemic responses to acute aerobic exercise inhibit colon cancer cell proliferation in vitro, and this may be driven by IL-6-induced regulation of DNA damage and repair. This mechanism of action may partly underlie epidemiological associations linking regular physical activity with reduced colon cancer risk.

Effectiveness of diet and physical activity interventions amongst adults attending colorectal and breast cancer screening: a systematic review and meta-analysis.

PURPOSE: To estimate the effectiveness of tailored physical activity and dietary interventions amongst adults attending colorectal and breast cancer screening. METHODS: Five literature databases were systematically searched to identify randomised controlled trials (RCTs) of tailored physical activity and/or dietary interventions with follow-up support initiated through colorectal and breast cancer screening programmes. Outcomes included markers of body fatness, physical activity, and dietary intake. Mean differences (MDs) or standardised mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random effects models. RESULTS: Five RCTs met the inclusion criteria encompassing a total of 722 participants. Diet and physical activity interventions led to statistically significant reductions in body mass (MD - 1.6 kg, 95% CI - 2.7 to - 0.39 kg; I2 = 81%; low quality evidence), body mass index (MD - 0.78 kg/m2, 95% CI - 1.1 to - 0.50 kg/m2; I2 = 21%; moderate quality evidence), and waist circumference (MD - 2.9 cm, 95% CI - 3.8 to - 1.91; I2 = 0%; moderate quality evidence), accompanied by an increase in physical activity (SMD 0.31, 95% CI 0.13 to 0.50; I2 = 0%; low quality evidence) and fruit and vegetable intake (SMD 0.33, 95% CI 0.01 to 0.64; I2 = 51%; low quality evidence). CONCLUSION: There is low quality evidence that lifestyle interventions involving follow-up support lead to modest weight loss and increased physical activity and fruit and vegetable intake. Due to the modest intervention effects, low quality of evidence and small number of studies, further rigorously designed RCTs with long-term follow-up of modifiable risk factors and embedded cost-benefit analyses are warranted (PROSPERO ref: CRD42020179960).

Prolonging the duration of cooling does not enhance recovery following a marathon.

Runners commonly utilize cryotherapy as part of their recovery strategy. Cryotherapy has been ineffective in mitigating signs and symptoms of muscle damage following marathon running and is limited by its duration of application. Phase change material (PCM) packs can prolong the duration of cooling. This study aimed to test the efficacy of prolonging the duration of cooling using PCM on perceptual recovery, neuromuscular function, and blood markers following a marathon run. Thirty participants completed a marathon run and were randomized to receive three hours of 15°C PCM treatment covering the quadriceps or recover without an intervention (control). Quadriceps soreness, strength, countermovement jump (CMJ) height, creatine kinase (CK), and high sensitivity C-reactive protein (hsCRP) were recorded at baseline, 24, 48, and 72 hours after the marathon. Following the marathon, strength decreased in both groups (P < .0001), with no difference between groups. Compared to baseline, strength was reduced 24 (P = .004) and 48 hours after the marathon (P = .008) in the control group, but only 24 hours (P = .028) in the PCM group. Soreness increased (P < .0001) and CMJ height decreased (P < .0001) in both groups, with no difference between groups. Compared to baseline, CMJ height was not reduced on any days in the PCM group but was reduced in the control group 24 (P < .0001) and 48 hours (P = .003) after the marathon. CK and hsCRP increased in both groups (P < .0001). Although the marathon run induced significant muscle damage, prolonging the duration of cooling using PCM did not accelerate the resolution of any dependent variables.

The Reliability of Potential Fatigue-Monitoring Measures in Elite Youth Soccer Players.

ABSTRACT: Fitzpatrick, JF, Hicks, KM, Russell, M, and Hayes, PR. The reliability of potential fatigue-monitoring measures in elite youth soccer players. J Strength Cond Res 35(12): 3448-3452, 2021-Monitoring fatigue is of vital importance to practitioners; however, logistics and concerns about reliability may impede the use of certain measures. This study aimed to quantify the reliability of potential measures of fatigue; a subjective wellness questionnaire, jump performance tests, and tri-axial accelerometer variables derived during submaximal shuttle running in elite youth soccer players. A secondary aim was to establish the minimum test duration that could be used for the submaximal shuttle run while maintaining good reliability. Seventeen male youth team players (age: 17.4 ± 0.5 years) were assessed on 2 occasions, spaced 7 days apart. Typical error, coefficient of variation (CV%), interclass correlation (ICC), and minimum detectable change were calculated for a subjective wellness questionnaire, countermovement jump (CMJ), squat jump (SJ) and drop jump contact time (DJ-CT), drop jump height (DJ-JH), and reactive strength (DJ-RSI). A novel submaximal shuttle running test was also used to assess tri-axial accelerometer data reliability. Results suggest that CMJ, SJ, DJ-CT, and DJ-RSI have good test-retest reliability (CV% = 4.5-7.7; ICC = 0.80-0.88); however DJ-JH did not show acceptable reliability (CV% = 6.0; ICC = 0.76). Good reliability was found for all tri-axial accelerometer variables during a 3-minute (2-minute analysis) submaximal shuttle run (CV% = 2.4-8.0; ICC = 0.81-0.95), except for % PlayerLoad anterior-posterior (%PLAP) (CV% = 7.2; ICC = 0.63). The subjective wellness questionnaire demonstrated poor reliability for all items (CV% = 11.2-30.0; ICC = 0.00-0.78). The findings from this study provide practitioners with valuable information about the reliability of a range of potential fatigue-monitoring measures. This can be used to help make accurate decisions about the magnitude of change in these assessments when used in practice.

Sex differences in fatigability following exercise normalised to the power-duration relationship.

KEY POINTS: Knee-extensors demonstrate greater fatigue resistance in females compared to males during single-limb and whole-body exercise. For single-limb exercise, the intensity-duration relationship is different between sexes, with females sustaining a greater relative intensity of exercise. This study established the power-duration relationship during cycling, then assessed fatigability during critical power-matched exercise within the heavy and severe intensity domains. When critical power and the curvature constant were expressed relative to maximal ramp test power, no sex difference was observed. No sex difference in time to task failure was observed in either trial. During heavy and severe intensity cycling, females experienced lesser muscle de-oxygenation. Following both trials, females experienced lesser reductions in knee-extensor contractile function, and following heavy intensity exercise, females experienced less reduction in voluntary activation. These data demonstrate that whilst the relative power-duration relationship is not different between males and females, the mechanisms of fatigability during critical power-matched exercise are mediated by sex. ABSTRACT: Due to morphological differences, females demonstrate greater fatigue resistance of locomotor muscle during single-limb and whole-body exercise modalities. Whilst females sustain a greater relative intensity of single-limb, isometric exercise than males, limited investigation has been performed during whole-body exercise. Accordingly, this study established the power-duration relationship during cycling in 18 trained participants (eight females). Subsequently, constant-load exercise was performed at critical power (CP)-matched intensities within the heavy and severe domains, with the mechanisms of fatigability assessed via non-invasive neurostimulation, near-infrared spectroscopy and pulmonary gas exchange during and following exercise. Relative CP (72 ± 5 vs. 74 ± 2% Pmax , P = 0.210) and curvature constant (51 ± 11 vs. 52 ± 10 J Pmax-1 , P = 0.733) of the power-duration relationship were similar between males and females. Subsequent heavy (P = 0.758) and severe intensity (P = 0.645) exercise time to task failures were not different between sexes. However, females experienced lesser reductions in contractile function at task failure (P ≤ 0.020), and greater vastus lateralis oxygenation (P ≤ 0.039) during both trials. Reductions in voluntary activation occurred following both trials (P < 0.001), but were less in females following the heavy trial (P = 0.036). Furthermore, during the heavy intensity trial only, corticospinal excitability was reduced at the cortical (P = 0.020) and spinal (P = 0.036) levels, but these reductions were not sex-dependent. Other than a lower respiratory exchange ratio in the heavy trial for females (P = 0.039), no gas exchange variables differed between sexes (P ≥ 0.052). Collectively, these data demonstrate that whilst the relative power-duration relationship is not different between males and females, the mechanisms of fatigability during CP-matched exercise above and below CP are mediated by sex.

Physiological sex differences affect the integrative response to exercise: acute and chronic implications.

NEW FINDINGS: What is the topic of this review? We review sex differences within physiological systems implicated in exercise performance; specifically, how they integrate to determine metabolic thresholds and fatigability. Thereafter, we discuss the implications that these sex differences might have for long-term adaptation to exercise. What advances does it highlight? The review collates evidence from recent physiological studies that have investigated sex as a biological variable, demonstrating that the physiological response to equivalent 'dosages' of exercise is not the same in males and females; thus, highlighting the need to research diversity in physiological responses to interventions. ABSTRACT: The anatomical and physiological differences between males and females are thought to determine differences in the limits of human performance. The notion of studying sex as a biological variable has recently been emphasized in the biosciences as a vital step in enhancing human health. In this review, we contend that the effects of biological sex on acute and chronic responses must be studied and accounted for when prescribing aerobic exercise, much like any intervention targeting the optimization of physiological function. Emerging evidence suggests that the response of physiological systems to exercise differs between males and females, potentially mediating the beneficial effects in healthy and clinical populations. We highlight evidence that integrative metabolic thresholds during exercise are influenced by phenotypical sex differences throughout many physiological systems. Furthermore, we discuss evidence that female skeletal muscle is more resistant to fatigue elicited by equivalent dosages of high-intensity exercise. How the different acute responses affect the long-term trainability of males and females is considered, with discussion about tailoring exercise to the characteristics of the individual presented within the context of biological sex. Finally, we highlight the influence of endogenous and exogenous sex hormones on physiological responses to exercise in females. Sex is one of many mediating influences on the outcomes of exercise, and with careful experimental designs, physiologists can advance the collective understanding of diversity in physiology and optimize outcomes for both sexes.

Task-specific strength increases after lower-limb compound resistance training occurred in the absence of corticospinal changes in vastus lateralis.

NEW FINDINGS: What is the central question of the study? Are corticospinal responses to acute and short-term squat resistance training task-specific? What is the main finding and its importance? A single bout of resistance training increased spinal excitability, but no changes in corticospinal responses were noted following 4 weeks of squat training despite task-specific increases in strength. The present data suggest that processes along the corticospinal pathway of the knee extensors play a limited role in the task-specific increase in strength following resistance training. ABSTRACT: Neural adaptations subserving strength increases have been shown to be task-specific, but responses and adaptation to lower-limb compound exercises such as the squat are commonly assessed in a single-limb isometric task. This two-part study assessed neuromuscular responses to an acute bout (Study A) and 4 weeks (Study B) of squat resistance training at 80% of one-repetition-maximum, with measures taken during a task-specific isometric squat (IS) and non-specific isometric knee extension (KE). Eighteen healthy volunteers (25 ± 5 years) were randomised into either a training (n = 10) or a control (n = 8) group. Neural responses were evoked at the intracortical, corticospinal and spinal levels, and muscle thickness was assessed using ultrasound. The results of Study A showed that the acute bout of squat resistance training decreased maximum voluntary contraction (MVC) for up to 45 min post-exercise (-23%, P < 0.001). From 15-45 min post-exercise, spinally evoked responses were increased in both tasks (P = 0.008); however, no other evoked responses were affected (P ≥ 0.240). Study B demonstrated that following short-term resistance training, participants improved their one repetition maximum squat (+35%, P < 0.001), which was reflected by a task-specific increase in IS MVC (+49%, P = 0.001), but not KE (+1%, P = 0.882). However, no training-induced changes were observed in muscle thickness (P = 0.468) or any evoked responses (P = 0.141). Adjustments in spinal motoneuronal excitability are evident after acute resistance training. After a period of short-term training, there were no changes in the responses to central nervous system stimulation, which suggests that alterations in corticospinal properties of the vastus lateralis might not contribute to increases in strength.

Sex differences in fatigability and recovery relative to the intensity-duration relationship.

KEY POINTS: Females demonstrate greater fatigue resistance than males during contractions at intensities relative to maximum force. However, previous studies have not accounted for the influence of metabolic thresholds on fatigability. This study is the first to test whether sex differences in fatigability exist when exercise intensity is normalised relative to a metabolic threshold: the critical intensity derived from assessment of the intensity-duration relationship during intermittent, isometric knee extensor contractions. We show that critical intensity in females occurred at a higher percentage of maximum force compared to males. Furthermore, females demonstrated greater fatigue resistance at exercise intensities above and below this metabolic threshold. Our data suggest that the sex difference was mediated by lesser deoxygenation of the knee extensors during exercise. These data highlight the importance of accounting for metabolic thresholds when comparing fatigability between sexes, whilst emphasising the notion that male data are not generalisable to female populations. ABSTRACT: Females are less fatigable than males during isometric exercise at intensities relative to maximal voluntary contraction (MVC); however, whether a sex difference in fatigability exists when exercise is prescribed relative to a critical intensity is unknown. This study established the intensity-duration relationship, and compared fatigability and recovery between sexes following intermittent isometric contractions normalised to critical intensity. Twenty participants (10 females) completed four intermittent isometric knee extension trials to task failure to determine critical intensity and the curvature constant (W'), followed by fatiguing tasks at +10% and -10% relative to critical intensity. Neuromuscular assessments were completed at baseline and for 45 min post-exercise. Non-invasive neurostimulation, near-infrared spectroscopy, and non-invasive haemodynamic monitoring were used to elucidate the physiological mechanisms responsible for sex differences. Females demonstrated a greater critical intensity relative to MVC than males (25 ± 3 vs. 21 ± 2% MVC, P = 0.003), with no sex difference for W' (18,206 ± 6331 vs. 18,756 ± 5762 N s, P = 0.850). Time to task failure was greater for females (62.37 ± 17.25 vs. 30.43 ± 12.75 min, P < 0.001) during the +10% trial, and contractile function recovered faster post-exercise (P = 0.034). During the -10% trial females experienced less contractile dysfunction (P = 0.011). Throughout the +10% trial, females demonstrated lesser decreases in deoxyhaemoglobin (P = 0.007) and an attenuated exercise pressor reflex. These data show that a sex difference in fatigability exists even when exercise is matched for critical intensity. We propose that greater oxygen availability during exercise permits females to sustain a higher relative intensity than males, and is an explanatory factor for the sex difference in fatigability during intermittent, isometric contractions.

Corticospinal excitability of tibialis anterior and soleus differs during passive ankle movement.

The purpose of this study was to assess corticospinal excitability of soleus (SOL) and tibialis anterior (TA) at a segmental level during passive ankle movement. Four experimental components were performed to assess the effects of passive ankle movement and muscle length on corticospinal excitability (MEP/Mmax) at different muscle lengths, subcortical excitability at the level of lumbar spinal segments (LEP/Mmax), intracortical inhibition (SICI) and facilitation (ICF), and H-reflex in SOL and TA. In addition, the degree of fascicle length changes between SOL and TA was assessed in a subpopulation during passive ankle movement. Fascicles shortened and lengthened with joint movement during passive shortening and lengthening of SOL and TA to a similar degree (p < 0.001). Resting motor threshold was greater in SOL compared to TA (p ≤ 0.014). MEP/Mmax was facilitated in TA during passive shortening relative to the static position (p ≤ 0.023) and passive lengthening (p ≤ 0.001), but remained similar during passive ankle movement in SOL (p ≥ 0.497), regardless of muscle length at the point of stimulus (p = 0.922). LEP/Mmax (SOL: p = 0.075, TA: p = 0.071), SICI (SOL: p = 0.427, TA: p = 0.540), and ICF (SOL: p = 0.177, TA: p = 0.777) remained similar during passive ankle movement. H-reflex was not different across conditions in TA (p = 0.258), but was reduced during passive lengthening compared to shortening in SOL (p = 0.048). These results suggest a differential modulation of corticospinal excitability between plantar and dorsiflexors during passive movement. The corticospinal behaviour observed might be mediated by an increase in corticospinal drive as a result of reduced afferent input during muscle shortening and appears to be flexor-biased.

Repeatability and Specificity of Eccentric Force Output and the Implications for Eccentric Training Load Prescription.

Harden, M, Wolf, A, Haff, GG, Hicks, KM, and Howatson, G. Repeatability and specificity of eccentric force output and the implications for eccentric training load prescription. J Strength Cond Res 33(3): 676-683, 2019-Prescribing supramaximal eccentric (ECC) loads based on repetition maximum, isometric (ISO), or concentric-only (CON) strength overlooks the possibility that individuals have a different tolerance for ECC exercise. To inform the prescription of ECC training regimes, this study implemented a test battery that included maximal accentuated-eccentric (ECC+), traditional coupled eccentric-concentric (TRAD), and 2 ISO conditions (90 and 120° knee-joint angle [ISO90 and ISO120, respectively]). The study aimed to determine the repeatability and specificity of ECC+ force output and assess the methodological accuracy when using nonspecific measures of strength to prescribe ECC+ training loads. Results show that the test battery was repeatable (p > 0.05, intraclass correlation coefficient >0.95, coefficient of variation: <5.8%) and force output was specific to each task; ECC+ (4,034 ± 592 N) was higher (p < 0.001) than ISO90 (3,122 ± 579 N) and TRAD (3,574 ± 581 N), but less (p < 0.001) than ISO120 (6,285 ± 1,546 N). Although estimations of ECC+ strength were not different from observed ECC+ values (p > 0.05), estimations were associated with up to a 7% error. This investigation confirms that force output is task-specific; therefore, prescribing ECC loads based on strength during another task will likely lead to discrepancies in intended and actual ECC exercise intensity. Consequently, using an ECC-specific approach to assess ECC strength qualities will provide a more accurate platform to prescribe individualized ECC training programs and a more definitive evaluation of ECC strength.

An Evaluation of Supramaximally Loaded Eccentric Leg Press Exercise.

Harden, M, Wolf, A, Russell, M, Hicks, KM, French, D, and Howatson, G. An evaluation of supramaximally loaded eccentric leg press exercise. J Strength Cond Res 32(10): 2708-2714, 2018-High-intensity eccentric exercise is a potent stimulus for neuromuscular adaptation. A greater understanding of the mechanical stimuli afforded by this exercise will aid the prescription of future eccentric training regimens. This study sought to investigate the mechanical characteristics of supramaximally loaded eccentric exercise when using a custom-built leg press machine. Using a within-subject, repeated-measures design, 15 strength trained subjects (age, 31 ± 7 years; height, 180.0 ± 6.8 cm; body mass, 81.5 ± 13.9 kg) were assessed under 3 different conditions: low (LO), moderate (MOD), and high (HI) intensity, which were equivalent in intensity to 110, 130, and 150%, respectively, of peak force during an isometric maximal voluntary contraction (IMVC) performed on leg press at 90° knee flexion. All loading conditions demonstrated a similar pattern of mechanical profile; however, the variables underpinning each profile showed significant (p < 0.01) load-dependent response (LO vs. MOD, MOD vs. HI, LO vs. HI) for all variables, except for average acceleration. Average force associated with each loading conditions exceeded IMVC but equated to a lower intensity than what was prescribed. Repetitions under higher relative load intensity stimulated greater average force output, faster descent velocity, greater magnitude of acceleration, shorter time under tension, and a decline in force output at the end range of motion. This research provides new data regarding the fundamental mechanical characteristics underpinning supramaximally loaded eccentric leg press exercise. The information gathered in the study provides a foundation for practitioners to consider when devising loading strategies and implementing or evaluating supramaximally loaded eccentric exercise when using a similar exercise and device.

CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6+ cells in an experimental suction blister.

AIMS: GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. METHODS: This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers. RESULTS: GSK3050002 (0.1-20 mg kg-1 ) was well tolerated and no safety concerns were identified. The PK was linear over the dose range, with a half-life of approximately 2 weeks. Complex of GSK3050002/CCL20 increased in serum and blister fluid with increasing doses of GSK3050002. There were dose-dependent decreases in CCR6+ cell recruitment to skin blisters with maximal effects at doses of 5 mg kg-1 and higher, doses at which GSK3050002/CCL20 complex in serum and blister fluid also appeared to reach maximum levels. CONCLUSIONS: These results indicate a relationship between PK, target engagement and PD, suggesting a selective inhibition of recruitment of CCR6+ cells by GSK3050002 and support further development of GSK3050002 in autoimmune and inflammatory diseases.

A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer.

PURPOSE: Endocrine-based therapy is the initial primary treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2- mBC. PATIENTS AND METHODS: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2- breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. RESULTS: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8-20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73-4.83; P < 0.0001). CONCLUSIONS: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.

The effect of lower inter-limb asymmetries on athletic performance: A systematic review and meta-analysis.

Inter-limb asymmetry refers to an imbalance in performance between the left and right limbs. Discrepancies throughout asymmetry research does not allow practitioners to confidently understand the effect of inter-limb asymmetries on athletic performance. Therefore, this review summarized the current literature using a meta-analytic approach, conforming to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to identify the association between inter-limb asymmetry and athletic performance. A literature search using PubMed, Web of Science and SPORTDiscus databases yielded 11-studies assessing the effect of inter-limb asymmetries, measured via unilateral jump performance, on bilateral jump, change of direction (COD) and sprint performance in adult sports players. The quality of evidence was assessed via a modified Downs and Black checklist and in compliance with the Grading of Recommendations Assessment Development and Evaluation. Correlation coefficients were transformed via Fishers z (Zr), meta-analysed and then re-converted to correlation coefficients. Egger's regression presented no significant risk of bias. Vertical jump performance was not significantly affected by asymmetry (Zr = 0.053, r = 0.05; P = 0.874), whereas COD and sprint both presented significant weak associations (COD, Zr = 0.243, r = 0.24; Sprint, Zr = 0.203, r = 0.2; P < 0.01). The results demonstrate that inter-limb asymmetries seem to present a negative impact to COD and sprint performance but not vertical jump performance. Practitioners should consider implementing monitoring strategies to identify, monitor and possibly address inter-limb asymmetries, specifically for performance tests underpinned by unilateral movements such as COD and sprint performance.

B-Mode Ultrasonography Is a Reliable and Valid Alternative to Magnetic Resonance Imaging for Measuring Patellar Tendon Cross-Sectional Area.

This study investigated the validity and reliability of measuring patellar tendon (PT) cross-sectional area (CSA) using magnetic resonance imaging (MRI) and ultrasound (US) imaging. Nineteen healthy participants (10 women, 9 men) participated in three imaging sessions of the PT, once via MRI and twice via US, with image acquisition conducted by two raters, one experienced (rater 2) and one inexperienced (rater 1). All PT segmentations were analyzed by both raters. The validity of US-derived estimates of PT CSA against MRI estimates was analyzed using linear regression. Within-day reliability of US and MRI measurements and between-day reliability of US measurements were quantified using typical error (TE) and intra-class correlation coefficients (ICC3,1). There was good agreement between US- and MRI-derived estimations of PT CSA (standard errors of the estimate of 3.3 mm2 for rater 1 and 2.6 mm2 for rater 2; Pearson's r = 0.97 and 0.98 for raters 1 and 2, respectively). Within-session reliability for estimations of total PT CSA from US and MRI were excellent (ICC3,1 >0.95, coefficient of variation [CV] <4.1%, TE = 1.3-3.6 mm2. Between-day reliability for US was excellent (ICC3,1 >0.97, CV <2.7%, TE = 1.6-2.3 mm2), with little difference between raters. These findings suggest that MRI and US both provide reliable estimates of PT CSA and that US can provide a valid measure of PT CSA.