Fifteen-minute consultation: The efficient investigation of infantile and childhood epileptic encephalopathies in the era of modern genomics

The investigation of children presenting with infantile and childhood epileptic encephalopathies (ICEE) is challenging due to diverse aetiologies, overlapping phenotypes and the relatively low diagnostic yield of MRI, electroencephalography (EEG) and biochemical investigations. Careful history and thorough examination remain essential as these may identify an acquired cause or indicate more targeted investigation for a genetic disorder. Whole exome sequencing (WES) with analysis of a panel of candidate epilepsy genes has increased the diagnostic yield. Whole genome sequencing (WGS), particularly as a trio with both parents' DNA, is likely to supersede WES. Modern genomic investigation impacts on the timing and necessity of other testing. We propose a structured approach for children presenting with ICEE where there is diagnostic uncertainty, emphasising the importance of WGS or, if unavailable, WES early in the investigative process. We note the importance of expert review of all investigations, including radiology, neurophysiology and biochemistry, to confirm the technique used was appropriate as well as the results. It is essential to counsel families on the risks associated with the procedures, the yield of the procedures, findings that are difficult to interpret and implication of 'negative' results. Where children remain without a diagnosis despite comprehensive investigation, we note the importance of ongoing multidisciplinary care

Uneven onset and pace of ice-dynamical imbalance in the Amundsen Sea Embayment, West Antarctica

We combine measurements acquired by five satellite altimeter missions to obtain an uninterrupted record of ice-sheet elevation change over the Amundsen Sea Embayment, West Antarctica, since 1992. Using these data, we examine the onset of surface lowering arising through ice-dynamical imbalance, and the pace at which it has propagated inland, by tracking elevation changes along glacier flowlines. Surface lowering has spread slowest (<6 km/yr) along the Pope, Smith, and Kohler (PSK) Glaciers, due to their small extent. Pine Island Glacier (PIG) is characterized by a continuous inland spreading of surface lowering, notably fast at rates of 13 to 15 km/yr along tributaries draining the southeastern lobe, possibly due to basal conditions or tributary geometry. Surface lowering on Thwaites Glacier (THG) has been episodic, and has spread inland fastest (10 to 12 km/yr) along its central flowlines. The current episodes of surface lowering started approximately 10 yr before the first measurements on PSK, around 1990 on PIG, and around 2000 on THG. Ice-dynamical imbalance across the sector has therefore been uneven during the satellite record

Prevention of elastase-induced emphysema in placenta growth factor knock-out mice

<p>Abstract</p> <p>Background</p> <p>Although both animal and human studies suggested the association between placenta growth factor (PlGF) and chronic obstructive pulmonary disease (COPD), especially lung emphysema, the role of PlGF in the pathogenesis of emphysema remains to be clarified. This study hypothesizes that blocking PlGF prevents the development of emphysema.</p> <p>Methods</p> <p>Pulmonary emphysema was induced in PlGF knock-out (KO) and wild type (WT) mice by intra-tracheal instillation of porcine pancreatic elastase (PPE). A group of KO mice was then treated with exogenous PlGF and WT mice with neutralizing anti-VEGFR1 antibody. Tumor necrosis factor alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), and VEGF were quantified. Apoptosis measurement and immuno-histochemical staining for VEGF R1 and R2 were performed in emphysematous lung tissues.</p> <p>Results</p> <p>After 4 weeks of PPE instillation, lung airspaces enlarged more significantly in WT than in KO mice. The levels of TNF-α and MMP-9, but not VEGF, increased in the lungs of WT compared with those of KO mice. There was also increased in apoptosis of alveolar septal cells in WT mice. Instillation of exogenous PlGF in KO mice restored the emphysematous changes. The expression of both VEGF R1 and R2 decreased in the emphysematous lungs.</p> <p>Conclusion</p> <p>In this animal model, pulmonary emphysema is prevented by depleting PlGF. When exogenous PlGF is administered to PlGF KO mice, emphysema re-develops, implying that PlGF contributes to the pathogenesis of emphysema.</p

Comparison of primary care models in the prevention of cardiovascular disease - a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Primary care providers play an important role in preventing and managing cardiovascular disease. This study compared the quality of preventive cardiovascular care delivery amongst different primary care models.</p> <p>Methods</p> <p>This is a secondary analysis of a larger randomized control trial, known as the Improved Delivery of Cardiovascular Care (IDOCC) through Outreach Facilitation. Using baseline data collected through IDOCC, we conducted a cross-sectional study of 82 primary care practices from three delivery models in Eastern Ontario, Canada: 43 fee-for-service, 27 blended-capitation and 12 community health centres with salary-based physicians. Medical chart audits from 4,808 patients with or at high risk of developing cardiovascular disease were used to examine each practice's adherence to ten evidence-based processes of care for diabetes, chronic kidney disease, dyslipidemia, hypertension, weight management, and smoking cessation care. Generalized estimating equation models adjusting for age, sex, rurality, number of cardiovascular-related comorbidities, and year of data collection were used to compare guideline adherence amongst the three models.</p> <p>Results</p> <p>The percentage of patients with diabetes that received two hemoglobin A1c tests during the study year was significantly higher in community health centres (69%) than in fee-for-service (45%) practices (Adjusted Odds Ratio (AOR) = 2.4 [95% CI 1.4-4.2], p = 0.001). Blended capitation practices had a significantly higher percentage of patients who had their waistlines monitored than in fee-for-service practices (19% vs. 5%, AOR = 3.7 [1.8-7.8], p = 0.0006), and who were recommended a smoking cessation drug when compared to community health centres (33% vs. 16%, AOR = 2.4 [1.3-4.6], p = 0.007). Overall, quality of diabetes care was higher in community health centres, while smoking cessation care and weight management was higher in the blended-capitation models. Fee-for-service practices had the greatest gaps in care, most noticeably in diabetes care and weight management.</p> <p>Conclusions</p> <p>This study adds to the evidence suggesting that primary care delivery model impacts quality of care. These findings support current Ontario reforms to move away from the traditional fee-for-service practice.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00574808">NCT00574808</a></p

Good adherence to HAART and improved survival in a community HIV/AIDS treatment and care programme: the experience of The AIDS Support Organization (TASO), Kampala, Uganda

BACKGROUND: Poor adherence to highly active antiretroviral therapy (HAART) may result in treatment failure and death. Most reports of the effect of adherence to HAART on mortality come from studies where special efforts are made to provide HAART under ideal conditions. However, there are few reports of the impact of non-adherence to HAART on mortality from community HIV/AIDS treatment and care programmes in developing countries. We therefore conducted a study to assess the effect of adherence to HAART on survival in The AIDS Support Organization (TASO) community HAART programme in Kampala, Uganda. METHODS: The study was a retrospective cohort of 897 patients who initiated HAART at TASO clinic, Kampala, between May 2004 and December 2006. A total of 7,856 adherence assessments were performed on the data. Adherence was assessed using a combination of self-report and pill count methods. Patients who took 95%. The crude death rate was 12.2 deaths per 100 patient-years, with a rate of 42.5 deaths per 100 patient-years for non-adherent patients and 6.1 deaths per 100 patient-years for adherent patients. Non-adherence to ART was significantly associated with mortality. Patients with a CD4 count of less than 50 cells/mm3 had a higher mortality (HR = 4.3; 95% CI: 2.22-5.56) compared to patients with a CD4 count equal to or greater than 50 cells/mm3 (HR = 2.4; 95% CI: 1.79-2.38). CONCLUSION: Our study showed that good adherence and improved survival are feasible in community HIV/AIDS programmes such as that of TASO, Uganda. However, there is need to support community HAART programmes to overcome the challenges of funding to provide sustainable supplies particularly of antiretroviral drugs; provision of high quality clinical and laboratory support; and achieving a balance between expansion and quality of services. Measures for the early identification and treatment of HIV infected people including home-based VCT and HAART should be strengthened

Concise Reporting of Benign Endometrial Biopsies is an Acceptable Alternative to Descriptive Reporting

In the United Kingdom, endometrial biopsy reports traditionally consist of a morphologic description followed by a conclusion. Recently published consensus guidelines for reporting benign endometrial biopsies advocate the use of standardized terminology. In this project we aimed to assess the acceptability and benefits of this simplified "diagnosis only" format for reporting non-neoplastic endometrial biopsies. Two consultants reported consecutive endometrial biopsies using 1 of 3 possible formats: (i) diagnosis only, (ii) diagnosis plus an accompanying comment, and (iii) the traditional descriptive format. Service users were asked to provide feedback on this approach via an anonymized online survey. The reproducibility of this system was assessed on a set of 53 endometrial biopsies among consultants and senior histopathology trainees. Of 370 consecutive benign endometrial biopsies, 245 (66%) were reported as diagnosis only, 101 (27%) as diagnosis plus a brief comment, and 24 (7%) as diagnosis following a morphologic description. Of the 43 survey respondents (28 gynecologists, 11 pathologists, and 4 clinical nurse specialists), 40 (93%) preferred a diagnosis only, with 3 (7%) being against/uncertain about a diagnosis only report. Among 3 histopathology consultants and 4 senior trainees there was majority agreement on the reporting format in 53/53 (100%) and 52/53 (98%) biopsies. In summary, we found that reporting benign specimens within standardized, well-understood diagnostic categories is an acceptable alternative to traditional descriptive reporting, with the latter reserved for the minority of cases that do not fit into specific categories. This revised approach has the potential to improve reporting uniformity and reproducibility

Different regulation of cigarette smoke induced inflammation in upper versus lower airways

Background: Cigarette smoke (CS) is known to initiate a cascade of mediator release and accumulation of immune and inflammatory cells in the lower airways. We investigated and compared the effects of CS on upper and lower airways, in a mouse model of subacute and chronic CS exposure. Methods: C57BL/6 mice were whole-body exposed to mainstream CS or air, for 2, 4 and 24 weeks. Bronchoalveolar lavage fluid (BAL) was obtained and tissue cryosections from nasal turbinates were stained for neutrophils and T cells. Furthermore, we evaluated GCP-2, KC, MCP-1, MIP-3 alpha, RORc, IL-17, FoxP3, and TGF-beta 1 in nasal turbinates and lungs by RT-PCR. Results: In both upper and lower airways, subacute CS-exposure induced the expression of GCP-2, MCP-1, MIP-3a and resulted in a neutrophilic influx. However, after chronic CS-exposure, there was a significant downregulation of inflammation in the upper airways, while on the contrary, lower airway inflammation remained present. Whereas nasal FoxP3 mRNA levels already increased after 2 weeks, lung FoxP3 mRNA increased only after 4 weeks, suggesting that mechanisms to suppress inflammation occur earlier and are more efficient in nose than in lungs. Conclusions: Altogether, these data demonstrate that CS induced inflammation may be differently regulated in the upper versus lower airways in mice. Furthermore, these data may help to identify new therapeutic targets in this disease model

General Practice and Pandemic Influenza: A Framework for Planning and Comparison of Plans in Five Countries

BACKGROUND: Although primary health care, and in particular, general practice will be at the frontline in the response to pandemic influenza, there are no frameworks to guide systematic planning for this task or to appraise available plans for their relevance to general practice. We aimed to develop a framework that will facilitate planning for general practice, and used it to appraise pandemic plans from Australia, England, USA, New Zealand and Canada. METHODOLOGY/PRINCIPAL FINDINGS: We adapted the Haddon matrix to develop the framework, populating its cells through a multi-method study that incorporated the peer-reviewed and grey literature, interviews with general practitioners, practice nurses and senior decision-makers, and desktop simulation exercises. We used the framework to analyse 89 publicly-available jurisdictional plans at similar managerial levels in the five countries. The framework identifies four functional domains: clinical care for influenza and other needs, public health responsibilities, the internal environment and the macro-environment of general practice. No plan addressed all four domains. Most plans either ignored or were sketchy about non-influenza clinical needs, and about the contribution of general practice to public health beyond surveillance. Collaborations between general practices were addressed in few plans, and inter-relationships with the broader health system, even less frequently. CONCLUSIONS: This is the first study to provide a framework to guide general practice planning for pandemic influenza. The framework helped identify critical shortcomings in available plans. Engaging general practice effectively in planning is challenging, particularly where governance structures for primary health care are weak. We identify implications for practice and for research

Application and Validation of Case-Finding Algorithms for Identifying Individuals with Human Immunodeficiency Virus from Administrative Data in British Columbia, Canada

Objective To define a population-level cohort of individuals infected with the human immunodeficiency virus (HIV) in the province of British Columbia from available registries and administrative datasets using a validated case-finding algorithm. Methods Individuals were identified for possible cohort inclusion from the BC Centre for Excellence in HIV/AIDS (CfE) drug treatment program (antiretroviral therapy) and laboratory testing datasets (plasma viral load (pVL) and CD4 diagnostic test results), the BC Centre for Disease Control (CDC) provincial HIV surveillance database (positive HIV tests), as well as databases held by the BC Ministry of Health (MoH); the Discharge Abstract Database (hospitalizations), the Medical Services Plan (physician billing) and PharmaNet databases (additional HIV-related medications). A validated case-finding algorithm was applied to distinguish true HIV cases from those likely to have been misclassified. The sensitivity of the algorithms was assessed as the proportion of confirmed cases (those with records in the CfE, CDC and MoH databases) positively identified by each algorithm. A priori hypotheses were generated and tested to verify excluded cases. Results A total of 25,673 individuals were identified as having at least one HIV-related health record. Among 9,454 unconfirmed cases, the selected case-finding algorithm identified 849 individuals believed to be HIV-positive. The sensitivity of this algorithm among confirmed cases was 88%. Those excluded from the cohort were more likely to be female (44.4% vs. 22.5%; p&lt;0.01), had a lower mortality rate (2.18 per 100 person years (100PY) vs. 3.14/100PY; p&lt;0.01), and had lower median rates of health service utilization (days of medications dispensed: 9745/100PY vs. 10266/100PY; p&lt;0.01; days of inpatient care: 29/100PY vs. 98/100PY; p&lt;0.01; physician billings: 602/100PY vs. 2,056/100PY; p&lt;0.01). Conclusions The application of validated case-finding algorithms and subsequent hypothesis testing provided a strong framework for defining a population-level cohort of HIV infected people in BC using administrative databases