Making Information About Cladribine Tablets Accessible to People with Multiple Sclerosis: A Patient-Survey-Led Narrative Review for Healthcare Professionals.

Cladribine tablets have been granted marketing authorization in Europe and approved by the Food and Drug Administration (FDA) in the USA to treat relapsing forms of multiple sclerosis (MS). However, people with MS (PwMS) may be more familiar, and therefore more confident, with treatments requiring long-term and frequent dosing. Differences in such treatment strategies can lead to questions relating to how short-course non-continuous treatments, such as cladribine tablets, can work and how well they are tolerated. In response to this, we aimed to create an evidence-based report on patient-focused aspects of treatment with cladribine. To inform development, MS experts, including healthcare professionals (HCPs) and PwMS, proposed topics that PwMS and their families and caregivers would most like to discuss with HCPs during consultations to help them better understand cladribine treatment. The statements regarding each topic were then ranked by PwMS and used to inform the topics covered in this report. We explain here the use of cladribine tablets, which includes explanations of how cladribine tablets work, how to take cladribine tablets, and considerations required prior to and while taking cladribine tablets. We also describe how cladribine tablets affect relapse rate and quality of life and detail side effects, when they are likely to happen, and for how long. We also discuss how cladribine tablets affect family planning, fertility, and the use of vaccines. Alongside each section is a brief, plain language description of what is covered and an accompanying visual to aid conversations between HCPs and PwMS. Improved understanding by PwMS of treatments, such as cladribine, can empower them to play a bigger role in shared decision-making regarding their treatment. Additionally, the open dialogue we aim to promote with this type of report could lead to treatment choices being better tailored for individuals with chronic diseases on the basis of personal experiences, preferences, and circumstances.

The effect of piling behavior on the production and mortality of free-range laying hens.

Piling, a dense cluster of hens, is a behavior of major concern to the cage-free egg industry. It can cause large numbers of mortalities at which point it is considered smothering. The aim of this study was to quantify whether piling can also have consequences on production and non-smothering mortalities, which have not previously been described. Additionally, we aimed to describe characteristics of piling behavior relevant to for management. Video footage from 12 flocks of laying hens was analyzed for piling behavior across 3 wks. Production and mortality data were accessed using an integrated online management system. Bayesian linear mixed-effect models were used for formal statistical testing of the relationships between piling and production. Accounting for some missing data, a total of 252 d amounting to approximately 15,624 h were analyzed for the presence or absence of piling behavior, which we believe constitutes the largest analysis of piling behavior in the scientific literature to date. All flocks observed exhibited piling behavior even if they had no history of smothering. On average, flocks piled more than 4 times per day for around 44 min per event and the peak piling time occurred between 1300 and 1359. We found that the number of piling events was associated with a reduction in the number of eggs produced the next day; based on the average of 4 piles per day this amounted to 7.35 fewer eggs per 1,000 birds per day. Contrary to our hypothesis, we found total piling duration per day was positively associated with fewer Grade B eggs, with a decrease of 0.74 Grade B eggs for every hour of piling per day. No relationship was observed between piling and mortality not attributed to smothering. We discuss possible causes and explanations for these results including birds' response to stress, crowd dynamics, and daily rhythms. Here we show the potential for piling behavior to have sublethal consequences on production even in the absence of smothering-related deaths.

Infant feeding policies and monitoring systems: A qualitative study of European Countries.

Implementation of the Global Strategy for Infant and Young Child Feeding varies widely among countries. Policymakers would benefit from insights into obstacles and enablers. Our aim was to explore the processes behind the development and implementation of national infant and young child feeding policies and monitoring systems in Europe. A qualitative study design was employed to analyze open text responses from six European countries (Croatia, Germany, Lithuania, Spain, Turkey and Ukraine) using inductive thematic analysis. Countries were selected based on their World Breastfeeding Trends Initiative scores on national policy and monitoring systems. The 33-item online questionnaire was distributed to country representatives and completed by country teams. Key enablers and strengths included strong and continuous government commitment to infant and young child feeding, an operational national breastfeeding authority, a national and active monitoring and evaluation system, implementation of the International Code of Marketing of Breastmilk Substitutes in national legislation, the integration of skilled breastfeeding supporters, the implementation of the Baby-friendly Hospital Initiative, and positive cultural norms and traditions supporting optimal infant and young child feeding. In some countries, UNICEF played a key role in funding and designing policies and monitoring systems. Weak government leadership, the strong influence of the industry, lack of adequate national legislation on the International Code and cultural norms which devalued breastfeeding were particularly noted as obstacles. Government commitment, funding and protection of optimal infant and young child feeding are essential to the implementation of strong national policies and monitoring systems.

Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease.

INTRODUCTION: Inflammatory markers have long been observed in the brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients, suggesting that inflammation contributes to AD and might be a therapeutic target. However, non-steroidal anti-inflammatory drug trials in AD and mild cognitive impairment (MCI) failed to show benefit. Our previous work seeking to understand why people with the inflammatory disease rheumatoid arthritis are protected from AD found that short-term treatment of transgenic AD mice with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory to normal. These results called into question the consensus view that inflammation is solely detrimental in AD. Here, we tested our hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans by investigating the ability of GM-CSF/sargramostim to safely ameliorate AD symptoms/pathology. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in mild-to-moderate AD participants (NCT01409915). Treatments (20 participants/group) occurred 5 days/week for 3 weeks plus two follow-up (FU) visits (FU1 at 45 days and FU2 at 90 days) with neurological, neuropsychological, blood biomarker, and imaging assessments. RESULTS: Sargramostim treatment expectedly changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At end of treatment (EOT), the Mini-Mental State Examination score of the sargramostim group increased compared to baseline (P = .0074) and compared to placebo (P = .0370); the treatment effect persisted at FU1 (P = .0272). Plasma markers of amyloid beta (Aß40 [decreased in AD]) increased 10% (P = .0105); plasma markers of neurodegeneration (total tau and UCH-L1) decreased 24% (P = .0174) and 42% (P = .0019), respectively, after sargramostim treatment compared to placebo. DISCUSSION: The innate immune system is a viable target for therapeutic intervention in AD. An extended treatment trial testing the long-term safety and efficacy of GM-CSF/sargramostim in AD is warranted.

Why Do Hens Pile? Hypothesizing the Causes and Consequences.

Piling is a behavior in laying hens whereby individuals aggregate in larger densities than would be normally expected. When piling behavior leads to mortalities it is known as smothering and its frequent but unpredictable occurrence is a major concern for many egg producers. There are generally considered to be three types of piling: panic, nest box and recurring piling. Whilst nest box and panic piling have apparent triggers, recurring piling does not, making it an enigmatic and ethologically intriguing behavior. The repetitive nature of recurring piling may result in a higher incidence of smothering and could have unconsidered, sub-lethal consequences. Here, we consider the possible causes of recurring piling from an ethological perspective and outline the potential welfare and production consequences. Drawing on a wide range of literature, we consider different timescales of causes from immediate triggers to ontogeny and domestication processes, and finally consider the evolution of collective behavior. By considering different timescales of influence, we built four hypotheses relevant to the causes of piling, which state that the behavior: (i) is caused by hens moving toward or away from an attractant/repellent; (ii) is socially influenced; (iii) is influenced by early life experiences and; (iv) can be described as a maladaptive collective behavior. We further propose that the following could be welfare consequences of piling behavior: Heat stress, physical injury (such as keel bone damage), and behavioral and physiological stress effects. Production consequences include direct and indirect mortality (smothering and knock-on effects of piling, respectively), potential negative impacts on egg quality and on worker welfare. In future studies the causes of piling and smothering should be considered according to the different timescales on which causes might occur. Here, both epidemiological and modeling approaches could support further study of piling behavior, where empirical studies can be challenging.

Are our babies off to a healthy start? The state of implementation of the Global strategy for infant and young child feeding in Europe.

BACKGROUND: To protect children's right to optimal nutrition, WHO/UNICEF developed a Global Strategy for Infant and Young Child Feeding, endorsed by all 53 WHO/EURO Member States. The World Breastfeeding Trends Initiative (WBTi) is a tool for monitoring implementation of the Global Strategy. It comprises 15 indicators, ten referring to policies and programmes, and five to feeding practices. Each is scored on a scale of 10, giving a total score of 150 for Global Strategy implementation. To date, 18 WHO/EURO Member States - Armenia, Austria, Belgium, Bosnia and Herzegovina, Croatia, France, Georgia, Germany, Italy, Lithuania, North Macedonia, Malta, Moldova, Portugal, Spain, Turkey, Ukraine and United Kingdom - have conducted a WBTi assessment and produced a report. METHODS: Between June 2018 and May 2019, all 18 WBTi European reports were carefully read and analysed by a group of national WBTi coordinators. Descriptive data analysis, including inter-country comparisons, was conducted using frequencies and percentages. This paper summarises the findings. The full 88-page report will be published on the WBTi website. RESULTS: Three-quarters of 18 European countries have adequate maternity protection, and two-thirds have breastfeeding initiation rates of 50% or higher. However, 'Preparedness and planning for appropriate and safe Infant and Young Child Feeding (IYCF) in emergencies' is seriously neglected. Breastfeeding duration is far below WHO recommendations, with an average of 8.7 months. Only three European countries have a budget allocated for implementing IYCF policies and plans, and a third currently have no Baby-friendly designated maternity facilities. Bottle feeding is prevalent, despite its inherent risks, monitoring of IYCF practices is inadequate, with most countries not routinely collecting data, and violations of the International Code of Marketing of Breast-milk Substitutes are commonplace. CONCLUSIONS: European governments are not doing enough to protect, promote and support sound infant and young child feeding practices. Political commitment at the highest level and adequate funding are required to ensure optimal IYCF for Europe's babies. This report highlights worrying gaps, thereby providing governments, international organisations and other concerned parties with an opportunity to invest in priority areas and, by doing so, hopefully create a better future for our babies.

Rapid cancer diagnosis for patients with vague symptoms: a cost-effectiveness study.

BACKGROUND: A pilot rapid diagnosis centre (RDC) allows GPs within targeted clusters to refer adults with vague and/or non-specific symptoms suspicious of cancer, who do not meet criteria for referral under an urgent suspected cancer (USC) pathway, to a multidisciplinary RDC clinic where they are seen within 1 week. AIM: To explore the cost-effectiveness of the RDC compared with standard clinical practice. DESIGN AND SETTING: Cost-effectiveness modelling using routine data from Neath Port Talbot Hospital, Wales. METHOD: Discrete-event simulation modelled a cohort of 1000 patients from referral to radiological diagnosis based on routine RDC and hospital data. Control patients were those referred to a USC pathway but then downgraded. Published sources provided estimates of patient quality of life (QoL) and pre-diagnosis anxiety. The model calculates time to diagnosis, costs, and quality-adjusted life years (QALYs), and estimates the probability of the RDC being a cost-effective strategy. RESULTS: The RDC reduces mean time to diagnosis from 84.2 days in usual care to 5.9 days if a diagnosis is made at clinic, or 40.8 days if further investigations are booked during RDC. RDC provision is the superior strategy (that is, less costly and more effective) compared with standard clinical practice when run near or at full capacity. However, it is not cost-effective if capacity utilisation drops below 80%. CONCLUSION: An RDC for patients presenting with vague or non-specific symptoms suspicious of cancer in primary care reduces time to diagnosis and provides excellent value for money if run at ≥80% capacity.

Establishing an advanced care academy and its role in advanced practitioner development.

Advanced clinical practice (ACP) roles evolved to fill gaps in healthcare provision and improve consistency in standards of care. Historically, variance in service specific requirements, combined with inconsistent approaches to role governance and education, resulted in a multitude of ACP roles and remits. Definitions of roles and titles vary, but there is agreement on academic level and role competency assessment. Irrespective of these definitions, staff and services need support to operationalise guidance. In Scotland, development of advanced practice roles is supported through regional NHS Advanced Practice Academies. One Scottish Board has initiated a local board level advanced care academy to fulfil the three key components of advanced practitioner development: master's level theoretical knowledge, effective supervision and robust clinical competency assessment in practice. This development model, known as the 'triangle of capability', has allowed rapid progress with the advanced practice agenda, which is a central component of sustainable healthcare provision.

Automatic Individual Pig Detection and Tracking in Pig Farms.

Individual pig detection and tracking is an important requirement in many video-based pig monitoring applications. However, it still remains a challenging task in complex scenes, due to problems of light fluctuation, similar appearances of pigs, shape deformations, and occlusions. In order to tackle these problems, we propose a robust on-line multiple pig detection and tracking method which does not require manual marking or physical identification of the pigs and works under both daylight and infrared (nighttime) light conditions. Our method couples a CNN-based detector and a correlation filter-based tracker via a novel hierarchical data association algorithm. In our method, the detector gains the best accuracy/speed trade-off by using the features derived from multiple layers at different scales in a one-stage prediction network. We define a tag-box for each pig as the tracking target, from which features with a more local scope are extracted for learning, and the multiple object tracking is conducted in a key-points tracking manner using learned correlation filters. Under challenging conditions, the tracking failures are modelled based on the relations between responses of the detector and tracker, and the data association algorithm allows the detection hypotheses to be refined; meanwhile the drifted tracks can be corrected by probing the tracking failures followed by the re-initialization of tracking. As a result, the optimal tracklets can sequentially grow with on-line refined detections, and tracking fragments are correctly integrated into respective tracks while keeping the original identifications. Experiments with a dataset captured from a commercial farm show that our method can robustly detect and track multiple pigs under challenging conditions. The promising performance of the proposed method also demonstrates the feasibility of long-term individual pig tracking in a complex environment and thus promises commercial potential.

Using preferred fluids and different reward schedules to motivate rhesus macaques (Macaca mulatta) in cognitive tasks.

Rhesus macaques (Macaca mulatta) used in behavioural neuroscience are often required to complete cognitively complex tasks, for which a high level of motivation is essential. To induce motivation, researchers may implement fluid-restriction protocols, whereby freely available water is limited, such that fluid can be used as a reward in the laboratory. A variety of different rewards and schedules are used, but there exists a lack of data assessing their effectiveness. In this study, we aimed to quantify fluid preference in rhesus macaques and to use these preferences to compare the motivational quality of different reward schedules: the monkey's previous reward (i.e. the fluid used to reward them in past studies), their new preferred reward, a variable schedule of previous and preferred reward, and a choice between the previous and preferred rewards. We found that it may be possible to reduce the level of restriction if an adequately motivating preferred reward is identified, but that this is dependent on the animal. Each monkey responded differently to both the fluid-preference assessments and to the different reward schedules. As such, monkeys should not be subject to 'blanket' protocols but should be assessed individually to maintain adequate scientific data collection at the least severe level of fluid restriction.

Factors Influencing Individual Variation in Farm Animal Cognition and How to Account for These Statistically.

For farmed species, good health and welfare is a win-win situation: both the animals and producers can benefit. In recent years, animal welfare scientists have embraced cognitive sciences to rise to the challenge of determining an animal's internal state in order to better understand its welfare needs and by extension, the needs of larger groups of animals. A wide range of cognitive tests have been developed that can be applied in farmed species to assess a range of cognitive traits. However, this has also presented challenges. Whilst it may be expected to see cognitive variation at the species level, differences in cognitive ability between and within individuals of the same species have frequently been noted but left largely unexplained. Not accounting for individual variation may result in misleading conclusions when the results are applied both at an individual level and at higher levels of scale. This has implications both for our fundamental understanding of an individual's welfare needs, but also more broadly for experimental design and the justification for sample sizes in studies using animals. We urgently need to address this issue. In this review, we will consider the latest developments on the causes of individual variation in cognitive outcomes, such as the choice of cognitive test, sex, breed, age, early life environment, rearing conditions, personality, diet, and the animal's microbiome. We discuss the impact of each of these factors specifically in relation to recent work in farmed species, and explore the future directions for cognitive research in this field, particularly in relation to experimental design and analytical techniques that allow individual variation to be accounted for appropriately.

Appetitive olfactory learning and memory in the honeybee depend on sugar reward identity.

One of the most important tasks of the brain is to learn and remember information associated with food. Studies in mice and Drosophila have shown that sugar rewards must be metabolisable to form lasting memories, but few other animals have been studied. Here, we trained adult, worker honeybees (Apis mellifera) in two olfactory tasks (massed and spaced conditioning) known to affect memory formation to test how the schedule of reinforcement and the nature of a sugar reward affected learning and memory. The antennae and mouthparts of honeybees were most sensitive to sucrose but glucose and fructose were equally phagostimulatory. Whether or not bees could learn the tasks depended on sugar identity and concentration. However, only bees rewarded with glucose or sucrose formed robust long-term memory. This was true for bees trained in both the massed and spaced conditioning tasks. Honeybees fed with glucose or fructose exhibited a surge in haemolymph sugar of greater than 120mM within 30s that remained elevated for as long as 20min after a single feeding event. For bees fed with sucrose, this change in haemolymph glucose and fructose occurred with a 30s delay. Our data showed that olfactory learning in honeybees was affected by sugar identity and concentration, but that olfactory memory was most strongly affected by sugar identity. Taken together, these data suggest that the neural mechanisms involved in memory formation sense rapid changes in haemolymph glucose that occur during and after conditioning.

The use of preferred social stimuli as rewards for rhesus macaques in behavioural neuroscience.

Macaques are often motivated to perform in neuroscientific experiments by implementing fluid restriction protocols. Daily access to water is controlled and the monkeys are rewarded with droplets of fluid for performing correct trials in the laboratory. Although these protocols are widely used and highly effective, it is important from a 3Rs perspective to investigate refinements that may help to lessen the severity of the fluid restriction applied. We assessed the use of social stimuli (images of conspecifics) as rewards for four rhesus macaques performing simple cognitive tasks. We found that individual preferences for images of male faces, female perinea and control stimuli could be identified in each monkey. However, using preferred images did not translate into effective motivators on a trial-by-trial basis: animals preferred fluid rewards, even when fluid restriction was relaxed. There was no difference in the monkeys' performance of a task when using greyscale versus colour images. Based on our findings, we cannot recommend the use of social stimuli, in this form, as a refinement to current fluid restriction protocols. We discuss the potential alternatives and possibilities for future research.

Physiological, Behavioral, and Scientific Impact of Different Fluid Control Protocols in the Rhesus Macaque (Macaca mulatta).

Rhesus macaques are an important model in behavioral neuroscience due to their advanced cognitive abilities. To motivate animals to engage in complex tasks, fluid rewards, in conjunction with fluid control protocols, are often used. The impact of these protocols on animal welfare is controversial. We compared two fluid control protocols against a protocol providing free access to water and evaluated the impacts on physiological states of hydration, behavioral measures of welfare, and scientific output. Blood physiology did not significantly differ between any of the protocols, and urine measures were indicative of well functioning, healthy kidneys. Changes in behaviors were limited, the main one being an increase in motivation to drink on the stricter fluid control protocol, and improved task performance early in the week. Overall, fluid control protocols had little measurable impact on the welfare of rhesus macaques while ensuring that scientific data of high quality could be obtained.

Single amino acids in sucrose rewards modulate feeding and associative learning in the honeybee.

Obtaining the correct balance of nutrients requires that the brain integrates information about the body's nutritional state with sensory information from food to guide feeding behaviour. Learning is a mechanism that allows animals to identify cues associated with nutrients so that they can be located quickly when required. Feedback about nutritional state is essential for nutrient balancing and could influence learning. How specific this feedback is to individual nutrients has not often been examined. Here, we tested how the honeybee's nutritional state influenced the likelihood it would feed on and learn sucrose solutions containing single amino acids. Nutritional state was manipulated by pre-feeding bees with either 1M sucrose or 1M sucrose containing 100mM of isoleucine, proline, phenylalanine, or methionine 24h prior to olfactory conditioning of the proboscis extension response. We found that bees pre-fed sucrose solution consumed less of solutions containing amino acids and were also less likely to learn to associate amino acid solutions with odours. Unexpectedly, bees pre-fed solutions containing an amino acid were also less likely to learn to associate odours with sucrose the next day. Furthermore, they consumed more of and were more likely to learn when rewarded with an amino acid solution if they were pre-fed isoleucine and proline. Our data indicate that single amino acids at relatively high concentrations inhibit feeding on sucrose solutions containing them, and they can act as appetitive reinforcers during learning. Our data also suggest that select amino acids interact with mechanisms that signal nutritional sufficiency to reduce hunger. Based on these experiments, we predict that nutrient balancing for essential amino acids during learning requires integration of information about several amino acids experienced simultaneously.

Visiting all hours: a focus group study on staff's views of open visiting in a hospice.

St Columba's Hospice, Edinburgh, is a busy specialist palliative care unit with 30 inpatient beds. A previous publication reported the first strand of a qualitative exploratory study evaluating the impact of open visiting on patients at the hospice. This paper reports on the second strand, which sought to elicit the views of the hospice staff through focus group interviews. The main themes identified were valuing the family and friends as visitors, involving the family as part of the care team, patient powerlessness over visiting, shared rooms and their impact on visitors and patients, and the staff role as advocates or gatekeepers. Several strategies for developing a flexible and 'patient-controlled' visiting policy were identified, including quiet times without visitors, restriction of visitor numbers in shared rooms, and encouraging breaks from visiting. Since the study was completed, the hospice's visiting policy has been modified to ensure that it is patient-centred and meets the needs of patients and families.

Open all hours: a qualitative exploration of open visiting in a hospice.

Over the past 20 years, visiting policies within adult care settings have progressed from strictly enforced times to more flexible arrangements. The Scottish Commission for the Regulation of Care (SCRC, 2003) advocates open visiting in hospices, which allows access at all times of day. However, little research has been carried out to investigate the assumption that an 'open visiting' policy in a hospice benefits patients and carers and improves the quality of care. This article describes the first strand of a qualitative exploratory study designed to evaluate the impact that open visiting has on patients and the multidisciplinary team in a hospice. A purposive sample of ten inpatients was interviewed. Data were analysed thematically. Patients acknowledged the benefits of contact with family and friends, such as maintaining links with the outside world and improvement in mood. However, they also reported that visitors could be intrusive and, depending on the nature of the relationship, were not always sensitive to cues that the patient was tiring or in pain. Patients indicated a need for more control of visiting arrangements, particularly related to timing, visitor numbers and restrictions on who could visit. These data will contribute to the second strand of the study which involves interviewing multidisciplinary team members.

Electron magnetic resonance study of gamma-irradiated poly(lactide-co-glycolide) microspheres.

A series of poly(lactide-co-glycolide) samples of compositions ranging from (75:25) to (65:35) to (50% (65:35):50% (50:50)) were gamma-irradiated under ambient conditions in air. The irradiation doses used were 15, 20, 25, and 30 kGy. The generation of radicals resulting from the gamma-irradiation was confirmed using EPR. Two major radical species were observed and identified as centered at alkyl and alkyl peroxy groups. The indication from the X-band (9 GHz) frequencies showed that alkyl radicals gave rise to a quartet hyperfine pattern. However, measurements performed at higher W-band frequencies (90 GHz) showed that the X-band spectra are actually a composite profile arising from a series of overlapping individual resonances. Using combined EPR and ENDOR (Electron-Nuclear DOuble Resonance) measurements, an alkyl peroxy radical was identified. For increasing glycolide concentration from 75:25 to the 50:50 blend, there was a factor of 7 increase in the concentration of radicals A and B. Furthermore, both radical species were found to be stable for several weeks after storage at ambient temperature conditions. At elevated temperatures and humidities, radical stability decreased--the decay rate was estimated at approximately 3x10(-8) mol K(-1). The stability characteristics of the radicals under different conditions are attributed to changes in the morphology of the polymer.