Psychedelics: Threshold of a Therapeutic Revolution.

This Special Issue of Neuropharmacology on psychedelics provides a timely and comprehensive update on progress following the previous Neuropharmacology Special Issue "Psychedelics: New Doors, Altered Perceptions". Remarkable advances have been made in basic and clinical research on psychedelics in the five years since 2018. It is partly based on the seminar series focused on psilocybin organized by the National Institutes of Health (NIH), USA from April to June 2021, the "NIH Psilocybin Research Speaker Series". Participants were world leading experts, including scientists, medical practitioners, clinical psychologists and oncologists, and attendees from additional disciplines of patient advocacy, law, government science policy and regulatory policy. To provide a global perspective, their contributions are complemented with reviews by some of the world's most eminent scientists in the field. The US Food and Drug Administration (FDA) has granted two breakthrough therapy designations for psilocybin in treatment resistant depression (TRD) in 2018 and major depressive disorder (MDD) in 2019, as well as for MDMA for the treatment of post-traumatic stress disorder (PTSD) in 2017. Clinical trials are in progress to assess the therapeutic value of psilocybin in MDD and TRD, and in other indications such as cancer-related anxiety and depression, anorexia, PTSD, substance use disorders and various types of chronic pain. The contributors' insights should assist basic and applied science for transition of psychedelics from bench to potential mainstream therapies. The implications are global, because FDA approval of these new medicines will increase international interest and efforts.

Experimental strategies to discover and develop the next generation of psychedelics and entactogens as medicines.

Research on classical psychedelics (psilocybin, LSD and DMT) and entactogen, MDMA, has produced a renaissance in the search for more effective drugs to treat psychiatric, neurological and various peripheral disorders. Psychedelics and entactogens act though interaction with 5-HT2A and other serotonergic receptors and/or monoamine reuptake transporters. 5-HT, which serves as a neurotransmitter and hormone, is ubiquitously distributed in the brain and peripheral organs, tissues and cells where it has vasoconstrictor, pro-inflammatory and pro-nociceptive actions. Serotonergic psychedelics and entactogens have known safety and toxicity risks. For these drugs, the risks been extensively researched and empirically assessed through human experience. However, novel drug-candidates require thorough non-clinical testing not only to predict clinical efficacy, but also to address the risks they pose during clinical development and later after approval as prescription medicines. We have defined the challenges researchers will encounter when developing novel serotonergic psychedelics and entactogens. We describe screening techniques to predict clinical efficacy and address the safety/toxicity risks emerging from our knowledge of the existing drugs: 1) An early-stage, non-clinical screening cascade to pharmacologically characterise novel drug-candidates. 2) Models to detect hallucinogenic activity. 3) Models to differentiate hallucinogens from entactogens. 4) Non-clinical preclinical lead optimisation technology (PLOT) screening to select drug-candidates. 5) Modified animal models to evaluate the abuse and dependence risks of novel psychedelics in Safety Pharmacology testing. Our intention has been to design non-clinical screening strategies that will reset the balance between benefits and harms to deliver more effective and safer novel psychedelics for clinical use. This article is part of the Special Issue on 'National Institutes of Health Psilocybin Research Speaker Series'.

Predicting pregnancy status from mid-infrared spectroscopy in dairy cow milk using deep learning.

Accurately identifying pregnancy status is imperative for a profitable dairy enterprise. Mid-infrared (MIR) spectroscopy is routinely used to determine fat and protein concentrations in milk samples. Mid-infrared spectra have successfully been used to predict other economically important traits, including fatty acid content, mineral content, body energy status, lactoferrin, feed intake, and methane emissions. Machine learning has been used in a variety of fields to find patterns in vast quantities of data. This study aims to use deep learning, a sub-branch of machine learning, to establish pregnancy status from routinely collected milk MIR spectral data. Milk spectral data were obtained from National Milk Records (Chippenham, UK), who collect large volumes of data continuously on a monthly basis. Two approaches were followed: using genetic algorithms for feature selection and network design (model 1), and transfer learning with a pretrained DenseNet model (model 2). Feature selection in model 1 showed that the number of wave points in MIR data could be reduced from 1,060 to 196 wave points. The trained model converged after 162 epochs with validation accuracy and loss of 0.89 and 0.18, respectively. Although the accuracy was sufficiently high, the loss (in terms of predicting only 2 labels) was considered too high and suggested that the model would not be robust enough to apply to industry. Model 2 was trained in 2 stages of 100 epochs each with spectral data converted to gray-scale images and resulted in accuracy and loss of 0.97 and 0.08, respectively. Inspection on inference data showed prediction sensitivity of 0.89, specificity of 0.86, and prediction accuracy of 0.88. Results indicate that milk MIR data contains features relating to pregnancy status and the underlying metabolic changes in dairy cows, and such features can be identified by means of deep learning. Prediction equations from trained models can be used to alert farmers of nonviable pregnancies as well as to verify conception dates.

Evidence of exposure to SARS-CoV-2 in cats and dogs from households in Italy.

SARS-CoV-2 emerged from animals and is now easily transmitted between people. Sporadic detection of natural cases in animals alongside successful experimental infections of pets, such as cats, ferrets and dogs, raises questions about the susceptibility of animals under natural conditions of pet ownership. Here, we report a large-scale study to assess SARS-CoV-2 infection in 919 companion animals living in northern Italy, sampled at a time of frequent human infection. No animals tested PCR positive. However, 3.3% of dogs and 5.8% of cats had measurable SARS-CoV-2 neutralizing antibody titers, with dogs from COVID-19 positive households being significantly more likely to test positive than those from COVID-19 negative households. Understanding risk factors associated with this and their potential to infect other species requires urgent investigation.

Evidence of exposure to SARS-CoV-2 in cats and dogs from households in Italy.

SARS-CoV-2 originated in animals and is now easily transmitted between people. Sporadic detection of natural cases in animals alongside successful experimental infections of pets, such as cats, ferrets and dogs, raises questions about the susceptibility of animals under natural conditions of pet ownership. Here we report a large-scale study to assess SARS-CoV-2 infection in 817 companion animals living in northern Italy, sampled at a time of frequent human infection. No animals tested PCR positive. However, 3.4% of dogs and 3.9% of cats had measurable SARS-CoV-2 neutralizing antibody titers, with dogs from COVID-19 positive households being significantly more likely to test positive than those from COVID-19 negative households. Understanding risk factors associated with this and their potential to infect other species requires urgent investigation. ONE SENTENCE SUMMARY: SARS-CoV-2 antibodies in pets from Italy.

Predicting bovine tuberculosis status of dairy cows from mid-infrared spectral data of milk using deep learning.

Bovine tuberculosis (bTB) is a zoonotic disease in cattle that is transmissible to humans, distributed worldwide, and considered endemic throughout much of England and Wales. Mid-infrared (MIR) analysis of milk is used routinely to predict fat and protein concentration, and is also a robust predictor of several other economically important traits including individual fatty acids and body energy. This study predicted bTB status of UK dairy cows using their MIR spectral profiles collected as part of routine milk recording. Bovine tuberculosis data were collected as part of the national bTB testing program for Scotland, England, and Wales; these data provided information from over 40,500 bTB herd breakdowns. Corresponding individual cow life-history data were also available and provided information on births, movements, and deaths of all cows in the study. Data relating to single intradermal comparative cervical tuberculin (SICCT) skin-test results, culture, slaughter status, and presence of lesions were combined to create a binary bTB phenotype labeled 0 to represent nonresponders (i.e., healthy cows) and 1 to represent responders (i.e., bTB-affected cows). Contemporaneous individual milk MIR spectral data were collected as part of monthly routine milk recording and matched to bTB status of individual animals on the single intradermal comparative cervical tuberculin test date (±15 d). Deep learning, a sub-branch of machine learning, was used to train artificial neural networks and develop a prediction pipeline for subsequent use in national herds as part of routine milk recording. Spectra were first converted to 53 × 20-pixel PNG images, then used to train a deep convolutional neural network. Deep convolutional neural networks resulted in a bTB prediction accuracy (i.e., the number of correct predictions divided by the total number of predictions) of 71% after training for 278 epochs. This was accompanied by both a low validation loss (0.71) and moderate sensitivity and specificity (0.79 and 0.65, respectively). To balance data in each class, additional training data were synthesized using the synthetic minority over sampling technique. Accuracy was further increased to 95% (after 295 epochs), with corresponding validation loss minimized (0.26), when synthesized data were included during training of the network. Sensitivity and specificity also saw a 1.22- and 1.45-fold increase to 0.96 and 0.94, respectively, when synthesized data were included during training. We believe this study to be the first of its kind to predict bTB status from milk MIR spectral data. We also believe it to be the first study to use milk MIR spectral data to predict a disease phenotype, and posit that the automated prediction of bTB status at routine milk recording could provide farmers with a robust tool that enables them to make early management decisions on potential reactor cows, and thus help slow the spread of bTB.

Effects of Theileria orientalis Ikeda type infection on libido and semen quality of bulls.

There is an epidemic in New Zealand of infectious bovine anaemia associated with Theileria orientalis Ikeda type, an obligate intracellular protozoan parasite. To establish whether T. orientalis Ikeda type infection adversely affects fertility of bulls used for natural mating, a randomised controlled experimental study was conducted. Ten of 17 2-year-old Friesian bulls that had not been previously infected with T. orientalis were infected with T. orientalis Ikeda type and then evaluations occurred during a 20-week period. There were semen and libido evaluations every 2 weeks, starting 4 weeks before the date of infection. In addition, there were blood collections, for haematocrit and infection intensity evaluations, rectal temperatures recorded, and bulls weighed three times weekly for 13 weeks after infection and then once weekly until completion of the study. Physical activity meters were also attached from Days 9-60 and 65-124 post-infection. The ten bulls were successfully infected with T. orientalis Ikeda type and this resulted in a decrease in HCT to about 0.25 by 70 days post-infection. There were no effects of infection on semen quality; however, during the acute phase of infection, when the infection intensity was rapidly increasing, the infected bulls took a longer time period for repeated mounting of females, and were less dominant in the herd social heiracrchy. In conclusion, although the transitory effects on libido could reduce conception rates, the overall effects of T. orientalis Ikeda type infection on bull fertility will probably be little.

Energy profiling of dairy cows from routine milk mid-infrared analysis.

The balance of body energy within and across lactations can have health and fertility consequences for the dairy cow. This study aimed to create a large calibration data set of dairy cow body energy traits across the cow's productive life, with concurrent milk mid-infrared (MIR) spectral data, to generate a prediction tool for use in commercial dairy herds. Detailed phenotypic data from 1,101 Holstein Friesian cows from the Langhill research herd (SRUC, Scotland) were used to generate energy balance (EB) and effective energy intake (EI), both in megajoules per day. Pretreatment of spectral data involved standardization to account for drift over time and machine. Body energy estimates were aligned with their spectral data to generate a prediction of these traits based on milk MIR spectroscopy. After data edits, partial least squares analysis generated prediction equations with a coefficient of determination from split sample 10-fold cross validation of 0.77 and 0.75 for EB and EI, respectively. These prediction equations were applied to national milk MIR spectra on over 11 million animal test dates (January 2013 to December 2016) from 4,453 farms. The predictions generated from these were subject to phenotypic analyses with a fixed regression model highlighting differences between the main dairy breeds in terms of energy traits. Genetic analyses generated heritability estimates for EB and EI ranging from 0.12 to 0.17 and 0.13 to 0.15, respectively. This study shows that MIR-based predictions from routinely collected national data can be used to generate predictions of dairy cow energy turnover profiles for both animal management and genetic improvement of such difficult and expensive-to-record traits.

Closing the gap: decentralising mental health care to primary care centres in one rural district of Rwanda.

Setting: Programmes that integrate mental health care into primary care settings could reduce the global burden of mental disorders by increasing treatment availability in resource-limited settings, including Rwanda. Objective: We describe patient demographics, service use and retention of patients in care at health centres (HC) participating in an innovative primary care integration programme, compared to patients using existing district hospital-based specialised out-patient care. Design: This was a retrospective cohort study using routinely collected data from six health centres and one district hospital from October 2014 to March 2015. Results: Of 709 patients, 607 were cared for at HCs; HCs accounted for 88% of the total visits for mental disorders. Patients with psychosis used HC services more frequently, while patients with affective disorders were seen more frequently at the district hospital. Of the 68% of patients who returned to care within 90 days of their first visit, 76% had a third visit within a further 90 days. There were no significant differences in follow-up rates between clinical settings. Conclusion: This study suggests that a programme of mentorship for primary care nurses can facilitate the decentralisation of out-patient mental health care from specialised district hospital mental health services to HCs in rural Rwanda.

Contexte : Les programmes qui intègrent les soins de santé mentale dans les structures de soins de santé primaires pourraient réduire le fardeau mondial des troubles mentaux en augmentant la disponibilité du traitement dans des contextes de ressources limitées, notamment au Rwanda.Objectif : Nous décrivons les caractéristiques démographiques des patients, leur utilisation des services et la rétention des patients en traitement dans les centres de santé (HC) participant à un programme innovant d'intégration dans les soins de santé primaires, comparés aux patients recourant aux consultations spécialisées existantes, basées dans les hôpitaux de district.Schéma : Une étude rétrospective de cohorte basée sur des données recueillies en routine dans six centres de santé et dans un hôpital de district, entre octobre 2014 et mars 2015.Résultats : De 709 patients, 607 ont été soignés dans les HC et les HC ont totalisé 88% de l'ensemble des consultations pour troubles mentaux. Les patients atteints de psychose ont plus souvent utilisé les services des HC, tandis que les patients atteints de troubles affectifs ont été plus souvent vus à l'hôpital de district. De 68% des patients qui sont revenus dans les 90 jours suivant leur première consultation, 76% ont eu une troisième consultation au cours des 90 jours suivants. Il n'y a pas eu de différences significatives en termes de taux de suivi entre les deux contextes cliniques.Conclusion : Cette étude suggère qu'un programme de tutorat destiné aux infirmiers de soins de santé primaires peut faciliter la décentralisation de la prise en charge de la santé mentale en consultation externe des services de santé mentale des hôpitaux spécialisés de district vers les HC dans le Rwanda rural.

Marco de referencia: Los programas que integran la atención de la salud mental al entorno de la atención primaria podrían reducir la carga mundial de morbilidad por trastornos mentales, al aumentar la disponibilidad del tratamiento en los medios con escasos recursos, por ejemplo en Rwanda.Objetivo: Se describen las características demográficas, la utilización de los servicios y la retención en la atención, de los pacientes atendidos en los centros de salud que participan en un programa innovador de atención primaria y se comparan con los pacientes que acuden a la consulta ambulatoria especializada que se presta en un hospital distrital.Método: Fue este un estudio de cohortes retrospectivo a partir de los datos recogidos de manera sistemática en seis centros de salud y un hospital distrital, de octubre del 2014 a marzo del 2015.Resultados: De los 709 pacientes, se atendieron 607 en los centros de salud y estos centros realizaron el 88% del total de consultas por trastornos mentales. Los pacientes con trastornos psicóticos utilizaban con mayor frecuencia los servicios en los centros de salud, pero los pacientes con trastornos del afecto se atendían con mayor frecuencia en el hospital distrital. El 68% de los pacientes regresaron al servicio de atención en los 90 días que siguieron a su primera consulta y el 76% de ellos acudió a una tercera consulta en los siguientes 90 días. No se observaron diferencias significativas en las tasas de seguimiento en los diferentes entornos clínicos.Conclusión: Los resultados del presente estudio ponen de manifiesto que un programa tutorial dirigido al personal de enfermería de los centros de atención primaria puede facilitar la descentralización de la atención ambulatoria de los pacientes con trastornos de salud mental, desde el hospital distrital con servicios especializados hacia los centros de salud en zonas rurales de Rwanda.

Knee internal contact force in a varus malaligned phenotype in knee osteoarthritis (KOA).

PURPOSE: Multiple phenotypes characterized by different disease mechanisms have been hypothesized to explain the large variability in the knee osteoarthritis (KOA) population. The purpose of this study was: to estimate and compare the medial and lateral knee compression forces (CF) during gait of three subgroups of KOA subjects characterized by different alignment and cartilage disruption patterns. METHODS: A secondary data analysis was conducted on a sample of 39 KOA subjects and 18 controls (C). The patients were classified in the different groups according to the following criteria: Varus medial disease (VMD) (12): varus alignment and predominant medial cartilage degeneration Varus generalized disease (VGD) (17): varus alignment and cartilage degeneration that extends to the lateral compartment. Neutral alignment (NA) (10): neutral alignment. The total, medial and lateral CF corrected for body weight were estimated using an inverse dynamics model (AnyBody Modeling System, AnyBody Technology) during stance. RESULTS: The impulse of the medial compressive force (MCF) (overall effect of the CF over the stance) was significantly higher (P < 0.01) in the VMD compared to all the other groups. Peak MCF was higher in the VMD compared to all the other groups, but the difference reached significance only when compared to the VGD group (P < 0.05). The results of the regression analysis showed a significant relationship in the VMD group between alignment and impulse of the MCF (R2 = 0.62; P < 0.01). This relationship disappears in the other groups. CONCLUSIONS: These findings suggest the existence of a phenotype characterized by increased MCF.

Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Growth of the maxillary sinus in children and adolescents: A longitudinal study.

Maxillary sinus volumetric and surface area data and growth models from longitudinal samples of children and adolescents are presented. Cone-beam radiographic CT scans from two small retrospective longitudinal samples, one from the Baylor College of Dentistry, Dallas, TX (N=17, 12 females, 5 males, 10.9-17.4 years) and one from a group private orthodontic practice in Nevada (N=15, 9 females, 6 males, 6.4-13.4 years) were used to collect maxillary sinus volumes and surface areas from each individual imaged at two times separated by variable intervals. Volume and surface area values were collected in Analyze® (Mayo Clinic) and growth models were produced in MLwiN®, a multi-level modeling program. There is a large degree of inter-individual variation. Surface area and surface-area-to-volume ratio (SA:V) changes are particularly variable. Growth models suggest linear growth in both volume and surface area, without growth spurts.

Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature.

BACKGROUND: Knee Osteoarthritis (KOA) is a heterogeneous pathology characterized by a complex and multifactorial nature. It has been hypothesised that these differences are due to the existence of underlying phenotypes representing different mechanisms of the disease. METHODS: The aim of this study is to identify the current evidence for the existence of groups of variables which point towards the existence of distinct clinical phenotypes in the KOA population. A systematic literature search in PubMed was conducted. Only original articles were selected if they aimed to identify phenotypes of patients aged 18 years or older with KOA. The methodological quality of the studies was independently assessed by two reviewers and qualitative synthesis of the evidence was performed. Strong evidence for existence of specific phenotypes was considered present if the phenotype was supported by at least two high-quality studies. RESULTS: A total of 24 studies were included. Through qualitative synthesis of evidence, six main sets of variables proposing the existence of six phenotypes were identified: 1) chronic pain in which central mechanisms (e.g. central sensitisation) are prominent; 2) inflammatory (high levels of inflammatory biomarkers); 3) metabolic syndrome (high prevalence of obesity, diabetes and other metabolic disturbances); 4) Bone and cartilage metabolism (alteration in local tissue metabolism); 5) mechanical overload characterised primarily by varus malalignment and medial compartment disease; and 6) minimal joint disease characterised as minor clinical symptoms with slow progression over time. CONCLUSIONS: This study identified six distinct groups of variables which should be explored in attempts to better define clinical phenotypes in the KOA population.

Pulmonary radiofrequency ablation in a district general hospital: is it a safe and effective treatment?

AIM: To analyse the technical success of ablation therapy and the incidence of complications in patients treated with pulmonary ablation and to assess factors affecting local disease control and patient survival in a subgroup with metastatic colorectal cancer. MATERIALS AND METHODS: Technical success and complications in all patients undergoing lung ablation between June 2009 and July 2015 were recorded. Overall survival and local disease control in a subgroup with metastases from a colorectal primary were calculated. Factors influencing outcome were explored. RESULTS: Two hundred and seven pulmonary ablations were performed in 86 patients at 156 attendances. Technical success was achieved in 207/207 (100%). Thirty and 90-day mortality was 0%. The major complication rate was 13/86 (15%). One hundred and one metastases were treated in 46 patients with a colorectal primary. This group had a mean ± standard error survival time of 53.58±3.47 months with a 1, 2, 3, 4, and 5-year survival rate of 97.4%, 91.3%, 81.5%, 59.8%, and 48%. There was no statistically significant difference in survival regarding time to development of metastatic disease, the total number of lesions ablated, the initial number of lesions ablated, the maximum size of lesion treated, or unilateral versus bilateral disease. Patients with extrapulmonary disease were found to have a shorter survival from the primary diagnosis. Seventy-eight (77.2%) of the 101 lesions were stable after first RFA. Local relapse was more likely when a metastasis was close to a large (>3 mm) vessel. CONCLUSION: RFA is a safe and effective procedure that can be performed without on-site cardiothoracic support. Good outcomes depend upon careful patient selection. This study supports its use in oligometastatic disease.

Thalidomide pharmacokinetics in sheep.

AIM: To determine the half life (T1/2), time taken to reach maximum plasma concentration (Tmax) and maximum plasma concentration (Cmax) of thalidomide in sheep following I/V, oral and topical treatment with a single dose of thalidomide. METHOD: Three groups of 4-6-month-old ram lambs were treated with thalidomide dissolved in dimethylsulphoxide (DMSO). The first group (n=10) was treated I/V with 100 mg thalidomide in 2 mL DMSO; the second group (n=8) received 400 mg thalidomide in 2 mL DMSO orally, and the third group (n=8) had 400 mg thalidomide in 4 mL DMSO applied topically. Plasma samples were collected up to 36 hours after treatment, snap-frozen at -80°C and analysed for concentrations of thalidomide using high performance liquid chromatography. RESULTS: Following I/V administration, T1/2 was 5.0 (SEM 0.4) hours, volume of distribution was 3,372.0 (SEM 244.3) mL/kg and clearance was 487.1 (SEM 46.1) mL/hour.kg. Topical application of 400 mg thalidomide did not increase plasma concentrations. Following oral administration, thalidomide bioavailability was 89%, with T1/2, Tmax, and Cmax being 7.2 (SEM 0.8) hours, 3.0 (SEM 0.4) hours and 1,767.3 (SEM 178.1) ng/mL, respectively. CONCLUSION: Topical administration using DMSO as a solvent did not increase concentrations of thalidomide in plasma. The mean pharmacokinetic parameters determined following oral treatment with 400 mg of thalidomide were similar to those reported in humans receiving a single 400 mg oral dose (T1/2 7.3 hours; Tmax 4.3 hours and Cmax 2,820 ng/mL). There is potential for thalidomide to be used as a model for the treatment of chronic inflammatory conditions in sheep, such as Johne's disease, where tumour necrosis factor alpha plays a pathogenic role.

Role of CO2 in the cerebral hyperemic response to incremental normoxic and hyperoxic exercise.

Cerebral blood flow (CBF) is temporally related to exercise-induced changes in partial pressure of end-tidal carbon dioxide (PetCO2 ); hyperoxia is known to enhance this relationship. We examined the hypothesis that preventing PetCO2 from rising (isocapnia) during submaximal exercise with and without hyperoxia [end-tidal Po2(PetO2 ) = 300 mmHg] would attenuate the increases in CBF. Additionally, we aimed to identify the magnitude that breathing, per se, influences the CBF response to normoxic and hyperoxic exercise. In 14 participants, CBF (intra- and extracranial) measurements were measured during exercise [20, 40, 60, and 80% of maximum workload (Wmax)] and during rest while ventilation (V̇e) was volitionally increased to mimic volumes achieved during exercise (isocapnic hyperpnea). While V̇ewas uncontrolled during poikilocapnic exercise, during isocapnic exercise and isocapnic hyperpnea, V̇ewas increased to prevent PetCO2 from rising above resting values (∼40 mmHg). Although PetCO2 differed by 2 ± 3 mmHg during normoxic poikilocapnic and isocapnic exercise, except for a greater poikilocapnic compared with isocapnic increase in blood velocity in the posterior cerebral artery at 60% Wmax, the between condition increases in intracranial (∼12-15%) and extracranial (15-20%) blood flow were similar at each workload. The poikilocapnic hyperoxic increases in both intra- and extracranial blood-flow (∼17-29%) were greater compared with poikilocapnic normoxia (∼8-20%) at intensities >40% Wmax(P< 0.01). During both normoxic and hyperoxic conditions, isocapnia normalized both the intracranial and extracranial blood-flow differences. Isocapnic hyperpnea did not alter CBF. Our findings demonstrate a differential effect of PetCO2 on CBF during exercise influenced by the prevailing PetO2.

In vitro wear testing of a contemporary design of reverse shoulder prosthesis.

Reverse shoulder arthroplasty is an increasingly common surgical intervention. However there are concerns and known limitations in relation to such joint replacement, while novel designs of reverse shoulder prostheses continue to appear on the market. Many claim to offer improvements over older designs but such assertions are difficult to validate when there is no consensus as to how such implants should be tested in vitro or even if such testing is necessary. In order to permit appropriate in vitro testing of reverse shoulder prostheses a unique, multi-station test rig was designed which was capable of applying motion in three axes to test prostheses. The shoulder simulator can apply up to 110° of motion in the flexion-extension and abduction-adduction axes and up to 90° in the internal-external rotation axis. Dynamic loading of up to 1500 N can be provided. The simulator is computer controlled so that the motions and loading associated with particular activities of daily living can be applied. A 4.5 million cycle wear test of commercially available reverse shoulder prostheses was undertaken using a 'mug to mouth' activity of daily living. Gravimetric analysis was used to characterise wear. After 4.5 million cycles of 'mug to mouth', the average wear rate of the test components was 14.3mm(3)/million cycles. Polyethylene test components showed a reduction in roughness and the median wear particle diameter was 167 nm. A three axis shoulder simulator has been designed and used to successfully test multiple samples of a commercially available reverse shoulder prosthesis.

Lung radiofrequency and microwave ablation: a review of indications, techniques and post-procedural imaging appearances.

Lung ablation can be used to treat both primary and secondary thoracic malignancies. Evidence to support its use, particularly for metastases from colonic primary tumours, is now strong, with survival data in selected cases approaching that seen after surgery. Because of this, the use of ablative techniques (particularly thermal ablation) is growing and the Royal College of Radiologists predict that the number of patients who could benefit from such treatment may reach in excess of 5000 per year in the UK. Treatment is often limited to larger regional centres, and general radiologists often have limited awareness of the current indications and the techniques involved. Furthermore, radiologists without any prior experience are frequently expected to interpret post-treatment imaging, often performed in the context of acute complications, which have occurred after discharge. This review aims to provide an overview of the current indications for pulmonary ablation, together with the techniques involved and the range of post-procedural appearances.

Adaptation of a commercial ELISA to determine the IgG avidity in sheep experimentally and naturally infected with Neospora caninum.

Recent reports indicate Neospora caninum has a possible role in causing abortions in sheep in New Zealand. Knowledge about the epidemiology of neosporosis in sheep is limited. This study aimed to adapt and validate a commercially available ELISA assay as an IgG avidity assay to discriminate between acute (primary and re-inoculated) and chronic N. caninum infections in sheep. In addition, it was used to compare the antibody avidity values between lambs from ewes inoculated with N. caninum either during the pregnancy or in the previous year. The avidity assay was undertaken by using 6M urea for the first wash after incubation with the primary antibody in the commercial ELISA (Chekit* Neospora antibody test kit, IDEXX Laboratories, Australia). Sequential serum samples were obtained from naïve ewes (n=16) experimentally inoculated with live N. caninum tachyzoites. All ewes were seropositive by two weeks post-inoculation and remained seropositive for 20 weeks post-inoculation. There was a linear relationship between time after inoculation and avidity values (p<0.05) over the first 24 weeks. In Week 4, all animals had avidity values <35% and by Week 8, 8/16 animals had avidity values of >35%. These results suggest that an avidity value of <35% indicates a recent primary infection while a value of >35% is indicative of a chronic infection. The assay was then validated using samples from other groups of experimentally inoculated sheep as well as samples from naturally infected ewes. When comparing sample to positive ratio (S/P) and avidity values from lambs born from recently inoculated ewes with those from ewes inoculated the previous year and re-inoculated in the current year, it was possible to differentiate the lambs at 2 weeks of age. Lambs from recently inoculated ewes had low S/P and avidity values at 2 weeks of age which increased by 12 weeks of age. In comparison, lambs from re-inoculated ewes had high S/P and avidity values at 2 weeks of age, due to maternal antibody influence but values were similar to those from lambs that were born from recently inoculated ewes at 12 weeks of age. Avidity values for four naturally infected ewes were all >60% indicating chronic infection. These results suggest that the assay is able to discriminate between recent and chronic infection in sheep as well as able to differentiate lambs with maternal immunity compared to their own de novo immunity. As such it can be utilized to understand the kinetics of N. caninum infection in sheep.