Mechanisms of opsonized HIV entry in normal B lymphocytes

AbstractUsing our in vitro model of normal B cell infection that functions with low doses of HIV but requires virus opsonization by seropositive patient serum, and complement, we analyzed what receptors allowed virus entry. Here, we show that HIV infection of B cells occurs through 2 major receptors: the CD4 antigen and the CR1/CR2 complex. These 2 pathways work independently since a complete inhibition of virus entry requires both CD4 and CD21/CD35 blockade on CD4dim tonsillar B cells whereas only the latter is critical on CD4-negative B cells

A Genome-Wide Association Study of the Protein C Anticoagulant Pathway

The Protein C anticoagulant pathway regulates blood coagulation by preventing the inadequate formation of thrombi. It has two main plasma components: protein C and protein S. Individuals with protein C or protein S deficiency present a dramatically increased incidence of thromboembolic disorders. Here, we present the results of a genome-wide association study (GWAS) for protein C and protein S plasma levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. A total number of 397 individuals from 21 families were typed for 307,984 SNPs using the Infinium® 317 k Beadchip (Illumina). Protein C and protein S (free, functional and total) plasma levels were determined with biochemical assays for all participants. Association with phenotypes was investigated through variance component analysis. After correcting for multiple testing, two SNPs for protein C plasma levels (rs867186 and rs8119351) and another two for free protein S plasma levels (rs1413885 and rs1570868) remained significant on a genome-wide level, located in and around the PROCR and the DNAJC6 genomic regions respectively. No SNPs were significantly associated with functional or total protein S plasma levels, although rs1413885 from DNAJC6 showed suggestive association with the functional protein S phenotype, possibly indicating that this locus plays an important role in protein S metabolism. Our results provide evidence that PROCR and DNAJC6 might play a role in protein C and free protein S plasma levels in the population studied, warranting further investigation on the role of these loci in the etiology of venous thromboembolism and other thrombotic diseases

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

No abstract available

Variation in general supportive and preventive intensive care management of traumatic brain injury: a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study

Abstract Background General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. Methods We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. Results The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36–40 mmHg (4.8–5.3 kPa) in case of controlled intracranial pressure (ICP) < 20 mmHg (n = 45, 69%) and PaCO2 target of 30–35 mmHg (4–4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%). Conclusions Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Historical Epidemics Cartography Generated by Spatial Analysis: Mapping the Heterogeneity of Three Medieval "Plagues" in Dijon.

International audienceThis work was designed to adapt Geographical Information System-based spatial analysis to the study of historical epidemics. We mapped "plague" deaths during three epidemics of the early 15th century, analyzed spatial distributions by applying the Kulldorff's method, and determined their relationships with the distribution of socio-professional categories in the city of Dijon. Our study was based on a database including 50 annual tax registers (established from 1376 to 1447) indicating deaths and survivors among the heads of households, their home location, tax level and profession. The households of the deceased and survivors during 6 years with excess mortality were individually located on a georeferenced medieval map, established by taking advantage of the preserved geography of the historical center of Dijon. We searched for clusters of heads of households characterized by shared tax levels (high-tax payers, the upper decile; low-tax payers, the half charged at the minimum level) or professional activities and for clusters of differential mortality. High-tax payers were preferentially in the northern intramural part, as well as most wealthy or specialized professionals, whereas low-tax payers were preferentially in the southern part. During two epidemics, in 1400-1401 and 1428, areas of higher mortality were found in the northern part whereas areas of lower mortality were in the southern one. A high concentration of housing and the proximity to food stocks were common features of the most affected areas, creating suitable conditions for rats to pullulate. A third epidemic, lasting from 1438 to 1440 had a different and evolving geography: cases were initially concentrated around the southern gate, at the confluence of three rivers, they were then diffuse, and ended with residual foci of deaths in the northern suburb. Using a selected historical source, we designed an approach allowing spatial analysis of urban medieval epidemics. Our results fit with the view that the 1400-1401 epidemic was a Black Death recurrence. They suggest that this was also the case in 1428, whereas in 1438-1440 a different, possibly waterborne, disease was involved

Mortality and demographic recovery in early post-black death epidemics: Role of recent emigrants in medieval Dijon

International audienceObjective and methodsWe analyze the influence of population movement on susceptibility to death and resilience during two epidemics occurring in Dijon soon after the Black Death. Using a specific program designed to propose links between entries in annual tax registers, we define tentative heads of household, the elapsed time since their first registration and their ties with other persons within the city.ResultsDuring the 1400 epidemic heads of household who were registered for 1–3 years die in large numbers, whereas during years without epidemics, their death rate is lower than that of heads of household who were registered longer. Recent registration is an epidemic vulnerability factor only in association with a low taxation status, which, when isolated, does not influence mortality. A lack of familial ties within Dijon is another vulnerability factor among the recently registered. This suggests that poor, recent emigrants are more affected by epidemic mortality. In contrast, the mortality of recently registered heads of household is indistinct during a later epidemic occurring after several years of major famine that may have selected the more resistant emigrants and/or excluded the more miserable of them from our analysis. In contrast to the first one, this second epidemic is followed by rapid demographic recovery. This latter recovery is fully explained by the contribution of poor, newly registered heads of household without ties in Dijon.ConclusionOur results outline the interaction between population movement and low socioeconomic status on death susceptibility in historical plagues and show that poor recent emigrants may also be key players in the resilience of the population after an epidemic

Cartography of death in 1400.

<p>Georeferenced map of medieval Dijon. Rivers as blue lines. Parish churches, abbeys and a number of prominent places are indicated. The streets mentioned in the text are italicized. The 12th century rampart is shown by dotted lines. Each point corresponds to a surviving head of household (green points) or to a registered death (larger red points). Yellow areas circled in red: clusters with a higher relative risk of grouped death. Yellow areas circled in green: clusters with a lower or null relative risk of grouped death. Empty area circled in purple: cluster of higher density of butchers in the <i>Bourg</i> district. The <i>Bourg</i> district stood between the ancient fortification of the <i>castrum</i> (1) and the Suzon River (2) and its northern end was contiguous to <i>Forges</i> Street (3). Historical evidence of the location of the statistically significant clusters is presented in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143866#pone.0143866.s012" target="_blank">S9 Text</a></b>.</p