Memory efficient constrained optimization of scanning-beam lithography.

This article describes a memory efficient method for solving large-scale optimization problems that arise when planning scanning-beam lithography processes. These processes require the identification of an exposure pattern that minimizes the difference between a desired and predicted output image, subject to constraints. The number of free variables is equal to the number of pixels, which can be on the order of millions or billions in practical applications. The proposed method splits the problem domain into a number of smaller overlapping subdomains with constrained boundary conditions, which are then solved sequentially using a constrained gradient search method (L-BFGS-B). Computational time is reduced by exploiting natural sparsity in the problem and employing the fast Fourier transform for efficient gradient calculation. When it comes to the trade-off between memory usage and computational time we can make a different trade-off compared to previous methods, where the required memory is reduced by approximately the number of subdomains at the cost of more computations. In an example problem with 30 million variables, the proposed method reduces memory requirements by 67% but increases computation time by 27%. Variations of the proposed method are expected to find applications in the planning of processes such as scanning laser lithography, scanning electron beam lithography, and focused ion beam deposition, for example.

Clinical Decision Support Tools for Predicting Outcomes in Patients Undergoing Total Knee Arthroplasty: A Systematic Review.

BACKGROUND: Total knee arthroplasty is the standard surgical treatment for end-stage osteoarthritis. Although widely accepted as a successful procedure, approximately 30% of patients are not satisfied due to non-optimal postoperative outcomes. Clinical decision support tools that are able to accurately predict post-surgery outcomes would assist in providing individualized advice or services to help alleviate possible issues, resulting in significant benefits to both the healthcare system and individuals. METHODS: Five databases (Ovid Medline, Ovid EMBASE, CINAHL complete, Cochrane Library, and Scopus) were searched for the key phrases "knee replacement" or "knee arthroplasty" and "decision support tool," "decision tool," "predict∗ tool," "predict∗ model," "algorithm" or "nomogram." Searches were limited to peer-reviewed journal articles published between January 2000 and June 2019. Reference lists of included articles were examined. Authors came to a consensus on the final list of included articles. RESULTS: Eighteen articles were included for review. Most models reported low predictive success and inability to externally validate. Both candidate and final predictor variables were inconsistent between studies. Only 1 model was considered strongly predictive (AUROC >0.8), and only 2 studies were able to externally validate their developed model. In general, models that performed well used large patient numbers, were tested on similar demographics, and used either nonlinear input transformations or a completely nonlinear model. CONCLUSION: Some models do show promise; however, there remains the question of whether the reported predictive success can continue to be replicated. Furthermore, clinical applicability and interpretation of predictive tools should be considered during development.

Elderly woman with subacute lower limb weakness and rapid systemic decline.

A 74-year-old woman developed bilateral leg weakness, with fluctuating cognitive and systemic symptoms that progressed despite treatment. Her diagnosis was confirmed at autopsy. Her case was discussed at the Edinburgh Clinical Neurology Course 2019 Clinicopathological Conference.

Tracheostomy and salivary gland radiotherapy for severe sialorrhoea in motor neurone disease.

The management of excessive secretions in patients with motor neurone disease can be challenging. In this paper, we highlight the main issues from the perspectives of a patient, specialist nurse and neurologist and the importance of a multidisciplinary approach.

The use of botulinum toxin injections to manage drooling in amyotrophic lateral sclerosis/motor neurone disease: a systematic review.

Difficulty in managing oral secretions is commonly experienced by patients with amyotrophic lateral sclerosis (ALS)/motor neurone disease (MND) and associated bulbar weakness including dysphagia. There are no definitive evidence-based treatment guidelines to manage the distressing symptom of drooling. We reviewed the evidence for the effectiveness of botulinum toxin injections to reduce saliva in ALS/MND. The search strategy was conducted in four stages: (1) electronic search of relevant databases, (2) hand searches of all international ALS/MND symposium journals, (3) email request to MND care centres in the UK and Ireland, and (4) hand searching of reference lists. All studies were critically appraised and relevant data extracted. Botulinum toxin type A and type B were analysed separately. Due to heterogeneity, it was not possible to calculate a pooled estimate of effect. Twelve studies met the inclusion criteria (9 for type A and 3 for type B). Only two randomised controlled trials were identified. Study sample sizes were small with a mean of 12.5 subjects. The most frequently reported outcomes were weight of cotton rolls and number of tissues used. All studies claimed the intervention tested was effective, but only seven studies (4 for type A and 3 for type B) reported statistically significant differences. Although there is evidence to suggest that botulinum toxin B can reduce drooling, the evidence base is limited by a lack of randomized controlled trials. Evidence to support the use of botulinum toxin A is weaker. Larger trials will help remove the uncertainty practitioners face in treating this disabling symptom.

Using Presurgical Biopsychosocial Features to Develop an Advanced Clinical Decision-Making Support Tool for Predicting Recovery Trajectories in Patients Undergoing Total Knee Arthroplasty: Protocol for a Prospective Observational Study.

BACKGROUND: Following total knee arthroplasty (TKA), 10% to 20% of patients report dissatisfaction with procedural outcomes. There is growing recognition that postsurgical satisfaction is shaped not only by the quality of surgery but also by psychological and social factors. Surprisingly, information on the psychological and social determinants of surgical outcomes is rarely collected before surgery. A comprehensive collection of biopsychosocial information could assist clinicians in making recommendations in relation to rehabilitation, particularly if there is robust evidence to support the ability of presurgical constructs to predict postsurgical outcomes. Clinical decision support tools can help identify factors influencing patient outcomes and support the provision of interventions or services that can be tailored to meet individuals' needs. However, despite their potential clinical benefit, the application of such tools remains limited. OBJECTIVE: This study aims to develop a clinical decision tool that will assist with patient stratification and more precisely targeted clinical decision-making regarding prehabilitation and rehabilitation for TKA, based on the identified individual biopsychosocial needs. METHODS: In this prospective observational study, all participants provided written or electronic consent before study commencement. Patient-completed questionnaires captured information related to a broad range of biopsychosocial parameters during the month preceding TKA. These included demographic factors (sex, age, and rurality), psychological factors (mood status, pain catastrophizing, resilience, and committed action), quality of life, social support, lifestyle factors, and knee symptoms. Physical measures assessing mobility, balance, and functional lower body strength were performed via video calls with patients in their home. Information related to preexisting health issues and concomitant medications was derived from hospital medical records. Patient recovery outcomes were assessed 3 months after the surgical procedure and included quality of life, patient-reported knee symptoms, satisfaction with the surgical procedure, and mood status. Machine learning data analysis techniques will be applied to determine which presurgery parameters have the strongest power for predicting patient recovery following total knee replacement. On the basis of these analyses, a predictive model will be developed. Predictive models will undergo internal validation, and Bayesian analysis will be applied to provide additional metrics regarding prediction accuracy. RESULTS: Patient recruitment and data collection commenced in November 2019 and was completed in June 2022. A total of 1050 patients who underwent TKA were enrolled in this study. CONCLUSIONS: Our findings will facilitate the development of the first comprehensive biopsychosocial prediction tool, which has the potential to objectively predict a patient's individual recovery outcomes following TKA once selected by an orthopedic surgeon to undergo TKA. If successful, the tool could also inform the evolution rehabilitation services, such that factors in addition to physical performance can be addressed and have the potential to further enhance patient recovery and satisfaction. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48801.

Arterial and venous thrombotic stroke after ChAdOx1 nCoV-19 vaccine.

Vaccine-induced thrombosis with thrombocytopenia (VITT) is a recently-described condition associated with arterial and venous thrombosis following vaccination with the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. This report describes two cases of stroke caused by arterial and venous thromboses presenting within 28 days of receiving the AstraZeneca vaccine. The patients were otherwise young and healthy with minimal risk factors for thrombosis yet developed a rapid, ultimately fatal neurological deterioration.The patients were significantly thrombocytopenic with disproportionately raised D-dimers, both of which are widely reported in this condition. Both cases had measurable immunoglobulin G platelet factor-4 antibodies detected via enzyme-linked immunosorbent assay, similar to those described in heparin-induced thrombocytopenia.These cases illustrate that physicians should be especially mindful of VITT in the context of evolving evidence on treatment and in view of the potentially rapid and catastrophic neurological deterioration, leading to fatality despite best supportive care.

Accessory nerve palsies.

Accessory nerve palsies may cause considerable functional disability and they unfortunately continue to occur as a complication of surgery in and, around the posterior triangle of the neck. Here the causes of accessory nerve palsies are reviewed and the symptoms and signs arising as a consequence are summarised. In addition, the various treatments and their indications are highlighted and discussed.

Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation.

Neuroferritinopathy is a progressive potentially treatable adult-onset movement disorder caused by mutations in the ferritin light chain gene (FTL1). Features overlap with common extrapyramidal disorders: idiopathic torsion dystonia, idiopathic Parkinson's disease and Huntington's disease, but the phenotype and natural history have not been defined. We studied a genetically homogeneous group of 41 subjects with the 460InsA mutation in FTL1, documenting the presentation, clinical course, biochemistry and neuroimaging. The mean age of onset was 39.4 years (SD = 13.3, range 13-63), beginning with chorea in 50%, focal lower limb dystonia in 42.5% and parkinsonism in 7.5%. The majority reported a family history of a movement disorder often misdiagnosed as Huntington's disease. The disease progressed relentlessly, becoming generalized over a 5-10 year period, eventually leading to aphonia, dysphagia and severe motor disability with subcortical/frontal cognitive dysfunction as a late feature. A characteristic action-specific facial dystonia was common (65%), and in 63% there was asymmetry throughout the disease course. Serum ferritin levels were low in the majority of males and post-menopausal females, but within normal limits for pre-menopausal females. MR brain imaging was abnormal on all affected individuals and one presymptomatic carrier. In conclusion, isolated parkinsonism is unusual in neuroferritinopathy, and unlike Huntington's disease, cognitive changes are absent or subtle in the early stages. Depressed serum ferritin is common and provides a useful screening test in routine practice, and gradient echo brain MRI will identify all symptomatic cases.

Cerebellar ataxia, peripheral neuropathy, "gluten sensitivity" and anti-neuronal autoantibodies.

"Gluten sensitive" neurological syndromes (ataxia, peripheral neuropathy, and other conditions) have been hypothesised in patients with various idiopathic neuropathologies, detectable anti-gliadin antibodies and HLA-DQ2 or DQ7. Further investigation of these cases has suggested a high incidence of anti-neuronal antibodies (anti-Purkinje, anti- neuronal nuclear, anti-GAD). This study investigates this contentious area. Over a two-year period, from a local UK population base of two million, seeing over 5000 general neurology referrals per year, we collected 20 cases with idiopathic ataxia, and 32 with idiopathic peripheral neuropathy, and referred them all for blinded antibody testing. 30 adult healthy blood donors, and 7 cases of hereditary ataxia were used as control subjects. Anti-gliadin antibodies (IgG and or IgA) were found in 40% of cases with idiopathic ataxia, 34% with idiopathic peripheral neuropathy, 17% healthy blood donors and 43% with hereditary ataxia. None was positive for antiPurkinje cell or anti-neuronal nuclear antibodies. Only two patients with idiopathic ataxia were positive for antiGAD antibodies (one also being anti-gliadin positive). We were unable to confirm the findings of other groups. First, cases of so-called "gluten sensitive" neurological syndromes were extremely rare in our centre. Second, our idiopathic cases, whether they be gliadin antibody seropositive or not (i.e. "gluten sensitive" or not) were rarely neuronal autoantibody positive.

Assessment of professional development of neurology trainees: a UK perspective.

The European Working Time Directive has led to concerns that trainees' hours of work will decrease, with negative effects on their training. Various changes to the curriculum are needed to equip trainees for self-directed learning. A strong lobby argues for the introduction of examinations before entry to the consultant grade. Meanwhile, there is intense political pressure (in the UK at least), to shorten the duration of postgraduate training so that pledges for consultant numbers can be met. Reconciliation of these conflicting demands is a challenge for the future. Additional assessment procedures should be piloted. To successfully introduce changes, trainees and trainers will need to work in partnership. Course assessment and student feedback should be formalised. In this paper I summarise the assessment procedures in the UK and US, and suggest a model of best practice.

A clinical, genetic and candidate gene study of Silver syndrome, a complicated form of hereditary spastic paraplegia.

Silver syndrome (SS) is a complicated form of hereditary spastic paraplegia associated with distal wasting of the small muscles of the hands. We have previously described a large kindred with SS and mapped a genetic locus (SPG17) to chromosome 11q12-q14. In the current study we analyse the clinical phenotype and perform linkage analysis in three new SS families. In addition we analyse candidate genes mapping to the SS locus (SPG17). Clinical assessments were performed on 25 (15 affected) individuals from each family in which SS segregates with variable clinical expression. Neurophysiological studies, performed in the index case of two families, suggested anterior horn cell or nerve root involvement. Linkage analysis using microsatellite markers mapping to the SPG17 locus was performed and only one of the three families had a microsatellite segregation pattern compatible with linkage. Candidate genes mapping to the SS critical region were analysed in this and one other SPG17-linked family. Mutation analysis of genes encoding calpain 1 ( CAPN1), copper chaperone for superoxide dismutase ( CCS), ADP ribosylation factor-like 2 ( ARL2), LOC120664, a putative homologue of atlastin ( ATLSTL-1) and sorting nexin 15 ( SNX15) failed to identify any disease-specific mutations. SS therefore exhibits both clinical and genetic heterogeneity and the SPG17 locus may account for a significant proportion of SS mutations in the UK.

Recovering the spectrum of a low level signal from two noisy measurements using the cross power spectral density.

The article describes a method for estimating the spectrum or RMS value of a low-level signal corrupted by noise. If two identical sensors can be employed simultaneously and the additive noise sources are uncorrelated, the cross power spectrum can recover the power spectrum of the underlying signal. When using the Welch method to estimate the cross power spectrum, the estimation process is shown to be biased but consistent, with a variance that is inversely proportional to the number of data sets. The proposed technique is demonstrated experimentally to recover the vibration spectrum of a piezoelectric cantilever. The dual sensor method reduces the effective noise floor by three orders of magnitude and recovers spectral features that were otherwise lost in noise.

The management of drooling in adults with neurological conditions.

PURPOSE OF REVIEW: Drooling is a distressing symptom for adults with neurological conditions and can be challenging for health professionals. This review will consider the physical and psychosocial impact of drooling and will discuss the current management options including behavioural, pharmacological and surgical approaches. RECENT FINDINGS: A number of studies describe the use of botulinum toxin injections and irradiation of the salivary glands but no conclusive guidelines exist to recommend the most efficient dose or technique. The majority of saliva management studies focus on children with physical and/or cognitive disabilities and this evidence cannot be generalized to adults. There are relatively few studies that focus on saliva management in the adult neurological population. SUMMARY: Drooling is distressing for patients and their families. Ideally an individual would have easy access to the most efficient treatment with the fewest side effects. More evidence is now available but a lack of consensus on management approach, treatment dose and administration technique still exists. The symptom of drooling is best managed by a multidisciplinary team, starting with a conservative approach and then leading to more invasive procedures as appropriate.

Ankle foot orthoses for people with Charcot Marie Tooth disease--views of users and orthotists on important aspects of use.

PURPOSE: To explore important aspects of the benefits, important characteristics, barriers to use and disadvantages of using ankle foot orthoses (AFOs) as seen by people with Charcot Marie Tooth disease (CMT) and the orthotists who will fit and supply them. METHOD: This qualitative study used the nominal group technique and individual semi-structured interviews, according to participant preference and ability to travel. Propositions were put to 15 participants (eight females) with CMT regarding benefits, disadvantages, barriers to use and important characteristics of ankle foot orthoses AFOs and regarding benefits and disadvantages to seven orthotists. Priorities in these areas were ranked and a thematic analysis of the free text was made separately by two observers and a joint decision made of final themes. RESULTS: Fifteen people (eight females) with CMT and seven orthotists participated. Users' themes concerned functional mobility walking, pain/discomfort, choice of AFOs and associated footwear, custom made design, use in practical situations and support for foot and ankle. They noted that AFOs improved walking, but practical aspects of use and provision, as well as consideration of cosmetic aspects, were frequently problematic. Orthotists had similar themes, but with a difference in emphasis, that included prevention of future complications, education regarding device limitations and craftsmanship as a further theme. CONCLUSIONS: Users understood the potential benefits of AFOs and could identify disadvantages which might be remedied, but were frustrated by the difficulties in translating this into practice. Further refinement of current orthoses and delivery of orthotic services may assist in addressing these issues.

Reversible hypomagnesaemia-induced subacute cerebellar syndrome.

Magnesium is the second most abundant intracellular cation and is a fundamental cofactor in a multitude of cellular enzymatic reactions. Magnesium deficiency causes diverse clinical features predominantly due to cardio- and neurotoxicity. We describe a case of severe hypomagnesaemia associated with intermittent downbeat nystagmus, cerebellar ataxia, generalised convulsions and a supraventricular tachycardia. On MRI imaging, a transient lesion of the cerebellar nodulus was observed, which has not, to our knowledge, been previously described in isolated hypomagnesaemia.