Childhood infections, vaccinations, and tonsillectomy and risk of first clinical diagnosis of CNS demyelination in the Ausimmune Study.

BACKGROUND: The association between childhood vaccinations and infections and risk of multiple sclerosis is unclear; few studies have considered age at vaccination/infection. OBJECTIVE: To explore age-related associations between childhood vaccinations, infection and tonsillectomy and risk of a first clinical diagnosis of CNS demyelination. METHODS: Data on case (n = 275, 76.6% female; mean age 38.6 years) and age- and sex-matched control (n = 529) participants in an incident population-based case-control study included self-reported age at time of childhood vaccinations, infections, and tonsillectomy. Conditional logistic regression models were used to calculate adjusted odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: Poliomyelitis vaccination prior to school-age was associated with increased risk of a first clinical diagnosis of CNS demyelination (AOR = 2.60, 95%CI 1.02-6.68), based on a very small unvaccinated reference group. Late (11-15 years) rubella vaccination (compared to none) was associated with lower odds of being a case (AOR = 0.47, 95%CI 0.27-0.83). Past infectious mononucleosis at 11-15 years (AOR = 2.84, 95%CI 1.0-7.57) and 16-20 years (AOR = 1.92, 95%CI 1.12-3.27) or tonsillectomy in adolescence (11-15 years: AOR = 2.45, 95%CI 1.12-5.35), including after adjustment for IM, were associated with increased risk of a first clinical diagnosis of CNS demyelination. CONCLUSIONS: Age at vaccination, infection or tonsillectomy may alter the risk of subsequent CNS demyelination. Failing to account for age effects may explain inconsistencies in past findings.

Health state utility values measured using the EuroQol 5-dimensions questionnaire in adults with chronic hepatitis C: a systematic literature review and meta-analysis.

PURPOSE: Chronic hepatitis C infection and its treatment can considerably affect patients' health-related quality-of-life (HRQoL). This study aimed to identify and summarise the current evidence base for health state utility values (HSUVs) in patients with chronic hepatitis C infection, generated using the EuroQol 5-dimensions (EQ-5D) questionnaire. METHODS: MEDLINE, Embase, the Cochrane Library and EconLit were searched from database inception through 31 August 2017. Eligible studies reported HSUVs elicited using the EQ-5D questionnaire in adults with chronic hepatitis C infection. Study quality and risk of bias were assessed. RESULTS: Of 1480 records identified, 26 studies were included. The most commonly defined health states described different stages of chronic hepatitis C infection and specific liver-related disease states, including METAVIR score, compensated and decompensated cirrhosis, hepatocellular carcinoma and liver transplantation. Patients with higher METAVIR scores tended to have lower EQ-5D scores compared to patients with lower METAVIR scores. Patients that achieved sustained virologic responses tended to have higher EQ-5D scores compared to those that did not. A meta-analysis conducted on three studies confirmed that patients with decompensated cirrhosis have significantly lower HSUVs than patients with compensated cirrhosis [mean difference - 0.11 (95% CI - 0.19 to - 0.04)], implying worse HRQoL. However, there was not sufficient evidence to compare how different treatments for chronic hepatitis C infection affect EQ-5D scores. CONCLUSIONS: This study provides a summary of EQ-5D HSUVs for patients with chronic hepatitis C infection, and demonstrates that clinically important disease stages associated with treatment decisions are associated with differences in HRQoL.

A qualitative study exploring views and experiences of people with stroke undergoing transcranial direct current stimulation and upper limb robot therapy.

Background Neurorehabilitation technologies used mainly in research such as robot therapy (RT) and transcranial direct current stimulation (tDCS) can promote upper limb motor recovery after stroke. Understanding the feasibility and efficacy of stroke rehabilitation technologies for upper limb impairments is crucial for effective implementation in practice. Small studies have explored views of RT by people with stroke; however experiences of people receiving tDCS in combination with RT have never been explored. Objective To explore views and experiences of people with sub-acute and chronic stroke that had previously taken part in a randomised controlled trial involving tDCS and RT for their impaired upper limb. Methods An interview study includes open and closed questions. Face-to-face interviews were audio recorded. Open-ended question responses were transcribed and analyzed using thematic analysis; closed questions were analyzed using descriptive analysis. Results Participants felt that RT was enjoyable (90%) and beneficial for their affected arm (100%). From the open question data, it was found that the intervention was effective for the impaired arm especially in the sub-acute stage. Main reported concerns were that tDCS caused painful, itching and burning sensations and RT was sometimes tiring and difficult. Participants recommended that future research should focus on designing a more comfortable method of tDCS and develop a robot that promotes hand movements. Conclusions This study provides new knowledge about the benefits and barriers associated with these technologies which are crucial to the future effective implementation of these tools in practice.

An attention and interpretation bias for illness-specific information in chronic fatigue syndrome.

BACKGROUND: Studies have shown that specific cognitions and behaviours play a role in maintaining chronic fatigue syndrome (CFS). However, little research has investigated illness-specific cognitive processing in CFS. This study investigated whether CFS participants had an attentional bias for CFS-related stimuli and a tendency to interpret ambiguous information in a somatic way. It also determined whether cognitive processing biases were associated with co-morbidity, attentional control or self-reported unhelpful cognitions and behaviours. METHOD: A total of 52 CFS and 51 healthy participants completed self-report measures of symptoms, disability, mood, cognitions and behaviours. Participants also completed three experimental tasks, two designed specifically to tap into CFS salient cognitions: (i) visual-probe task measuring attentional bias to illness (somatic symptoms and disability) v. neutral words; (ii) interpretive bias task measuring positive v. somatic interpretations of ambiguous information; and (iii) the Attention Network Test measuring general attentional control. RESULTS: Compared with controls, CFS participants showed a significant attentional bias for fatigue-related words and were significantly more likely to interpret ambiguous information in a somatic way, controlling for depression and anxiety. CFS participants had significantly poorer attentional control than healthy individuals. Attention and interpretation biases were associated with fear/avoidance beliefs. Somatic interpretations were also associated with all-or-nothing behaviour and catastrophizing. CONCLUSIONS: People with CFS have illness-specific biases which may play a part in maintaining symptoms by reinforcing unhelpful illness beliefs and behaviours. Enhancing adaptive processing, such as positive interpretation biases and more flexible attention allocation, may provide beneficial intervention targets.

Upper-limb stroke rehabilitation using electrode-array based functional electrical stimulation with sensing and control innovations.

Functional electrical stimulation (FES) has shown effectiveness in restoring upper-limb movement post-stroke when applied to assist participants' voluntary intention during repeated, motivating tasks. Recent clinical trials have used advanced controllers that precisely adjust FES to assist functional reach and grasp tasks with FES applied to three muscle groups, showing significant reduction in impairment. The system reported in this paper advances the state-of-the-art by: (1) integrating an FES electrode array on the forearm to assist complex hand and wrist gestures; (2) utilising non-contact depth cameras to accurately record the arm, hand and wrist position in 3D; and (3) employing an interactive touch table to present motivating virtual reality (VR) tasks. The system also uses iterative learning control (ILC), a model-based control strategy which adjusts the applied FES based on the tracking error recorded on previous task attempts. Feasibility of the system has been evaluated in experimental trials with 2 unimpaired participants and clinical trials with 4 hemiparetic, chronic stroke participants. The stroke participants attended 17, 1 hour training sessions in which they performed functional tasks, such as button pressing using the touch table and closing a drawer. Stroke participant results show that the joint angle error norm reduced by an average of 50.3% over 6 attempts at each task when assisted by FES.

Multiple sessions of transcranial direct current stimulation and upper extremity rehabilitation in stroke: A review and meta-analysis.

OBJECTIVE: To systematically review the methodology in particular treatment options and outcomes and the effect of multiple sessions of transcranial direct current stimulation (tDCS) with rehabilitation programmes for upper extremity recovery post stroke. METHODS: A search was conducted for randomised controlled trials involving tDCS and rehabilitation for the upper extremity in stroke. Quality of included studies was analysed using the Modified Downs and Black form. The extent of, and effect of variation in treatment parameters such as anodal, cathodal and bi-hemispheric tDCS on upper extremity outcome measures of impairment and activity were analysed using meta-analysis. RESULTS: Nine studies (371 participants with acute, sub-acute and chronic stroke) were included. Different methodologies of tDCS and upper extremity intervention, outcome measures and timing of assessments were identified. Real tDCS combined with rehabilitation had a small non-significant effect of +0.11 (p=0.44) and +0.24 (p=0.11) on upper extremity impairments and activities at post-intervention respectively. CONCLUSION: Various tDCS methods have been used in stroke rehabilitation. The evidence so far is not statistically significant, but is suggestive of, at best, a small beneficial effect on upper extremity impairment. SIGNIFICANCE: Future research should focus on which patients and rehabilitation programmes are likely to respond to different tDCS regimes.

Comparison of arthroscopic and MRI findings of osteochondral damage in knees.

Magnetic resonance imaging (MRI) scans are widely used in the assessment of knees, often prior to arthroscopic procedures. The reporting of osteochondral damage on MRI scans can be variable. The correlation between MRI reports of osteochondral damage and that found at arthroscopy is often inconsistent. A retrospective case-note review of a single-surgeon series of 175 arthroscopic procedures was performed. Eighty-three patients were included in the study. The remainder were excluded if an MRI scan had not been performed or had been performed more than 3-months before surgery. The condition of the articular cartilage demonstrated by MRI was compared to that found at arthroscopy. Data was analysed for presence and extent of osteochondral damage. Comparison between MRI and arthroscopy findings showed high specificity (90%) and negative predictive values (89%) for osteochondral damage but low sensitivity (46%). Cohen's kappa values < 0.2 revealed very poor correlation for the extent of damage. This study demonstrates MRI as a good identifier of osteochondral damage but an unreliable descriptor for such change.

Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially.

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case-control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n = 282) were aged 18-59 years; controls (n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR) = 3·11; 95% confidence interval (CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD (OR = 0·68; 95% CI: 0·49, 0·95) but not asthma (OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend = 0·04) but not FCD (P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative 'sibling effect'.

Boron neutron capture therapy for oral precancer: proof of principle in an experimental animal model.

OBJECTIVES: Field-cancerized tissue can give rise to second primary tumours, causing therapeutic failure. Boron neutron capture therapy (BNCT) is based on biological targeting and would serve to treat undetectable foci of malignant transformation. The aim of this study was to optimize BNCT for the integral treatment for oral cancer, with particular emphasis on the inhibitory effect on tumour development originating in precancerous conditions, and radiotoxicity of different BNCT protocols in a hamster cheek pouch oral precancer model. MATERIALS AND METHODS: Groups of cancerized hamsters were locally exposed to single or double (2 or 4 weeks apart) applications of BNCT at different dose levels, mediated by the boron compounds boronophenylalanine (BPA) or BPA and decahydrodecaborate (GB-10) administered jointly. Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumour development from field-cancerized tissue and mucositis were followed for 8 months. RESULTS: A double application (4 weeks apart) of BNCT mediated by GB-10+ BPA at a total dose of 10 Gy in two 5-Gy doses rendered the best therapeutic advantage (63-100% inhibition of tumour development from field-cancerized tissue), minimizing dose-limiting mucositis. CONCLUSION: BNCT can be optimized for the integral treatment for head and neck cancer, considering the implications for field-cancerized tissue.

Epstein-Barr virus and multiple sclerosis.

This review of the considerable evidence linking Epstein-Barr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a dose-response relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified.

Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations.

The dog leukocyte antigen (DLA) system contains many of the functional genes of the immune system, thereby making it a candidate region for involvement in immune-mediated disorders. A number of studies have identified associations between specific DLA class II haplotypes and canine immune hemolytic anemia, thyroiditis, immune polyarthritis, type I diabetes mellitus, hypoadrenocorticism, systemic lupus erythematosus-related disease complex, necrotizing meningoencephalitis (NME) and anal furunculosis. These studies have relied on sequencing approximately 300 bases of exon 2 of each of the DLA class II genes: DLA-DRB1, DLA-DQA1 and DLA-DQB1. In the present study, an association (odds ratio=4.29) was identified by this method between Weimaraner dogs with hypertrophic osteodystrophy (HOD) and DLA-DRB1∗01501. To fine map the association with HOD, a genotyping assay of 126 coding single nucleotide polymorphisms (SNPs) from across the entire DLA, spanning a region of 2.5 Mb (3,320,000-5,830,000) on CFA12, was developed and tested on Weimaraners with HOD, as well as two additional breeds with diseases associated with DLA class II: Nova Scotia duck tolling retrievers with hypoadrenocorticism and Pug dogs with NME. No significant associations were found between Weimaraners with HOD or Nova Scotia duck tolling retrievers with hypoadrenocorticism and SNPs spanning the DLA region. In contrast, significant associations were found with NME in Pug dogs, although the associated region extended beyond the class II genes. By including a larger number of genes from a larger genomic region, a SNP genotyping assay was generated that provides coverage of the extended DLA region and may be useful in identifying and fine mapping DLA associations in dogs.

Design & control of a 3D stroke rehabilitation platform.

An upper limb stroke rehabilitation system is developed which combines electrical stimulation with mechanical arm support, to assist patients performing 3D reaching tasks in a virtual reality environment. The Stimulation Assistance through Iterative Learning (SAIL) platform applies electrical stimulation to two muscles in the arm using model-based control schemes which learn from previous trials of the task. This results in accurate movement which maximises the therapeutic effect of treatment. The principal components of the system are described and experimental results confirm its efficacy for clinical use in upper limb stroke rehabilitation.

Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers.

Canine hypoadrenocorticism (Addison's disease) is due to a deficiency of corticosteroids and mineralocorticoids produced by the adrenals. Although this is a relatively uncommon disease in the general dog population, some breeds, including the Nova Scotia Duck Tolling Retriever (NSDTR), are at increased risk for developing hypoadrenocorticism. A prior study has shown that the increased risk is due to a heritable component. This potentially lethal disorder is hypothesized to have an autoimmune etiology, thus the aim of this study was to determine whether genetic susceptibility to hypoadrenocorticism in NSDTRs is associated with genes of the canine major histocompatibility complex [MHC; dog leukocyte antigen system (DLA)]. Samples were collected from NSDTRs diagnosed with hypoadrenocorticism and healthy siblings or country-matched controls. The DLA class II alleles and haplotypes were determined and compared between cases and controls. We found seven different haplotypes of which the haplotype DLA-DRB1*01502/DQA*00601/DQB1*02301 was significantly more prevalent in the diseased dogs (P = 0.044). In addition, these affected dogs also were more likely to be homozygous across the DLA class II region than the control dogs (OR = 6.7, CI = 1.5-29.3, P = 0.011). We also found that homozygous dogs, regardless of their haplotype, tended to have earlier disease onset compared with heterozygous dogs. These data indicate a limited MHC diversity in North American NSDTRs and suggest that the MHC may play a role in the development of hypoadrenocorticism in the NSDTR, supporting the autoimmune origin of the disease.

Shoulder and elbow muscle activity during fully supported trajectory tracking in people who have had a stroke.

An inability to perform tasks involving reaching is a common problem for stroke patients. This paper provides an insight into mechanisms associated with recovery of upper limb function by examining how stroke participants' upper limb muscle activation patterns differ from those of neurologically intact participants, and how they change in response to an intervention. In this study, five chronic stroke participants undertook nine tracking tasks in which trajectory (orientation and length), speed and resistance to movement were varied. During these tasks, EMG signals were recorded from triceps, biceps, anterior deltoid, upper, middle and lower trapezius and pectoralis major. Data collection was performed in sessions both before, and after, an intervention in which participants performed a similar range of tracking tasks with the addition of responsive electrical stimulation applied to their triceps muscle. The intervention consisted of eighteen one hour treatment sessions, with two participants attending an additional seven sessions. During all sessions, each participant's arm was supported by a hinged arm-holder which constrained their hand to move in a two dimensional plane. Analysis of the pre intervention EMG data showed that timing and amplitude of peak EMG activity for all stroke participants differed from neurologically intact participants. Analysis of post intervention EMG data revealed that statistically significant changes in these quantities had occurred towards those of neurologically intact participants.

Feasibility of iterative learning control mediated by functional electrical stimulation for reaching after stroke.

BACKGROUND: An inability to perform tasks involving reaching is a common problem following stroke. Evidence supports the use of robotic therapy and functional electrical stimulation (FES) to reduce upper limb impairments, but current systems may not encourage maximal voluntary contribution from the participant because assistance is not responsive to performance. OBJECTIVE: This study aimed to investigate whether iterative learning control (ILC) mediated by FES is a feasible intervention in upper limb stroke rehabilitation. METHODS: Five hemiparetic participants with reduced upper limb function who were at least 6 months poststroke were recruited from the community. No participants withdrew. INTERVENTION: Participants undertook supported tracking tasks using 27 different trajectories augmented by responsive FES to their triceps brachii muscle, with their hand movement constrained in a 2-dimensional plane by a robot. Eighteen 1-hour treatment sessions were used with 2 participants receiving an additional 7 treatment sessions. OUTCOME MEASURES: The primary functional outcome measure was the Action Research Arm Test (ARAT). Impairment measures included the upper limb Fugl-Meyer Assessment (FMA), tests of motor control (tracking accuracy), and isometric force. RESULTS: Compliance was excellent and there were no adverse events. Statistically significant improvements were measured (P

A robotic workstation for stroke rehabilitation of the upper extremity using FES.

An experimental test facility is developed for use by stroke patients in order to improve sensory-motor function of their upper limb. Subjects are seated at the workstation and their task is to repeatedly follow reaching trajectories that are projected onto a target above their arm. To do this they use voluntary control with the addition of electrical stimulation mediated by advanced control schemes applied to muscles in their impaired shoulder and arm. Full details of the design of the workstation and its periphery systems are given, together with a description of its use during the treatment of stroke patients.

Shoulder and elbow muscle activity during fully supported trajectory tracking in neurologically intact older people.

An inability to perform tasks involving reaching is a common problem for stroke patients. Knowledge of normal muscle activation patterns during these tasks is essential to the identification of abnormal patterns in post-stroke hemiplegia. Findings will provide insight into changes in muscle activation patterns associated with recovery of upper limb function. In this study with neurologically intact participants the co-ordination of shoulder and elbow muscle activity during two dimensional reaching tasks is explored. Eight participants undertook nine tracking tasks in which trajectory (orientation and length), duration, speed and resistance to movement were varied. The participants' forearm was supported using a hinged arm-holder, which constrained their hand to move in a two dimensional plane. EMG signals were recorded from triceps, biceps, anterior deltoid, upper, middle and lower trapezius and pectoralis major. A wide variation in muscle activation patterns, in terms of timing and amplitude, was observed between participants performing the same task. EMG amplitude increased significantly with length, duration and resistance of the task for all muscles except anterior deltoid. Co-activation between biceps and triceps was significantly dependent on both task and trajectory orientation. Activation pattern of pectoralis major was dependent on trajectory. Neither trajectory orientation nor task condition affected the activation pattern of anterior deltoid. Normal ranges of timing of muscle activity during the tasks were identified.

Occupational exposure to power frequency magnetic fields and risk of non-Hodgkin lymphoma.

OBJECTIVES: To investigate the risk of non-Hodgkin lymphoma (NHL) using a job-exposure matrix (JEM) to assess exposure to occupational magnetic fields at the power frequencies of 50/60 Hz. METHODS: The study population consisted of 694 cases of NHL, first diagnosed between 1 January 2000 and 31 August 2001, and 694 controls from two regions in Australia, matched by age, sex and region of residence. A detailed occupational history was given by each subject. Exposure to power frequency magnetic fields was estimated using a population-based JEM which was specifically developed in the United States to assess occupational magnetic field exposure. The cumulative exposure distribution was divided into quartiles and adjusted odds ratios were calculated using the lowest quartile as the referent group. RESULTS: For the total work history, the odds ratio (OR) for workers in the upper quartile of exposure was 1.48 (95% CI 1.02 to 2.16) compared to the referent (p value for trend was 0.006). When the exposure was lagged by 5 years the OR was 1.59 (95% CI 1.07 to 2.36) (p value for trend was 0.003). Adjusting for other occupational exposures did not significantly alter the results. CONCLUSIONS: These findings provide weak support for the hypothesis that occupational exposure to 50/60 Hz magnetic fields increases the risk of NHL.