A study of lymphocyte dysfunction in multi-transfused haemophilic patients: mechanisms and clinical significance

Contradictory evidence of activation and inhibition of the immune system has been described in haemophiliacs and attributed to infusion of clotting factor concentrate used in their haemostatic maintenance. The purpose of the study was two-fold. Firstly to assess if the concentrates were activating patients' lymphocytes and thus potentially influencing the progression of HIV disease; and secondly, to assess the mechanisms of the reported concentrate-induced inhibition of T cell function in vitro. Methods were established and markers of acute and chronic T and B lymphocyte activation were measured in matched groups of HIV+ve and HIV-ve haemophiliacs and controls. HIV-ve haemophiliacs had elevated levels of soluble IL2 receptor (sIL2-R) (p<0.05) which were unrelated to concentrate infusion, but related to active liver disease attributed primarily to HCV infection. All other markers were normal. HIV+ve haemophiliacs showed lymphocyte activation consistent with that seen in other HIV+ve groups with significant increases in expression of HLA-DR (p<0.0001), CD45RO (p=0.0058), SIL2-R levels (p<0.02) and all B cell activation markers (p<0.001). These did not correlate with concentrate infusion. Raised sIL2-R levels were associated with chronic liver dysfunction suggesting reactivated liver virus infection. In conclusion infusion of concentrate did not appear to be causing lymphocyte disturbances per se. Immune activation was related to viral infection: either HIV or HCV. A detailed analysis of the inhibitory effects of intermediate purity FVIII/FIX concentrates on T cell activation in vitro showed depression of HLA-DR and CD25 expression. This was not seen with monoclonal purified FVIII/FIX products. Inhibitory products caused a decrease in free calcium levels in the culture medium which correlated with their inhibitory effects. All products inhibited mitogen-induced calcium flux into the cells. Reduction in calcium in culture medium by the concentrates is important in inhibiting T cell activation in vitro. Inhibition of calcium mobilisation suggests that events preceding calcium flux - eg, signal transduction may also be contributing to their inhibitory effects. To conclude concentrate inhibition of T cell function in vitro is probably a laboratory artefact and the lymphocyte disturbances that have been reported are probably related to infection with virus

Virus Dynamics in High-Nutrient, Low-Chlorophyll Marine Surface Waters

Iron (Fe) limitation of primary productivity in high-nutrient, low-chlorophyll (HNLC) regions is relatively well-studied. Iron fertilization experiments as well as bottle incubations have been used to study changes in phytoplankton community biomass and diversity, changes in bacterial growth rates, etc. However, viral activity has been largely ignored in these studies. Viral activity was monitored during an iron budget study (FeCycle) in the HNLC waters of the Southern Ocean southwest of New Zealand as well as during a mesoscacle iron fertilization in the subarctic Pacific (SEEDS II). The goal of these studies was to evaluate the role of viruses in the lysis of bacterial cells and the subsequent regeneration of iron and other key nutrients. Two methods, a transmission electron microscopy (TEM) approach and a dilution assay, were used to measure viral production in each study and comparisons were made as to the appropriateness of each. From these studies, it appears that the viral community indirectly responds to changes in trophic production as observed by changes in virus abundance and production, while burst size and frequency of infection remain constant. These results suggest that there is a decrease in the length of lytic cycle after productivity is stimulated. Virus-induced lysis was found to regenerate up to 70 pM Fe in the Southern Ocean, and nearly 200 pM Fe in the subarctic Pacific. While there is little doubt as to the usefulness of TEM and its importance in determining lytic burst sizes in natural populations, the observations in this study suggest that there are problems associated with inferences concerning community mortality from such observations, especially during periods of trophic change

Advanced Gun System (AGS) Backfit

U.S. Navy, Naval Sea Systems Command and Program Executive Office SHIPS, PMS 500 DD X Progra

The Belfast Youth Development Study (BYDS): A prospective cohort study of the initiation, persistence and desistance of substance use from adolescence to adulthood in Northern Ireland

Background: Substance misuse persists as a major public health issue worldwide with significant costs for society. The development of interventions requires methodologically sound studies to explore substance misuse causes and consequences. This Cohort description paper outlines the design of the Belfast Youth Development (BYDS), one of the largest cohort studies of its kind in the UK. The study was established to address the need for a long-term prospective cohort study to investigate the initiation, persistence and desistance of substance use, alongside life course processes in adolescence and adulthood. The paper provides an overview of BYDS as a longitudinal data source for investigating substance misuse and outlines the study measures, sample retention and characteristics. We also outline how the BYDS data have been used to date and highlight areas ripe for future work by interested researchers. Methods: The study began in 2000/1 when participants (n = 3,834) were pupils in their first year of post-primary education (age 10/11 years, school year 8) from over 40 schools in Northern Ireland. Children were followed during the school years: Year 9 (in 2002; aged 12; n = 4,343), Year 10 (in 2003; aged 13; n = 4,522), Year 11 (in 2004; aged 14; n = 3,965) and Year 12 (in 2005; aged 15; n = 3,830) and on two more occasions: 2006/07 (aged 16/17; n = 2,335) and 2010/11 (aged 20/21; n = 2,087). Data were collected on substance use, family, schools, neighbourhoods, offending behaviour and mental health. The most novel aspect of the study was the collection of detailed social network data via friendship nominations allowing the investigation of the spread of substance use via friendship networks. In 2004 (school year 11; respondents aged 14), a sub-sample of participants’ parents (n = 1,097) and siblings (n = 211) also completed measures on substance use and family dynamics. Results: The most recent wave (in 2010/2011; respondents aged 20/21 years) indicated lifetime use of alcohol, tobacco and cannabis among the cohort was 94, 70 and 45 per cent, respectively. The paper charts the development of drug use behaviour and some of the key results to date are presented. We have also identified a number of key areas ripe for analysis by interested researchers including sexual health and education. Conclusions: We have established a cohort with detailed data from adolescence to young adulthood, supplemented with parent and sibling reports and peer network data. The dataset, allowing for investigation of trajectories of adolescent substance use, associated factors and subsequent long-term outcomes, constitutes an important resource for longitudinal substance misuse research. A planned further wave as the cohort enter their late twenties and potential to link to administrative data sources, will further enrich the datasets

Data mining in clinical trial text: transformers for classification and question answering tasks

This research on data extraction methods applies recent advances in natural language processing to evidence synthesis based on medical texts. Texts of interest include abstracts of clinical trials in English and in multilingual contexts. The main focus is on information characterized via the Population, Intervention, Comparator, and Outcome (PICO) framework, but data extraction is not limited to these fields. Recent neural network architectures based on transformers show capacities for transfer learning and increased performance on downstream natural language processing tasks such as universal reading comprehension, brought forward by this architecture’s use of contextualized word embeddings and self-attention mechanisms. This paper contributes to solving problems related to ambiguity in PICO sentence prediction tasks, as well as highlighting how annotations for training named entity recognition systems are used to train a high-performing, but nevertheless flexible architecture for question answering in systematic review automation. Additionally, it demonstrates how the problem of insufficient amounts of training annotations for PICO entity extraction is tackled by augmentation. All models in this paper were created with the aim to support systematic review (semi)automation. They achieve high F1 scores, and demonstrate the feasibility of applying transformer-based classification methods to support data mining in the biomedical literature

Longitudinal social network analysis of peer, family and school contextual influences on adolescent drinking frequency

Purpose: The aim of the study was to identify the mechanisms relating to parental control, adolescent secrecy, and school context that shape patterns of adolescent drinking frequency and appraise the implications for systems-level intervention. Methods: The Belfast Youth Development Study collected information on friendship networks in schools, alcohol use, and Stattin and Kerr's parental monitoring subscales across 5 years of postprimary school education in annual waves from age 11–15 years. Stochastic Actor-Oriented Models were fitted to 22 schools (N = 3,220) to assess friendship formation and peer influence processes related to drinking frequency and their variation by parental control or child secrecy. Meta-regressions and summary statistic ego-alter selection tables assessed how network and behavior co-evolution varied according to school gender and the proportion of weekly or more frequent drinkers in each school. Results: Adolescents tended to mimic their peers' drinking levels, and frequent drinkers befriended those who drank similarly to them. Those with high parental control were less likely to befriend low-control peers, whereas low-control pupils were more likely to befriend each other. Adolescents with low-control parents nominated fewer friends in schools with higher proportions of drinking frequently. There was a tendency toward befriending highly secretive peers in boys schools only. Conclusions: Our results suggest that the optimal strategy for selecting seed nodes in a diffusion of innovations network intervention may vary according to school context, and that targeting family interventions around parent characteristics may modify the wider school network, potentially augmenting network intervention processes

Steps on the Critical Path: Arresting HIV/AIDS in Developing Countries

The director of the United States Centers for Disease Control and Prevention gives a personal view of how the world should tackle the HIV pandemi

Litigation and Lobbying in Support of the Marque: The Scotch Whisky Association, c. 1945–c. 1990

We examine the Scotch Whisky Association’s (SWA) role in protecting “Scotch whisky” between c. 1945 and c. 1990. Using new archival evidence, we demonstrate that the SWA intensively lobbied the UK government to achieve coordination between domestic and European regulations governing Scotch whisky and whisky. The SWA’s nonmarket activities were consonant with some trade associations but in other respects they were atypical. The SWA extended its activities to supranational bodies and engaged in extensive domestic and foreign litigation. The key message from this article is that the SWA built the world-renowned appellation “Scotch whisky” even though this marque was not registered as an appellation until the late twentieth century

Detection and subtyping of Herpes simplex virus in clinical samples by LightCycler PCR, enzyme immunoassay and cell culture

BACKGROUND: Prompt laboratory diagnosis of Herpes simplex virus (HSV) infection facilitates patient management and possible initiation of antiviral therapy. In our laboratory, which receives various specimen types for detection of HSV, we use enzyme immunoassay (EIA) for rapid detection and culture of this virus. The culture of HSV has traditionally been accepted as the diagnostic 'gold standard'. In this study, we compared the use of real time PCR (LightCycler) for amplification, detection and subtyping of specific DNA with our in-house developed rapid and culture tests for HSV. RESULTS: The LightCycler PCR (LC-PCR) detected and subtyped HSV in 99% (66/67) of HSV positive specimens, compared to 81% (54/67) by rapid antigen EIA or 57% (36/63) by culture. A specimen was considered positive when two or more tests yielded HSV identifications or was culture positive. Discordant results were confirmed with an in-house developed PCR-ELISA or DNA sequence analysis. The typing results obtained with the LC-PCR and by culture amplified test were completely concordant. CONCLUSIONS: This study showed that the LC-PCR provided a highly sensitive test for simultaneous detection and subtyping of HSV in a single reaction tube. In addition to increased sensitivity, the LightCycler PCR provided reduced turn-around-times (2 hours) when compared to enzyme immunoassay (4 hours) or culture (4 days)

Saline-saturated DMSO-EDTA as a storage medium for microbial DNA analysis from coral mucus swab samples

The mucus surface layer of corals plays a number of integral roles in their overall health and fitness. This mucopolysaccharide coating serves as vehicle to capture food, a protective barrier against physical invasions and trauma, and serves as a medium to host a community of microorganisms distinct from the surrounding seawater. In healthy corals the associated microbial communities are known to provide antibiotics that contribute to the coral’s innate immunity and function metabolic activities such as biogeochemical cycling. Culture-dependent (Ducklow and Mitchell, 1979; Ritchie, 2006) and culture-independent methods (Rohwer, et al., 2001; Rohwer et al., 2002; Sekar et al., 2006; Hansson et al., 2009; Kellogg et al., 2009) have shown that coral mucus-associated microbial communities can change with changes in the environment and health condition of the coral. These changes may suggest that changes in the microbial associates not only reflect health status but also may assist corals in acclimating to changing environmental conditions. With the increasing availability of molecular biology tools, culture-independent methods are being used more frequently for evaluating the health of the animal host. Although culture-independent methods are able to provide more in-depth insights into the constituents of the coral surface mucus layer’s microbial community, their reliability and reproducibility rely on the initial sample collection maintaining sample integrity. In general, a sample of mucus is collected from a coral colony, either by sterile syringe or swab method (Woodley, et al., 2008), and immediately placed in a cryovial. In the case of a syringe sample, the mucus is decanted into the cryovial and the sealed tube is immediately flash-frozen in a liquid nitrogen vapor shipper (a.k.a., dry shipper). Swabs with mucus are placed in a cryovial, and the end of the swab is broken off before sealing and placing the vial in the dry shipper. The samples are then sent to a laboratory for analysis. After the initial collection and preservation of the sample, the duration of the sample voyage to a recipient laboratory is often another critical part of the sampling process, as unanticipated delays may exceed the length of time a dry shipper can remain cold, or mishandling of the shipper can cause it to exhaust prematurely. In remote areas, service by international shipping companies may be non-existent, which requires the use of an alternative preservation medium. Other methods for preserving environmental samples for microbial DNA analysis include drying on various matrices (DNA cards, swabs), or placing samples in liquid preservatives (e.g., chloroform/phenol/isoamyl alcohol, TRIzol reagent, ethanol). These methodologies eliminate the need for cold storage, however, they add expense and permitting requirements for hazardous liquid components, and the retrieval of intact microbial DNA often can be inconsistent (Dawson, et al., 1998; Rissanen et al., 2010). A method to preserve coral mucus samples without cold storage or use of hazardous solvents, while maintaining microbial DNA integrity, would be an invaluable tool for coral biologists, especially those in remote areas. Saline-saturated dimethylsulfoxide-ethylenediaminetetraacetic acid (20% DMSO-0.25M EDTA, pH 8.0), or SSDE, is a solution that has been reported to be a means of storing tissue of marine invertebrates at ambient temperatures without significant loss of nucleic acid integrity (Dawson et al., 1998, Concepcion et al., 2007). While this methodology would be a facile and inexpensive way to transport coral tissue samples, it is unclear whether the coral microbiota DNA would be adversely affected by this storage medium either by degradation of the DNA, or a bias in the DNA recovered during the extraction process created by variations in extraction efficiencies among the various community members. Tests to determine the efficacy of SSDE as an ambient temperature storage medium for coral mucus samples are presented here