CCL2/MCP-I Genotype-Phenotype Relationship in Latent Tuberculosis Infection

Among the known biomarkers, chemokines, secreted by activated macrophages and T cells, attract groups of immune cells to the site of infection and may determine the clinical outcome. Association studies of CCL-2/MCP-1 -2518 A/G functional SNP linked to high and low phenotypes with tuberculosis disease susceptibility have shown conflicting results in tuberculosis. Some of these differences could be due the variability of latent infection and recent exposure in the control groups. We have therefore carried out a detailed analysis of CCL-2 genotype SNP -2518 (A/G transition) with plasma CCL-2 levels and related these levels to tuberculin skin test positivity in asymptomatic community controls with no known exposure to tuberculosis and in recently exposed household contacts of pulmonary tuberculosis patients. TST positivity was linked to higher concentrations of plasma CCL2 (Mann Whitney U test; p = 0.004) and was more marked when the G allele was present in TST+ asymptomatic controls (A/G; p = 0.01). Recent exposure also had a significant effect on CCL-2 levels and was linked to the G allele (p = 0.007). Therefore association studies for susceptibility or protection from disease should take into consideration the PPD status as well as recent exposure of the controls group used for comparison. Our results also suggest a role for CCL-2 in maintaining the integrity of granuloma in asymptomatic individuals with latent infection in high TB burden settings. Therefore additional studies into the role of CCL-2 in disease reactivation and progression are warranted

Integrating an early childhood development programme into Bangladeshi primary health-care services: an open-label, cluster-randomised controlled trial

BACKGROUND: Poor development in young children in developing countries is a major problem. Child development experts are calling for interventions that aim to improve child development to be integrated into health services, but there are few robust evaluations of such programmes. Previous small Bangladeshi trials that used individual play sessions with mothers and their children (at home or in clinics), which were predominantly run by employed women, found moderate improvements on child development. We aimed to integrate an early childhood development programme into government clinics that provide primary health care and to evaluate the effects of this intervention on child cognition, language, and motor development, growth, and behaviour in a subsample of the children. METHODS: In this open-label cluster-randomised controlled trial, we recruited individuals from community clinics in Narsingdi district, Bangladesh. These clinics were randomly selected from a larger sample of eligible clinics, and they were assigned (1:1) to either deliver an intervention of 25 sessions, in which mothers of eligible children were shown how to support their child's development through play and interactions, or to deliver no intervention (control group). Participants were underweight children, defined as a weight-for-age Z score of -2 SDs of the WHO standard, who were aged 5-24 months and who lived near the clinic (defined as a walk of less than 30 min). Government health workers ran these sessions at the clinics as part of their routine work, and mothers and children attended fortnightly in pairs (instead of individual weekly home visits that were specified in the original programme). A subsample of children from each clinic was randomly selected for impact evaluation, and these children were assessed on the Bayley Scales of Infant and Toddler Development for their cognitive, language, and motor performance and for their behaviour with Wolke's ratings, before and after implementation of the intervention. The primary outcomes were the performance of this evaluation subsample on the Bayley and Wolke scales and their anthropometric measurements (weight, length or height, and head circumference) after 1 year of the intervention. This study is registered with ClinicalTrials.gov, number NCT02208531. FINDINGS: Between Nov 29, 2014, and April 30, 2015, 12 054 children in 90 clinics were screened, and between six and 25 underweight children were enrolled from each clinic. From the 2423 (20%) underweight children, we excluded 656 (27%) children who lived more than 30-min walking distance from the community clinics, and 30 (1%) children whose mothers did not consent to participate. We therefore enrolled 1737 (72%) children from these 90 clinics. After randomisation, the control group clinics included 878 (51%) children (who all received no intervention) and the intervention group clinics included 859 (49%) children (who all received the child development programme sessions). Eight children from each clinic (360 [41%] children from the control group clinics and 358 [42%] children from the intervention group clinics) were randomly selected for inclusion in the evaluation subsample. Between Feb 24, 2016, and Sept 7, 2016, 344 (96%) children in control group clinics and 343 (96%) children in intervention group clinics were assessed for the primary outcome. 16 (5%) children in the control group clinics and 15 (4%) children in the intervention group clinics did not provide all data and were not included in final analyses. An intention-to-treat analysis showed that the intervention significantly improved children's cognition (effect size 1·3 SDs, 95% CI 1·1 to 1·5; p=0·006), language (1·1 SDs, 0·9 to 1·2; p=0·01), and motor composite scores (1·2 SDs, 1·0 to 1·3; p=0·006) and behaviour ratings (ranging from 0·7 SDs, 0·5 to 0·9; p=0·02; to 1·1 SDs, 1·0 to 1·2; p=0·007), but the intervention had no significant effect on growth (p values ranged from 0·05 to 0·74). Three (1%) children in the intervention group died, but their deaths were not related to the intervention. INTERPRETATION: The extent and range of benefits of our intervention are encouraging. Health workers ran most of the sessions effectively and attendance was good, which is promising for scale-up of the intervention model. However, researchers trained and supervised the health workers, and the next step will be to determine whether the Bangladeshi ministry of health can perform these tasks. In future programmes, more attention needs to be paid to the nutrition of the children. FUNDING: Grand Challenges Canada (Saving Brains)

An Introductory Guide to Aligning Networks Using SANA, the Simulated Annealing Network Aligner.

Sequence alignment has had an enormous impact on our understanding of biology, evolution, and disease. The alignment of biological networks holds similar promise. Biological networks generally model interactions between biomolecules such as proteins, genes, metabolites, or mRNAs. There is strong evidence that the network topology-the "structure" of the network-is correlated with the functions performed, so that network topology can be used to help predict or understand function. However, unlike sequence comparison and alignment-which is an essentially solved problem-network comparison and alignment is an NP-complete problem for which heuristic algorithms must be used.Here we introduce SANA, the Simulated Annealing Network Aligner. SANA is one of many algorithms proposed for the arena of biological network alignment. In the context of global network alignment, SANA stands out for its speed, memory efficiency, ease-of-use, and flexibility in the arena of producing alignments between two or more networks. SANA produces better alignments in minutes on a laptop than most other algorithms can produce in hours or days of CPU time on large server-class machines. We walk the user through how to use SANA for several types of biomolecular networks

Topography of the Chimpanzee Corpus Callosum

The corpus callosum (CC) is the largest commissural white matter tract in mammalian brains, connecting homotopic and heterotopic regions of the cerebral cortex. Knowledge of the distribution of callosal fibers projecting into specific cortical regions has important implications for understanding the evolution of lateralized structures and functions of the cerebral cortex. No comparisons of CC topography in humans and great apes have yet been conducted. We investigated the topography of the CC in 21 chimpanzees using high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Tractography was conducted based on fiber assignment by continuous tracking (FACT) algorithm. We expected chimpanzees to display topographical organization similar to humans, especially concerning projections into the frontal cortical regions. Similar to recent studies in humans, tractography identified five clusters of CC fibers projecting into defined cortical regions: prefrontal; premotor and supplementary motor; motor; sensory; parietal, temporal and occipital. Significant differences in fractional anisotropy (FA) were found in callosal regions, with highest FA values in regions projecting to higher-association areas of posterior cortical (including parietal, temporal and occipital cortices) and prefrontal cortical regions (p<0.001). The lowest FA values were seen in regions projecting into motor and sensory cortical areas. Our results indicate chimpanzees display similar topography of the CC as humans, in terms of distribution of callosal projections and microstructure of fibers as determined by anisotropy measures

Silencing and Un-silencing of Tetracycline-Controlled Genes in Neurons

To identify the underlying reason for the controversial performance of tetracycline (Tet)-controlled regulated gene expression in mammalian neurons, we investigated each of the three components that comprise the Tet inducible systems, namely tetracyclines as inducers, tetracycline-transactivator (tTA) and reverse tTA (rtTA), and tTA-responsive promoters (Ptets). We have discovered that stably integrated Ptet becomes functionally silenced in the majority of neurons when it is inactive during development. Ptet silencing can be avoided when it is either not integrated in the genome or stably-integrated with basal activity. Moreover, long-term, high transactivator levels in neurons can often overcome integration-induced Ptet gene silencing, possibly by inducing promoter accessibility

Hepatitis B Virus Impairs TLR9 Expression and Function in Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection

Hospital Readmission in General Medicine Patients: A Prediction Model

Background: Previous studies of hospital readmission have focused on specific conditions or populations and generated complex prediction models. Objective: To identify predictors of early hospital readmission in a diverse patient population and derive and validate a simple model for identifying patients at high readmission risk. Design: Prospective observational cohort study. Patients: Participants encompassed 10,946 patients discharged home from general medicine services at six academic medical centers and were randomly divided into derivation (n = 7,287) and validation (n = 3,659) cohorts. Measurements: We identified readmissions from administrative data and 30-day post-discharge telephone follow-up. Patient-level factors were grouped into four categories: sociodemographic factors, social support, health condition, and healthcare utilization. We performed logistic regression analysis to identify significant predictors of unplanned readmission within 30 days of discharge and developed a scoring system for estimating readmission risk. Results: Approximately 17.5% of patients were readmitted in each cohort. Among patients in the derivation cohort, seven factors emerged as significant predictors of early readmission: insurance status, marital status, having a regular physician, Charlson comorbidity index, SF12 physical component score, ≥1 admission(s) within the last year, and current length of stay >2 days. A cumulative risk score of ≥25 points identified 5% of patients with a readmission risk of approximately 30% in each cohort. Model discrimination was fair with a c-statistic of 0.65 and 0.61 for the derivation and validation cohorts, respectively. Conclusions: Select patient characteristics easily available shortly after admission can be used to identify a subset of patients at elevated risk of early readmission. This information may guide the efficient use of interventions to prevent readmission

Total ankle prostheses in rheumatoid arthropathy: Outcome in 52 patients followed for 1–9 years

Background and purpose The first generations of total ankle replacements (TARs) showed a high rate of early failure. In the last decades, much progress has been made in the development of TARs, with the newer generation showing better results. We evaluated TARs implanted with rheumatoid arthritis (RA) or juvenile inflammatory arthritis (JIA) as indication

Unplanned readmission rates, length of hospital stay, mortality, and medical costs of ten common medical conditions: a retrospective analysis of Hong Kong hospital data

<p>Abstract</p> <p>Background</p> <p>Studies on readmissions attributed to particular medical conditions, especially heart failure, have generally not addressed the factors associated with readmissions and the implications for health outcomes and costs. This study aimed to investigate the factors associated with 30-day unplanned readmission for 10 common conditions and to determine the cost implications.</p> <p>Methods</p> <p>This population-based retrospective cohort study included patients admitted to all public hospitals in Hong Kong in 2007. The sample consisted of 337,694 hospitalizations in Internal Medicine. The disease-specific risk-adjusted odd ratio (OR), length of stay (LOS), mortality and attributable medical costs for the year were examined for unplanned readmissions for 10 medical conditions, namely malignant neoplasms, heart diseases, cerebrovascular diseases, pneumonia, injury and poisoning, nephritis and nephrosis, diabetes mellitus, chronic liver disease and cirrhosis, septicaemia, and aortic aneurysm.</p> <p>Results</p> <p>The overall unplanned readmission rate was 16.7%. Chronic liver disease and cirrhosis had the highest OR (1.62, 95% confidence interval (CI) 1.39-1.87). Patients with cerebrovascular disease had the longest LOS, with mean acute and rehabilitation stays of 6.9 and 3.0 days, respectively. Malignant neoplasms had the highest mortality rate (30.8%) followed by aortic aneurysm and pneumonia. The attributed medical cost of readmission was highest for heart disease (US$3 199 418, 95$2 579 443-803 393).</p> <p>Conclusions</p> <p>Our findings showed variations in readmission rates and mortality for different medical conditions which may suggest differences in the quality of care provided for various medical conditions. In-hospital care, comprehensive discharge planning, and post-discharge community support for patients need to be reviewed to improve the quality of care and patient health outcomes.</p