Susceptibility-Weighted Imaging Provides Insight into White Matter Damage in Amyotrophic Lateral Sclerosis

Background

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder, characterised by widespread white matter damage. There is growing evidence that disturbances in iron metabolism contribute to white matter alterations.

Materials & Methods

We analysed the data of susceptibility-weighted imaging (SWI) of white matter in a cohort of 27 patients with ALS and 30 healthy age-matched controls.

Results

Signal alterations were found on SWI in the corpus callosum; along the corticospinal tract (subcortical motor cortex, posterior limb of the internal capsule and brainstem levels) and in the subgyral regions of frontal, parietal, temporal, occipital and limbic lobes. Alterations of white matter in the corpus callosum correlated with disease severity as assessed by the revised ALS functional rating scale.

Conclusion

SWI is capable of indicating iron and myelin disturbances in white matter of ALS patients. The SWI patterns observed in this study suggest that widespread alterations due to iron disturbances occur in patients with ALS and correlate with disease severity.     

Wastewater-Based Epidemiology of Stimulant Drugs: Functional Data Analysis Compared to Traditional Statistical Methods

Background

Wastewater-based epidemiology (WBE) is a new methodology for estimating the drug load in a population. Simple summary statistics and specification tests have typically been used to analyze WBE data, comparing differences between weekday and weekend loads. Such standard statistical methods may, however, overlook important nuanced information in the data. In this study, we apply functional data analysis (FDA) to WBE data and compare the results to those obtained from more traditional summary measures.

Methods

We analysed temporal WBE data from 42 European cities, using sewage samples collected daily for one week in March 2013. For each city, the main temporal features of two selected drugs were extracted using functional principal component (FPC) analysis, along with simpler measures such as the area under the curve (AUC). The individual cities’ scores on each of the temporal FPCs were then used as outcome variables in multiple linear regression analysis with various city and country characteristics as predictors. The results were compared to those of functional analysis of variance (FANOVA).

Results

The three first FPCs explained more than 99% of the temporal variation. The first component (FPC1) represented the level of the drug load, while the second and third temporal components represented the level and the timing of a weekend peak. AUC was highly correlated with FPC1, but other temporal characteristic were not captured by the simple summary measures. FANOVA was less flexible than the FPCA-based regression, and even showed concordance results. Geographical location was the main predictor for the general level of the drug load.

Conclusion

FDA of WBE data extracts more detailed information about drug load patterns during the week which are not identified by more traditional statistical methods. Results also suggest that regression based on FPC results is a valuable addition to FANOVA for estimating associations between temporal patterns and covariate information.     

Probabilistic MRI Tractography of the Optic Radiation Using Constrained Spherical Deconvolution: A Feasibility Study

Background and Purpose

Imaging the optic radiation (OR) is of considerable interest in studying diseases affecting the visual pathway and for pre-surgical planning of temporal lobe resections. The purpose of this study was to investigate the clinical feasibility of using probabilistic diffusion tractography based on constrained spherical deconvolution (CSD) to image the optic radiation. It was hypothesized that CSD would provide improved tracking of the OR compared with the widely used ball-and-stick model.

Methods

Diffusion weighted MRI (30 directions) was performed on twenty patients with no known visual deficits. Tractography was performed using probabilistic algorithms based on fiber orientation distribution models of local white matter trajectories. The performance of these algorithms was evaluated by comparing computational times and receiver operating characteristic results, and by correlation of anatomical landmark distances to dissection estimates.

Results

The results showed that it was consistently feasible to reconstruct individual optic radiations from clinically practical (4.5 minute acquisition) diffusion weighted imaging data sets using CSD. Tractography based on the CSD model resulted in significantly shorter computational times, improved receiver operating characteristic results, and shorter Meyer’s loop to temporal pole distances (in closer agreement with dissection studies) when compared to the ball-and-stick based algorithm.

Conclusions

Accurate tractography of the optic radiation can be accomplished using diffusion MRI data collected within a clinically practical timeframe. CSD based tractography was faster, more accurate and had better correlation with known anatomical landmarks than ball-and-stick tractography.     

Pattern of Drug Resistance and Risk Factors Associated with Development of Drug Resistant Mycobacterium tuberculosis in Pakistan

Background

Drug resistant tuberculosis (DR-TB) is a major public health problem in developing countries such as Pakistan.

Objective

The current study was conducted to assess the frequency of drug resistant tuberculosis including multi drug resistance (MDR- TB) as well as risk factors for development of DR-TB, in Punjab, Pakistan.

Methodology

Drug susceptibility testing (DST) was performed, using proportion method, for 2367 culture positive Mycobacterium tuberculosis (MTB) cases that were enrolled from January 2012 to December 2013 in the province of Punjab, Pakistan, against first-line anti-tuberculosis drugs. The data was analyzed using statistical software; SPSS version 18.

Results

Out of 2367 isolates, 273 (11.5%) were resistant to at least one anti-TB drug, while 221 (9.3%) showed MDR- TB. Risk factors for development of MDR-TB were early age (ranges between 10–25 years) and previously treated TB patients.

Conclusion

DR-TB is a considerable problem in Pakistan. Major risk factors are previous history of TB treatment and younger age group. It emphasizes the need for effective TB control Program in the country.     

Is High Temporal Resolution Achievable for Paediatric Cardiac Acquisitions during Several Heart Beats? Illustration with Cardiac Phase Contrast Cine-MRI

Background

During paediatric cardiac Cine-MRI, data acquired during cycles of different lengths must be combined. Most of the time, Feinstein’s model is used to project multiple cardiac cycles of variable lengths into a mean cycle.

Objective

To assess the effect of Feinstein projection on temporal resolution of Cine-MRI.

Methods

1/The temporal errors during Feinstein’s projection were computed in 306 cardiac cycles fully characterized by tissue Doppler imaging with 6-phase analysis (from a population of 7 children and young adults). 2/The effects of these temporal errors on tissue velocities were assessed by simulating typical tissue phase mapping acquisitions and reconstructions. 3/Myocardial velocities curves, extracted from high-resolution phase-contrast cine images, were compared for the 6 volunteers with lowest and highest heart rate variability, within a population of 36 young adults.

Results

1/The mean of temporal misalignments was 30 ms over the cardiac cycle but reached 60 ms during early diastole. 2/During phase contrast MRI simulation, early diastole velocity peaks were diminished by 6.1 cm/s leading to virtual disappearance of isovolumic relaxation peaks. 3/The smoothing and erasing of isovolumic relaxation peaks was confirmed on tissue phase mapping velocity curves, between subjects with low and high heart rate variability (p = 0.05).

Conclusions

Feinstein cardiac model creates temporal misalignments that impair high temporal resolution phase contrast cine imaging when beat-to-beat heart rate is changing.     

Specific EEG Sleep Pattern in the Prefrontal Cortex in Primary Insomnia

Objective

To assess the specific prefrontal activity in comparison to those in the other main cortical areas in primary insomnia patients and in good sleepers.

Methods

Fourteen primary insomnia patients and 11 good sleepers were included in the analysis. Participants completed one night of polysomnography in the sleep lab. Power spectra were calculated during the NREM (Non-rapid eyes movements) and the REM (Rapid eyes movements) sleep periods at prefrontal, occipital, temporal and central electrode positions.

Results

During the NREM sleep, the power spectra did not differ between groups in the prefrontal cortex; while primary insomnia patients exhibited a higher beta power spectrum and a lower delta power spectrum compared to good sleepers in other areas. During the REM sleep, the beta1 power spectrum was lower in the prefrontal cortex in primary insomnia patients compared to good sleepers; while no significant difference between groups was obtained for the other areas.

Conclusions

The present study shows a specific prefrontal sleep pattern during the whole sleep period. In addition, we suggest that primary insomnia patients displayed a dysfunction in the reactivation of the limbic system during the REM sleep and we give additional arguments in favor of a sleep-protection mechanism displayed by primary insomnia patients.     

Recommendations for a Core Outcome Set for Measuring Standing Balance in Adult Populations: A Consensus-Based Approach

Background

Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.

Objective

To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.

Methodology

A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.

Data sources

The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.

Results

Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.

Limitations

Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.

Conclusions

The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally.     

Therapeutic Hypothermia Modifies Perinatal Asphyxia-Induced Changes of the Corpus Callosum and Outcome in Neonates

What Is Known about this Subject?

Diffusion-weighted MRI has demonstrated changes in the corpus callosum of term neonates with perinatal asphyxia. The severity of cerebral changes demonstrated using diffusion-weighted MRI is difficult to assess without measuring values of the Apparent Diffusion Coefficient (ADC).

What Is New?

ADC values of the anterior part of the corpus callosum are slightly higher than of the posterior part in full term infants with perinatal asphyxia. Low ADC values of the corpus callosum were associated with an adverse outcome in infants with perinatal asphyxia. In infants treated with hypothermia lower ADC values than with normothermia were associated with a poor outcome, supporting neuroprotective effects of hypothermia

Background

Using MRI, changes can be detected in the corpus callosum (CC) following perinatal asphyxia which are associated with later neurodevelopmental outcome.

Aim

To study the association between the apparent diffusion coefficient of water (ADC) in the CC on MRI in neonates with perinatal asphyxia and neurodevelopmental outcome at 18 months of age.

Subjects, Methods

Of 121 infants 32 (26%) died and 13 (11%) survived with an adverse neurological outcome. Sixty-five (54%) received therapeutic hypothermia. MRI was performed within 7 days after birth using a 1.5 T or 3.0 T system, and ADC values were measured in the anterior and posterior CC. The association between ADC and composite outcome (death or abnormal neurodevelopment) was analyzed for both normothermia and hypothermia cases using receiver operating characteristics.

Results

ADC values of the posterior CC were lower than of the anterior part (mean difference 0.050 x 10^-3 mm²/s, p<0.001). Field strength did not affect ADC values. ADC values of the posterior part of the CC were significantly lower in infants with basal ganglia/thalamus or near total brain injury (p<0.001). Lower ADC values were associated with an adverse outcome, but cut-off levels were lower after hypothermia (1.024 x 10^-3 mm²/s vs 0.969 x 10^-3 mm²/s)

Conclusion

Low ADC values of the posterior part of the corpus callosum are associated with an adverse outcome in term or near term neonates with perinatal asphyxia. Therapeutic hypothermia slightly modifies this association, showing that lower values were needed for an adverse outcome.     

HIV-1 Coreceptor Usage Assessment by Ultra-Deep Pyrosequencing and Response to Maraviroc

Background

Maraviroc is an HIV entry inhibitor that alters the conformation of CCR5 and is poorly efficient in patients infected by viruses that use CXCR4 as an entry coreceptor. The goal of this study was to assess the capacity of ultra-deep pyrosequencing (UDPS) and different data analysis approaches to characterize HIV tropism at baseline and predict the therapeutic outcome on maraviroc treatment.

Methods

113 patients with detectable HIV-1 RNA on HAART were treated with maraviroc. The virological response was assessed at months 1, 3 and 6. The sequence of the HIV V3 loop was determined at baseline and prediction of maraviroc response by different software and interpretation algorithms was analyzed.

Results

UDPS followed by analysis with the Pyrotrop software or geno2pheno algorithm provided better prediction of the response to maraviroc than Sanger sequencing. We also found that the H34Y/S substitution in the V3 loop was the strongest individual predictor of maraviroc response, stronger than substitutions at positions 11 or 25 classically used in interpretation algorithms.

Conclusions

UDPS is a powerful tool that can be used with confidence to predict maraviroc response in HIV-1-infected patients. Improvement of the predictive value of interpretation algorithms is possible and our results suggest that adding the H34S/Y substitution would substantially improve the performance of the 11/25/charge rule.     

Automatic Prediction of Cardiovascular and Cerebrovascular Events Using Heart Rate Variability Analysis

Background

There is consensus that Heart Rate Variability is associated with the risk of vascular events. However, Heart Rate Variability predictive value for vascular events is not completely clear. The aim of this study is to develop novel predictive models based on data-mining algorithms to provide an automatic risk stratification tool for hypertensive patients.

Methods

A database of 139 Holter recordings with clinical data of hypertensive patients followed up for at least 12 months were collected ad hoc. Subjects who experienced a vascular event (i.e., myocardial infarction, stroke, syncopal event) were considered as high-risk subjects. Several data-mining algorithms (such as support vector machine, tree-based classifier, artificial neural network) were used to develop automatic classifiers and their accuracy was tested by assessing the receiver-operator characteristics curve. Moreover, we tested the echographic parameters, which have been showed as powerful predictors of future vascular events.

Results

The best predictive model was based on random forest and enabled to identify high-risk hypertensive patients with sensitivity and specificity rates of 71.4% and 87.8%, respectively. The Heart Rate Variability based classifier showed higher predictive values than the conventional echographic parameters, which are considered as significant cardiovascular risk factors.

Conclusions

Combination of Heart Rate Variability measures, analyzed with data-mining algorithm, could be a reliable tool for identifying hypertensive patients at high risk to develop future vascular events.     

Engaging the Public to Identify Opportunities to Improve Critical Care: A Qualitative Analysis of an Open Community Forum

Objective

To engage the public to understand how to improve the care of critically ill patients.

Design

A qualitative content analysis of an open community forum (Café Scientifique).

Setting

Public venue in Calgary, Alberta, Canada.

Participants

Members of the general public including patients, families of patients, health care providers, and members of the community at large.

Methods

A panel of researchers, decision-makers, and a family member led a Café Scientifique, an informal dialogue between the populace and experts, over three-hours to engage the public to understand how to improve the care of critically ill patients. Conventional qualitative content analysis was used to analyze the data. The inductive analysis occurred in three phases: coding, categorizing, and developing themes.

Results

Thirty-eight members of the public (former ICU patients, family members of patients, providers, community members) attended. Participants focused the discussion and provided concrete suggestions for improvement around communication (family as surrogate voice, timing of conversations, decision tools) and provider well-being and engagement, as opposed to medical interventions in critical care.

Conclusions

Café participants believe patient and family centered care is important to ensure high-quality care in the ICU. A Café Scientifique is a valuable forum to engage the public to contribute to priority setting areas for research in critical care, as well as a platform to share lived experience. Research stakeholders including health care organizations, governments, and funding organizations should provide more opportunities for the public to engage in meaningful conversations about how to best improve healthcare.     

Stigma and Human Rights Abuses against People Who Inject Drugs in Russia—A Qualitative Investigation to Inform Policy and Public Health Strategies

Introduction

Drug policing practices in the Russian Federation (Russia) are often punitive and have been shown to be associated with HIV risk behaviors among people who inject drugs (PWID). Less is known about strategies to address the problem in that setting, where substance use stigma is highly persistent. A better understanding of forms, causes and consequences of drug policing in Russia could inform drug policy in a context of substantial policy resistance. This qualitative study’s goal is to characterize the phenomenon of police involvement with Russian PWID and to explore strategies for drug policing in the Russian country context.

Methods

Using a semi-structured interview guide, we collected data from a purposive sample of 23 key informants including PWID, police officers, and experts from civil society and international organizations in Russia. We used a thematic analysis approach to inductively generate new insight into the phenomenon of police involvement and potential strategies to address it.

Results

Policing practices involving PWID include unjustified arrests, planting of false evidence and extrajudicial syringe confiscations, and often constitute human rights violations. Russian PWID personally experienced police violence as ubiquitous, taking on various forms such as beating, unjustified arrests, verbal harassment, and coercion. The persistent societal stigma dehumanizes PWID, and such stigmatization facilitates police abuse. To address stigma and overcome the PWID-police adversity, study participants suggested fostering a mutual understanding between the police and public health sectors.

Conclusions

Participants describe substantial human rights violations as part of policing illicit drug use in Russia. Police should include principles of effective prevention of substance use and HIV risk reduction in their trainings. Alignment of public safety and public health goals could address drug use-related risks and HIV prevention among key populations in Russia.     

Elimination and Eradication of Neglected Tropical Diseases with Mass Drug Administrations: A Survey of Experts

Background

Lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminths, and trachoma are the five most prevalent neglected tropical diseases in the world, and each is frequently treated with mass drug administrations. We performed a survey of neglected tropical diseases experts to elicit their opinions on the role of mass drug administrations for the elimination of these infections.

Methodology/Principal Findings

We sent an online survey to corresponding authors who had published an article about a neglected tropical disease from 2007 to 2011. Of 825 unique authors who were invited to complete the survey, 365 (44.2%) responded, including 234 (28.4%) who answered questions regarding one of the five most prevalent neglected tropical diseases. Respondents had varying opinions about the goals of programmatic activities for their chosen neglected tropical disease, with elimination or eradication identified as the most important goal by 87% of lymphatic filariasis respondents, 66% of onchocerciasis respondents, 55% of trachoma respondents, 24% of schistosomiasis respondents, and 21% of soil-transmitted helminth respondents. Mass drug administrations, other non-medication health measures, and education were generally thought to be more important for elimination than vector control, development of a new tool, or the presence of a secular trend. Drug resistance was thought to be a major limitation of mass drug administrations for all five neglected tropical diseases. Over half of respondents for lymphatic filariasis and trachoma thought that repeated mass drug administrations could eliminate infection within ten years of the initiation of mass treatments.

Conclusions/Significance

Respondents for lymphatic filariasis, onchocerciasis, and trachoma were more enthusiastic about the prospects of elimination and eradication than were respondents for schistosomiasis or soil-transmitted helminths. Mass drug administrations were generally believed to be among the most important factors for the success of elimination efforts for each of the five neglected tropical diseases, highlighting the opportunity for integrating drug distributions.     

Identifying Heat Waves in Florida: Considerations of Missing Weather Data

Background

Using current climate models, regional-scale changes for Florida over the next 100 years are predicted to include warming over terrestrial areas and very likely increases in the number of high temperature extremes. No uniform definition of a heat wave exists. Most past research on heat waves has focused on evaluating the aftermath of known heat waves, with minimal consideration of missing exposure information.

Objectives

To identify and discuss methods of handling and imputing missing weather data and how those methods can affect identified periods of extreme heat in Florida.

Methods

In addition to ignoring missing data, temporal, spatial, and spatio-temporal models are described and utilized to impute missing historical weather data from 1973 to 2012 from 43 Florida weather monitors. Calculated thresholds are used to define periods of extreme heat across Florida.

Results

Modeling of missing data and imputing missing values can affect the identified periods of extreme heat, through the missing data itself or through the computed thresholds. The differences observed are related to the amount of missingness during June, July, and August, the warmest months of the warm season (April through September).

Conclusions

Missing data considerations are important when defining periods of extreme heat. Spatio-temporal methods are recommended for data imputation. A heat wave definition that incorporates information from all monitors is advised.     

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective

To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.

Design

Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.

Results

We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation.

Conclusions

We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.     

Elicitation of Expert Prior Opinion: Application to the MYPAN Trial in Childhood Polyarteritis Nodosa

Objectives

Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa).

Methods

A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis.

Results

A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available.

Conclusions

We suggest that the methodological template we propose could be applied to trial design for other rare diseases.