Extending OCaml’s open

We propose a harmonious extension of OCaml's 'open' construct. OCaml's existing construct 'open M' imports the names exported by the module 'M' into the current scope. At present 'M' is required to be the path to a module. We propose extending 'open' to instead accept an arbitrary module expression, making it possible to succinctly address a number of existing scope-related difficulties that arise when writing OCaml programs

The regulation of coralline algal physiology, an in situ study of Corallina officinalis (Corallinales, Rhodophyta)

Calcified macroalgae are critical components of marine ecosystems worldwide, but face considerable threat both from climate change (increasing water temperatures) and ocean acidification (decreasing ocean pH and carbonate saturation). It is thus fundamental to constrain the relationships between key abiotic stressors and the physiological processes that govern coralline algal growth and survival. Here we characterize the complex relationships between the abiotic environment of rock pool habitats and the physiology of the geniculate red coralline alga, Corallina officinalis (Corallinales, Rhodophyta). Paired assessment of irradiance, water temperature and carbonate chemistry, with C. officinalis net production (NP), respiration (R) and net calcification (NG) was performed in a south-western UK field site, at multiple temporal scales (seasonal, diurnal and tidal). Strong seasonality was observed in NP and night-time R, with a Pmax of 22.35 µmol DIC (g DW)−1 h−1, Ek of 300 µmol photons m−2 s−1 and R of 3.29 µmol DIC (g DW)−1 h−1 determined across the complete annual cycle. NP showed a significant exponential relationship with irradiance (R2 = 0.67), although was temperature dependent given ambient irradiance > Ek for the majority of the annual cycle. Over tidal emersion periods, dynamics in NP highlighted the ability of C. officinalis to acquire inorganic carbon despite significant fluctuations in carbonate chemistry. Across all data, NG was highly predictable (R2 = 0.80) by irradiance, water temperature and carbonate chemistry, providing a NGmax of 3.94 µmol CaCO3 (g DW)−1 h−1 and Ek of 113 µmol photons m−2 s−1. Light NG showed strong seasonality and significant coupling to NP (R2 = 0.65) as opposed to rock pool water carbonate saturation. In contrast, the direction of dark NG (dissolution vs. precipitation) was strongly related to carbonate saturation, mimicking abiotic precipitation dynamics. Data demonstrated that C. officinalis is adapted to both long-term (seasonal) and short-term (tidal) variability in environmental stressors, although the balance between metabolic processes and the external environment may be significantly impacted by future climate change

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

Developing a manufacturing process to deliver a cost effective and stable liquid human rotavirus vaccine

Despite solid evidence of the success of rotavirus vaccines in saving children from fatal gastroenteritis, more than 82 million infants worldwide still lack access to a rotavirus vaccine. The main barriers to global rotavirus vaccine coverage include cost, manufacturing capacity and suboptimal efficacy in low- and lower-middle income countries. One vaccine candidate with the potential to address the latter is based on the novel, naturally attenuated RV3 strain of rotavirus, RV3-BB vaccine administered in a birth dose strategy had a vaccine efficacy against severe rotavirus gastroenteritis of 94% at 12 months of age in infants in Indonesia. To further develop this vaccine candidate, a well-documented and low-cost manufacturing process is required. A target fully loaded cost of goods (COGs) of ≤$3.50 per course of three doses was set based on predicted market requirements. COGs modelling was leveraged to develop a process using Vero cells in cell factories reaching high titers, reducing or replacing expensive reagents and shortening process time to maximise output. Stable candidate liquid formulations were developed allowing two-year storage at 2–8 °C. In addition, the formulation potentially renders needless the pretreatment of vaccinees with antacid to ensure adequate gastric acid neutralization for routine oral vaccination. As a result, the formulation allows small volume dosing and reduction of supply chain costs. A dose ranging study is currently underway in Malawi that will inform the final clinical dose required. At a clinical dose of ≤6.3 log10 FFU, the COGs target of ≤$3.50 per three dose course was met. At a clinical dose of 6.5 log10 FFU, the final manufacturing process resulted in a COGs that is substantially lower than the current average market price, 2.44 USD per dose. The manufacturing and formulation processes were transferred to BioFarma in Indonesia to enable future RV3-BB vaccine production

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

Algae Drive Enhanced Darkening of Bare Ice on the Greenland Ice Sheet

Surface ablation of the Greenland ice sheet is amplified by surface darkening caused by light-absorbing impurities such as mineral dust, black carbon, and pigmented microbial cells. We present the first quantitative assessment of the microbial contribution to the ice sheet surface darkening, based on field measurements of surface reflectance and concentrations of light-absorbing impurities, including pigmented algae, during the 2014 melt season in the southwestern part of the ice sheet. The impact of algae on bare ice darkening in the study area was greater than that of nonalgal impurities and yielded a net albedo reduction of 0.038&nbsp;±&nbsp;0.0035 for each algal population doubling. We argue that algal growth is a crucial control of bare ice darkening, and incorporating the algal darkening effect will improve mass balance and sea level projections of the Greenland ice sheet and ice masses elsewhere

Changes in microphytobenthos fluorescence over a tidal cycle: implications for sampling designs

Intertidal microphytobenthos (MPB) are important primary producers and provide food for herbivores in soft sediments and on rocky shores. Methods of measuring MPB biomass that do not depend on the time of collection relative to the time of day or tidal conditions are important in any studies that need to compare temporal or spatial variation, effects of abiotic factors or activity of grazers. Pulse amplitude modulated (PAM) fluorometry is often used to estimate biomass of MPB because it is a rapid, non-destructive method, but it is not known how measures of fluorescence are altered by changing conditions during a period of low tide. We investigated this experimentally using in situ changes in minimal fluorescence (F) on a rocky shore and on an estuarine mudflat around Sydney (Australia), during low tides. On rocky shores, the time when samples are taken during low tide had little direct influence on measures of fluorescence as long as the substratum is dry. Wetness from wave-splash, seepage from rock pools, run-off, rainfall, etc., had large consequences for any comparisons. On soft sediments, fluorescence was decreased if the sediment dried out, as happens during low-spring tides on particularly hot and dry days. Surface water affected the response of PAM and therefore measurements used to estimate MPB, emphasising the need for care to ensure that representative sampling is done during low tide

Algae drive enhanced darkening of bare ice on the Greenland ice sheet

Surface ablation of the Greenland ice sheet is amplified by surface darkening caused by light-absorbing impurities such as mineral dust, black carbon, and pigmented microbial cells. We present the first quantitative assessment of the microbial contribution to the ice sheet surface darkening, based on field measurements of surface reflectance and concentrations of light-absorbing impurities, including pigmented algae, during the 2014 melt season in the southwestern part of the ice sheet. The impact of algae on bare ice darkening in the study area was greater than that of non-algal impurities and yielded a net albedo reduction of 0.038 ± 0.0035 for each algal population doubling. We argue that algal growth is a crucial control of bare ice darkening, and incorporating the algal darkening effect will improve mass balance and sea level projections of the Greenland ice sheet and ice masses elsewhere