Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study

Peer reviewe

CRISPR-Cas9 interrogation of a putative fetal globin repressor in human erythroid cells

Sickle Cell Disease and beta-thalassemia, which are caused by defective or deficient adult beta-globin (HBB) respectively, are the most common serious genetic blood diseases in the world. Persistent expression of the fetal beta-like globin, also known gamma-globin, can ameliorate both disorders by serving in place of the adult beta-globin as a part of the fetal hemoglobin tetramer (HbF). Here we use CRISPR-Cas9 gene editing to explore a potential gamma-globin silencer region upstream of the delta-globin gene identified by comparison of naturally-occurring deletion mutations associated with up-regulated gamma-globin. We find that deletion of a 1.7 kb consensus element or select 350 bp sub-regions from bulk populations of cells increases levels of HbF. Screening of individual sgRNAs in one sub-region revealed three single guides that caused increases gamma-globin expression. Deletion of the 1.7 kb region in HUDEP-2 clonal sublines, and in colonies derived from CD34+ hematopoietic stem/progenitor cells (HSPCs), does not cause significant up-regulation of gamma-globin. These data suggest that the 1.7 kb region is not an autonomous gamma-globin silencer, and thus by itself is not a suitable therapeutic target for gene editing treatment of beta-hemoglobinopathies.Peer reviewe

A perspective on migration and community engagement in Smart Cities

This is a conceptual paper interfacing community engagement and migration flows in relation to smart cities’ development. The paper notes community engagement as a crucial variable, in general and with reference to the aspired for impact on migration flows. It conceptualizes community engagement as an operationalizable construct for strategic design. The idea of community engagement is there in most multi-stakeholder projects and initiatives. Enhancing design and execution for making it count for superior performance of smart city initiatives is what we seek to develop here. The paper is also oriented to deliver an agenda for field research based on hypotheses it comes forth with

Differential Effects of Migration and Deportation on HIV Infection among Male and Female Injection Drug Users in Tijuana, Mexico

HIV prevalence is rising, especially among high risk females in Tijuana, Baja California, a Mexico-US border city situated on major migration and drug trafficking routes. We compared factors associated with HIV infection among male and female injection drug users (IDUs) in Tijuana in an effort to inform HIV prevention and treatment programs. IDUs aged ≥18 years were recruited using respondent-driven sampling and underwent testing for HIV, syphilis and structured interviews. Logistic regression identified correlates of HIV infection, stratified by gender. Among 1056 IDUs, most were Mexican-born but 67% were born outside Tijuana. Reasons for moving to Tijuana included deportation from the US (56% for males, 29% for females), and looking for work/better life (34% for females, 15% for males). HIV prevalence was higher in females versus males (10.2% vs. 3.5%, p = 0.001). Among females (N = 158), factors independently associated with higher HIV prevalence included younger age, lifetime syphilis infection and living in Tijuana for longer durations. Among males (N = 898), factors independently associated with higher HIV prevalence were syphilis titers consistent with active infection, being arrested for having ‘track-marks’, having larger numbers of recent injection partners and living in Tijuana for shorter durations. An interaction between gender and number of years lived in Tijuana regressed on HIV infection was significant (p = 0.03). Upon further analysis, deportation from the U.S. explained the association between shorter duration lived in Tijuana and HIV infection among males; odds of HIV infection were four-fold higher among male injectors deported from the US, compared to other males, adjusting for all other significant correlates (p = 0.002). Geographic mobility has a profound influence on Tijuana's evolving HIV epidemic, and its impact is significantly modified by gender. Future studies are needed to elucidate the context of mobility and HIV acquisition in this region, and whether US immigration policies adversely affect HIV risk

Measuring urban social sustainability:Scale development and validation

Despite the significant role of social sustainability in the sustainable development agenda, there is a lack of research to clearly define and fully operationalise the concept of urban social sustainability. The aim of this study is to contribute to the existing literature by developing a comprehensive measurement scale to assess urban social sustainability at the neighbourhood level. We argue that urban social sustainability is a multidimensional concept that incorporates six main dimensions of social interaction, sense of place, social participation, safety, social equity and neighbourhood satisfaction. Failure to consider each of these dimensions may lead to an incomplete picture of social sustainability. Validity, reliability and dimensionality of the urban social sustainability scale are examined using factor analysis. We also illustrate the application of the urban social sustainability scale by investigating the influence of quality of design, as one of the least studied factors of urban form, on different dimensions of social sustainability. The paper uses data collected from the household questionnaire survey in a sample of 251 respondents from five case study neighbourhoods of Dunedin city, New Zealand. This study provides new evidence on the significance of improving neighbourhood quality of design and its positive and significant relationship with different dimensions of social sustainability and the overall social sustainability

Quality Assessment of Dried Blood Spots from Tuberculosis Patients from Four Countries

BACKGROUND: Dried blood spot (DBS) sampling is a blood collection tool that uses a finger prick to obtain a blood drop on a DBS card. It can be used for therapeutic drug monitoring, a method that uses blood drug concentrations to optimize individual treatment. DBS sampling is believed to be a simpler way of blood collection compared with venous sampling. The aim of this study was to evaluate the quality of DBSs from patients with tuberculosis all around the world based on quality indicators in a structured assessment procedure. METHODS: Total 464 DBS cards were obtained from 4 countries: Bangladesh, Belarus, Indonesia, and Paraguay. The quality of the DBS cards was assessed using a checklist consisting of 19 questions divided into 4 categories: the integrity of the DBS materials, appropriate drying time, blood volume, and blood spot collection. RESULTS: After examination, 859 of 1856 (46%) blood spots did not comply with present quality criteria. In 625 cases (34%), this was due to incorrect blood spot collection. The DBS cards from Bangladesh, Indonesia, and Paraguay seemed to be affected by air humidity, causing the blood spots not to dry appropriately. CONCLUSIONS: New tools to help obtain blood spots of sufficient quality are necessary and environmental specific recommendations to determine plasma concentration correctly. In addition, 3% of the DBS cards were rejected because the integrity of the materials suggesting that the quality of plastic ziplock bags currently used to protect the DBS cards against contamination and humidity may not be sufficient

Modulation of Bax and mTOR for Cancer Therapeutics.

A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistanc

Similarity Check: Quality Assessment of Dried Blood Spots from Patients With Tuberculosis from 4 Countries

Background: Dried blood spot (DBS) sampling is a blood collection tool that uses a finger prick to obtain a blood drop on a DBS card. It can be used for therapeutic drug monitoring, a method that uses blood drug concentrations to optimize individual treatment. DBS sampling is believed to be a simpler way of blood collection compared with venous sampling. The aim of this study was to evaluate the quality of DBSs from patients with tuberculosis all around the world based on quality indicators in a structured assessment procedure. Methods: Total 464 DBS cards were obtained from 4 countries: Bangladesh, Belarus, Indonesia, and Paraguay. The quality of the DBS cards was assessed using a checklist consisting of 19 questions divided into 4 categories: the integrity of the DBS materials, appropriate drying time, blood volume, and blood spot collection. Results: After examination, 859 of 1856 (46%) blood spots did not comply with present quality criteria. In 625 cases (34%), this was due to incorrect blood spot collection. The DBS cards from Bangladesh, Indonesia, and Paraguay seemed to be affected by air humidity, causing the blood spots not to dry appropriately. Conclusions: New tools to help obtain blood spots of sufficient quality are necessary and environmental specific recommendations to determine plasma concentration correctly. In addition, 3% of the DBS cards were rejected because the integrity of the materials suggesting that the quality of plastic ziplock bags currently used to protect the DBS cards against contamination and humidity may not be sufficient. Key Words: DBS, TB, quality, TDM, plasma concentration

Using Differential Item Functioning to evaluate potential bias in a high stakes postgraduate knowledge based assessment

BACKGROUND: Fairness is a critical component of defensible assessment. Candidates should perform according to ability without influence from background characteristics such as ethnicity or sex. However, performance differs by candidate background in many assessment environments. Many potential causes of such differences exist, and examinations must be routinely analysed to ensure they do not present inappropriate progression barriers for any candidate group. By analysing the individual questions of an examination through techniques such as Differential Item Functioning (DIF), we can test whether a subset of unfair questions explains group-level differences. Such items can then be revised or removed. METHODS: We used DIF to investigate fairness for 13,694 candidates sitting a major international summative postgraduate examination in internal medicine. We compared (a) ethnically white UK graduates against ethnically non-white UK graduates and (b) male UK graduates against female UK graduates. DIF was used to test 2773 questions across 14 sittings. RESULTS: Across 2773 questions eight (0.29%) showed notable DIF after correcting for multiple comparisons: seven medium effects and one large effect. Blinded analysis of these questions by a panel of clinician assessors identified no plausible explanations for the differences. These questions were removed from the question bank and we present them here to share knowledge of questions with DIF. These questions did not significantly impact the overall performance of the cohort. Group-level differences in performance between the groups we studied in this examination cannot be explained by a subset of unfair questions. CONCLUSIONS: DIF helps explore fairness in assessment at the question level. This is especially important in high-stakes assessment where a small number of unfair questions may adversely impact the passing rates of some groups. However, very few questions exhibited notable DIF so differences in passing rates for the groups we studied cannot be explained by unfairness at the question level