The impact of physically active learning during the school day on children's physical activity levels, time on task and learning behaviours and academic outcomes.

The benefits of physical activity in school settings and its impact on health and academic outcomes are of interest from public health and educational contexts. This study investigates how physically active learning (PAL): (i) contributes to children's physical activity levels, (ii) impacts on academic outcomes and (iii) influences children's focus and concentration, defined as time on task (ToT). METHODS: Over a 2-week period, participants were exposed to PAL and non-active learning (NAL) lessons in a counterbalanced design. Physiological responses and ToT behaviour were recorded throughout PAL and NAL lessons. Academic outcomes were assessed the week before, during and the week after each mode of delivery. RESULTS: Children were more active during PAL (196�542 steps per week) compared to NAL (152�395 steps per week, P = 0.003). The physiological demands of PAL (73% HRmax), were significantly greater (P < 0.001) than NAL (51% HRmax). Children's ToT was significantly higher (P < 0.001) with PAL (97%) than NAL (87%). There were no differences in academic outcomes when PAL and NAL were compared. CONCLUSIONS: Modest levels of PAL increased activity levels. No evidence was found to suggest PAL had a negative effect on children's academic outcomes, and PAL could positively impact on children's concentration.

NMR-Based Serum Metabolomics Discriminates Takayasu Arteritis from Healthy Individuals: A Proof-of-Principle Study.

Takayasu arteritis (TA) is a debilitating, systemic disease that involves the aorta and large arteries in a chronic inflammatory process that leads to vessel stenosis. Initially, the disease remains clinically silent (or remains undetected) until the patients present with vascular occlusion. Therefore, new methods for appropriate and timely diagnosis of TA cases are needed to start proper therapy on time and also to monitor the patient's response to the given treatment. In this context, NMR-based serum metabolomic profiling has been explored in this proof-of-principle study for the first time to determine characteristic metabolites that could be potentially helpful for diagnosis and prognosis of TA. Serum metabolic profiling of TA patients (n = 29) and healthy controls (n = 30) was performed using 1D (1)H NMR spectroscopy, and possible biomarker metabolites were identified. Using projection to least-squares discriminant analysis, we could distinguish TA patients from healthy controls. Compared to healthy controls, TA patients had (a) increased serum levels of choline metabolites, LDL cholesterol, N-acetyl glycoproteins (NAGs), and glucose and (b) decreased serum levels of lactate, lipids, HDL cholesterol, and glucogenic amino acids. The results of this study are preliminary and need to be confirmed in a prospective study.

Effects of changes in click-evoked otoacoustic emission (CEOAE) pass criteria, as used in the English newborn hearing screening program, on screening outcome.

OBJECTIVE: There were two objectives, firstly what effect does a change in the pass criteria of a click-evoked otoacoustic emission (CEOAE) newborn hearing screen have on the number of cases of significant hearing impairment detected by follow up diagnostics, and secondly how does this change affect the screen pass rate? DESIGN: Changes in the pass criteria were: reduction in the signal-to-noise ratio (SNR); reduction in the minimum signal level (MSL); inclusion of the 1-kHz half-octave band; reduction from two to a single half-octave band. STUDY SAMPLE: Data from three screening sites was used within the English newborn hearing screening program from the period 2002 to 2006, with a total number of births of about 40,000. There were 42 bilateral and 43 unilateral cases of significant hearing impairment. RESULTS: No effect on the number of cases detected by follow up diagnostics was observed when: (1) SNR was reduced to a minimum of 5 dB; (2) MSL was reduced to -10 dB SPL; and (3) the 1-kHz band was included. With all these changes the percentage pass rate improved by 0.36%. CONCLUSIONS: The current choice of SNR and MSL criteria appears robust. Only a small increase in pass rate is possible without affecting case detection.

Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010).

OBJECTIVES: There are no valid instruments to measure disease activity in Takayasu arteritis (TA). We aim to provide a valid measure to assess clinical disease activity with or without incorporating acute phase reactants. METHODS: The Indian Takayasu Clinical Activity Score (ITAS) was initially derived from disease manifestations scored in the Disease Extent Index (DEI.Tak). The ITAS was validated by a group of physicians scoring both live and paper cases for inter-rater reliability (IRR), convergence with BVAS, correlation with the Physician's Global Assessment (PGA) and ESR/CRP. It was further validated at a single centre in 177 patients for its ability to discriminate between active and inactive disease state at first visit and sensitivity to change in 132 active patients measured serially at two follow-up visits. ITAS-A also included graded scores for ESR/CRP. RESULTS: The final ITAS2010 contains 44 items with 33 features arising from the cardiovascular system. Seven key items are weighted to score 2 and all others score 1 only. Inter-observer variability was highly satisfactory (IRR 0.97). The ITAS showed superior inter-rater agreement compared with the BVAS (IRR 0.9) and PGA (IRR 0.82). In the single-centre study, median ITAS scores at first visit were significantly higher in active disease (5.62 ± 3.14) compared with grumbling (3.36 ± 1.96) and inactive disease (1.27 ± 1.26, P < 0.0001). The therapy induced a significant decrease in the ITAS2010 but the higher ITAS-A scores remained elevated. CONCLUSION: The ITAS2010, validated in over 300 TA patients and sensitive to change, is a useful measure of clinical disease activity for patient monitoring. Higher ITAS-A scores suggest poor control of active disease by current therapy.

Vasculitis integrated clinical assessment database: a data management system to support studies into systemic vasculitis.

BACKGROUND: The systemic vasculitides are characterized by immune inflammation affecting blood vessels, which can lead to organ and tissue damage. Treatment has improved but optimum long-term management still remains unsatisfactory, requiring ongoing therapeutic studies. These often base their measures of efficacy on the outcome of clinical assessments which include the Birmingham Vasculitis Activity Score and the Vasculitis Damage Index. OBJECTIVES: Efficient management of assessment data is complex and often hampered by working with time-consuming paper-based systems. The Vasculitis Integrated Clinical Assessment Database (VICAD) was created to improve the process. METHODS: VICAD was developed using Microsoft Access. Visual Basic for Applications and the Data Access Objects Application Programming Interface provide the functionality to assist with scoring, calculation of results, and storing of data. RESULTS: VICAD is an efficient system for managing data. Evaluation of its use showed an improvement in the completeness of patient assessments from 77% (paper based: n = 44) to 98% (computer based: n = 30). During development clinicians (n = 4) rated it at 8/10 for its layout and visual presentation and 8/10 for easy to use (intuitiveness and navigability). CONCLUSIONS: The development of an integrated and standardized system of data collection (VICAD) helps to support clinical decision making processes and report findings in a more timely manner. It is available free for use and modification under the GNU General Public License. The open source nature of VICAD could help to inform the design of other databases where management of complex information into important multisystem diseases is needed.

Long-term outcome of 251 patients with Takayasu arteritis on combination immunosuppressant therapy: Single centre experience from a large tertiary care teaching hospital in Southern India.

INTRODUCTION: Long-term outcome studies in Takayasu arteritis (TA) are few and limited by small sample size. In this study, we analysed the outcome of treatment in a large series of TA patients with a minimum follow-up period of ≥12 months by objective instruments. MATERIALS AND METHODS: Patients with TA satisfying the 1990 ACR, Ishikawa's, Sharma's or EULAR/PRESS criteria were recruited from our clinics between 1998 and 2016. Only patients with a minimum follow up of 12 months were studied. Data related to clinical presentation, disease extent (DEI.Tak score), activity [Indian Takayasu arteritis clinical activity score, that is, ITAS-A (CRP)] and damage score [Takayasu arteritis damage score (TADS)], angiography and treatment were collected for all patients. Response to treatment was categorised as complete response (CR), partial response (PR) or refractory disease. Patients with sustained CR on prednisolone dose of ≤5mg/day were classified as having sustained inactive disease. Appropriate statistical tests were used for parametric and non-parametric data. Relapse free survival was projected by Kaplan-Meir curve. Cox proportional hazards regression plot was used to compare the efficacy of medications. Predictors of sustained response were identified by logistic regression and a prediction model was constructed. RESULTS: Among 503 TA patients examined during study period, 251 had follow-up of ≥12 months and were included in this study. Median follow-up duration was 42 months (IQR: 24-81, maximum 240 months). Patients (81.7% females, mean age of 29.2 ± 11.8 years, symptom duration of 24 [6-70] months) were treated by a uniform protocol that included high dose steroids (n = 239) plus concurrent steroid-sparing immunosuppressant (n = 235) with mycophenolate in majority. Biological agents (n = 44 patients) and revascularisation procedures were used in symptomatic patients after control of disease activity. At 1st follow-up, CR (ITAS2010 = 0, CRP < 6mg/L and non-progressive disease on angiography) was observed in 173 (68.9%), partial response (PR) in 42 (16.7%) and no response was seen in only 36 (14%) patients. CR was sustained till the last follow up in 116 (65.9%) of 173 patients with initial CR, while 87 (49.4%) of them achieved sustained inactive disease. Disease activity relapsed at a median duration of 37 (29.9-44.1) months in 56 patients. Cumulative relapse free survival was 93%, 73%, 66% and 52% at 1, 3, 5 and 10 years, respectively. Baseline CRP < 6.2, DEI.Tak < 9 and angiographic type 4 disease predicted sustained inactive disease and a model comprising these parameters showed sensitivity and specificity of 70% and 61.1%. Two fatalities were observed. New vascular lesions during follow up were observed in 50 (19.9%) patients. Overall, 92.8% had at least one period of CR or PR while 7.2% were refractory to treatment till the last follow up. Damage progression (∆TADS > 1) was arrested in 68% of patients and was lower in patients with sustained inactive disease [0 (0-1)] as compared to the rest [1 (0-2.75)], p = 0.000. Both early response as well as cumulative hazard for relapse were similar between patients initiated on 0.5 and 1mg/kg/day steroids. CONCLUSIONS: Our strategy of upfront combination immunosuppressant therapy stabilised disease activity in 92.8% of patients, while 7.2% had true refractory disease. Relapse free survival was 66% at 5 years and 52% at 10 years. Damage progression was arrested in 68% and only 2 fatalities were observed. Initial steroid dose of 0.5mg/kg/day had similar efficacy as 1mg/kg/day dose.

Soluble-HLA-E: A follow up biomarker in Takayasu arteritis, independent of HLA-E genotype.

AIM: Disease activity assessment in Takayasu arteritis (TA) is challenging. Human leukocyte antigen E (HLA-E) is shed from endothelium into serum as a soluble molecule (sHLA-E) in response to inflammation. We aimed to study: (i) utility of sHLA-E as a biomarker of disease activity; and (ii) association of HLA-E polymorphism rs1264457 with clinical disease in Asian-Indian TA patients. MATERIALS AND METHODS: In phase-1, sHLA-E levels were estimated in sera of 50 consecutive TA patients at baseline visit and 27 healthy controls. Serial estimations were performed in 27 of them. In phase-2, DNA of 150 TA patients and 264 healthy controls were genotyped for rs1264457 polymorphism. RESULTS: At baseline visit, disease was classified as active, stable and grumbling in 23, 18 and nine patients, respectively. sHLA-E levels were higher in active TA (43; interquartile range [IQR]: 25.3-64.6) pg/mL) than stable disease (12.9; IQR: 7.6-21.6 pg/mL) (P = 0.001). At first follow-up visit, sHLA-E levels were numerically higher in active disease than stable disease (P = 0.06) but this trend was blunted at second follow-up. sHLA-E levels increased in 54% versus 25% of patients with persistently active/relapsing and persistent stable course, respectively. rs1264457 polymorphism was not associated with susceptibility to TA and did not affect sHLA-E levels. CONCLUSION: sHLA-E level is useful as a biomarker of disease activity and course in TA patients. rs1264457 polymorphism is neither associated with susceptibility nor did it influence sHLA-E levels in TA.

A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.

BACKGROUND: The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener's granulomatosis and microscopic polyangiitis. We investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission. METHODS: We studied patients with a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg per deciliter (500 micromol per liter) or less. All patients received at least three months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg per kilogram of body weight per day) or a substitute regimen of azathioprine (2 mg per kilogram per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end point. RESULTS: Of 155 patients studied, 144 (93 percent) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5 percent), seven of them during the first three months. Eleven relapses occurred in the azathioprine group (15.5 percent), and 10 occurred in the cyclophosphamide group (13.7 percent, P=0.65). Severe adverse events occurred in 15 patients during the induction phase (10 percent), in 8 patients in the azathioprine group during the remission phase (11 percent), and in 7 patients in the cyclophosphamide group during the remission phase (10 percent, P=0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with microscopic polyangiitis than among those with Wegener's granulomatosis (P=0.03). CONCLUSIONS: In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.

TNFR1-induced sphingomyelinase activation modulates TCR signaling by impairing store-operated Ca2+ influx.

Tumor necrosis factor alpha (TNF-alpha) is a potent, pleiotrophic cytokine, which is proinflammatory but can also suppress T lymphocyte function. In chronic inflammatory disease such as rheumatoid arthritis, exposure of T cells to TNF-alpha alters their ability to mount a response by modulating the T cell receptor (TCR) signaling pathway, but the mechanisms involved remain obscure. Here, we investigated the specific role of TNF receptor 1 (TNFR1) signaling in the modulation of the TCR signaling pathway. We observed a down-regulation of the intracellular calcium ([Ca(2+)](i)) signal in Jurkat T cells after just 30 min exposure to TNF-alpha, and maximum suppression was reached after 3 h. This effect was transient, and signals returned to normal after 12 h. This depression of [Ca(2+)](i) was also observed in human CD4+ T lymphocytes. The change in Ca(2+) signal was related to a decrease in the plasma membrane Ca(2+) influx, which was apparent even when the TCR signal was bypassed using thapsigargin to induce a Ca(2+) influx. The role of TNF-alpha-induced activation of the sphingolipid cascade in this pathway was examined. The engagement of TNFR1 by TNF-alpha led to a time-dependent increase in acid sphingomyelinase (SMase; ASM) activity, corresponding with a decrease in cellular sphingomyelin. In parallel, there was an increase in cellular ceramide, which correlated directly with the decrease in the magnitude of the Ca(2+) response to phytohemagglutinin. Exogenous addition of SMase or ceramide mimicked the effects of TNFR1 signals on Ca(2+) responses in Jurkat T cells. Direct evidence for the activation of ASM in this pathway was provided by complete abrogation of the TNF-alpha-induced inhibition of the Ca(2+) influx in an ASM-deficient murine T cell line (OT-II(+/+)ASM(-/-)). This potent ability of TNF-alpha to rapidly modulate the TCR Ca(2+) signal via TNFR1-induced ASM activation can explain its suppressive effect on T cell function. This TNFR1 signaling pathway may play a role as an important regulator of T cell responses.

NMR based serum metabolomics reveals a distinctive signature in patients with Lupus Nephritis.

Management of patient with Lupus Nephritis (LN) continues to remain a challenge for the treating physicians because of considerable morbidity and even mortality. The search of biomarkers in serum and urine is a focus of researchers to unravel new targets for therapy. In the present study, the utility of NMR-based serum metabolomics has been evaluated for the first time in discriminating LN patients from non-nephritis lupus patients (SLE) and further to get new insights into the underlying disease processes for better clinical management. Metabolic profiling of sera obtained from 22 SLE patients, 40 LN patients and 30 healthy controls (HC) were performed using high resolution 1D 1H-CPMG and diffusion edited NMR spectra to identify the potential molecular biomarkers. Using multivariate analysis, we could distinguish SLE and LN patients from HC and LN from SLE patients. Compared to SLE patients, the LN patients had increased serum levels of lipid metabolites (including LDL/VLDL lipoproteins), creatinine and decreased levels of acetate. Our results revealed that metabolic markers especially lipids and acetate derived from NMR spectroscopy has high sensitivity and specificity to distinguish LN among SLE patients and has the potential to be a useful adjunctive tool in diagnosis and clinical management of LN.

Persistent TNF-alpha exposure impairs store operated calcium influx in CD4+ T lymphocytes.

Persistent tumour necrosis factor alpha (TNF-alpha) exposure uncouples proximal T-cell receptor (TCR)-signalling events. Here, we demonstrate that chronic TNF-alpha exposure also attenuates signalling distal to the TCR, by specifically inhibiting Ca2+ influx evoked by thapsigargin in CD4+ T-cells. Mitogen-induced Ca2+ responses were impaired in a dose dependent manner, and TCR-induced Ca2+ responses were also significantly reduced. The impairment of Ca2+ influx strongly correlated with poor function as proliferative responses to both mitogen and anti-CD3/CD28 stimulation were suppressed. Our findings show that persistent TNF-alpha exposure of T-cells specifically inhibits store operated Ca2+ influx. This may affect gene activation and contribute to the poor T-cell function in chronic inflammatory disease.

Childhood-onset Takayasu arteritis -- experience from a tertiary care center in South India.

OBJECTIVE: To study the clinical profile and outcome of Asian Indian children with childhood-onset Takayasu arteritis (c-TA). METHODS: Records were studied of patients with c-TA onset prior to age 16. Disease Extent Index-Takayasu (DEI.TAK), Indian Takayasu Arteritis Score 2010, and Takayasu Arteritis Damage Score (TADS) were calculated retrospectively from electronic records. Cumulative incidence of sustained remission was estimated using the Kaplan-Meier curve. RESULTS: There were 40 patients with c-TA, with median age of onset of 12.5 years (range 1-16) and median diagnostic delay of 11.3 months (range 1-60). The most common presenting features were hypertension, headache, malaise, and fever. Pulseless disease was observed in 25 cases (62.5%). The majority (n = 28) had active disease with raised inflammatory markers, high baseline median DEI.TAK score of 10 (range 3-24), and high median TADS of 7 (range 1-14). Of the 34 patients followed for 21.5 months (range 3-192), remission was attained in 30. However, cumulative sustained remission was achieved in only 29% of them at 5 years. Median period of sustained remission was 22.5 months (95% CI 17.1-26.8). New areas of vessel involvement were observed in 13 patients (38%). Disease progression was arrested in the majority (n = 22, 66%) through aggressive medical management and endovascular intervention. All 11 patients with an increment in TADS of ≥ 4 during followup had persistently active or relapsing disease. There was a single fatality. CONCLUSION: Despite aggressive immunosuppression, damage progressed in one-third of patients with c-TA in association with persistent inflammation, warranting surveillance with clinical instruments and followup imaging.

Auditory and visual health after ten years of exposure to metal-on-metal hip prostheses: a cross-sectional study follow up.

Case reports of patients with mal-functioning metal-on-metal hip replacement (MoMHR) prostheses suggest an association of elevated circulating metal levels with visual and auditory dysfunction. However, it is unknown if this is a cumulative exposure effect and the impact of prolonged low level exposure, relevant to the majority of patients with a well-functioning prosthesis, has not been studied. Twenty four male patients with a well-functioning MoMHR and an age and time since surgery matched group of 24 male patients with conventional total hip arthroplasty (THA) underwent clinical and electrophysiological assessment of their visual and auditory health at a mean of ten years after surgery. Median circulating cobalt and chromium concentrations were higher in patients after MoMHR versus those with THA (P<0.0001), but were within the Medicines and Healthcare Products Regulatory Agency (UK) investigation threshold. Subjective auditory tests including pure tone audiometric and speech discrimination findings were similar between groups (P>0.05). Objective assessments, including amplitude and signal-to-noise ratio of transient evoked and distortion product oto-acoustic emissions (TEOAE and DPOAE, respectively), were similar for all the frequencies tested (P>0.05). Auditory brainstem responses (ABR) and cortical evoked response audiometry (ACR) were also similar between groups (P>0.05). Ophthalmological evaluations, including self-reported visual function by visual functioning questionnaire, as well as binocular low contrast visual acuity and colour vision were similar between groups (P>0.05). Retinal nerve fibre layer thickness and macular volume measured by optical coherence tomography were also similar between groups (P>0.05). In the presence of moderately elevated metal levels associated with well-functioning implants, MoMHR exposure does not associate with clinically demonstrable visual or auditory dysfunction.

Breaking communication barriers for RA patients of South Asian origin: the use of a bilingual educational audio CD and linguistically appropriate peer support and education.

BACKGROUND: People from the Indian subcontinent represent one of the largest ethnic groups in the UK. Patient education resources are required to address language barriers, poor literacy and (potentially discordant) cultural beliefs. We have investigated a novel strategy to meet this need. METHODS: Rheumatoid arthritis (RA) patients of South Asian origin who prefer to communicate in a South Asian language were invited to a face-to-face interaction with a trained patient volunteer to provide linguistically appropriate peer support and education, and given a bilingual educational audio CD. Qualitative methods were used to assess this approach; three focus groups were held and 15 patients participated in total. RESULTS: Four important themes were identified: (1) The need for information about RA; all patients agreed that this was vital to learn how to live with their chronic disease. (2) Currently available approaches to education; particular concerns related to a lack of time in clinic, language barriers, difficulties in communicating via interpreters and that most written information was available only in English. (3) Support provided by a trained patient volunteer; patients appreciated that they were listened to, and were motivated by the volunteers' positive attitude. (4) The usefulness of the audio CD; patients appreciated that information was presented in a language they could understand, via a convenient medium and which offered a helpful perspective on their illness. CONCLUSIONS: This approach is a successful way of delivering information and encouraged patients from a difficult-to-reach community to become more involved in their disease management.