Engaging a community to focus on upper limb function in people with multiple sclerosis: the ThinkHand campaign case study.

BACKGROUND: Solving complex research challenges requires innovative thinking and alternative approaches to traditional methods. One such example is the problem of arm and hand, or upper limb function in multiple sclerosis (MS), a neurological condition affecting approximately 2.9 million people worldwide and more than 150,000 in the United Kingdom. Historically, clinical trials and research have focused on mobility and walking ability. This excludes a large number of patients who are wheelchair users, limiting their quality of life and restricting access to possibly helpful medications. To address this issue, the ThinkHand campaign was launched in 2016, aiming to raise awareness about the importance of upper limb function in MS and develop alternative ways to measure, record, and account for hand and arm function changes. MAIN BODY: The campaign utilised innovative strategies at scientific conferences and online surveys to engage people affected by MS, healthcare professionals, charities, and researchers in discussing the importance of preserving upper limb function. Through co-design and interdisciplinary collaboration, the campaign developed new tools like the low-cost cardboard version of the Nine-Hole Peg Test, facilitating remote monitoring of hand function. Additionally, the campaign co-created the "Under & Over" rehabilitation tool, allowing individuals with advanced MS to participate in a remote rehabilitation program.The impact of the ThinkHand campaign has been significant, helping to shift the focus of both academic and industry-supported trials, including the O'HAND and ChariotMS trials, both using upper limb function as their primary end point. The campaign's patient-centred approach highlighted the importance of recognising patients' perspectives in research and challenged established assumptions and practices. It demonstrated the effectiveness of interdisciplinary collaboration, systems thinking, and co-creation with stakeholders in tackling complex problems. CONCLUSION: The ThinkHand campaign provides valuable insights for health research practices. By involving patients at all stages, researchers can gain a deeper understanding of the impact of disease on their lives, identify gaps and focus research on their needs. Experimentation and iteration can lead to innovative solutions, and openness to unconventional methods can drive widespread change. The ThinkHand campaign exemplifies the potential of patient-centred approaches to address complex research challenges and revolutionise the field of MS research and management. Embracing such approaches will contribute to more inclusive and impactful research in the future.

Solving complex research challenges requires creative thinking and new ways of doing things. One such challenge is understanding the problems with arm and hand function in multiple sclerosis (MS), a neurological condition that affects more than 150,000 in the United Kingdom. In the past, research focused mainly on walking ability, leaving out many people who use wheelchairs.To tackle this issue, we created the ThinkHand campaign in 2016. Its goal was to raise awareness about the importance of hand and arm function for people with MS (pwMS) and find better ways to measure changes in these functions such that they can become outcomes in clinical trials. This could provide a pathway to better treatments for pwMS who cannot walk.The campaign used various methods, including surveys, social media posts, exhibitions and music to involve pwMS, healthcare professionals, charities, and researchers in discussions about the issues. Working together, they created tools to support pwMS, particularly those at an advanced stage of the disease (pwAMS), to take part in research and measure their hand and arm function. Through our collaborative approach focusing on patients' perspectives, the campaign challenged old ideas and deeply embedded practices. It showed that collaboration between different areas of expertise involving pwMS at all stages of research can help solve complex problems. This campaign teaches us valuable lessons for health research. When researchers listen to patients and try new things, they can better understand how a disease affects people's lives and develop better solutions.In conclusion, we show how embracing a patient-centred approach can address complex research challenges and improve how we study and manage MS and other conditions in the future.

Under & Over: A randomised controlled study to develop an upper limb rehabilitation tool for people with Multiple Sclerosis.

BACKGROUND: Impairment of upper limb function is common in Multiple Sclerosis (MS). Rehabilitation remains a key strategy to manage symptoms and improve quality of life. The Under & Over study assessed the effectiveness of a rehabilitation programme in people with advanced MS. OBJECTIVE: To determine if repeated use of Under & Over can improve upper limb function for people with MS. METHODS: One hundred and six (N = 106) people with MS participated in this 3-month study. The primary outcome measure was the cardboard 9-hole peg test (c9HPT), with secondary outcomes including the EuroQol-5Dimensions, 5-Level Questionnaire (EQ5D-5 L) questionnaire. There were three arms: Arm 1a, the 'Daily Group', engaged with the Under & Over tool daily for 30 min. Arm 1b, the 'Free Use Group', used the same tool without time constraints, with the added feature of a community sharing platform. Arm 2, the 'Delayed Start Group', initially completed the c9HPT for three months before switching to the 'Free Use' programme. RESULTS: 43/106 (41 %) of those randomised completed the primary end point. No significant difference between c9HPT at baseline and 3 months was seen in Arm 1a or 1b. Participants in Arm 2 who had been completing the c9HPT 5 days a week for 3 months showed a training effect in the dominant hand (mean speed at baseline 0.0455 (s-1), mean at 3 months 0.0341, difference 0.011; 95 % CI 0.0080 to 0.0148, p < 0.001). No significant difference was seen in c9HPT time following 3 months of active use of the Under & Over tool. The study faced significant limitations, notably in participant adherence, with fewer than half (43/106 (41 %)) completing the final assessment. CONCLUSIONS: This study demonstrates how a small, engaged, and motivated group were able to complete a remote rehabilitation programme. Future remote intervention studies could benefit from incorporating adaptive engagement strategies, such as personalised reminders and participant-tailored activity adjustments, to enhance adherence and capture a broader spectrum of patient experiences.

Delays in Multiple Sclerosis diagnosis (DIMES): protocol for a multicentre, observational study of multiple sclerosis diagnostic pathways in the United Kingdom and Republic of Ireland.

BACKGROUND: Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. Accumulating evidence indicates early diagnosis and early treatment improves long-term outcomes. However, the MS diagnostic pathway is increasingly complex, and delays may occur at several stages. Factors causing delays remain understudied. We aim to quantify the time taken for MS to be diagnosed, and characterise the diagnostic pathway and initial care provided, in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Delays In MultiplE Sclerosis diagnosis (DIMES) in the UK and ROI is a multicentre, observational, retrospective study that will be conducted via the Neurology and Neurosurgery Interest Group (NANSIG) collaborative network. Any hospital in the UK and ROI providing an MS diagnostic service is eligible to participate. Data on consecutive individuals newly diagnosed with MS between 1st July 2022 and 31st December 2022 will be collected. The primary outcomes are 1) time from symptoms/signs prompting referral to neurology, to MS diagnosis; and 2) time from referral to neurology for suspected MS, to MS diagnosis. Secondary outcomes include: MS symptoms, referring specialties, investigations performed, neurology appointments, functional status, use of disease modifying treatments, and support at diagnosis including physical activity, and follow up. Demographic characteristics of people newly diagnosed with MS will be summarised, adherence to quality standards summarised as percentages, and time-to-event variables presented with survival curves. Multivariable models will be used to investigate the association of demographic and clinical factors with time to MS diagnosis, as defined in our primary outcomes. DISCUSSION: DIMES aims to be the largest multicentre study of the MS diagnostic pathway in the UK and ROI. The proposed data collection provides insights that cannot be provided from contemporary registries, and the findings will inform approaches to MS services nationally in the future.

A physiological approach to renal clearance: From premature neonates to adults.

AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.

Use of Machine Learning for Dosage Individualization of Vancomycin in Neonates.

BACKGROUND AND OBJECTIVE: High variability in vancomycin exposure in neonates requires advanced individualized dosing regimens. Achieving steady-state trough concentration (C0) and steady-state area-under-curve (AUC0-24) targets is important to optimize treatment. The objective was to evaluate whether machine learning (ML) can be used to predict these treatment targets to calculate optimal individual dosing regimens under intermittent administration conditions. METHODS: C0 were retrieved from a large neonatal vancomycin dataset. Individual estimates of AUC0-24 were obtained from Bayesian post hoc estimation. Various ML algorithms were used for model building to C0 and AUC0-24. An external dataset was used for predictive performance evaluation. RESULTS: Before starting treatment, C0 can be predicted a priori using the Catboost-based C0-ML model combined with dosing regimen and nine covariates. External validation results showed a 42.5% improvement in prediction accuracy by using the ML model compared with the population pharmacokinetic model. The virtual trial showed that using the ML optimized dose; 80.3% of the virtual neonates achieved the pharmacodynamic target (C0 in the range of 10-20 mg/L), much higher than the international standard dose (37.7-61.5%). Once therapeutic drug monitoring (TDM) measurements (C0) in patients have been obtained, AUC0-24 can be further predicted using the Catboost-based AUC-ML model combined with C0 and nine covariates. External validation results showed that the AUC-ML model can achieve an prediction accuracy of 80.3%. CONCLUSION: C0-based and AUC0-24-based ML models were developed accurately and precisely. These can be used for individual dose recommendations of vancomycin in neonates before treatment and dose revision after the first TDM result is obtained, respectively.

The importance of the patient's perspective in decision-making in multiple sclerosis: Results of the OwnMS patient perspectives study.

BACKGROUND: Research is needed to identify the unmet disease education and communication needs of people with multiple sclerosis (PwMS) to support informed decision-making, enable self-management and maintain independence for PwMS for as long as possible. METHODS: An Expert Steering Group co-developed two studies for PwMS aged 18 years and over: a qualitative, online, patient community activity and a quantitative anonymised online survey. The quantitative survey was conducted in the UK from 12 September 2019 to 18 November 2019 amongst PwMS recruited via the Multiple Sclerosis (MS) Trust newsletter and their closed Facebook group. Questions explored the goals, desires, and knowledge gaps of PwMS. Self-reported data from people with relapsing-remitting multiple sclerosis (RRMS) were collated and reviewed, and discussed by the Steering Group. This paper presents descriptive statistics of the quantitative survey findings. RESULTS: The sample consisted of 117 participants with RRMS. Most respondents (73%) had personal goals related to lifestyle and many (69%) were concerned about maintaining independence. More than half of respondents were worried about planning for the future in relation to income (56%), housing (40%) and most respondents also indicated MS had a negative impact on their lives, including their work life (73%) and social life (69%). Limited occupational support was forthcoming (17% were not provided with any support and only 27% report their work environment being adjusted to suit their needs). The ability to plan for the future and to understand the course of MS were highlighted as key priorities by respondents. A positive trend was observed between those who felt able to plan for the future and their knowledge of MS progression. The proportion of patients who report knowing a 'great deal' about MS prognosis and disability progression was low (16% and 9%, respectively), suggesting an increased role for clinical teams to provide information and education for PwMS. Communication between respondents and their clinical teams highlighted the role of specialist nurses for PwMS to provide holistic, informative support and demonstrated the level of comfort that PwMS have in discussing less clinical topics with these providers. CONCLUSION: This UK nationwide survey highlighted some of the unmet needs in disease education and communication in a subgroup of UK patients with RRMS, which can impact quality of life. Discussing goals and planning alongside prognosis and disability progression with MS care teams may enable people with RRMS not only to make informed treatment decisions, but also to self-manage and plan for the future, factors which are important to maintain independence.

Microvasculopathy in spinal muscular atrophy is driven by a reversible autonomous endothelial cell defect.

Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by deficiency of the ubiquitously expressed SMN protein. Here, we present a retinal vascular defect in patients, recapitulated in SMA transgenic mice, driven by failure of angiogenesis and maturation of blood vessels. Importantly, the retinal vascular phenotype was rescued by early, systemic SMN restoration therapy in SMA mice. We also demonstrate in patients an unfavorable imbalance between endothelial injury and repair, as indicated by increased circulating endothelial cell counts and decreased endothelial progenitor cell counts in blood circulation. The cellular markers of endothelial injury were associated with disease severity and improved following SMN restoration treatment in cultured endothelial cells from patients. Finally, we demonstrated autonomous defects in angiogenesis and blood vessel formation, secondary to SMN deficiency in cultured human and mouse endothelial cells, as the underlying cellular mechanism of microvascular pathology. Our cellular and vascular biomarker findings indicate microvasculopathy as a fundamental feature of SMA. Our findings provide mechanistic insights into previously described SMA microvascular complications, and highlight the functional role of SMN in the periphery, including the vascular system, where deficiency of SMN can be addressed by systemic SMN-restoring treatment.

Motor unit recovery following Smn restoration in mouse models of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a childhood motor neuron disease caused by anomalies in the SMN1 gene. Although therapeutics have been approved for the treatment of SMA, there is a therapeutic time window, after which efficacy is reduced. Hallmarks of motor unit pathology in SMA include loss of motor-neurons and neuromuscular junction (NMJs). Following an increase in Smn levels, it is unclear how much damage can be repaired and the degree to which normal connections are re-established. Here, we perform a detailed analysis of motor unit pathology before and after restoration of Smn levels. Using a Smn-inducible mouse model of SMA, we show that genetic restoration of Smn results in a dramatic reduction in NMJ pathology, with restoration of innervation patterns, preservation of axon and endplate number and normalized expression of P53-associated transcripts. Notably, presynaptic swelling and elevated Pmaip levels remained. We analysed the effect of either early or delayed treated of an antisense oligonucleotide (ASO) targeting SMN2 on a range of differentially vulnerable muscles. Following ASO administration, the majority of endplates appeared fully occupied. However, there was an underlying loss of axons and endplates, which was more prevalent following a delay in treatment. There was an increase in average motor unit size following both early and delayed treatment. Together this work demonstrates the remarkably regenerative capacity of the motor neuron following Smn restoration, but highlights that recovery is incomplete. This work suggests that there is an opportunity to enhance neuromuscular junction recovery following administration of Smn-enhancing therapeutics.

Evaluation of remote assessments for multiple sclerosis in an in-home setting.

BACKGROUND: There is an urgent clinical need for reliable remote monitoring methods in Multiple Sclerosis (MS). We evaluated the use of remotely patient-recorded timed 25-foot walk (rT25FW) and nine-hole peg test (r9HPT). METHODS: Seventy-one people with MS completed a previously-validated online EDSS (webEDSS) and r9HPT, and 108 completed the webEDSS and rT25FW. RESULTS: There was a mild-moderate positive correlation between webEDSS and rT25FW, and no significant correlation between webEDSS and r9HPT. Distributions of rT25FW and r9HPT times were positively skewed. CONCLUSIONS: Our results provide pilot evidence that remote monitoring of MS is potentially valid but requires refinement before wide-scale implementation. With a median EDSS of 4.5 and EDSS range of 0 - 8.0, at least some patients with ambulatory difficulty are able to complete the assessments.

Drug Clearance in Neonates: A Combination of Population Pharmacokinetic Modelling and Machine Learning Approaches to Improve Individual Prediction.

BACKGROUND: Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data. OBJECTIVE: The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates. METHODS: Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods. RESULTS: The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods. CONCLUSION: A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.

Digesting science: Developing educational activities about multiple sclerosis, prevention and treatment to increase the confidence of affected families.

BACKGROUND: The majority of information sources for children of people with multiple sclerosis (MS) are paper, or text, based and require high levels of literacy. OBJECTIVE: To develop educational activities to inform children who have a parent with MS about a number of aspects around MS and to improve the confidence levels of both parents and children to discuss MS. METHODS: A structured interactive event, Digesting Science (DS), was developed. This covers the effect MS can have on: vision, bladder function, walking, the mechanisms of action of disease-modifying treatments, the potential importance of vitamin D supplementation, and risk factors for developing MS. Qualitative and semi-quantitative feedback and other data were collected from event questionnaires and a follow-up online survey. RESULTS: In total, 86 DS events have been delivered internationally, reaching approximately 345 families affected by MS. Confidence ratings around discussing MS improved in 57/77 families (74%; 95% CI: 62.6-83.1) following a DS event. 39/87 (45%) families who attended DS events reported taking vitamin D prior to the event, and 48/87 (55%) were not supplementing. Of those not taking vitamin D supplements, 71% now take vitamin D supplements, 6% have not changed their behaviour, and the remainder were unsure. CONCLUSION: Educational activities that explain complex neurological diseases to children can be developed and successfully implemented at an international level. These activities give families the confidence to discuss the impact of MS on their lives and also have the potential to change health-related behaviour. IMPLICATIONS FOR PRACTICE: Creative approaches to health behaviour communication can inform children of parents with MS and may affect their behaviour with the aim of potentially reducing their risk of developing MS in the future. Now more than ever, we need educational resources that can facilitate conversations within families that can respond to health information needs in a timely manner.

Do Vancomycin Pharmacokinetics Differ Between Obese and Non-obese Patients? Comparison of a General-Purpose and Four Obesity-Specific Pharmacokinetic Models.

BACKGROUND: Over the past decade, numerous obesity-specific pharmacokinetic (PK) models and dosage regimens have been developed. However, it is unclear whether vancomycin PKs differ between obese and other patients after accounting for weight, age, and kidney function. In this study, the authors investigated whether using obesity-specific population PK models for vancomycin offers any advantage in accuracy and precision over using a recently developed general-purpose model. METHODS: Vancomycin plasma concentrations in a cohort of 49 obese patients (body mass index [BMI] >30 kg/m2), not previously used in the development of any of the evaluated models, were used to validate the performance of 4 obesity-specific models and a general model. Bias and imprecision were calculated for the a priori and a posteriori predictive performance. RESULTS: The bias of the a priori prediction was lowest for one of the obesity-specific models (-1.40%) and that of the general model was a close second (-7.0%). The imprecision was lowest for the general model (4.34 mg/L). The predictive performance for the a posteriori predictions was best for the general model, both for bias (1.96%) and imprecision (2.75 mg/L). CONCLUSIONS: The results of the external validation of vancomycin PK in obese patients showed that currently available obesity-specific models do not necessarily outperform a broadly supported general-purpose model. Based on these results, the authors conclude that there is no advantage in using vancomycin PK models specifically tailored to obese patients over the general-purpose model reported by Colin et al.

Population pharmacokinetic evaluation and optimization of amikacin dosage regimens for the management of mycobacterial infections.

BACKGROUND: There is limited information on amikacin pharmacokinetics (PK) and dose requirements in patients with mycobacterial infections. OBJECTIVES: To conduct a population PK analysis of amikacin data from patients with mycobacterial infections and compare predicted concentrations from standard and modified dosage guidelines with recommended target ranges. METHODS: A population PK model was developed using NONMEM. Cmax, Cmin, concentration 1 h post-infusion (C1h) and AUC0-24 using 15 mg/kg daily (once daily), the WHO table, 25 mg/kg three times weekly (TTW) and modified guidelines were compared using Monte Carlo simulations of 1000 patients. RESULTS: Data were available from 124 patients (684 concentrations) aged 16-92 years. CL was 4.64 L/h per 100 mL/min CLCR; V was 0.344 L/kg. With once-daily regimens, Cmax was 35-45 mg/L in 30%-35% of patients and 35-50 mg/L in 46%-48%; C1h was 25-40 mg/L in 53%-59%. The WHO table produced high Cmax values in patients <60 kg and low in patients >75 kg. With TTW dosing, around 30% of Cmax values were 65-80 mg/L, 40% were 60-80 mg/L, and 48% of C1h were 45-65 mg/L. Increasing the dosage interval for patients with CLCR <50 mL/min reduced Cmin values >2 mg/L from 34% to 25% for once-daily dosing and from 18% to 13% for TTW. In patients whose Cmin was <2 mg/L, 82% of AUC0-24 values were 100-300 mg.h/L. CONCLUSIONS: Standard amikacin dosing guidelines achieve low percentages of target concentrations for mycobacterial infections. Extending the dosing interval in renal impairment and widening target ranges would reduce the need for dose adjustment.

Genetic Algorithms as a Tool for Dosing Guideline Optimization: Application to Intermittent Infusion Dosing for Vancomycin in Adults.

This paper demonstrates the use of a genetic algorithm (GA) for the optimization of a dosing guideline. GAs are well-suited to derive combinations of doses and dosing intervals that go into a dosing guideline when the number of possible combinations rule out the calculation of all possible outcomes. GAs also allow for different constraints to be imposed on the optimization process to safeguard the clinical feasibility of the dosing guideline. In this work, we demonstrate the use of a GA for the optimization of intermittent vancomycin administration in adult patients. Constraints were placed on the dose strengths, the length of the dosing intervals, and the maximum infusion rate. In addition, flexibility with respect to the timing of the first maintenance dose was included in the optimization process. The GA-based optimal solution is compared with the Scottish Antimicrobial Prescribing Group vancomycin guideline.

Synaptic withdrawal following nerve injury is influenced by postnatal maturity, muscle-specific properties, and the presence of underlying pathology in mice.

Axonal and synaptic degeneration occur following nerve injury and during disease. Traumatic nerve injury results in rapid fragmentation of the distal axon and loss of synaptic terminals, in a process known as Wallerian degeneration (WD). Identifying and understanding factors that influence the rate of WD is of significant biological and clinical importance, as it will facilitate understanding of the mechanisms of neurodegeneration and identification of novel therapeutic targets. Here, we investigate levels of synaptic loss following nerve injury under a range of conditions, including during postnatal development, in a range of anatomically distinct muscles and in a mouse model of motor neuron disease. By utilising an ex vivo model of nerve injury, we show that synaptic withdrawal is slower during early postnatal development. Significantly more neuromuscular junctions remained fully innervated in the cranial nerve/muscle preparations analysed at P15 than at P25. Furthermore, we demonstrate variability in the level of synaptic withdrawal in response to injury in different muscles, with retraction being slower in abdominal preparations than in cranial muscles across all time points analysed. Importantly, differences between the cranial and thoracoabdominal musculature seen here are not consistent with differences in muscle vulnerability that have been previously reported in mouse models of the childhood motor neuron disease, spinal muscular atrophy (SMA), caused by depletion of survival motor neuron protein (Smn). To further investigate the relationship between synaptic degeneration in SMA and WD, we induced WD in preparations from the Smn2B/- mouse model of SMA. In a disease-resistant muscle (rostral band of levator auris longus), where there is minimal denervation, there was no change in the level of synaptic loss, which suggests that the process of synaptic withdrawal following injury is Smn-independent. However, in a muscle with ongoing degeneration (transvs. abdominis), the level of synaptic loss significantly increased, with the percentage of denervated endplates increasing by 33% following injury, compared to disease alone. We therefore conclude that the presence of a die-back can accelerate synaptic loss after injury in Smn2B/- mice.

Development and evaluation of a national gentamicin and vancomycin quality improvement programme.

BACKGROUND: Scottish Antimicrobial Prescribing Group (SAPG) recommendations to reduce broad-spectrum antimicrobial use led to an increase in gentamicin and vancomycin prescribing. In 2009, SAPG introduced national guidance to standardize dosage regimens, reduce calculation errors and improve the monitoring of these antibiotics. Studies conducted in 2010 and 2011 identified limitations in guideline implementation. OBJECTIVES: To develop, implement and assess the long-term impact of quality improvement (QI) resources to support gentamicin and vancomycin prescribing, administration and monitoring. METHODS: New resources, comprising revised guidelines, online and mobile app dose calculators, educational material and specialized prescribing and monitoring charts were developed in collaboration with antimicrobial specialists and implemented throughout Scotland during 2013-16. An online survey in 2017 evaluated the use of these resources and a before (2011) and after (2018) point prevalence study assessed their impact. RESULTS: All 12 boards who responded to the survey (80%) were using the guidance, electronic calculators and gentamicin prescription chart; 8 used a vancomycin chart. The percentage of patients who received the recommended gentamicin dose increased from 44% to 89% (OR 10.99, 95% CI = 6.37-18.95) between 2011 and 2018. For vancomycin, the correct loading dose increased from 50% to 85% (OR = 5.69, CI = 2.76-11.71) and the correct maintenance dose from 55% to 90% (OR = 7.17, CI = 3.01-17.07). CONCLUSIONS: This study demonstrated improvements in the national prescribing of gentamicin and vancomycin through the development and coordinated implementation of a range of QI resources and engagement with local and national multidisciplinary teams.

The impact of social capital on patients with multiple sclerosis.

OBJECTIVE: To evaluate the association between social capital (SC) and the physical and psychological impact of multiple sclerosis (MS). MATERIALS & METHODS: A cross-sectional study was conducted among people with MS (pwMS) at The Royal London Hospital, London, UK. Participants completed a survey including the Multiple Sclerosis Impact Scale-29 (MSIS-29), the Hospital Anxiety and Depression Scale (HADS), the self-reported EDSS and a SC questionnaire (SCQ). The SCQ assessed personal relationships, social support networks, civic engagement, and trust and cooperative norms. Kendall's tau correlation test was performed to measure the correlation between SC and MSIS-29 scores, and multiple linear regressions were conducted to find the best outcome prediction model. RESULTS: 236 pwMS participated in the study. Median age was 43.5 years (IQR 35-52). Of the total, 168 (71.2%) were female and 180 (76.3%) had relapsing-remitting MS. Median MSIS-29 scores were 23.7 (IQR 8.8-57.5) for the physical scale and 38.9 (IQR 16.7-55.6) for the psychological scales. Total SC scores were significantly correlated with the MSIS-29 physical (τb = -0.09, P = .02) and psychological scores (τb = -0.23, P < .001). After adjusting for possible confounders, the "personal relationships" domain had a significant effect on the MSIS-29 physical scores (ß = -2.70, SE = 1.34; P = .045). Total SC (ß = -1.08, SE = 0.33; P = .001) and the "personal relationships" (ß = -2.60, SE = 1.20; P = .031) and "trust and cooperative norms" (ß = -1.40, SE = 0.61; P = .024) domains had a significant effect on the MSIS-29 psychological scores. CONCLUSIONS: Higher levels of SC were associated with lower physical and psychological impact of MS. Emerging evidence on SC and its effects on MS should be translated into interventions designed to promote the health and well-being of pwMS.

Professional development beyond foundation training: a study of pharmacists working in Scotland.

OBJECTIVES: In Scotland, post-registration hospital pharmacists typically undertake a vocational foundation training programme. Beyond this, there are no mandatory structures for ongoing professional training. To support progression to a more advanced level, competency frameworks are increasingly being used. This study aimed to measure the self-reported competence of pharmacists against a relevant framework and to determine what support was required to enable further professional development. METHODS: An online survey was completed by pharmacists working across six acute hospital sites within NHS Greater Glasgow and Clyde who had completed foundation training between Jan 2013 and Jan 2018. Participants self-reported competency against the Royal Pharmaceutical Society's Advanced Practice Framework Advanced Stage 1 competencies and gave qualitative feedback through free-text questions. KEY FINDINGS: Twenty out of twenty-eight eligible pharmacists (71.4%) responded to the survey and three core areas requiring further support were identified: leadership, management and research. Participants reported that a strategic plan for professional development, more opportunities and managerial support were needed to help them develop these areas. Mentorship programmes and postgraduate qualifications were suggested as formats to support development. CONCLUSION: Pharmacists working towards advanced practice reported high levels of competence in expert professional practice, collaborative working relationships and education, training and development. While these results are promising, additional support is likely to be needed to cultivate leadership, management and research skills. Future training strategies need to consider this imbalance if we are to achieve national and international workforce goals for the professional development of pharmacists.

Reduced P53 levels ameliorate neuromuscular junction loss without affecting motor neuron pathology in a mouse model of spinal muscular atrophy.

Spinal Muscular Atrophy (SMA) is a childhood motor neuron disease caused by mutations or deletions within the SMN1 gene. At endstages of disease there is profound loss of motor neurons, loss of axons within ventral roots and defects at the neuromuscular junctions (NMJ), as evidenced by pathological features such as pre-synaptic loss and swelling and post-synaptic shrinkage. Although these motor unit defects have been widely described, the time course and interdependancy of these aspects of motor unit degeneration are unclear. Recent reports have also revealed an early upregulation of transcripts associated with the P53 signalling pathway. The relationship between the upregulation of these transcripts and pathology within the motor unit is also unclear. In this study, we exploit the prolonged disease timecourse and defined pre-symptomatic period in the Smn2B/- mouse model to perform a temporal analysis of the different elements of motor unit pathology. We demonstrate that NMJ loss occurs prior to cell body loss, and coincides with the onset of symptoms. The onset of NMJ pathology also coincides with an increase in P53-related transcripts at the cell body. Finally, using a tamoxifen inducible P53 knockout, we demonstrate that post-natal reduction in P53 levels can reduce NMJ loss, but does not affect other aspects of NMJ pathology, motor neuron loss or the phenotype of the Smn2B/- mouse model. Together this work provides a detailed temporal description of pathology within motor units of an SMA mouse model, and demonstrates that NMJ loss is a P53-dependant process. This work supports the role for P53 as an effector of synaptic and axonal degeneration in a die-back neuropathy.