Biomechanical comparison of the track start and the modified one-handed track start in competitive swimming: an intervention study

This study compared the conventional track and a new one-handed track start in elite age group swimmers to determine if the new technique had biomechanical implications on dive performance. Five male and seven female GB national qualifiers participated (mean ± SD: age 16.7 ± 1.9 years, stretched stature 1.76 ± 0.8 m, body mass 67.4 ± 7.9 kg) and were assigned to a control group (n = 6) or an intervention group (n = 6) that learned the new onehanded dive technique. All swimmers underwent a 4-week intervention comprising 12 ± 3 thirty-minute training sessions. Video cameras synchronized with an audible signal and timing suite captured temporal and kinematic data. A portable force plate and load cell handrail mounted to a swim starting block collected force data over 3 trials of each technique. A MANCOVA identified Block Time (BT), Flight Time (FT), Peak Horizontal Force of the lower limbs (PHF) and Horizontal Velocity at Take-off (Vx) as covariates. During the 10-m swim trial, significant differences were found in Time to 10 m (TT10m), Total Time (TT), Peak Vertical Force (PVF), Flight Distance (FD), and Horizontal Velocity at Take-off (Vx) (p < .05). Results indicated that the conventional track start method was faster over 10 m, and therefore may be seen as a superior start after a short intervention. During training, swimmers and coaches should focus on the most statistically significant dive performance variables: peak horizontal force and velocity at take-off, block and flight time

Insight into imiquimod skin permeation and increased delivery using microneedle pre-treatment

Basal cell carcinoma (BCC) is the most common skin cancer in humans. Topical treatment with imiquimod provides a non-invasive, self-administered treatment with relatively low treatment cost. Despite displaying excellent efficacy, imiquimod is only licensed by the FDA for superficial BCC. The current work employed HPLC and ToF-SIMS analysis to provide a novel assessment of imiquimod permeation from Aldara™ cream in skin depth and lateral distribution. Using Aldara™ cream and in vitro Franz cell studies with subsequent HPLC analysis, it is apparent that most of the topically applied imiquimod cream is left on the skin surface with more than 80% of the drug being recovered from skin wash. In addition, ToF-SIMS chemical imaging of recovered tape stripped skin samples illustrated significant detection of imiquimod signal over the entire skin area for the upper tape strips, whereas the deeper strips show large portions of the skin area without detected imiquimod. Given the limited permeation depth and non-uniform permeation observed at tape strips 6–18 when applied as a topical imiquimod cream, a permeation enhancement strategy utilising a skin pre-treatment with a microneedle device was investigated as a method to improve intradermal delivery. The recovered amount of imiquimod in tape strips and remaining skin determined by HPLC was approximately three times higher when Aldara™ was applied on microneedle pre-treated skin relative to intact skin. The ToF-SIMS ion images of the tape strips and cross-sections illustrated the existence of imiquimod in the microchannels which then laterally diffuses to peripheral epidermal strata. The current work demonstrates the first known attempt to enhance intradermal delivery of imiquimod using a microneedle device as well as underscoring the complementary role of ToF-SIMS analysis in chemically mapping imiquimod permeation into the skin with high sensitivity

On the suitability of high vacuum electrospray deposition for the fabrication of molecular electronic devices

We present a series of three studies investigating the potential application of high vacuum electrospray deposition to construct molecular electronic devices. Through the use of time of flight secondary ion mass spectrometry we explore the use of this novel deposition technique to fabricating multilayer structures using materials that are compatible with the same solvents and films containing a mixture of molecules from orthogonal solvents. Using x-ray photoelectron spectroscopy we study the deposition of a polymer blend using electrospray and find evidence of preferential deposition of one of the components

Characterisation of mechanical insertion of commercial microneedles

The protection provided by the human skin is mostly attributed to the stratum corneum. However, this barrier also limits the range of molecules that can be delivered into and across the skin. One of the methods to overcome this physiological barrier and improve the delivery of molecules into and across the skin is via the use of microneedles. This work evaluates the mechanical insertion of two different commercially available microneedle systems, Dermapen® and Dermastamp™. The influence of biaxial skin strain on the penetration of the two microneedle systems was evaluated ex vivo using a biaxial stretch rig. From the skin insertion study, it was apparent that for all levels of biaxial strain investigated, the Dermapen® required less force than the Dermastamp™ to puncture the skin. In addition, it was observed that the oscillating microneedle system, the Dermapen®, resulted in deeper skin insertion ex vivo in comparison to the Dermastamp™. The use of this new biaxial stretch rig and the ex vivo skin insertion depth study highlights that the oscillating Dermapen® required less force to perforate the skin at varying biaxial strain whilst resulting in deeper skin penetration ex vivo in comparison to the Dermastamp™. Although the Dermapen® punctured the skin deeper than the Dermastamp™, such difference in penetration did not influence the permeation profile of the model drug, imiquimod across the skin as evidenced from a 24-h ex vivo permeation study

The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen-specificity: implications for vaccine design

The oncofoetal antigen 5T4 is a promising T cell target in the context of colorectal cancer, as demonstrated by a recent clinical study where 5T4-specific T cell responses, induced by vaccination or cyclophosphamide, were associated with a significantly prolonged survival of patients with metastatic disease. Whilst Th1-type (IFN-γ+) responses specific to 5T4, and other oncofoetal antigens, are often readily detectable in early stage CRC patients and healthy donors, their activity is suppressed as the cancer progresses by CD4+CD25hiFoxp3+ regulatory T cells (Treg) which contribute to the immunosuppressive environment conducive to tumour growth. This study mapped the fine specificity of Th1 and Treg cell responses to the 5T4 protein. Surprisingly, both immunogenic peptides and those recognised by Tregs clustered in the same HLA-DR transcending epitope-rich hotspots within the 5T4 protein. Similarly, regions of low Th1-cell immunogenicity also did not contain peptides capable of stimulating Tregs, further supporting the notion that Treg and Th1 cells recognise the same peptides. Understanding the rules which govern the balance of Th1 and Treg cells responding to a given peptide specificity is, therefore, of fundamental importance to designing strategies for manipulating the balance in favour of Th1 cells, and thus the most effective anti-cancer T cell responses

PUF60-related developmental disorder:A case series and phenotypic analysis of 10 additional patients with monoallelic PUF60 variants

PUF60-related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of PUF60, is associated with multiple congenital anomalies affecting a wide range of body systems. These anomalies include ophthalmic coloboma, and congenital anomalies of the heart, kidney, and musculoskeletal system. Behavioral and intellectual difficulties are also observed. While less common than other features associated with PUF60-related developmental disorder, for instance hearing impairment and short stature, identification of specific anomalies such as ophthalmic coloboma can aid with diagnostic identification given the limited spectrum of genes linked with this feature. We describe 10 patients with PUF60 gene variants, bringing the total number reported in the literature, to varying levels of details, to 56 patients. Patients were recruited both via locally based exome sequencing from international sites and from the DDD study in the United Kingdom. Eight of the variants reported were novel PUF60 variants. The addition of a further patient with a reported c449-457del variant to the existing literature highlights this as a recurrent variant. One variant was inherited from an affected parent. This is the first example in the literature of an inherited variant resulting in PUF60-related developmental disorder. Two patients (20%) were reported to have a renal anomaly consistent with 22% of cases in previously reported literature. Two patients received specialist endocrine treatment. More commonly observed were clinical features such as: cardiac anomalies (40%), ocular abnormalities (70%), intellectual disability (60%), and skeletal abnormalities (80%). Facial features did not demonstrate a recognizable gestalt. Of note, but remaining of unclear causality, we describe a single pediatric patient with pineoblastoma. We recommend that stature and pubertal progress should be monitored in PUF60-related developmental disorder with a low threshold for endocrine investigations as hormone therapy may be indicated. Our study reports an inherited case with PUF60-related developmental disorder which has important genetic counseling implications for families.Published version, accepted version (12 month embargo)The article is available via Open Access. Click on the 'Additional link' above to access the full-text

3D ToF-SIMS imaging of polymer multilayer films using argon cluster sputter depth profiling

ToF-SIMS imaging with argon cluster sputter depth profiling has provided detailed insight into the three-dimensional (3D) chemical composition of a series of polymer multilayer structures. Depths of more than 15 μm were profiled in these samples while maintaining uniform sputter rates. The 3D chemical images provide information regarding the structure of the multilayer systems that could be used to inform future systems manufacturing and development. This also includes measuring the layer homogeneity, thickness, and interface widths. The systems analyzed were spin-cast multilayers comprising alternating polystyrene (PS) and polyvinylpyrrolidone (PVP) layers. These included samples where the PVP and PS layer thickness values were kept constant throughout and samples where the layer thickness was varied as a function of depth in the multilayer. The depth profile data obtained was observed to be superior to that obtained for the same materials using alternative ion sources such as C60 n+. The data closely reflected the “as manufactured” sample specification, exhibiting good agreement with ellipsometry measurements of layer thickness, while also maintaining secondary ion intensities throughout the profiling regime. The unprecedented quality of the data allowed a detailed analysis of the chemical structure of these systems, revealing some minor imperfections within the polymer layers and demonstrating the enhanced capabilities of the argon cluster depth profiling technique

Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope

CD4+ T-cells recognize peptide antigens, in the context of human leukocyte antigen (HLA) class II molecules (HLA-II), which through peptide-flanking residues (PFRs) can extend beyond the limits of the HLA binding. The role of the PFRs during antigen recognition is not fully understood; however, recent studies have indicated that these regions can influence T-cell receptor (TCR) affinity and pHLA-II stability. Here, using various biochemical approaches including peptide sensitivity ELISA and ELISpot assays, peptide-binding assays and HLA-II tetramer staining, we focused on CD4+ T-cell responses against a tumor antigen, 5T4 oncofetal trophoblast glycoprotein (5T4), which have been associated with improved control of colorectal cancer. Despite their weak TCR-binding affinity, we found that anti-5T4 CD4+ T-cells are polyfunctional and that their PFRs are essential for TCR recognition of the core bound nonamer. The high-resolution (1.95 Å) crystal structure of HLA-DR1 presenting the immunodominant 20-mer peptide 5T4111–130, combined with molecular dynamic simulations, revealed how PFRs explore the HLA-proximal space to contribute to antigen reactivity. These findings advance our understanding of what constitutes an HLA-II epitope and indicate that PFRs can tune weak affinity TCR–pHLA-II interactions

Cantú syndrome with coexisting familial pituitary adenoma

Context: Pseudoacromegaly describes conditions with an acromegaly related physical appearance without abnormalities in the growth hormone (GH) axis. Acromegaloid facies, together with hypertrichosis, are typical manifestations of Cantú syndrome. Case description: We present a three-generation family with 5 affected members, with marked acromegaloid facies and prominent hypertrichosis, due to a novel missense variant in the ABCC9 gene. The proband, a 2-year-old girl, was referred due to marked hypertrichosis, noticed soon after birth, associated with coarsening of her facial appearance. Her endocrine assessment, including of the GH axis, was normal. The proband's father, paternal aunt, and half-sibling were referred to the Endocrine department for exclusion of acromegaly. Although the GH axis was normal in all, two subjects had clinically non-functioning pituitary macroadenomas, a feature which has not previously been associated with Cantú syndrome. Conclusions: Activating mutations in the ABCC9 and, less commonly, KCNJ8 genes—representing the two subunits of the ATP-sensitive potassium channel—have been linked with Cantú syndrome. Interestingly, minoxidil, a well-known ATP-sensitive potassium channel agonist, can cause a similar phenotype. There is no clear explanation why activating this channel would lead to acromegaloid features or hypertrichosis. This report raises awareness for this complex condition, especially for adult or pediatric endocrinologists who might see these patients referred for evaluation of acromegaloid features or hirsutism. The link between Cantú syndrome and pituitary adenomas is currently unclear