First-class subtypes

First class type equalities, in the form of generalized algebraic data types (GADTs), are commonly found in functional programs. However, first-class representations of other relations between types, such as subtyping, are not yet directly supported in most functional programming languages. We present several encodings of first-class subtypes using existing features of the OCaml language (made more convenient by the proposed modular implicits extension), show that any such encodings are interconvertible, and illustrate the utility of the encodings with several examples

Microbial dynamics in a High Arctic glacier forefield: A combined field, laboratory, and modelling approach

Modelling the development of soils in glacier forefields is necessary in order to assess how microbial and geochemical processes interact and shape soil development in response to glacier retreat. Furthermore, such models can help us predict microbial growth and the fate of Arctic soils in an increasingly ice-free future. Here, for the first time, we combined field sampling with laboratory analyses and numerical modelling to investigate microbial community dynamics in oligotrophic proglacial soils in Svalbard. We measured low bacterial growth rates and growth efficiencies (relative to estimates from Alpine glacier forefields) and high sensitivity of bacterial growth rates to soil temperature (relative to temperate soils). We used these laboratory measurements to inform parameter values in a new numerical model and significantly refined predictions of microbial and biogeochemical dynamics of soil development over a period of roughly 120 years. The model predicted the observed accumulation of autotrophic and heterotrophic biomass. Genomic data indicated that initial microbial communities were dominated by bacteria derived from the glacial environment, whereas older soils hosted a mixed community of autotrophic and heterotrophic bacteria. This finding was simulated by the numerical model, which showed that active microbial communities play key roles in fixing and recycling carbon and nutrients. We also demonstrated the role of allochthonous carbon and microbial necromass in sustaining a pool of organic material, despite high heterotrophic activity in older soils. This combined field, laboratory, and modelling approach demonstrates the value of integrated model-data studies to understand and quantify the functioning of the microbial community in an emerging High Arctic soil ecosystem

Effect of Formulation Variables on the Stability of a Live, Rotavirus (RV3-BB) Vaccine Candidate using in vitro Gastric Digestion Models to Mimic Oral Delivery

In this work, two different in vitro gastric digestion models were used to evaluate the stability of a live attenuated rotavirus vaccine candidate (RV3-BB) under conditions designed to mimic oral delivery in infants. First, a forced-degradation model was established at low pH to assess the buffering capacity of formulation excipients and to screen for RV3-BB stabilizers. Second, a sequential-addition model was implemented to examine RV3-BB stability under conditions more representative of oral administration to infants. RV3-BB rapidly inactivated at < pH 5.0 (37 °C, 1 h) as measured by an infectivity RT-qPCR assay. Pre-neutralization with varying volumes of infant formula (Enfamil®) or antacid (Mylanta®) conferred partial to full protection of RV3-BB. Excipients with sufficient buffering capacity to minimize acidic pH inactivation of RV3-BB were identified (e.g., succinate, acetate, adipate), however, they concomitantly destabilized RV3-BB in accelerated storage stability studies. Both effects were concentration dependent, thus excipient optimization was required to design candidate RV3-BB formulations which minimize acid-induced viral inactivation during oral delivery while not destabilizing the vaccine during long-term 2–8 °C storage. Finally, a statistical Design -of-Experiments (DOE) study examining RV3-BB stability in the in vitro sequential-addition model identified key formulation parameters likely affecting RV3-BB stability during in vivo oral delivery

Formulation development of a live attenuated human rotavirus (RV3-BB) vaccine candidate for use in low- and middle-income countries

Formulation development was performed with the live, attenuated, human neonatal rotavirus vaccine candidate (RV3-BB) with three main objectives to facilitate use in low- and middle- income countries including (1) a liquid, 2–8°C stable vaccine, (2) no necessity for pre-neutralization of gastric acid prior to oral administration of a small-volume dose, and (3) a low-cost vaccine dosage form. Implementation of a high-throughput RT-qPCR viral infectivity assay for RV3-BB, which correlated well with traditional FFA assays in terms of monitoring RV3-BB stability profiles, enabled more rapid and comprehensive formulation development studies. A wide variety of different classes and types of pharmaceutical excipients were screened for their ability to stabilize RV3-BB during exposure to elevated temperatures, freeze-thaw and agitation stresses. Sucrose (50–60% w/v), PEG-3350, and a solution pH of 7.8 were selected as promising stabilizers. Using a combination of an in vitro gastric digestion model (to mimic oral delivery conditions) and accelerated storage stability studies, several buffering agents (e.g., succinate, adipate and acetate at ~200 to 400 mM) were shown to protect RV3-BB under acidic conditions, and at the same time, minimize virus destabilization during storage. Several optimized RV3-BB candidate formulations were identified based on negligible viral infectivity losses during storage at 2–8°C and −20°C for up to 12 months, as well as by relative stability comparisons at 15°C and 25°C (up to 12 and 3 months, respectively). These RV3-BB stability results are discussed in the context of stability profiles of other rotavirus serotypes as well as future RV3-BB formulation development activities

Assessment of ecological status in UK lakes using benthic diatoms

The European Union’s Water Framework Directive (WFD) requires that all water bodies in Europe achieve good ecological status (GES) by 2015. We developed an ecological classification tool for UK lakes based on benthic diatoms, a key component of the biological-quality element macrophytes and phytobenthos. A database of 1079 epilithic and epiphytic diatom samples and matching environmental data was assembled from 228 UK lakes. The data set was divided into 3 lake types: low, medium, and high alkalinity. A lake trophic diatom index (LTDI) was developed based on modification of the trophic diatom index (TDI) for rivers, and ecological quality ratios (EQRs) were generated for each lake type. The high/good status boundary was defined as the 25th percentile of EQRs of all reference sites (identified based on independent sedimentary-diatom-assemblage data or catchment point-source and landuse data), whereas the good/moderate boundary was set at the point at which nutrient-sensitive and nutrient-tolerant taxa were present in equal relative abundance. The moderate/poor and poor/bad boundaries were defined by equal division of the remaining EQR gradient. Samples from reference sites were used to predict the expected LTDI value for each sample, and these values were compared with the classifications derived from the LTDI. For lakes identified as reference sites, 68% were classified as having high status and 32% as having good. The model predicted 81% of nonreference lakes to have good or worse status. The model was applied to 17 English lakes (10 low- and 7 medium-alkalinity) for which classification based on other WFD tools was available. The classifications based on LTDI gave the same status (within 1 class) as other biological elements for 11 of the 17 lakes (65%). Thus, the LTDI gives a reliable assessment of the condition of the littoral biofilm and is a key component of a WFD-compliant tool kit for classifying UK standing waters

Development, implementation, and pilot study of a sentinel network ("The Watchtowers") for monitoring emergency primary health care activity in Norway

<p>Abstract</p> <p>Background</p> <p>In Norway there is a shortage of valid health activity statistics from the primary care out-of-hours services and the pre-hospital emergency health care system. There is little systematic information available because data registration is lacking or is only recorded periodically, and definitions of variables are not consistent.</p> <p>Method</p> <p>A representative sample of Norwegian municipalities and out-of-hours districts was contracted to establish a sentinel network, "The Watchtowers", and procedures were developed for collecting continuous data from out-of-hours services. All contacts, either per telephone or direct attendance, are recorded during day and night. The variables are registered in a computer program developed by the National Centre for Emergency Primary Health Care, and sent by email in Excel-file format to the Centre on a monthly basis.</p> <p>Results</p> <p>The selection process yielded a group of 18 municipalities, with a fair degree of representativeness for Norwegian municipalities as a whole. The sample has 212,921 inhabitants, which constitutes 4.6% of the total Norwegian population. During a pilot period lasting three months the Watchtowers recorded all individual contacts. The procedures for registration, submitting and checking data worked satisfactorily. There was little data missing, and during the last three months of 2006 a total of 23,346 contacts were registered.</p> <p>Conclusion</p> <p>We have been able to establish a sentinel network with a fair degree of representativeness for Norwegian out-of-hours districts and municipalities. The data collected reflect national activities from casualty clinics in Norway. Such data are useful for both research and system improvements.</p

Model-informed classification of broadband acoustic backscatter from zooplankton in an in situ mesocosm

Funding: The fieldwork was registered in the Research in Svalbard database (RiS ID 11578). Fieldwork and research were financed by Arctic Field Grant Project AZKABAN-light (Norwegian Research Council project no. 322 332), Deep Impact (Norwegian Research Council project no. 300 333), Deeper Impact (Norwegian Research Council project no. 329 305), Marine Alliance for Science and Technology in Scotland (MASTS), the Ocean Frontier Institute (SCORE grant no. HR09011), and Glider Phase II financed by ConocoPhillips Skandinavia AS. Geir Pedersen’s participation was co-funded by CRIMAC (Norwegian Research Council project no. 309 512). Maxime Geoffroy was financially supported by the Ocean Frontier Institute of the Canada First Research Excellence Fund, the Natural Sciences and Engineering Research Council Discovery Grant Programme, the ArcticNet Network of Centres of Excellence Canada, the Research Council of Norway Grant Deep Impact, and the Fisheries and Oceans Canada through the Atlantic Fisheries Fund.Classification of zooplankton to species with broadband echosounder data could increase the taxonomic resolution of acoustic surveys and reduce the dependence on net and trawl samples for ‘ground truthing’. Supervised classification with broadband echosounder data is limited by the acquisition of validated data required to train machine learning algorithms (‘classifiers’). We tested the hypothesis that acoustic scattering models could be used to train classifiers for remote classification of zooplankton. Three classifiers were trained with data from scattering models of four Arctic zooplankton groups (copepods, euphausiids, chaetognaths, and hydrozoans). We evaluated classifier predictions against observations of a mixed zooplankton community in a submerged purpose-built mesocosm (12 m3) insonified with broadband transmissions (185–255 kHz). The mesocosm was deployed from a wharf in Ny-Ålesund, Svalbard, during the Arctic polar night in January 2022. We detected 7722 tracked single targets, which were used to evaluate the classifier predictions of measured zooplankton targets. The classifiers could differentiate copepods from the other groups reasonably well, but they could not differentiate euphausiids, chaetognaths, and hydrozoans reliably due to the similarities in their modelled target spectra. We recommend that model-informed classification of zooplankton from broadband acoustic signals be used with caution until a better understanding of in situ target spectra variability is gained.Publisher PDFPeer reviewe

IMPLEmenting a clinical practice guideline for acute low back pain evidence-based manageMENT in general practice (IMPLEMENT) : cluster randomised controlled trial study protocol

Background: Evidence generated from reliable research is not frequently implemented into clinical practice. Evidence-based clinical practice guidelines are a potential vehicle to achieve this. A recent systematic review of implementation strategies of guideline dissemination concluded that there was a lack of evidence regarding effective strategies to promote the uptake of guidelines. Recommendations from this review, and other studies, have suggested the use of interventions that are theoretically based because these may be more effective than those that are not. An evidencebased clinical practice guideline for the management of acute low back pain was recently developed in Australia. This provides an opportunity to develop and test a theory-based implementation intervention for a condition which is common, has a high burden, and for which there is an evidence-practice gap in the primary care setting. Aim: This study aims to test the effectiveness of a theory-based intervention for implementing a clinical practice guideline for acute low back pain in general practice in Victoria, Australia. Specifically, our primary objectives are to establish if the intervention is effective in reducing the percentage of patients who are referred for a plain x-ray, and improving mean level of disability for patients three months post-consultation. Methods/Design: This study protocol describes the details of a cluster randomised controlled trial. Ninety-two general practices (clusters), which include at least one consenting general practitioner, will be randomised to an intervention or control arm using restricted randomisation. Patients aged 18 years or older who visit a participating practitioner for acute non-specific low back pain of less than three months duration will be eligible for inclusion. An average of twenty-five patients per general practice will be recruited, providing a total of 2,300 patient participants. General practitioners in the control arm will receive access to the guideline using the existing dissemination strategy. Practitioners in the intervention arm will be invited to participate in facilitated face-to-face workshops that have been underpinned by behavioural theory. Investigators (not involved in the delivery of the intervention), patients, outcome assessors and the study statistician will be blinded to group allocation. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN012606000098538 (date registered 14/03/2006).The trial is funded by the NHMRC by way of a Primary Health Care Project Grant (334060). JF has 50% of her time funded by the Chief Scientist Office3/2006). of the Scottish Government Health Directorate and 50% by the University of Aberdeen. PK is supported by a NHMRC Health Professional Fellowship (384366) and RB by a NHMRC Practitioner Fellowship (334010). JG holds a Canada Research Chair in Health Knowledge Transfer and Uptake. All other authors are funded by their own institutions