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Exercise-induced fatigue causes changes within the central nervous system that decrease force production capacity in fatigued muscles. The impact on unrelated, non-exercised muscle performance is still unclear. The primary aim of this study was to examine the impact of a bilateral forearm muscle contraction on the motor function of the distal and unrelated ankle plantar-flexor muscles. The secondary aim was to compare the impact of maximal and submaximal forearm contractions on the non-fatigued ankle plantar-flexor muscles. Maximal voluntary contractions (MVC) of the forearm and ankle plantar-flexor muscles as well as voluntary activation (VA) and twitch torque of the ankle plantar-flexor muscles were assessed pre-fatigue and throughout a 10-min recovery period. Maximal (100 % MVC) and submaximal (30 % MVC) sustained isometric handgrip contractions caused a decreased handgrip MVC (to 49.3 ± 15.4 and 45.4 ± 11.4 % of the initial MVC for maximal and submaximal contraction, respectively) that remained throughout the 10-min recovery period. The fatigue protocols also caused a decreased ankle plantar-flexor MVC (to 77 ± 8.3 and 92.4 ± 6.2 % of pre-fatigue MVC for maximal and submaximal contraction, respectively) and VA (to 84.3 ± 15.7 and 97.7 ± 16.1 % of pre-fatigue VA for maximal and submaximal contraction, respectively). These results suggest central fatigue created by the fatiguing handgrip contraction translated to the performance of the non-exercised ankle muscles. Our results also show that the maximal fatigue protocol affected ankle plantar-flexor MVC and VA more severely than the submaximal protocol, highlighting the task-specificity of neuromuscular fatigue.

The aim of this study was to determine whether and how young participants modulate their postural response to compensate for postural muscle fatigue during predictable but externally initiated continuous and oscillatory perturbations. Twelve participants performed ten postural trials before and after an ankle muscle fatigue protocol. Each postural trial was 1 min long and consisted of continuous backward and forward oscillations of the platform. Fatigue was induced by intermittent, bilateral isometric contractions of the ankle plantar- and dorsiflexors until the force production was reduced to 50 % of the pre-fatigue maximal voluntary contraction. Changes in the center of mass (COM) displacement, center of pressure (COP) displacement, and anterior–posterior location of the COP within the base of support were quantified as well as the activity of the tibialis anterior (TA), medial gastrocnemius (MG), quadriceps, and hamstring. All participants demonstrated postural stability post-fatigue by maintaining the displacement of their COM. Everyone also demonstrated a general forward shift in the anterior–posterior location of the COP within the base of support; however, two distinct postural modifications, corresponding to either an immediate fatigue-induced increase or decrease in the COP displacement during the backward platform translation, were recorded immediately post-fatigue. The changes in muscle onset latencies lasted beyond the recovery of the force production of the fatigued postural muscles. By 10 min post-fatigue, the participants showed a decrease in the COP displacement as well as an earlier activation of the postural muscles and an increased TA/MG co-activation relative to pre-fatigue. Although different strategies were used, the participants were able to adjust to and overcome postural muscle fatigue and remain balanced during the postural perturbations regardless of the direction of the platform movement. These adjustments lasted beyond the recovery of the ankle muscle force production indicating that they may be part of a centrally mediated protective response as opposed to a peripherally induced limitation to performance.

This study was designed to investigate the relationship between serum relaxin concentration (SRC) and menstrual history and hormonal contraceptive use among elite collegiate female athletes. Evaluation of SRC in athletes is necessary, because relaxin has been associated with increased knee joint laxity and decreased anterior cruciate ligament (ACL) strength in animal models. National Collegiate Athletic Association Division I female athletes participating in sports at high risk for ACL tears - basketball, field hockey, gymnastics, lacrosse, soccer, and volleyball - were invited to participate. All participants completed a questionnaire about their menstrual history and hormonal contraceptive use. Venipuncture was performed to obtain samples of serum progesterone and relaxin. Samples were obtained during the mid-luteal phase from ovulating participants, and between the actual or projected cycle days 21 to 24, from anovulatory participants. Serum concentration of relaxin and progesterone was determined by ELISA and the data were analyzed using SPSS statistical software with significance set at P = 0.05. 169 female athletes participated. The mean SRC among all participants was 3.08 ± 6.66 pg/mL). The mean SRC differed significantly between those participants using hormonal contraceptives (1.41 pg/mL) and those not using hormonal contraceptives (3.08 pg/mL, P = 0.002). Mean SRC was lowest among amenorrheic participants (1.02 pg/mL) and highest among oligomenorrheic participants (3.71 pg/mL) and eumenorrheic participants (3.06 pg/mL); these differences were not significant (P = 0.53). Mean serum progesterone concentration (SPC) differed significantly between those participants using hormonal contraceptives (2.80 ng/mL), and those not using hormonal contraceptives (6.99 ng/mL, P < 0.0001). There is a positive correlation between serum progesterone and SRC and an attenuation of SRC with hormonal contraceptive use. Our results underscore the significant role that hormonal contraceptives can play in decreasing relaxin levels, if future investigations establish a link between relaxin levels and ligamentous injury among female athletes.

Purpose The objective was to examine the impact of non-postural muscle fatigue on anticipatory postural control, during postural perturbations induced by platform translations. The experimental setup investigated the central changes caused by fatigue without the potential confounding influence of peripheral fatigue within the postural muscles. Methods Fatigue induced in forearm muscles by a maximal handgrip contraction has been previously shown to influence forearm force production for 10 min, reduce ankle plantarflexion force for 1 min and create measureable central fatigue for 30 s. The peak-to-peak anterior/posterior displacement of the center of mass and center of pressure (COP) and muscle activity were measured during the postural perturbation tasks performed before the fatigue protocol and for 10 min post-fatigue. Results The fatigue protocol decreased the peak-to-peak COP displacement from 128.0 ± 12.3 mm pre-fatigue to 81.9 ± 7.8 mm post-fatigue during the forwards platform translation ( p  < 0.05) and from 133.8 ± 12.0 to 89.2 ± 7.9 mm during the backwards translation ( p  < 0.05). The fatigue protocol also caused the tibialis anterior (TA pre-fatigue = −0.25 ± 0.04 s, TA post-fatigue = −0.41 ± 0.02 s, p  = 0.001) and medial gastrocnemius muscles (MG pre-fatigue = −0.39 ± 0.03 s, MG post-fatigue = −0.48 ± 0.02 s, p  = 0.028) to be recruited significantly earlier relative to the pre-fatigue condition. Conclusion This experimental setup ensured that peripheral fatigue did not develop in the postural muscles; therefore, a general fatigued-induced modification of the postural strategy is proposed as the origin of the postural changes and delayed recovery.

Respiration is a complex rhythmic motor behaviour that metabolically supports all physiological processes in the body and is continuous throughout the life of mammals. A failure to generate a respiratory rhythm can be fatal. Understanding how the respiratory rhythm is generated by the brainstem presents a substantial challenge within the field of respiratory neurobiology. Studies utilising in vitro and in vivo rodent models have provided compelling evidence that a small bilateral region of the ventrolateral medulla, known as the preBötzinger complex (preBötC), is the site for respiratory rhythmogenesis. There is also evidence to suggest a second distinct neuronal group, the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), plays a specialised role in respiratory rhythm generation in the neonatal rodent. During early life in rodents and humans, the respiratory system is immature and an irregular breathing pattern is generated, making this period of life potentially vulnerable to external perturbations. However a step in maturity occurs early in life after which breathing becomes regular. Currently, the underlying mechanisms involved in respiratory rhythm generation during early life are not fully understood. It is hypothesised that the RTN/pFRG functions as the dominant respiratory rhythm generating oscillator during early life when the respiratory system is immature, after which the preBötC becomes the dominant rhythm generator. However, how the preBötC and the RTN/pFRG interact in vivo to produce rhythmic breathing during postnatal development remains elusive. The first aim of this thesis was to assess postnatal maturation of breathing patterns in the mouse using non-invasive whole body plethysmography. Between postnatal day (P) 2 and P3, a critical maturation step occurred, whereby breathing transitioned from an unstable and dysrhythmic pattern to a regular and robust pattern. The second aim of the thesis was to investigate the influence of this postnatal maturation on central respiratory control. Mu (μ) opioid receptor agonists are known respiratory depressants. The activity of the preBötC is depressed by μ opioids in vitro. Furthermore, fentanyl, a potent μ opioid receptor agonist, evokes respiratory frequency depression in vivo by exclusively targeting and depressing preBötC neurons. Conversely, the RTN/pFRG is insensitive to μ opioids. Accordingly, fentanyl was utilised as a pharmacological tool to selectively perturb the preBötC in vivo throughout postnatal development and through to early adulthood. The acute respiratory depressive effects of fentanyl were measured in order to investigate the level of involvement of the preBötC in respiratory rhythm generation throughout this critical developmental time period. Based on the general hypothesis that the preBötC functions as the dominant respiratory rhythm generator when the respiratory system has matured, it was hypothesised that mice would be more susceptible to the respiratory depressive effects of fentanyl after the maturation step has occurred i.e. the respiratory sensitivity to fentanyl would be age-dependent. Initially, mice were repeatedly exposed to fentanyl throughout postnatal development. However, fentanyl failed to induce a respiratory depression at all postnatal ages, suggesting repeated exposure had induced a rapid desensitisation to fentanyl’s respiratory effects. The study design was consequently altered to allow the hypothesis to be sufficiently tested, whereby different mice were studied on each postnatal day i.e. each mouse was only exposed to fentanyl once. This study revealed a trend towards an age-dependent increase in respiratory sensitivity to fentanyl, where mice displayed a heightened respiratory frequency depression in response to fentanyl after the maturation step had occurred from P3 onwards. This data therefore lends support to the hypothesis that the preBötC functions as the dominant respiratory rhythm generator post-maturation. In the clinical setting fentanyl is widely utilised for treating chronic and acute pain. However, despite the potent respiratory depressive actions of fentanyl, the long-term respiratory consequences of repeated exposure remain unexplored both clinically and pre-clinically. Owing to the immaturity of the respiratory system and the corresponding fragile nature of breathing patterns during neonatal life in mammals, a further aim of the thesis was to determine the long-term effects of fentanyl exposure during this vulnerable respiratory time period in the mouse. To establish if the postnatal age of fentanyl-exposure influences long-term respiratory effects, fentanyl exposure during juvenile life, which is regarded as being post-respiratory maturation, was also assessed. Neonatal mice were exposed to fentanyl (0.04 mg/kg daily) from P1-P5 and juvenile mice were exposed from P9-P13. When mice reached adulthood, baseline respiratory activity and the respiratory response to a subsequent fentanyl challenge were assessed during wakefulness and under anaesthesia. When awake, neonatal-exposed mice exhibited a reduced baseline respiratory frequency and an attenuated respiratory sensitivity to fentanyl. Under anaesthesia, neonatal-exposed mice displayed a depressed baseline minute ventilation and a high frequency of spontaneous augmented breaths. In direct contrast to the wakeful state, when anaesthetised, neonatal-exposed mice exhibited a striking hypersensitivity to the acute respiratory depressive actions of fentanyl. In all neonatal-exposed mice, fentanyl evoked a respiratory failure. In juvenile-exposed mice, baseline respiratory activity remained unaltered in the wakeful state and fentanyl also failed to induce a respiratory depression. When anaesthetised, baseline minute ventilation remained unchanged and the high occurrence of augmented breaths exhibited by the neonatal-exposed mice was not observed. Unlike the wakeful state, fentanyl evoked a depression of respiratory activity in the juvenile-exposed mice when anaesthetised, however the augmented sensitivity to fentanyl and consequential respiratory arrest displayed by the neonatal-exposed was not observed. This data indicates that the anaesthetised state is more susceptible to respiratory depression. Furthermore, the data suggests that neonatal life represents a time period that is particularly vulnerable to the respiratory effects of opioid depression. The final aim of the thesis was to determine the long-term effects of neonatal fentanyl exposure on neurokinin-1 (NK1R) and μ opioid receptor expression within the ventral respiratory column (VRC), a region of the ventrolateral medulla comprising the preBötC. Neonatal-exposed mice exhibited significantly less NK1R and μ opioid receptor expressing cells in the region of the preBötC. This data suggests that repeated fentanyl exposure in neonatal life induces a long-term downregulation of these receptors. In conclusion, fentanyl’s acute respiratory effects were age-dependent, which lends supports to the hypothesis that the preBötC functions as the dominant rhythm generator post-maturation. Furthermore, this thesis highlights the vulnerabilities of neonatal life to the lasting effects of opioid respiratory depression, whilst also providing invaluable insight into state-dependent respiratory modulation and depression.

Ensuring sufficient gRNA transcript levels is critical for obtaining optimal CRISPR-Cas9 gene editing efficiency. The standard gRNA scaffold contains a sequence of four thymine nucleotides (4T), which is known to inhibit transcription from Pol III promoters such as the U6 promoter. Our study showed that using standard plasmid transfection protocols, the presence of these 4Ts did not significantly affect editing efficiency, as most of the gRNAs tested (55 gRNAs) achieved near-perfect editing outcomes. We observed that gRNAs with lower activity were T-rich and had reduced gRNA transcript levels. However, this issue can be effectively resolved by increasing transcript levels, which can be readily achieved by shortening the 4T sequences. In this study, we demonstrated this by modifying the sequences to 3TC. Although the 3TC scaffold modification did not improve editing efficiency for already efficient gRNAs when high vector quantities were available, it proved highly beneficial under conditions of limited vector availability, where the 3TC scaffold yielded higher editing efficiency. Additionally, we demonstrated that the 3TC scaffold is compatible with SpCas9 high-fidelity variants and ABEmax base editing, enhancing their editing efficiency. Another commonly used natural Cas9 variant, SaCas9, also benefited from the 3TC scaffold sequence modification, which increased gRNA transcription and subsequently improved editing activity. This modification was applied to the EDIT-101 therapeutic strategy, where it demonstrated marked improvements in performance. This study highlights the importance of shortening the 4T sequences in the gRNA scaffold to optimize gRNA transcript expression for enhanced CRISPR-Cas9 gene editing efficiency. This optimization is particularly important for therapeutic applications, where the quantity of vector is often limited, ensuring more effective and optimal outcomes.

Acute gastrointestinal graft versus host disease (GI-GVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT), and is characterised by severe morbidity, frequent treatment-refractoriness, and high mortality. Early, accurate identification of GI-GVHD could allow for therapeutic interventions to ameliorate its severity, improve response rates and survival; however, standard endoscopic biopsy is inadequately informative in terms of diagnostic sensitivity or outcome prediction. In an era where rapid technological and laboratory advances have dramatically expanded our understanding of GI-GVHD biology and potential therapeutic targets, there is substantial scope for novel investigations that can precisely guide GI-GVHD management. In particular, the combination of tissue-based biomarker assessment (plasma cytokines, faecal microbiome) and molecular imaging by positron emission tomography (PET) offers the potential for non-invasive, real-time in vivo assessment of donor:recipient immune activity within the GI tract for GI-GVHD prediction or diagnosis. In this article, we review the evidence regarding GI-GVHD diagnosis, and examine the potential roles and translational opportunities posed by these novel diagnostic tools, with a focus on the evolving role of PET.

IntroductionEvolving pressures on endoscopy services and shortened training curriculums have necessitated innovative approaches in the delivery of efficient and high-quality endoscopy training. We present a real-world experience of planning and running one of the UK’s first immersive endoscopy training hubs.MethodsWe established a training hub within our regional endoscopy academy and run an immersion period of 2 weeks with 18 colonoscopy training lists. Each immersion period is attended by 2 regional trainees, who alternate between performing the procedure or observing and actively reflecting. The focus of learning is on the technical aspects of intubation in diagnostic colonoscopy. We have identified and upskilled an expert local training faculty including consultant gastroenterologists, colorectal surgeons and clinical endoscopists.ResultsBetween March 2022 and May 2023, our immersion endoscopy hub has hosted 25 attendees. 15 (60%) had a gastroenterology background, 8 (32%) general surgery, and 2 (8%) were clinical endoscopists. 22 (88%) were specialist registrars or clinical fellows; the median grade being ST5. The mean number of procedures performed per participant was 26 (range 14–34). 21 (84%) and 12 (48%) of the cohort performed more procedures during their hub period than they had in the preceding three months and six months, respectively. Following attendance at our hub, the mean number of procedures performed per week by the 23 participants who did not already have provisional certification increased from 1.3 to 1.6. From this it is possible to extrapolate that the ‘average’ trainee would be expected to reach the requisite 280 procedures for full colonoscopy certification 40 weeks sooner having taken part in the hub (figure 1).Abstract P302 Figure 1Number of procedures pre- and post-immersion hub. Solid black line demonstrates procedures performed in the 48 weeks prior and 50 weeks following the hub period. Broken black line demonstrates expected rate of procedures post-hub. Broken grey line demonstrates expected rate of procedures without hub attendance. Broken vertical lines demonstrate expected time of achievement of 280 procedures with and without hub participation.ConclusionsWe present the first published experiential account of developing and running an immersive endoscopy training hub in the UK. Immersive training is well-received by trainees, and demonstrably accelerates their procedural skills, leading to earlier attainment of certification for independent practice in colonoscopy.

Background Youth with disability are less physically active and more likely to have chronic health conditions than their peers without disability. The aim of our study was to assess the effectiveness of a scalable school-based physical activity intervention for youth with disability on functional capacity and a range of secondary outcomes. Methods We conducted a two-arm cluster randomized controlled trial involving adolescents aged 15–19 years with diagnosed disabilities ( N  = 255) from 28 secondary schools in New South Wales, Australia. Schools were randomized to the Burn 2 Learn adapted (B2La) intervention, or a wait-list control. The B2La intervention included foundational resistance exercises (e.g., push-ups, bodyweight squats), aerobic exercises (e.g., shuttle runs), and sport skills (e.g., catching, kicking), delivered as classroom activity breaks 2–3 times per week by trained special education teachers. The primary outcome was functional capacity assessed using the 6-min walk or push test. Secondary outcomes were muscular fitness, body mass index, physical activity (accelerometers), resistance training motor competence, motivation for physical activity, high-intensity interval training self-efficacy, quality of life, and externalizing behaviors. Assessments were conducted at baseline, 6-months (primary endpoint), and 9-months (follow-up). Results At 6-months, the intervention group demonstrated a significant improvement in functional capacity, with a group-by-time effect of 20.3 m (95% CI, 3.1–37.1). At 9-months, the effect was 17.8 m (95% CI, 0.0–35.6). The intervention had a small effect on muscular fitness, resistance training motor competence, and high-intensity interval training self-efficacy. No effects were observed for the other outcomes and no adverse events were recorded. Conclusions Physical activity breaks delivered by special education teachers during the school day improved functional capacity and a range of secondary outcomes in youth with disability. Activity breaks may need to be longer, more frequent, or more intense to achieve clinically important health effects. Trial registration Australian New Zealand Clinical Trials Registry Number: ACTRN12621000884808; prospectively registered 15th November, 2021.

We have previously reported that haematopoietic progenitor cell transplantation recipients with biopsy-negative acute Gastrointestinal Graft versus Host Disease (Discordant GVHD) demonstrate superior survival compared to “True Positive” cases. We aimed to elucidate this discrepancy by examining clinical and laboratory predictors of survival among patients treated for True Positive or Discordant GVHD. Data were obtained by retrospective chart review. At diagnosis, the incidence of severe symptoms, hypoalbuminaemia, hyperbilirubinaemia, and poor performance status were recorded. Following treatment, the incidence of non-response to first-line corticosteroids was assessed. Differences between cohorts were compared using Fisher’s exact test. 74 patients were identified, comprising 55 (74%) True Positive and 19 (26%) Discordant GVHD cases. True Positive cases were significantly more likely to have baseline severe symptoms (84% vs. 36%; p = 0.0002) and hypoalbuminaemia (94% vs. 75%; p = 0.023). There was no significant difference between cohorts in terms of hyperbilirubinaemia or performance status. Non-response to corticosteroid therapy was observed significantly more frequently in the True Positive cohort (55% vs. 11%; p = 0.001). In summary, the superior survival observed in Discordant GVHD is explained by a less severe GI-GVHD phenotype at diagnosis and a greater likelihood of response to corticosteroids. Further research is warranted to explain biological mechanisms for these findings.