Northern Ireland farm-level management factors for recurrent bovine tuberculosis herd breakdowns.

Bovine tuberculosis (bTB) is a chronic, infectious and zoonotic disease of domestic and wild animals caused mainly by Mycobacterium bovis. This study investigated farm management factors associated with recurrent bTB herd breakdowns (n = 2935) disclosed in the period 23 May 2016 to 21 May 2018 and is a follow-up to our 2020 paper which looked at long duration bTB herd breakdowns. A case control study design was used to construct an explanatory set of farm-level management factors associated with recurrent bTB herd breakdowns. In Northern Ireland, a Department of Agriculture Environment and Rural Affairs (DAERA) Veterinarian investigates bTB herd breakdowns using standardised guidelines to allocate a disease source. In this study, source was strongly linked to carryover of infection, suggesting that the diagnostic tests had failed to clear herd infection during the breakdown period. Other results from this study associated with recurrent bTB herd breakdowns were herd size and type (dairy herds 43% of cases), with both these variables intrinsically linked. Other associated risk factors were time of application of slurry, badger access to silage clamps, badger setts in the locality, cattle grazing silage fields immediately post-harvest, number of parcels of land the farmer associated with bTB, number of land parcels used for grazing and region of the country.

Northern Ireland farm-level management factors for prolonged bovine tuberculosis herd breakdowns.

This study determined farm management factors associated with long-duration bovine tuberculosis (bTB) breakdowns disclosed in the period 23 May 2016 to 21 May 2018; a study area not previously subject to investigation in Northern Ireland. A farm-level epidemiological investigation (n = 2935) was completed when one or more Single Intradermal Comparative Cervical Test (SICCT) reactors or when one or more confirmed (positive histological and/or bacteriological result) lesion at routine slaughter were disclosed. A case-control study design was used to construct an explanatory set of management factors associated with long-duration bTB herd breakdowns; with a case (n = 191) defined as an investigation into a breakdown of 365 days or longer. Purchase of infected animal(s) had the strongest association as the most likely source of infection for long-duration bTB herd breakdowns followed by badgers and then cattle-to-cattle contiguous herd spread. However, 73.5% (95% CI 61.1-85.9%) of the herd type contributing to the purchase of infection source were defined as beef fattening herds. This result demonstrates two subpopulations of prolonged bTB breakdowns, the first being beef fattening herds with main source continuous purchase of infected animals and a second group of primary production herds (dairy, beef cows and mixed) with risk from multiple sources.

Role of Stone-Wales defects on the interfacial interactions among graphene, carbon nanotubes, and Nylon 6: A first-principles study.

We investigate computationally the role of Stone-Wales (SW) defects on the interfacial interactions among graphene, carbon nanotubes (CNTs), and Nylon 6 using density functional theory (DFT) and the empirical force-field. Our first-principles DFT calculations were performed using the Quantum ESPRESSO electronic structure code with the highly accurate van der Waals functional (vdW-DF2). Both pristine and SW-defected carbon nanomaterials were investigated. The computed results show that the presence of SW defects on CNTs weakens the CNT-graphene interactions. Our result that CNT-graphene interaction is much stronger than CNT-CNT interaction indicates that graphene would be able to promote the dispersion of CNTs in the polymer matrix. Our results demonstrate that carbon nanomaterials form stable complexes with Nylon 6 and that the van der Waals interactions, as revealed by the electronic charge density difference maps, play a key stabilizing role on the interfacial interactions among graphene, CNTs, and Nylon 6. Using the density of states calculations, we observed that the bandgaps of graphene and CNTs were not significantly modified due to their interactions with Nylon 6. The Young's moduli of complexes were found to be the averages of the moduli of their individual constituents.

Oral Medicine for undergraduate dental students in the United Kingdom and Ireland-A curriculum.

INTRODUCTION: Oral Medicine focuses on care for patients with chronic, recurrent and medically related disorders of the orofacial region that are distinct from diseases of the periodontal and tooth tissues, with an emphasis on non-surgical management. At present, there are no shared outcomes for Oral Medicine to define the standards to be achieved before new graduates become registered dentists engaged with ongoing professional development. CURRICULUM: We present a consensus undergraduate curriculum in Oral Medicine agreed by representatives from 18 Dental Schools in the United Kingdom and Republic of Ireland. The scope of Oral Medicine practice includes conditions involving the oral mucosa, salivary glands, neurological system or musculoskeletal tissues that are not directly attributable to dental (tooth and periodontium) pathology. Account is taken of the priorities for practice and learning opportunities needed to support development of relevance to independent clinical practice. The outcomes triangulate with the requirements set out by the respective regulatory bodies in the UK and Republic of Ireland prior to first registration and are consistent with the framework for European undergraduate dental education and greater harmonisation of dental education. CONCLUSIONS: This curriculum will act as a foundation for an increasingly shared approach between centres with respect to the outcomes to be achieved in Oral Medicine. The curriculum may also be of interest to others, such as those responsible for the training of dental hygienists and dental therapists. It provides a platform for future collective developments with the overarching goal of raising the quality of patient care.

Integrating EM and Patch-seq data: Synaptic connectivity and target specificity of predicted Sst transcriptomic types.

Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between those cell types 1 . Neural cell types have previously been defined by morphology 2, 3 , electrophysiology 4, 5 , transcriptomic expression 6-8 , connectivity 9-13 , or even a combination of such modalities 14-16 . More recently, the Patch-seq technique has enabled the characterization of morphology (M), electrophysiology (E), and transcriptomic (T) properties from individual cells 17-20 . Using this technique, these properties were integrated to define 28, inhibitory multimodal, MET-types in mouse primary visual cortex 21 . It is unknown how these MET-types connect within the broader cortical circuitry however. Here we show that we can predict the MET-type identity of inhibitory cells within a large-scale electron microscopy (EM) dataset and these MET-types have distinct ultrastructural features and synapse connectivity patterns. We found that EM Martinotti cells, a well defined morphological cell type 22, 23 known to be Somatostatin positive (Sst+) 24, 25 , were successfully predicted to belong to Sst+ MET-types. Each identified MET-type had distinct axon myelination patterns and synapsed onto specific excitatory targets. Our results demonstrate that morphological features can be used to link cell type identities across imaging modalities, which enables further comparison of connectivity in relation to transcriptomic or electrophysiological properties. Furthermore, our results show that MET-types have distinct connectivity patterns, supporting the use of MET-types and connectivity to meaningfully define cell types.

Clomifene citrate and intrauterine insemination as first-line treatments for unexplained infertility: are they cost-effective?

BACKGROUND: First-line treatments for unexplained infertility traditionally include clomifene citrate (CC) or unstimulated intrauterine insemination (IUI). A recently published randomized controlled trial considered the effectiveness of CC and IUI in patients with unexplained infertility and found that neither treatment offered a superior live birth rate when compared with expectant management (EM). This paper reports the economic evaluation conducted alongside this trial in order to assess whether health care providers are gaining value for money in this clinical area. METHODS: Five hundred and eighty women across five Scottish hospitals were randomized to either EM, CC or IUI for 6 months. The primary outcome measure was live births. Resource-use data were collected during the trial and costs were calculated from a UK National Health Service (NHS) perspective. Incremental cost-effectiveness ratios were calculated, expressed as cost per live birth, in order to compare the cost-effectiveness of CC and IUI with that of EM to treat unexplained infertility. RESULTS: Live birth rates in the three randomized groups were: EM = 32/193 (17%), CC = 26/194 (13%) and IUI = 43/193 (22%). The mean (standard deviation) costs per treatment cycle were £0 for EM, £83 (£17) for CC and £98 (£31) for IUI. The mean treatment costs per patient for EM, CC and IUI were £12 (£117), £350 (£220) and £331 (£222), respectively. The cost per live birth for EM, CC and IUI was £72 (95% confidence interval £0-£206), £2611 (£1870-£4166) and £1487 (£1116-£2155), respectively. The incremental cost-effectiveness ratio for IUI versus EM was £5604 (-£12204 to £2227), with CC dominated by IUI. CONCLUSIONS: Despite being more expensive, existing treatments such as empirical CC and unstimulated IUI do not offer superior live birth rates compared with EM of unexplained infertility. They are unlikely to be a cost-effective use of limited NHS resources. The study's main limitation is that it did not consider the psychological effects on couples. ISRCT Number: 71762042.

Clinical medical sciences for undergraduate dental students in the United Kingdom and Ireland - a curriculum.

The technical aspects of dentistry need to be practised with insight into the spectrum of human diseases and illnesses and how these impact upon individuals and society. Application of this insight is critical to decision-making related to the planning and delivery of safe and appropriate patient-centred healthcare tailored to the needs of the individual. Provision for the necessary training is included in undergraduate programmes, but in the United Kingdom and Ireland there is considerable variation between centres without common outcomes. In 2009 representatives from 17 undergraduate dental schools in the United Kingdom and Ireland agreed to move towards a common, shared approach to meet their own immediate needs and that might also be of value to others in keeping with the Bologna Process. To provide a clear identity the term 'Clinical Medical Sciences in Dentistry' was agreed in preference to other names such as 'Human Disease' or 'Medicine and Surgery'. The group was challenged to define consensus outcomes. Contemporary dental education documents informed, but did not drive the process. The consensus curriculum for undergraduate Clinical Medical Sciences in Dentistry teaching agreed by the participating centres is reported. Many of the issues are generic and it includes elements that are likely to be applicable to others. This document will act as a focus for a more unified approach to the outcomes required by graduates of the participating centres and act as a catalyst for future developments that ultimately aim to enhance the quality of patient care.

Remote telephone clinics in oral medicine: reflections on the place of virtual clinics in a specialty that relies so heavily on visual assessment. A note of caution.

During the COVID-19 pandemic, NHS services had to convert face-to-face consultations to remote consultations to facilitate the ongoing provision of healthcare. Many specialties including Oral and Maxillofacial Surgery and Rheumatology have found such virtual clinics effective and appreciated by both patients and clinicians. In Oral Medicine, whilst responses to virtual clinics have been positive, we have recognised that they are not sufficient. In this reflective piece, we describe our experiences and our approach to their use in the management of Oral Medicine and Behçet's disease patients, which has developed iteratively during the lockdown period. We also consider the role of virtual clinics in Oral Medicine in the post-COVID-19 era.

Screening for oral cancer utilising risk-factor analysis is ineffective in high-risk populations.

Screening for oral cancer by direct visual examination is believed to be ineffective because of the difficulty in differentiating a small number of malignancies from the much more prevalent benign oral mucosal lesions (OML) that are found in high-risk individuals. Standardised clinical diagnoses were recorded for all the OMLs identified during oral visual examination of 1111 individuals with risk factors for oral cancer, including tobacco and areca nut (paan) consumption. Suspicious lesions were referred for biopsy and definitive diagnosis. A total of 1438 OMLs with 32 different clinical diagnoses were identified in 604 participants. Analysis of referrals revealed two distinct groups: visually benign lesions (VBLs) none of which was referred, and visually complex lesions (VCLs) comprising 661 OMLs with nine different clinical diagnoses. After biopsy the VCLs included known potentially malignant disorders (PMDs) as well as benign lesions such as paan mucositis. VCLs (but not VBLs) share risk factors with oral cancer (p<0.05 for paan 5.82 (CI: 1.98 to 8.43), and smoking 3.59 (CI: 1.12 to 4.47)). They are clinically indistinguishable from, but much more prevalent than, oral cancer, and most will never undergo malignant change. They therefore can prevent dentists from accurately detecting malignancy during the clinical examination of high-risk patients. However, they can easily be differentiated from other benign lesions by visual examination alone. Further research into diagnostic technology is needed to help differentiate them from oral cancers.

Analysis of protein glycation using phenylboronate acrylamide gel electrophoresis.

The incorporation of the specialized carbohydrate affinity ligand methacrylamido phenylboronic acid in polyacrylamide gels for SDS-PAGE analysis has been successful for the separation of carbohydrates and has here been adapted for the analysis of post-translationally modified proteins. While conventional SDS-PAGE analysis cannot distinguish between glycated and unglycated proteins, methacrylamido phenylboronate acrylamide gel electrophoresis (mP-AGE) in low loading shows dramatic retention of delta-gluconolactone modified proteins, while the mobility of the unmodified proteins remains unchanged. With gels containing 1% methacrylamido phenylboronate, mP-AGE analysis of gluconoylated recombinant protein Sbi results in the retention of the modified protein at a position expected for a protein that has quadrupled its expected molecular size. Subsequently, mP-AGE was tested on HSA, a protein that is known to undergo glycation under physiological conditions. mP-AGE could distinguish between various carbohydrate-protein adducts, using in vitro glycated HSA, and discriminate early from late glycation states of the protein. Enzymatically glycosylated proteins show no altered retention in the phenylboronate-incorporated gels, rendering this method highly selective for glycated proteins. We reveal that a trident interaction between phenylboronate and the Amadori cis 1,2 diol and amine group provides the molecular basis of this specificity. These results epitomize mP-AGE as an important new proteomics tool for the detection, separation, visualization and identification of protein glycation. This method will aid the design of inhibitors of unwanted carbohydrate modifications in recombinant protein production, ageing, diabetes, cardiovascular diseases and Alzheimer's disease.

Methamphetamine sensitization attenuates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus.

Methamphetamine (MA) use is associated with activation of microglia and, at high doses, can induce neurotoxicity. Given the changes in the neuroinflammatory environment associated with MA, we investigated whether MA sensitization, a model of stimulant psychosis and an indicator of drug addiction, would interfere with the thermoregulatory and neuroinflammatory response to a subsequent peripheral immune stimulus. C57BL6/J mice were given either 1 mg/kg MA or saline i.p. once a day for 5 days to produce behavioral sensitization. Seventy-two hours following the last MA injection, 100 microg/kg LPS or saline was co-administered with 1 mg/kg MA or saline and blood and brains were collected. Here we report that while co-administration of LPS and MA did not affect the LPS-induced increase in central cytokine mRNA, mice sensitized to MA showed an attenuated central response to LPS. Interestingly, the peripheral response to LPS was not affected by MA sensitization. Plasma cytokines increased similarly in all groups after LPS. Further, c-Fos expression in the nucleus of the solitary tract did not differ between groups, suggesting that the periphery-to-brain immune signal is intact in MA-sensitized mice and that the deficit lies in the central cytokine compartment. We also show that MA sensitization decreased LPS- or acute MA-induced microglial Iba1 expression compared to non-sensitized mice. Taken together, these data show that MA sensitization interferes with the normal central immune response, preventing the CNS from efficiently responding to signals from the peripheral immune system.

The period prevalence of oral lichen planus in a cohort of patients with vulvar lichen sclerosus.

BACKGROUND: Lichen sclerosus and lichen planus are chronic inflammatory mucocutaneous disorders that may coexist. OBJECTIVE: The aim of this study was to estimate the period prevalence of oral lichen planus in a cohort of patients with vulvar lichen sclerosus and to document their clinical characteristics. METHODS: We report a series of cases of vulvar lichen sclerosus presenting to two dermatologist-led vulvar clinics in Oxfordshire, England between 1997 and 2007 with coexistent clinical signs of oral lichen planus. RESULTS: Thirteen cases with coexistent vulvar lichen sclerosus and oral lichen planus were identified, of which five had oral biopsies. Four oral biopsies showed histological features consistent with lichen planus. One oral biopsy was not diagnostic but compatible with oral lichen planus. No cases of oral lichen sclerosus were identified. The period prevalence of oral lichen planus was 6 per 1000 cases of vulvar lichen sclerosus. CONCLUSION: The period prevalence of oral lichen planus in women with vulvar lichen sclerosus (0.6%) is similar to that reported for oral lichen planus in the general population (1-2%).

Effect of prolactin, beta-lactoglobulin, and kappa-casein genotype on milk yield in East Friesian sheep.

The effect of prolactin (PRL), beta-lactoglobulin (beta-LG), and kappa-casein (CSN3) on milk yield was estimated in an East Friesian dairy sheep population from Old Chatham Sheepherding Company, New York. Genotypes were determined by PCR amplification followed by digestion with HaeIII and RsaI for PRL and beta-LG, respectively, and by PCR amplification for CSN3. Monthly milking records and pedigree information were used to evaluate the effect of each polymorphism on milk yield. Results indicated that PRL genotype had a significant effect on milk yield. Ewes carrying one A allele produced 110.6g more milk per day than ewes with no A alleles. There was no statistical difference between ewes with only one A allele and ewes with 2 A alleles. No association among polymorphisms at the beta-LG and CSN3 loci and milk yield was found. The results presented in this study indicate that the PRL gene is a potential marker that could be used in selection programs for improving milk yield in dairy sheep.

Golgi spectrin: identification of an erythroid beta-spectrin homolog associated with the Golgi complex.

Spectrin is a major component of a membrane-associated cytoskeleton involved in the maintenance of membrane structural integrity and the generation of functionally distinct membrane protein domains. Here, we show that a homolog of erythrocyte beta-spectrin (beta I sigma*) co-localizes with markers of the Golgi complex in a variety of cell types, and that microinjected beta-spectrin codistributes with elements of the Golgi complex. Significantly, we show a dynamic relationship between beta-spectrin and the structural and functional organization of the Golgi complex. Disruption of both Golgi structure and function, either in mitotic cells or following addition of brefeldin A, is accompanied by loss of beta-spectrin from Golgi membranes and dispersal in the cytoplasm. In contrast, perturbation of Golgi structure without a loss of function, by the addition of nocodazole, results in retention of beta-spectrin with the dispersed Golgi elements. These results indicate that the association of beta-spectrin with Golgi membranes is coupled to Golgi organization and function.

Newly identified 'glutamate interneurons' and their role in locomotion in the lamprey spinal cord.

A new class of excitatory premotor interneurons that are important in the generation of locomotion in the lamprey has now been described. In the isolated spinal cord, these neurons act simultaneously with their postsynaptic motoneurons during fictive swimming. They are small and numerous, and they monosynaptically excite both motoneurons and inhibitory premotor interneurons. The excitatory postsynaptic potentials are depressed by an antagonist of excitatory amino acids. These interneurons receive reticulospinal input from the brain stem and polysynaptic input form skin afferents. A model of the network underlying locomotion based on the synaptic interactions of these neurons can now be proposed for the lamprey.

Prolonged activation of mitochondrial conductances during synaptic transmission.

Although ion channels have been detected in mitochondria, scientists have not been able to record ion transport in mitochondria of intact cells. A variation of the patch clamp technique was used to record ion channel activity from intracellular organelles in the presynaptic terminal of the squid. Electron microscopy indicated that mitochondria are numerous in this terminal and are the only organelles compatible with the tips of the pipettes. Before synaptic stimulation, channel activity was infrequent and its conductance was small, although large conductances ( approximately 0.5 to 2.5 nanosiemens) could be detected occasionally. During a train of action potentials, the conductance of the mitochondrial membrane increased up to 60-fold. The conductance increased after a delay of several hundred milliseconds and continued to increase after stimulation had stopped. Recovery occurred over tens of seconds.

The heart is a target organ for androgen.

Autoradiographic and biochemical analyses of the hearts of female rhesus monkeys and baboons indicate that atrial and ventricular myocardial cells contain androgen receptors. Although the specific effects of nuclear uptake and retention of androgen on the function of heart muscle cells are not known, the presence of this receptor suggests that sex steroid hormones may affect myocardial function directly and may explain some of the peculiar differences in heart disease between men and women.

Identification of the cystic fibrosis gene: genetic analysis.

Approximately 70 percent of the mutations in cystic fibrosis patients correspond to a specific deletion of three base pairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the cystic fibrosis gene. Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8 percent) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The ability to detect mutations in the cystic fibrosis gene at the DNA level has important implications for genetic diagnosis.

Effect of Cellulose Nanofibrils and TEMPO-mediated Oxidized Cellulose Nanofibrils on the Physical and Mechanical Properties of Poly(vinylidene fluoride)/Cellulose Nanofibril Composites.

Cellulose nanofibrils (CNFs) are high aspect ratio, natural nanomaterials with high mechanical strength-to-weight ratio and promising reinforcing dopants in polymer nanocomposites. In this study, we used CNFs and oxidized CNFs (TOCNFs), prepared by a 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation process, as reinforcing agents in poly(vinylidene fluoride) (PVDF). Using high-shear mixing and doctor blade casting, we prepared free-standing composite films loaded with up to 5 wt % cellulose nanofibrils. For our processing conditions, all CNF/PVDF and TOCNF/PVDF films remain in the same crystalline phase as neat PVDF. In the as-prepared composites, the addition of CNFs on average increases crystallinity, whereas TOCNFs reduces it. Further, addition of CNFs and TOCNFs influences properties such as surface wettability, as well as thermal and mechanical behaviors of the composites. When compared to neat PVDF, the thermal stability of the composites is reduced. With regards to bulk mechanical properties, addition of CNFs or TOCNFs, generally reduces the tensile properties of the composites. However, a small increase (~18%) in the tensile modulus was observed for the 1 wt % TOCNF/PVDF composite. Surface mechanical properties, obtained from nanoindentation, show that the composites have enhanced performance. For the 5 wt % CNF/PVDF composite, the reduced modulus and hardness increased by ~52% and ~22%, whereas for the 3 wt % TOCNF/PVDF sample, the increase was ~23% and ~25% respectively.

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.