Global uncertainty in the diagnosis of neurological complications of SARS-CoV-2 infection by both neurologists and non-neurologists: An international inter-observer variability study.

INTRODUCTION: Uniform case definitions are required to ensure harmonised reporting of neurological syndromes associated with SARS-CoV-2. Moreover, it is unclear how clinicians perceive the relative importance of SARS-CoV-2 in neurological syndromes, which risks under- or over-reporting. METHODS: We invited clinicians through global networks, including the World Federation of Neurology, to assess ten anonymised vignettes of SARS-CoV-2 neurological syndromes. Using standardised case definitions, clinicians assigned a diagnosis and ranked association with SARS-CoV-2. We compared diagnostic accuracy and assigned association ranks between different settings and specialties and calculated inter-rater agreement for case definitions as "poor" (κ ≤ 0.4), "moderate" or "good" (κ > 0.6). RESULTS: 1265 diagnoses were assigned by 146 participants from 45 countries on six continents. The highest correct proportion were cerebral venous sinus thrombosis (CVST, 95.8%), Guillain-Barré syndrome (GBS, 92.4%) and headache (91.6%) and the lowest encephalitis (72.8%), psychosis (53.8%) and encephalopathy (43.2%). Diagnostic accuracy was similar between neurologists and non-neurologists (median score 8 vs. 7/10, p = 0.1). Good inter-rater agreement was observed for five diagnoses: cranial neuropathy, headache, myelitis, CVST, and GBS and poor agreement for encephalopathy. In 13% of vignettes, clinicians incorrectly assigned lowest association ranks, regardless of setting and specialty. CONCLUSION: The case definitions can help with reporting of neurological complications of SARS-CoV-2, also in settings with few neurologists. However, encephalopathy, encephalitis, and psychosis were often misdiagnosed, and clinicians underestimated the association with SARS-CoV-2. Future work should refine the case definitions and provide training if global reporting of neurological syndromes associated with SARS-CoV-2 is to be robust.

Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

Modeling hepatitis C micro-elimination among people who inject drugs with direct-acting antivirals in metropolitan Chicago.

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and mortality worldwide. Direct-acting antiviral (DAA) therapy leads to high cure rates. However, persons who inject drugs (PWID) are at risk for reinfection after cure and may require multiple DAA treatments to reach the World Health Organization's (WHO) goal of HCV elimination by 2030. Using an agent-based model (ABM) that accounts for the complex interplay of demographic factors, risk behaviors, social networks, and geographic location for HCV transmission among PWID, we examined the combination(s) of DAA enrollment (2.5%, 5%, 7.5%, 10%), adherence (60%, 70%, 80%, 90%) and frequency of DAA treatment courses needed to achieve the WHO's goal of reducing incident chronic infections by 90% by 2030 among a large population of PWID from Chicago, IL and surrounding suburbs. We also estimated the economic DAA costs associated with each scenario. Our results indicate that a DAA treatment rate of >7.5% per year with 90% adherence results in 75% of enrolled PWID requiring only a single DAA course; however 19% would require 2 courses, 5%, 3 courses and <2%, 4 courses, with an overall DAA cost of $325 million to achieve the WHO goal in metropolitan Chicago. We estimate a 28% increase in the overall DAA cost under low adherence (70%) compared to high adherence (90%). Our modeling results have important public health implications for HCV elimination among U.S. PWID. Using a range of feasible treatment enrollment and adherence rates, we report robust findings supporting the need to address re-exposure and reinfection among PWID to reduce HCV incidence.

An Evolutionary Algorithm to Personalize Stool-Based Colorectal Cancer Screening.

BACKGROUND: Fecal immunochemical testing (FIT) is an established method for colorectal cancer (CRC) screening. Measured FIT-concentrations are associated with both present and future risk of CRC, and may be used for personalized screening. However, evaluation of personalized screening is computationally challenging. In this study, a broadly applicable algorithm is presented to efficiently optimize personalized screening policies that prescribe screening intervals and FIT-cutoffs, based on age and FIT-history. METHODS: We present a mathematical framework for personalized screening policies and a bi-objective evolutionary algorithm that identifies policies with minimal costs and maximal health benefits. The algorithm is combined with an established microsimulation model (MISCAN-Colon), to accurately estimate the costs and benefits of generated policies, without restrictive Markov assumptions. The performance of the algorithm is demonstrated in three experiments. RESULTS: In Experiment 1, a relatively small benchmark problem, the optimal policies were known. The algorithm approached the maximum feasible benefits with a relative difference of 0.007%. Experiment 2 optimized both intervals and cutoffs, Experiment 3 optimized cutoffs only. Optimal policies in both experiments are unknown. Compared to policies recently evaluated for the USPSTF, personalized screening increased health benefits up to 14 and 4.3%, for Experiments 2 and 3, respectively, without adding costs. Generated policies have several features concordant with current screening recommendations. DISCUSSION: The method presented in this paper is flexible and capable of optimizing personalized screening policies evaluated with computationally-intensive but established simulation models. It can be used to inform screening policies for CRC or other diseases. For CRC, more debate is needed on what features a policy needs to exhibit to make it suitable for implementation in practice.

Is scan-negative cauda equina syndrome a functional neurological disorder? A pilot study.

BACKGROUND AND PURPOSE: Cauda equina syndrome (CES) is a neurosurgical emergency which warrants lumbar magnetic resonance imaging (MRI). Many patients with suggestive symptoms of CES have no radiological correlate. A functional (non-organic) aetiology has been proposed in some, but currently little is known about this patient group and their clinical outcomes. METHODS: At a tertiary referral centre, 155 adult patients underwent urgent lumbar MRI for suspected CES in 1 year from December 2014. Data regarding clinical symptoms and follow-up were obtained from records. Patients were divided into CES (n = 25), radiculopathy (n = 68) and scan-negative (SN) groups (n = 62) from scans. Up to 3 years post-discharge, postal questionnaires were sent to patients with Oswestry Disability Index, Pain Catastrophizing score, Patient Health Questionnaire (PHQ) 9, Generalized Anxiety Disorder (GAD) 7, PHQ 15 and Work and Social Adjustment Scale measures. RESULTS: No clinical symptoms were found to differentiate CES from SN patients. Functional comorbidities were significantly more common in SN patients but mental health diagnosis frequency did not differ. Follow-up was variable with no consistent referral pathways, particularly for the SN group. 33% (n = 47) responded to the postal questionnaires; high levels of pain, symptom chronicity and disability were ubiquitous but self-reported mental health diagnoses and PHQ 15 were higher for SN patients. CONCLUSIONS: Conflicting data suggest further research is needed to investigate the prevalence of mental illness and somatic symptoms in SN cases. SN patients have higher rates of comorbid functional disorders and inconsistent referral pathways. Self-report measures indicate impaired quality of life across all groups. The low response rate limits the generalizability of findings but neuropsychiatric assessment and care pathway optimization should be considered.

Characteristics of patients with motor functional neurological disorder in a large UK mental health service: a case-control study.

BACKGROUND: Functional neurological disorder (FND), previously known as conversion disorder, is common and often results in substantial distress and disability. Previous research lacks large sample sizes and clinical surveys are most commonly derived from neurological settings, limiting our understanding of the disorder and its associations in other contexts. We sought to address this by analysing a large anonymised electronic psychiatric health record dataset. METHODS: Data were obtained from 322 patients in the South London and Maudsley NHS Foundation Trust (SLaM) who had an ICD-10 diagnosis of motor FND (mFND) (limb weakness or disorders of movement or gait) between 1 January 2006 and 31 December 2016. Data were collected on a range of socio-demographic and clinical factors and compared to 644 psychiatric control patients from the same register. RESULTS: Weakness was the most commonly occurring functional symptom. mFND patients were more likely to be female, British, married, employed pre-morbidly, to have a carer and a physical health condition, but less likely to have had an inpatient psychiatric admission or to receive benefits. No differences in self-reported sexual or physical abuse rates were observed between groups, although mFND patients were more likely to experience life events linked to inter-personal difficulties. CONCLUSIONS: mFND patients have distinct demographic characteristics compared with psychiatric controls. Experiences of abuse appear to be equally prevalent across psychiatric patient groups. This study establishes the socio-demographic and life experience profile of this understudied patient group and may be used to guide future therapeutic interventions designed specifically for mFND.

Evaluation of Thickened Fluids Used in Dysphagia Management Using Extensional Rheology.

Recent studies show that understanding the rheological properties of thickened fluids, such as viscosity and yield stress, is advantageous in designing optimal thickened fluids for the treatment of dysphagia. To date, these studies have focused on the rheological behavior of thickened fluids in shear deformation, while limited information is available on the surface tension of thickened fluids or their rheological behavior in extensional deformation. Knowledge of the extensional properties of thickened fluids (extensional viscosity and cohesiveness) is important to fully understand the behavior of such fluids while swallowing. Our aim in this work, therefore, was to characterize water and skim milk thickened with a commercial thickener (xanthan gum based) to determine extensional deformation and surface tension properties. It was observed that the surface tension decreases as the thickener concentration increases due to the accumulation of the biopolymer at the surface of the fluid when it dissolves in water. In addition, the extensional viscosity of the fluid increased over time as the filament thinned (i.e., as the Hencky strain increased) until it reached a plateau. It was observed that the maximum extensional viscosity, which is related to the cohesiveness of the fluid, increases with the higher concentrations of thickener. However, the cohesiveness of thickened skim milk was lower than that of the thickened water at a given thickener concentration due to lower surface tension. This study confirms that by increasing the concentration of thickener, it will not only increase the shear viscosity (i.e., bolus thickness) of the fluid, but also the extensional viscosity (i.e., bolus cohesiveness).

MULTI-OBJECTIVE MODEL EXPLORATION OF HEPATITIS C ELIMINATION IN AN AGENT-BASED MODEL OF PEOPLE WHO INJECT DRUGS.

Hepatitis C (HCV) is a leading cause of chronic liver disease and mortality worldwide and persons who inject drugs (PWID) are at the highest risk for acquiring and transmitting HCV infection. We developed an agent-based model (ABM) to identify and optimize direct-acting antiviral (DAA) therapy scale-up and treatment strategies for achieving the World Health Organization (WHO) goals of HCV elimination by the year 2030. While DAA is highly efficacious, it is also expensive, and therefore intervention strategies should balance the goals of elimination and the cost of the intervention. Here we present and compare two methods for finding PWID treatment enrollment strategies by conducting a standard model parameter sweep and compare the results to an evolutionary multi-objective optimization algorithm. The evolutionary approach provides a pareto-optimal set of solutions that minimizes treatment costs and incidence rates.

Acceptability of a first-line anti-tuberculosis formulation for children: qualitative data from the SHINE trial.

SETTING: We conducted a qualitative exploration into the palatability and acceptability of a novel fixed-dose combination (FDC) anti-tuberculosis drug. This study was nested in the SHINE (Shorter treatment for minimal TB in children) trial, which compares the safety and efficacy of treating non-severe drug-susceptible tuberculosis (TB) with a 6 vs. 4 months anti-tuberculosis regimen in children aged 0-16 years. Participants were recruited in Cape Town, South Africa.OBJECTIVE: To describe the palatability and acceptability of a FDC of rifampicin, isoniazid and pyrazinamide among South African children and their caregivers in the SHINE trial.METHODS: We conducted 20 clinic observations of treatment administration, during which we conducted 16 semi-structured interviews with children and their caregivers. Data were organised thematically to report on experiences with administering and ingesting the FDC.RESULTS: Children and caregivers' experiences varied from delight to disgust. In general, participants said that the FDC compared favourably to other formulations. Pragmatic challenges such as dissolving the FDC and the time required to administer the FDC impeded caregivers' ability to integrate treatment into their daily routines. Drug manipulation was common among caregivers to improve TB treatment administration.CONCLUSION: This novel FDC appears acceptable for children, albeit with practical challenges to administration. Scale-up of FDC use should include supplementary intervention components to support caregivers.

CANDLE/Supervisor: a workflow framework for machine learning applied to cancer research.

BACKGROUND: Current multi-petaflop supercomputers are powerful systems, but present challenges when faced with problems requiring large machine learning workflows. Complex algorithms running at system scale, often with different patterns that require disparate software packages and complex data flows cause difficulties in assembling and managing large experiments on these machines. RESULTS: This paper presents a workflow system that makes progress on scaling machine learning ensembles, specifically in this first release, ensembles of deep neural networks that address problems in cancer research across the atomistic, molecular and population scales. The initial release of the application framework that we call CANDLE/Supervisor addresses the problem of hyper-parameter exploration of deep neural networks. CONCLUSIONS: Initial results demonstrating CANDLE on DOE systems at ORNL, ANL and NERSC (Titan, Theta and Cori, respectively) demonstrate both scaling and multi-platform execution.

Extreme-scale Dynamic Exploration of a Distributed Agent-based Model with the EMEWS Framework.

Agent-based models (ABMs) integrate multiple scales of behavior and data to produce higher-order dynamic phenomena and are increasingly used in the study of important social complex systems in biomedicine, socio-economics and ecology/resource management. However, the development, validation and use of ABMs is hampered by the need to execute very large numbers of simulations in order to identify their behavioral properties, a challenge accentuated by the computational cost of running realistic, large-scale, potentially distributed ABM simulations. In this paper we describe the Extreme-scale Model Exploration with Swift (EMEWS) framework, which is capable of efficiently composing and executing large ensembles of simulations and other "black box" scientific applications while integrating model exploration (ME) algorithms developed with the use of widely available 3rd-party libraries written in popular languages such as R and Python. EMEWS combines novel stateful tasks with traditional run-to-completion many task computing (MTC) and solves many problems relevant to high-performance workflows, including scaling to very large numbers (millions) of tasks, maintaining state and locality information, and enabling effective multiple-language problem solving. We present the high-level programming model of the EMEWS framework and demonstrate how it is used to integrate an active learning ME algorithm to dynamically and efficiently characterize the parameter space of a large and complex, distributed Message Passing Interface (MPI) agent-based infectious disease model.

Magnetic resonance imaging of the proximal upper extremity musculature in boys with Duchenne muscular dystrophy.

There is a pressing need for biomarkers and outcomes that can be used across disease stages in Duchenne muscular dystrophy (DMD), to facilitate the inclusion of a wider range of participants in clinical trials and to improve our understanding of the natural history of DMD. Quantitative magnetic resonance imaging (qMRI) and spectroscopy (MRS) biomarkers show considerable promise in both the legs and forearms of individuals with DMD, but have not yet been examined in functionally important proximal upper extremity muscles such as the biceps brachii and deltoid. The primary objective of this study was to examine the feasibility of implementing qMRI and MRS biomarkers in the proximal upper extremity musculature, and the secondary objective was to examine the relationship between MR measures of arm muscle pathology and upper extremity functional endpoints. Biomarkers included MRS and MRI measures of fat fraction and transverse relaxation time (T 2). The MR exam was well tolerated in both ambulatory and non-ambulatory boys. qMR biomarkers differentiated affected and unaffected participants and correlated strongly with upper extremity function (r = 0.91 for biceps brachii T 2 versus performance of upper limb score). These qMR outcome measures could be highly beneficial to the neuromuscular disease community, allowing measurement of the quality of functionally important muscles across disease stages to understand the natural history of DMD and particularly to broaden the opportunity for clinical trial participation.

Transcranial magnetic stimulation and sedation as treatment for functional neurologic disorders.

Functional neurologic disorder (FND), also known as conversion disorder, is common and often associated with a poor prognosis. It has been relatively neglected by research and as such there is a conspicuous lack of evidence-based treatments. Physical and psychologic therapies are the main treatment modalities, over and above reassurance and sensitive explanation of the diagnosis. However there are two other historic treatments that have seen a recent resurgence of interest and use. The first is electric stimulation, which was initially pioneered with direct stimulation of nerves but now used indirectly (and therefore noninvasively) in the form of transcranial magnetic stimulation (TMS). The second is (therapeutic) sedation, previously known as "abreaction," where it was mostly used in the context of psychologic investigation and treatment, but now increasingly advocated during rehabilitation as a way to therapeutically demonstrate reversibility of symptoms. This chapter introduces the background of these treatment modalities, their evolution into their current applications before critically evaluating their current evidence base and exploring possible mechanisms of action. It also tentatively suggests when they should be considered in current practice and briefly considers their future potential. In summary there is encouraging preliminary evidence to suggest that both TMS and sedation may be effective treatments for FNDs.

Life events and escape in conversion disorder.

BACKGROUND: Psychological models of conversion disorder (CD) traditionally assume that psychosocial stressors are identifiable around symptom onset. In the face of limited supportive evidence such models are being challenged. METHOD: Forty-three motor CD patients, 28 depression patients and 28 healthy controls were assessed using the Life Events and Difficulties Schedule in the year before symptom onset. A novel 'escape' rating for events was developed to test the Freudian theory that physical symptoms of CD could provide escape from stressors, a form of 'secondary gain'. RESULTS: CD patients had significantly more severe life events and 'escape' events than controls. In the month before symptom onset at least one severe event was identified in 56% of CD patients - significantly more than 21% of depression patients [odds ratio (OR) 4.63, 95% confidence interval (CI) 1.56-13.70] and healthy controls (OR 5.81, 95% CI 1.86-18.2). In the same time period 53% of CD patients had at least one 'high escape' event - again significantly higher than 14% in depression patients (OR 6.90, 95% CI 2.05-23.6) and 0% in healthy controls. Previous sexual abuse was more commonly reported in CD than controls, and in one third of female patients was contextually relevant to life events at symptom onset. The majority (88%) of life events of potential aetiological relevance were not identified by routine clinical assessments. Nine per cent of CD patients had no identifiable severe life events. CONCLUSIONS: Evidence was found supporting the psychological model of CD, the Freudian notion of escape and the potential aetiological relevance of childhood traumas in some patients. Uncovering stressors of potential aetiological relevance requires thorough psychosocial evaluation.

Collective atomic scattering and motional effects in a dense coherent medium.

We investigate collective emission from coherently driven ultracold (88)Sr atoms. We perform two sets of experiments using a strong and weak transition that are insensitive and sensitive, respectively, to atomic motion at 1 µK. We observe highly directional forward emission with a peak intensity that is enhanced, for the strong transition, by >10(3) compared with that in the transverse direction. This is accompanied by substantial broadening of spectral lines. For the weak transition, the forward enhancement is substantially reduced due to motion. Meanwhile, a density-dependent frequency shift of the weak transition (∼10% of the natural linewidth) is observed. In contrast, this shift is suppressed to <1% of the natural linewidth for the strong transition. Along the transverse direction, we observe strong polarization dependences of the fluorescence intensity and line broadening for both transitions. The measurements are reproduced with a theoretical model treating the atoms as coherent, interacting radiating dipoles.

Assessing potential risks of treatment with long-term azithromycin in COPD patients: long-term oxygen users beware?

INTRODUCTION: Long-term daily azithromycin therapy reduces the frequency of exacerbations in chronic obstructive pulmonary disease (COPD) in a randomized controlled clinical trial setting. Concerns exist regarding arrhythmic and auditory toxicities from chronic use in the real-world setting. We hypothesized that risk factors for adverse drug reactions to azithromycin would be more frequent than previously reported, that certain specific subgroups would have different frequencies of these risk factors and that the whispered voice test would be a useful test with which to test for hearing deficits. METHODS: Following ethical approval, 47 consecutive hospital-based patients with a mean age 69 years ± 8.2, and with physician-diagnosed COPD (mean FEV1 45.1 ± 18 % predicted), were screened for subjective hearing impairment (screening questions and whispered voice test) and by electrocardiogram for prolonged QTc. Other potential risk factors and contraindications to long-term daily azithromycin were sought. RESULTS: In total, 38 patients (80.9 %) had at least one risk factor or contraindication to azithromycin treatment. 19 patients (40.4 % of total) had subjective hearing impairment. 17 (36.1 %) had prolonged QTc intervals. 4 patients (8.51 %) had contraindicating co-morbidities. Those on long-term oxygen therapy were significantly more likely to have at least one risk factors or contraindications to azithromycin (p = 0.0025). CONCLUSION: In a COPD population who would otherwise potentially be candidates for long-term daily azithromycin therapy, over 80 % had risk factors for complications from long-term daily azithromycin. Preventative treatment with long-term daily azithromycin may be appropriate for fewer COPD patients than previously thought, especially in those on long-term oxygen therapy.

FROM DESKTOP TO LARGE-SCALE MODEL EXPLORATION WITH SWIFT/T.

As high-performance computing resources have become increasingly available, new modes of computational processing and experimentation have become possible. This tutorial presents the Extreme-scale Model Exploration with Swift/T (EMEWS) framework for combining existing capabilities for model exploration approaches (e.g., model calibration, metaheuristics, data assimilation) and simulations (or any "black box" application code) with the Swift/T parallel scripting language to run scientific workflows on a variety of computing resources, from desktop to academic clusters to Top 500 level supercomputers. We will present a number of use-cases, starting with a simple agent-based model parameter sweep, and ending with a complex adaptive parameter space exploration workflow coordinating ensembles of distributed simulations. The use-cases are published on a public repository for interested parties to download and run on their own.

Systematic evaluation of an atomic clock at 2 × 10(-18) total uncertainty.

The pursuit of better atomic clocks has advanced many research areas, providing better quantum state control, new insights in quantum science, tighter limits on fundamental constant variation and improved tests of relativity. The record for the best stability and accuracy is currently held by optical lattice clocks. Here we take an important step towards realizing the full potential of a many-particle clock with a state-of-the-art stable laser. Our (87)Sr optical lattice clock now achieves fractional stability of 2.2 × 10(-16) at 1 s. With this improved stability, we perform a new accuracy evaluation of our clock, reducing many systematic uncertainties that limited our previous measurements, such as those in the lattice ac Stark shift, the atoms' thermal environment and the atomic response to room-temperature blackbody radiation. Our combined measurements have reduced the total uncertainty of the JILA Sr clock to 2.1 × 10(-18) in fractional frequency units.