Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

A comparative clinical study of bioceramic and calcium hydroxide based root canal sealer in the treatment of non-vital permanent tooth with periapical lesion

Introduction: The use of Bioceramic sealer in the obduration of the root canal system has been expected by many of the previous studies. However, the clinical outcome has not yet been established. Objective: To compare the effectiveness of bioceramic and calcium hydroxide based root canal sealer in treatment of non-vital permanent teeth with periapical lesion (Periapical periodontitis). Materials and Methods: A total 100 mature permanent anterior teeth were selected after clinical and radiological examination which had non-vital pulp with periapical lesion. Clinically pulp vitality test, palpation and percussion test was performed maintaining standard procedure. Following cavity preparation and biomechanical preparation, each canal was obturated either with bioceramic (Endosequence BC) or calcium hydroxide based sealer (Sealapex, Kerr). All participants were evaluated immediately after obturation, at 3 and 6 months for the assessment of change in size of periapical lesion, condition of periodontal ligament space, lamina dura and incidence of post-operative pain, swelling. Statistical analysis was performed using Chi- square(X2) test and t-test. A value of p<0.05 was considered as statistically significant. Results: Bioceramic was more effective in reducing the lesion size than that of calcium hydroxide. At 6 months, the mean lesion size was reduced from 3.52±0.7 to 1.30±0.462 mm in Bioceramics and from 3.48±1.07 to 1.58± 0.498 mm in sealapex treated teeth.. Furthermore, 98% of bioceramic treated teeth and 94% of sealapex treated teeth showed absence of swelling. The differences between two groups were statistically significant (p<0.05). Conclusion: In this short period of study, Bioceramics based sealer seems to be more effective than calcium hydroxide based sealer in repair of periapical lesions of the nonvital teeth

A priori postulated and real power in cluster randomized trials: mind the gap

BACKGROUND: Cluster randomization design is increasingly used for the evaluation of health-care, screening or educational interventions. The intraclass correlation coefficient (ICC) defines the clustering effect and be specified during planning. The aim of this work is to study the influence of the ICC on power in cluster randomized trials. METHODS: Power contour graphs were drawn to illustrate the loss in power induced by an underestimation of the ICC when planning trials. We also derived the maximum achievable power given a specified ICC. RESULTS: The magnitude of the ICC can have a major impact on power, and with low numbers of clusters, 80% power may not be achievable. CONCLUSION: Underestimating the ICC during planning cluster randomized trials can lead to a seriously underpowered trial. Publication of a priori postulated and a posteriori estimated ICCs is necessary for a more objective reading: negative trial results may be the consequence of a loss of power due to a mis-specification of the ICC

Planning a cluster randomized trial with unequal cluster sizes: practical issues involving continuous outcomes

BACKGROUND: Cluster randomization design is increasingly used for the evaluation of health-care, screeening or educational interventions. At the planning stage, sample size calculations usually consider an average cluster size without taking into account any potential imbalance in cluster size. However, there may exist high discrepancies in cluster sizes. METHODS: We performed simulations to study the impact of an imbalance in cluster size on power. We determined by simulations to which extent four methods proposed to adapt the sample size calculations to a pre-specified imbalance in cluster size could lead to adequately powered trials. RESULTS: We showed that an imbalance in cluster size can be of high influence on the power in the case of severe imbalance, particularly if the number of clusters is low and/or the intraclass correlation coefficient is high. In the case of a severe imbalance, our simulations confirmed that the minimum variance weights correction of the variation inflaction factor (VIF) used in the sample size calculations has the best properties. CONCLUSION: Publication of cluster sizes is important to assess the real power of the trial which was conducted and to help designing future trials. We derived an adaptation of the VIF from the minimum variance weights correction to be used in case the imbalance can be a priori formulated such as "a proportion (γ) of clusters actually recruit a proportion (τ) of subjects to be included (γ ≤ τ)"

Imports, unionization and racial age discrimination in the US

Past studies of the relationship between competition and racial wages find that domestic competition reduces racial wage discrimination of nonunion workers. This article examines the effects of foreign competition on racial wages of union and nonunion workers utilizing an empirical model which allows for cluster-adjusted SEs by industry. Such a procedure allows independence of observations across industries but not within industries, thereby not overstating the significance of industry invariant controls. In this analysis, clustered SEs prevent the overstatement of the significance of imports as a means to reduce earnings discrimination. We find evidence of a wage premium for nonunion white workers in concentrated industries; however, imports cause the wages of nonunion whites to converge towards market rates. In contrast, for union workers in concentrated industries, wage standardization provides a sanctuary from market power initiated discrimination such that imports play a limited role in reducing discrimination

Foot pain and foot health in an educated population of adults: results from the Glasgow Caledonian University Alumni Foot Health Survey

Abstract Background Foot pain is common amongst the general population and impacts negatively on physical function and quality of life. Associations between personal health characteristics, lifestyle/behaviour factors and foot pain have been studied; however, the role of wider determinants of health on foot pain have received relatively little attention. Objectives of this study are i) to describe foot pain and foot health characteristics in an educated population of adults; ii) to explore associations between moderate-to-severe foot pain and a variety of factors including gender, age, medical conditions/co-morbidity/multi-morbidity, key indicators of general health, foot pathologies, and social determinants of health; and iii) to evaluate associations between moderate-to-severe foot pain and foot function, foot health and health-related quality-of-life. Methods Between February and March 2018, Glasgow Caledonian University Alumni with a working email address were invited to participate in the cross-sectional electronic survey (anonymously) by email via the Glasgow Caledonian University Alumni Office. The survey was constructed using the REDCap secure web online survey application and sought information on presence/absence of moderate-to-severe foot pain, patient characteristics (age, body mass index, socioeconomic status, occupation class, comorbidities, and foot pathologies). Prevalence data were expressed as absolute frequencies and percentages. Multivariate logistic and linear regressions were undertaken to identify associations 1) between independent variables and moderate-to-severe foot pain, and 2) between moderate-to-severe foot pain and foot function, foot health and health-related quality of life. Results Of 50,228 invitations distributed, there were 7707 unique views and 593 valid completions (median age [inter-quartile range] 42 [31–52], 67.3% female) of the survey (7.7% response rate). The sample was comprised predominantly of white Scottish/British (89.4%) working age adults (95%), the majority of whom were overweight or obese (57.9%), and in either full-time or part-time employment (82.5%) as professionals (72.5%). Over two-thirds (68.5%) of the sample were classified in the highest 6 deciles (most affluent) of social deprivation. Moderate-to-severe foot pain affected 236/593 respondents (39.8%). High body mass index, presence of bunions, back pain, rheumatoid arthritis, hip pain and lower occupation class were included in the final multivariate model and all were significantly and independently associated with moderate-to-severe foot pain (p < 0.05), except for rheumatoid arthritis (p = 0.057). Moderate-to-severe foot pain was significantly and independently associated lower foot function, foot health and health-related quality of life scores following adjustment for age, gender and body mass index (p < 0.05). Conclusions Moderate-to-severe foot pain was highly prevalent in a university-educated population and was independently associated with female gender, high body mass index, bunions, back pain, hip pain and lower occupational class. Presence of moderate-to-severe foot pain was associated with worse scores for foot function, foot health and health-related quality-of-life. Education attainment does not appear to be protective against moderate-to-severe foot pain

An Introduction to Advanced Machine Learning : Meta Learning Algorithms, Applications and Promises

In [1, 2], we have explored the theoretical aspects of feature extraction optimization processes for solving largescale problems and overcoming machine learning limitations. Majority of optimization algorithms that have been introduced in [1, 2] guarantee the optimal performance of supervised learning, given offline and discrete data, to deal with curse of dimensionality (CoD) problem. These algorithms, however, are not tailored for solving emerging learning problems. One of the important issues caused by online data is lack of sufficient samples per class. Further, traditional machine learning algorithms cannot achieve accurate training based on limited distributed data, as data has proliferated and dispersed significantly. Machine learning employs a strict model or embedded engine to train and predict which still fails to learn unseen classes and sufficiently use online data. In this chapter, we introduce these challenges elaborately. We further investigate Meta-Learning (MTL) algorithm, and their application and promises to solve the emerging problems by answering how autonomous agents can learn to learn?

Prospective evaluation of weekly concomitant tumor bed boost with three-week hypofractionated whole breast irradiation in early breast cancer

Objectives: A prospective study was conducted to assess the acute and late toxicity of hypofractionated whole breast irradiation with a weekly concomitant boost for women with early breast cancer (EBC). Methods: Women with EBC who underwent breast-conserving surgery were eligible. A dose of 40Gy in 15 fractions over 3 weeks was delivered to the whole breast with a concomitant weekly boost to the post-operative cavity of 3Gy in three fractions. Toxicity was graded using the Radiation Therapy Oncology Group (RTOG) acute toxicity and RTOG/EORTC late toxicity scales. Results: A total of 67 women were enrolled with a median age of 49 years (range 31–69). Median follow-up was 25 months (range 11–34). Acute skin reactions included grade (G) 1 (n = 47, 70%), G2 (n = 10, 13%), and G3 (n = 1, 1.5%). Late skin toxicity was observed in 13 patients (19%), all of whom experienced G1 toxicity only. On multivariable analysis, diabetes mellitus was predictive of acute skin toxicity (p = 0.003), while age less than 50 years (p = 0.029) and diabetes mellitus (p = 0.013) were predictive of late skin toxicity. Conclusions: Whole breast irradiation with concomitant weekly boost appears feasible and safe. Further investigation is required to fully evaluate this schedule as an alternative to conventional whole breast irradiation with a sequential boost

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.This work was funded by ERC starting grant Relieve IMDs (L.V., N.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.H., F.S.), the Evelyn trust (N.H.) and the EU Fp7 grant TissuGEN (M.CDB.). FS has been supported by an Addenbrooke’s Charitable Trust Clinical Research Training Fellowship and a joint MRC-Sparks Clinical Research Training Fellowship.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nbt.327

Work related complaints of neck, shoulder and arm among computer office workers: a cross-sectional evaluation of prevalence and risk factors in a developing country

<p>Abstract</p> <p>Background</p> <p>Complaints of arms, neck and shoulders (CANS) is common among computer office workers. We evaluated an aetiological model with physical/psychosocial risk-factors.</p> <p>Methods</p> <p>We invited 2,500 computer office workers for the study. Data on prevalence and risk-factors of CANS were collected by validated Maastricht-Upper-extremity-Questionnaire. Workstations were evaluated by Occupational Safety and Health Administration (OSHA) Visual-Display-Terminal workstation-checklist. Participants' knowledge and awareness was evaluated by a set of expert-validated questions. A binary logistic regression analysis investigated relationships/correlations between risk-factors and symptoms.</p> <p>Results</p> <p>Sample size was 2,210. Mean age 30.8 ± 8.1 years, 50.8% were males. The 1-year prevalence of CANS was 56.9%, commonest region of complaint was forearm/hand (42.6%), followed by neck (36.7%) and shoulder/arm (32.0%). In those with CANS, 22.7% had taken treatment from a health care professional, only in 1.1% seeking medical advice an occupation-related injury had been suspected/diagnosed. In addition 9.3% reported CANS-related absenteeism from work, while 15.4% reported CANS causing disruption of normal activities. A majority of evaluated workstations in all participants (88.4%,) and in those with CANS (91.9%) had OSHA non-compliant workstations. In the binary logistic regression analyses female gender, daily computer usage, incorrect body posture, bad work-habits, work overload, poor social support and poor ergonomic knowledge were associated with CANS and its' severity In a multiple logistic regression analysis controlling for age, gender and duration of occupation, incorrect body posture, bad work-habits and daily computer usage were significant independent predictors of CANS</p> <p>Conclusions</p> <p>The prevalence of work-related CANS among computer office workers in Sri Lanka, a developing, South Asian country is high and comparable to prevalence in developed countries. Work-related physical factors, psychosocial factors and lack of awareness were all important associations of CANS and effective preventive strategies need to address all three areas.</p