Performance in enduro mountain biking: the influence of training status, recovery, and vibration

Enduro mountain bike racing (enduro) consists of timed downhill race stages linked by non-competitive transition stages and general classification is determined by accumulated race stage time. Limited research is available on the physiological requirements of enduro despite a large population of professional elite riders. For this thesis, nine elite enduro athletes (n=8 male, n=1 female; top 100 world ranking) were recruited. Measures of daily training load (TL) and resting heart rate variability (HRV) were collected between three laboratory based tests throughout a season of training and racing. The demands of an international race event were assessed by heart rate, terrain induced accelerations and vibration exposure. Leukocyte subset (Neutrophils, CD4+ T-cell, CD8+ T-cell, and NK cell) redistribution, cortisol and IL-6 concentration were assessed at each laboratory test (pre, post, 1h-post) and the race event (pre, 1h-post, 19h-post). Main findings were that successful performance in enduro requires a large aerobic capacity (VO₂peak = 61.1 ± 5.2 ml.kg.min⁻¹, power VO₂peak = 410.9 ± 18.2W) coupled with adequate skill, technique and muscle mass to ensure high velocities can be sustained over differing types of terrain. Elevated TL appears to be a key component of training habit and the upper limit of training volume before negative adaptation was identified (>800 A.U. LuTRIMP). No relationship was found between TL and HRV. No significant changes were observed in leukocyte subset redistribution between laboratory tests. The race event induced significantly larger changes in circulating numbers of certain leukocyte subsets when compared to the laboratory test and the magnitude of redistribution of CD4⁺ senescent T-cells was partially explained by vibration exposure (ΔR² = -0.673, F₍₃,₁₎ = 12.12, p = 0.04). A subsequent novel assessment of vibration loading in mountain biking revealed potentially damaging levels of vibration exposure that could be associated with long term health implications in enduro athletes (Ai(8) range 5.47 to 6.61ms⁻²). It was concluded that vibration exposure needs to be considered in future models of physiological loading in this discipline

Elite mountain bike enduro competition: a study of rider hand-arm vibration exposure

Limited information is currently available regarding the hand-arm vibration (HAV) exposure 5 for professional off-road cyclists. Previous reports have suggested that commuting and 6 recreational cyclists are at risk of exceeding exposure limit values (ELV) in a single ride. 7 Therefore, further investigation of HAV exposure in competitive mountain biking is 8 warranted. Partial and total eight hour exposure data (Ai(8), A(8), ms⁻²) were computed for a 9 national level mountain bike enduro competitions. Hand-arm vibrations were measured using 10 a tri-axial accelerometer recording at a frequency of 3.2 kHz mounted on the handlebar and 11 accelerations were quantified after frequency weighting filters were applied (Wh). The data 12 presented shows that HAV exposure during one day of competitive enduro mountain bike 13 racing exceeds ELV (mean race exposure = 5.84 ms⁻² , minimum = 5.47ms⁻² , maximum = 14 6.61ms⁻²) and is greater than the HAV exposure observed in recreational cycling. This 15 suggests that further work is required to determine the exposure associated with changes in 16 equipment, technique and international racing events in professional athletes

Modulation of spontaneous locomotor and respiratory drives to hindlimb motoneurons temporally related to sympathetic drives as revealed by Mayer waves

In this study we investigated how the networks mediating respiratory and locomotor drives to lumbar motoneurons interact and how this interaction is modulated in relation to periodic variations in blood pressure (Mayer waves). Seven decerebrate cats, under neuromuscular blockade, were used to study central respiratory drive potentials (CRDPs, usually enhanced by added CO(2)) and spontaneously occurring locomotor drive potentials (LDPs) in hindlimb motoneurons, together with hindlimb and phrenic nerve discharges. In four of the cats both drives and their voltage-dependent amplification were absent or modest, but in the other three, one or other of these drives was common and the voltage-dependent amplification was frequently strong. Moreover, in these three cats the blood pressure showed marked periodic variation (Mayer waves), with a slow rate (periods 9–104 s, mean 39 ± 17 SD). Profound modulation, synchronized with the Mayer waves was seen in the occurrence and/or in the amplification of the CRDPs or LDPs. In one animal, where CRDPs were present in most cells and the amplification was strong, the CRDP consistently triggered sustained plateaux at one phase of the Mayer wave cycle. In the other two animals, LDPs were common, and the occurrence of the locomotor drive was gated by the Mayer wave cycle, sometimes in alternation with the respiratory drive. Other interactions between the two drives involved respiration providing leading events, including co-activation of flexors and extensors during post-inspiration or a locomotor drive gated or sometimes entrained by respiration. We conclude that the respiratory drive in hindlimb motoneurons is transmitted via elements of the locomotor central pattern generator. The rapid modulation related to Mayer waves suggests the existence of a more direct and specific descending modulatory control than has previously been demonstrated

First E region observations of mesoscale neutral wind interaction with auroral arcs

We report the first observations of E region neutral wind fields and their interaction with auroral arcs at mesoscale spatial resolution during geomagnetically quiet conditions at Mawson, Antarctica. This was achieved by using a scanning Doppler imager, which can observe thermospheric neutral line-of-sight winds and temperatures simultaneously over a wide field of view. In two cases, the background E region wind field was perpendicular to an auroral arc, which when it appeared caused the wind direction within ∼50 km of the arc to rotate parallel along the arc, reverting to the background flow direction when the arc disappeared. This was observed under both westward and eastward plasma convection. The wind rotations occurred within 7–16 min. In one case, as an auroral arc propagated from the horizon toward the local zenith, the background E region wind field became significantly weaker but remained unaffected where the arc had not passed through. We demonstrate through modeling that these effects cannot be explained by height changes in the emission layer. The most likely explanation seems to be the greatly enhanced ion drag associated with the increased plasma density and localized ionospheric electric field associated with auroral arcs. In all cases, the F region neutral wind appeared less affected by the auroral arc, although its presence is clear in the data

Border Terriers under primary veterinary care in England: demography and disorders

The Border Terrier is a working terrier type that is generally considered to be a relatively healthy and hardy breed. This study aimed to characterise the demography and common disorders of Border Terriers receiving veterinary care in England using de-identified electronic patient record data within the VetCompass™ Programme

Labrador retrievers under primary veterinary care in the UK: demography, mortality and disorders

Abstract Background Labrador retrievers are reportedly predisposed to many disorders but accurate prevalence information relating to the general population are lacking. This study aimed to describe demography, mortality and commonly recorded diseases in Labrador retrievers under UK veterinary care. Methods The VetCompass™ programme collects electronic patient record data on dogs attending UK primary-care veterinary practices. Demographic analysis covered all33,320 Labrador retrievers in the VetCompass™ database under veterinary care during 2013 while disorder and mortality data were extracted from a random sample of 2074 (6.2%) of these dogs. Results Of the Labrador retrievers with information available, 15,427 (46.4%) were female and 15,252 (53.6%) were male. Females were more likely to be neutered than males (59.7% versus 54.8%, P <  0.001). The overall mean adult bodyweight was 33.0 kg (SD 6.1). Adult males were heavier (35.2 kg, SD 5.9 kg) than adult females (30.4 kg, SD 5.2 kg) (P <  0.001). The median longevity of Labrador retrievers overall was 12.0 years (IQR 9.9–13.8, range 0.0–16.0). The most common recorded colours were black (44.6%), yellow (27.8%) and liver/chocolate (reported from hereon as chocolate) (23.8%). The median longevity of non-chocolate coloured dogs (n = 139, 12.1 years, IQR 10.2–13.9, range 0.0–16.0) was longer than for chocolate coloured animals (n = 34, 10.7 years, IQR 9.0–12.4, range 3.8–15.5) (P = 0.028). Of a random sample of 2074 (6.2%) Labrador retrievers under care in 2013 that had full disorder data extracted, 1277 (61.6%) had at least one disorder recorded. The total number of dogs who died at any date during the study was 176. The most prevalent disorders recorded were otitis externa (n = 215, prevalence 10.4%, 95% CI: 9.1–11.8), overweight/obesity (183, 8.8%, 95% CI: 7.6–10.1) and degenerative joint disease (115, 5.5%, 95% CI: 4.6–6.6). Overweight/obesity was not statistically significantly associated with neutering in females (8.3% of entire versus 12.5% of neutered, P = 0.065) but was associated with neutering in males (4.1% of entire versus 11.4% of neutered, P < 0.001). The prevalence of otitis externa in black dogs was 12.8%, in yellow dogs it was 17.0% but, in chocolate dogs, it rose to 23.4% (P < 0.001). Similarly, the prevalence of pyo-traumatic dermatitis in black dogs was 1.1%, in yellow dogs it was 1.6% but in chocolate dogs it rose to 4.0% (P = 0.011). Conclusions The current study assists prioritisation of health issues within Labrador retrievers. The most common disorders were overweight/obesity, otitis externa and degenerative joint disease. Males were significantly heavier females. These results can alert prospective owners to potential health issues and inform breed-specific wellness checks

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study.

BACKGROUND: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma. METHODS: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD <median had greater likelihood of response than those with either (OR=2.08) or both (OR=4.42) risk factors. The most common grade 3/4 treatment-emergent adverse events (≥30%) were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%). CONCLUSIONS: Investigational lifileucel demonstrated clinically meaningful activity in heavily pretreated patients with advanced melanoma and high tumor burden. Durable responses and a favorable safety profile support the potential benefit of one-time lifileucel TIL cell therapy in patients with limited treatment options in ICI-refractory disease

Modelling collective cell behaviour

The classical mean-field approach to modelling biological systems makes a number of simplifying assumptions which typically lead to coupled systems of reaction-diffusion partial differential equations. While these models have been very useful in allowing us to gain important insights into the behaviour of many biological systems, recent experimental advances in our ability to track and quantify cell behaviour now allow us to build more realistic models which relax some of the assumptions previously made. This brief review aims to illustrate the type of models obtained using this approach

Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update

Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented