Quantification of Visual Fixation in Multiple Sclerosis

Purpose: Eye movement abnormalities are common in multiple sclerosis (MS), and infrared oculography is a noninvasive method for quantification. This study aims to describe and classify abnormalities of visual fixation and their clinical relevance in MS. Methods: A validated standardized infrared oculography protocol, Demonstrate Eye Movement Networks with Saccades, was used for quantifying gaze stability during a fixation task in MS patients and healthy controls. Saccadic intrusions, gaze drift, and stability of fixation around the drift line were used to subclassify MS patients by performing receiver operating characteristic analyses of different parameters. The relationship between the presence of abnormalities of fixation and visual functioning was analyzed using logistic regression models, which was adjusted for possible confounders. Results: This cross-sectional study included 213 subjects with MS and 57 healthy controls. Square wave jerk abnormalities were present in 24% of MS patients. The prevalence was higher in more disabled subjects. The presence of larger square wave jerks (with a higher amplitude) in the MS patients was related to complaints of focusing on stationary objects (odds ratio, 2.2; P = 0.035) and a lower vision-related quality of life (odds ratio, 2.56; P = 0.012). Conclusions: This study provided a comprehensive overview of the characteristics of problems with visual fixation in subjects with MS. The most important and most common finding was the presence of larger square wave jerks during fixation, which was related to visual functioning in daily life

Saccadic fatigability in the oculomotor system

BACKGROUND: Fatigue is one of the most common and disabling symptoms in multiple sclerosis (MS), but challenging to quantify. This prospective study investigated if repeated saccadic eye movements enable measurement of oculomotor fatigability and can reflect on perceived fatigue in MS. METHODS: A standardized infrared oculography protocol (DEMoNS) was used for quantifying saccades in MS patients and healthy controls which included a first and a repeated pro-saccadic task (FPT and RPT). Saccadic peak velocity, latency, gain, area under the curve (AUC) and peak velocity divided by amplitude (Pv/Am) were calculated in both tasks. Perception based fatigue was assessed using the Checklist Individual Strength and the Neurological Fatigue Index (NFI). Linear regression models were used for assessing the relation between saccadic parameters and perceived fatigue. RESULTS: This study included 181 MS patients and 58 healthy controls subjects. From FPT to RPT, there were significant changes in saccadic parameters. Latency of both tasks was significantly related to NFI summary score (FPT: β = 0.022, p = .049, RPT: β 0.023, p = .021). These relationships were weakened after adjustment for Expanded Disability Status score (p > .05). There was however no significant group difference in changes in saccadic parameters. CONCLUSIONS: This study presents an objective and reproducible method for measuring saccadic fatigability. Saccadic fatigability was found to be of limited use in MS, and should be tested in conditions affecting ocular muscles or the neuromuscular junction

Using behavioural insights to increase HIV self-sampling kit returns: a randomized controlled text message trial to improve England's HIV self-sampling service.

OBJECTIVES: The aim of the study was to determine whether behaviourally informed short message service (SMS) primer and reminder messages could increase the return rate of HIV self-sampling kits ordered online. METHODS: The study was a 2 × 2 factorial design randomized control trial. A total of 9585 individuals who ordered a self-sampling kit from www.freetesting.hiv different SMS combinations: 1) standard reminders sent days 3 and 7 after dispatch (control); 2) primer sent 1 day after dispatch plus standard reminders; 3) behavioural insights (BI) reminders (no primer); or 4) primer plus BI reminders. The analysis was restricted to individuals who received all messages (n = 8999). We used logistic regression to investigate independent effects of the primer and BI reminders and their interaction. We explored the impact of sociodemographic characteristics on kit return as a secondary analysis. RESULTS: Those who received the primer and BI reminders had a return rate 4% higher than that of those who received the standard messages. We found strong evidence of a positive effect of the BI reminders (odds ratio 1.13; 95% confidence interval 1.04-1.23; P = 0.003) but no evidence for an effect of the primer, or for an interaction between the two interventions. Odds of kit return increased with age, with those aged ≥ 65 years being almost 2.5 times more likely to return the kit than those aged 25-34 years. Men who have sex with men were 1.5-4.5 times more likely to return the kit compared with other sexual behaviour and gender identity groups. Non-African black clients were 25% less likely to return the kit compared with other ethnicities. CONCLUSIONS: Adding BI to reminder messages was successful in improving return rates at no additional cost

Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer

BACKGROUND: The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis. In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer. METHODS: The entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma) of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE), followed by direct DNA sequencing to identify the mutations. RESULTS: Fourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively. Nine mutations (64%) were in the D-loop region. Numerous germline variations were found, at least 10 of them were novel and five were missense mutations, some of them occurred in evolutionarily conserved domains. Using real-time quantitative PCR analysis, the mtDNA content was found to increase in some tumors and decrease in others. Analysis of molecular and other clinicopathological findings does not reveal significant correlation between somatic mtDNA mutations and mtDNA content, or between mtDNA content and metastatic status. CONCLUSION: Our results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent. Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma. More extensive biochemical and molecular studies will be necessary to determine the pathological significance of these somatic mutations

Diagnosing and quantifying a common deficit in multiple sclerosis: Internuclear ophthalmoplegia

OBJECTIVE: We present an objective and quantitative approach for diagnosing internuclear ophthalmoplegia (INO) in multiple sclerosis (MS). METHODS: A validated standardized infrared oculography protocol (DEMoNS [Demonstrate Eye Movement Networks with Saccades]) was used for quantifying prosaccades in patients with MS and healthy controls (HCs). The versional dysconjugacy index (VDI) was calculated, which describes the ratio between the abducting and adducting eye. The VDI was determined for peak velocity, peak acceleration, peak velocity divided by amplitude, and area under the curve (AUC) of the saccadic trajectory. We calculated the diagnostic accuracy for the several VDI parameters by a receiver operating characteristic analysis comparing HCs and patients with MS. The National Eye Institute Visual Function Questionnaire-25 was used to investigate vision-related quality of life of MS patients with INO. RESULTS: Two hundred ten patients with MS and 58 HCs were included. The highest diagnostic accuracy was achieved by the VDI AUC of 15° horizontal prosaccades. Based on a combined VDI AUC and peak velocity divided by amplitude detection, the prevalence of an INO in MS calculated to 34%. In the INO group, 35.2% of the patients with MS reported any complaints of double vision, compared to 18.4% in the non-INO group (p = 0.010). MS patients with an INO had a lower overall vision-related quality of life (median 89.9, interquartile range 12.8) compared to patients without an INO (median 91.8, interquartile range 9.3, p = 0.011). CONCLUSIONS: This study provides an accurate quantitative and clinically relevant definition of an INO in MS. This infrared oculography-based INO standard will require prospective validation. The high prevalence of INO in MS provides an anatomically well described and accurately quantifiable model for treatment trials in MS

Time-to-birth prediction models and the influence of expert opinions

Preterm birth is the leading cause of death among children under five years old. The pathophysiology and etiology of preterm labor are not yet fully understood. This causes a large number of unnecessary hospitalizations due to high--sensitivity clinical policies, which has a significant psychological and economic impact. In this study, we present a predictive model, based on a new dataset containing information of 1,243 admissions, that predicts whether a patient will give birth within a given time after admission. Such a model could provide support in the clinical decision-making process. Predictions for birth within 48 h or 7 days after admission yield an Area Under the Curve of the Receiver Operating Characteristic (AUC) of 0.72 for both tasks. Furthermore, we show that by incorporating predictions made by experts at admission, which introduces a potential bias, the prediction effectiveness increases to an AUC score of 0.83 and 0.81 for these respective tasks

The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

The contractile actin-myosin cytoskeleton provides much of the force required for numerous cellular activities such as motility, adhesion, cytokinesis and changes in morphology. Key elements that respond to various signal pathways are the myosin II regulatory light chains (MLC), which participate in actin-myosin contraction by modulating the ATPase activity and consequent contractile force generation mediated by myosin heavy chain heads. Considerable effort has focussed on the role of MLC kinases, and yet the contributions of the myotonic dystrophy-related Cdc42-binding kinases (MRCK) proteins in MLC phosphorylation and cytoskeleton regulation have not been well characterized. In contrast to the closely related ROCK1 and ROCK2 kinases that are regulated by the RhoA and RhoC GTPases, there is relatively little information about the CDC42-regulated MRCKα, MRCKβ and MRCKγ members of the AGC (PKA, PKG and PKC) kinase family. As well as differences in upstream activation pathways, MRCK and ROCK kinases apparently differ in the way that they spatially regulate MLC phosphorylation, which ultimately affects their influence on the organization and dynamics of the actin-myosin cytoskeleton. In this review, we will summarize the MRCK protein structures, expression patterns, small molecule inhibitors, biological functions and associations with human diseases such as cancer

A standardized protocol for quantification of saccadic eye movements: DEMoNS

OBJECTIVE: Quantitative saccadic testing is a non-invasive method of evaluating the neural networks involved in the control of eye movements. The aim of this study is to provide a standardized and reproducible protocol for infrared oculography measurements of eye movements and analysis, which can be applied for various diseases in a multicenter setting. METHODS: Development of a protocol to Demonstrate Eye Movement Networks with Saccades (DEMoNS) using infrared oculography. Automated analysis methods were used to calculate parameters describing the characteristics of the saccadic eye movements. The two measurements of the subjects were compared with descriptive and reproducibility statistics. RESULTS: Infrared oculography measurements of all subjects were performed using the DEMoNS protocol and various saccadic parameters were calculated automatically from 28 subjects. Saccadic parameters such as: peak velocity, latency and saccade pair ratios showed excellent reproducibility (intra-class correlation coefficients > 0.9). Parameters describing performance of more complex tasks showed moderate to good reproducibility (intra-class correlation coefficients 0.63-0.78). CONCLUSIONS: This study provides a standardized and transparent protocol for measuring and analyzing saccadic eye movements in a multicenter setting. The DEMoNS protocol details outcome measures for treatment trial which are of excellent reproducibility. The DEMoNS protocol can be applied to the study of saccadic eye movements in various neurodegenerative and motor diseases