HEIDI: an experiment-management platform enabling high-throughput fragment and compound screening.

The Swiss Light Source facilitates fragment-based drug-discovery campaigns for academic and industrial users through the Fast Fragment and Compound Screening (FFCS) software suite. This framework is further enriched by the option to utilize the Smart Digital User (SDU) software for automated data collection across the PXI, PXII and PXIII beamlines. In this work, the newly developed HEIDI webpage (https://heidi.psi.ch) is introduced: a platform crafted using state-of-the-art software architecture and web technologies for sample management of rotational data experiments. The HEIDI webpage features a data-review tab for enhanced result visualization and provides programmatic access through a representational state transfer application programming interface (REST API). The migration of the local FFCS MongoDB instance to the cloud is highlighted and detailed. This transition ensures secure, encrypted and consistently accessible data through a robust and reliable REST API tailored for the FFCS software suite. Collectively, these advancements not only significantly elevate the user experience, but also pave the way for future expansions and improvements in the capabilities of the system.

Meningococcal Disease in Northern Ireland - Past, Present & Future: MeningoNI Forum.

Meningococcal disease has had devastating consequences in Northern Ireland since its first description locally in 1859. The incidence of this disease has significantly declined in recent years, however it is important to understand reasons for this changing epidemiology and to acknowledge the diagnostic and clinical management developments that have been made locally. This review aims to examine the changing face of this disease in Northern Ireland over the years, with particular reference to local disease prevention, epidemiology, diagnosis, clinical treatment and management, post-disease sequelae and the role of meningitis charities locally, in terms of patient support and research.

SynchWeb: a modern interface for ISPyB.

SynchWeb is a modern interface to the ISPyB database. It significantly simplifies sample registration and is targeted towards live data collection monitoring and remote access for macromolecular crystallography. It adds a variety of new features including project management, an integrated diffraction image viewer, and a map and model viewer, as well as displaying results from automated analysis pipelines. Virtually all aspects of an experiment can be monitored through the web browser and the success of each experiment can be evaluated.

Leuco-crystal-violet micelle gel dosimeters: II. Recipe optimization and testing.

In this study, recipe optimization of Leuco Crystal Violet (LCV) micelle gels made with the surfactant Cetyl Trimethyl Ammonium Bromide (CTAB) and the chemical sensitizer 2,2,2-trichloroethanol (TCE) was aided by a two-level three-factor designed experiment. The optimized recipe contains 0.75 mM LCV, 17.0 mM CTAB, 120 mM TCE, 25.0 mM tri-chloro acetic acid (TCAA), 4 wt% gelatin and ~96 wt% water. Dose sensitivity of the optimized gel is 1.5 times higher than that of Jordan's standard LCV micelle gel. Spatial integrity of the 3D dose distribution information in 1L phantoms filled with this recipe is maintained for >120 d. Unfortunately, phantoms made using the optimized recipe showed dose-rate dependence (14% difference in optical attenuation at the peak dose using electron beam irradiations at 100 and 400 MU min(-1)). Further testing suggests that the surfactant CTAB is the cause of this dose rate behaviour.

Leuco-crystal-violet micelle gel dosimeters: I. Influence of recipe components and potential sensitizers.

Radiochromic leuco crystal violet (LCV) micelle gel dosimeters are promising three-dimensional radiation dosimeters because of their spatial stability and suitability for optical readout. The effects of surfactant type and surfactant concentration on dose sensitivity of LCV micelle gels are tested, demonstrating that dose sensitivity and initial colour of the gel increases with increasing Triton x-100 (Tx100) concentration. Using Cetyl Trimethyl Ammonium Bromide (CTAB) in place of Tx100 produces gels that are nearly colourless prior to irradiation, but reduces the dose sensitivity. The separate effects of Tri-chloro acetic acid concentration and pH are investigated, revealing that controlling the pH near 3.6 is crucial for achieving high dose sensitivity. The sensitizing effect of chlorinated species on dose sensitivity is tested using 2,2,2-trichloroethanol (TCE), chloroform, and 1,1,1-trichloro-2-methyl-2-propanol hemihydrate. TCE gives the largest improvement in dose sensitivity and is recommended for use in micelle gel dosimeters because it is less volatile and safer to use than chloroform. Preliminary experiments on a new gel containing CTAB as the surfactant and TCE show that this new gel gives a dose sensitivity that is 24% higher than that of previous LCV micelle gels and is nearly colourless prior to irradiation.

Evaluation of the potential for diacetylenes as reporter molecules in 3D micelle gel dosimetry.

Radiochromic micelle gel dosimeters are promising for three-dimensional (3D) radiation dosimetry because they can be read out by optical CT techniques and they have superior spatial stability compared to polymer and Fricke gel dosimeters. This study evaluates the use of diacetylenes as reporter molecules in micelle gel dosimeters. Several gels containing pentacosa-10,12-diynoic acid (PCDA) emulsified using sodium dodecyl sulfate (SDS) changed from colourless to blue upon irradiation. Unfortunately, all phantoms that experienced a colour change were turbid and would be unsuitable for 3D dosimetry. Two techniques (use of organic solvent and aqueous-phase additives) were successful in increasing colloidal stability to prevent the turbidity problem, but none of the resulting transparent gels changed colour in response to radiation. Transparent PCDA emulsions were prepared using NaOH solutions with no SDS or other emulsifier, but these transparent emulsions also did not change colour. Only turbid gels and emulsions with precipitated particles responded to radiation. These results indicate that the colour change was due to the oligomerization within precipitated PCDA crystals, and that liquid-phase emulsified PCDA did not undergo oligomerization. As a result, PCDA is not suitable for use in micelle gel dosimeters, and other radiochromic reporter molecules will need to be identified.

Cosolvent-free polymer gel dosimeters with improved dose sensitivity and resolution for x-ray CT dose response.

This study reports new N-isopropylacrylamide (NIPAM) polymer gel recipes with increased dose sensitivity and improved dose resolution for x-ray CT readout. NIPAM can be used to increase the solubility of N, N'-methylenebisacrylamide (Bis) in aqueous solutions from approximately 3% to 5.5% by weight, enabling the manufacture of dosimeters containing up to 19.5%T, which is the total concentration of NIPAM and Bis by weight. Gelatin is shown to have a mild influence on dose sensitivity when gels are imaged using x-ray CT, and a stronger influence when gels are imaged optically. Phantoms that contain only 3% gelatin and 5 mM tetrakis hydroxymethyl phosphonium chloride are sufficiently stiff for dosimetry applications. The best cosolvent-free gel formulation has a dose sensitivity in the linear range (~0.88 H Gy(-1)) that is a small improvement compared to the best NIPAM-based gels that incorporate isopropanol as a cosolvent (~0.80 H Gy(-1)). This new gel formulation results in enhanced dose resolution (~0.052 Gy) for x-ray CT readout, making clinical applications of this imaging modality more feasible.

Polymer gel dosimeters with enhanced sensitivity for use in x-ray CT polymer gel dosimetry.

A primary limitation of current x-ray CT polymer gel dosimetry is the low contrast, and hence poor dose resolution, of dose images produced by the system. The low contrast is largely due to the low-dose sensitivity of current formulations of polymer gel for x-ray CT imaging. This study reports on the investigation of new dosimeter formulations with improved dose sensitivity for x-ray CT polymer gel dosimetry. We incorporate an isopropanol co-solvent into an N-isopropylacrylamide-based gel formulation in order to increase the total monomer/crosslinker concentration (%T) within the formulation. It is shown that gels of high %T exhibit enhanced dose sensitivity and dose resolutions over traditional formulations. The gels are shown to be temporally stable and reproducible. A single formulation (16%T) is used to demonstrate the capabilities of the x-ray CT polymer gel dosimetry system in measuring known dose distributions. A 1 L gel volume is exposed to three separate irradiations: a single-field percent depth dose, a two-field 'cross' and a three-field 'test case'. The first two irradiations are used to generate a dose calibration curve by which images are calibrated. The calibrated images are compared with treatment planning predictions and it is shown that the x-ray CT polymer gel dosimetry system is capable of capturing spatial and dose information accurately. The proposed new gel formulation is shown to be sensitive, stable and to improve the dose resolution over current formulations so as to provide a feasible gel for clinical applications of x-ray CT polymer gel dosimetry.

Polymer gel dosimetry.

Polymer gel dosimeters are fabricated from radiation sensitive chemicals which, upon irradiation, polymerize as a function of the absorbed radiation dose. These gel dosimeters, with the capacity to uniquely record the radiation dose distribution in three-dimensions (3D), have specific advantages when compared to one-dimensional dosimeters, such as ion chambers, and two-dimensional dosimeters, such as film. These advantages are particularly significant in dosimetry situations where steep dose gradients exist such as in intensity-modulated radiation therapy (IMRT) and stereotactic radiosurgery. Polymer gel dosimeters also have specific advantages for brachytherapy dosimetry. Potential dosimetry applications include those for low-energy x-rays, high-linear energy transfer (LET) and proton therapy, radionuclide and boron capture neutron therapy dosimetries. These 3D dosimeters are radiologically soft-tissue equivalent with properties that may be modified depending on the application. The 3D radiation dose distribution in polymer gel dosimeters may be imaged using magnetic resonance imaging (MRI), optical-computerized tomography (optical-CT), x-ray CT or ultrasound. The fundamental science underpinning polymer gel dosimetry is reviewed along with the various evaluation techniques. Clinical dosimetry applications of polymer gel dosimetry are also presented.

Preliminary investigation of the NMR, optical and x-ray CT dose-response of polymer gel dosimeters incorporating cosolvents to improve dose sensitivity.

This study reports on efforts to increase the dose sensitivity of polymer gel dosimeters used in 3D radiation dosimetry. The potential of several different cosolvents is investigated, with the aim of increasing the solubility of N,N'-methylene-bisacrylamide crosslinker in polymer gel dosimeters. Glycerol and isopropanol increase the limit for the crosslinker solubility from approximately 3% to 5% and 10% by weight, respectively. This enables the manufacture of polymer gel dosimeters with much higher levels of crosslinking than was previously possible. New dosimeter recipes containing up to 5 wt% N,N'-methylene-bisacrylamide were subjected to spatially uniform radiation and were studied using nuclear magnetic resonance (NMR), as well as x-ray and optical CT techniques. The resulting dosimeters exhibit dose sensitivities that are up to 2.7 times higher than measured for a typical dosimeters with 3% N,N'-methylene-bisacrylamide without the addition of cosolvent. Two additional cosolvents (n-propanol and sec-butanol) were deemed unsuitable for practical dosimeters due to incompatibility with gelatin, cloudiness prior to irradiation, and immiscibility with water when large quantities of cosolvent were used. The dosimeters with high N,N'-methylene-bisacrylamide content that used isopropanol or glycerol as cosolvents had high optical clarity prior to irradiation, but did not produce suitable optical CT results for non-uniformly irradiated gels due to polymer development outside of the high dose regions of the pencil beams and significant light scatter. Further experiments are required to determine whether cosolvents can be used to manufacture gels with sufficiently high dose sensitivity for readout using x-ray computed tomography.

Effects of glycerol co-solvent on the rate and form of polymer gel dose response.

A factor currently limiting the clinical utility of x-ray CT polymer gel dosimetry is the overall low dose sensitivity (and hence low dose resolution) of the system. Hence, active research remains in the investigation of polymer gel formulations with increased CT dose response. An ideal polymer gel dosimeter will exhibit a sensitive CT response which is linear over a suitable dose range, making clinical implementation reasonably straightforward. This study reports on the variations in rate and form of the CT dose response of irradiated polymer gels manufactured with glycerol, which is a co-solvent that permits dissolution of additional bisacrylamide above its water solubility limit (3% by weight). This study focuses on situations where the concentration of bisacrylamide is kept at or below its water solubility limit so that the influence of the co-solvent on the dose response can be explored separately from the effects of increased cross-linker concentration. CT imaging and Raman spectroscopy are used to construct dose-response curves for irradiated gels varying in (i) initial total monomer (%T) and (ii) initial co-solvent concentration. Results indicate that: (i) for a fixed glycerol concentration, gel response increases linearly with %T. Furthermore, the functional form of the dose response remains constant, in agreement with a previous model of polymer formation. (ii) Polymer gels with constant %T and increasing co-solvent concentrations also show enhanced CT response. In addition, the functional form of the response is altered in these gels as co-solvent concentration is increased. Raman data indicate that the fraction of bis-acrylamide incorporated into polymerization, as opposed to cyclization, increases as co-solvent concentration increases. The changes in functional form indicate varying polymer yields (per unit dose), akin to relative fractional monomer/cross-linker (i.e. %C) changes in earlier studies. These results are put into context of the model of polymer formation. The implications of these results on the clinical utility of polymer gels with co-solvent are highlighted.

Dose integration characteristics in normoxic polymer gel dosimetry investigated using sequential beam irradiation.

Dose integration properties were investigated for normoxic polymer gels based on methacrylic acid (nMAG) and acrylamide/N, N'-methylenebisacrylamide (nPAG). The effect of sequential irradiation was studied for different fractionation schemes and varying amounts of methacrylic acid for the nMAG gels. Magnetic resonance imaging (MRI) was used for read out of the absorbed dose response. The investigated gels exhibited a dependence on the fractionation scheme. The response when the total dose was divided into fractions of 0.5 Gy was compared with the response when the total dose was delivered in a single fraction. The slope of the R2 versus the absorbed dose response decreased when the absorbed dose per fraction was increased. Also, for higher amounts of methacrylic acid in the nMAG system the difference in the response increased. For gels containing 2, 4, 6 and 8% methacrylic acid, the R2 versus the absorbed dose response increased by 35, 37, 63 and 93%, respectively. Furthermore, the effect of the fractionation was larger when a higher total absorbed dose was given. The effect was less pronounced for the investigated nPAG, containing 3% acrylamide and 3% N, N'-methylenebisacrylamide, than for the nMAG systems. Consequently, this study indicates that the nPAG system has preferable beam integration characteristics compared with the nMAG system.

Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose-response using different monomers.

In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies.

Long-term effects of popular dietary approaches on weight loss and features of insulin resistance.

OBJECTIVE: High-carbohydrate (HC)-high-fibre diets are recommended for weight loss and for treating and preventing diseases such as diabetes and cardiovascular disease. We report a randomised trial comparing high-fat (HF) and high-protein (HP) diets with the conventional approach. RESEARCH DESIGN AND METHODS: A total of 93 overweight insulin-resistant women received advice following randomisation to HF, HP or HC dietary regimes, to achieve weight loss followed by weight maintenance over 12 months. Weight, body composition and measures of carbohydrate and lipid metabolism were investigated. RESULTS: Retention rates were 93% for HP and 75% for HC and HF. Features of the metabolic syndrome improved in all groups during the first 6 months, to a greater extent on HF and HP than an HC. During the second 6 months the HF group had increases in waist circumference (mean difference 4.4 cm (95% CI 3.0, 5.8)), fat mass (2.3 kg (1.5, 3.1)), triglycerides (0.28 mmol/l (0.09, 0.46)) and 2 h glucose (0.70 mmol/l (0.22, 1.18)). Overall there was substantial sustained improvement in waist circumference, triglycerides and insulin in the HP group and sustained but more modest changes on HC. Dietary compliance at 12 months was poor in all groups. CONCLUSIONS: HP and HC approaches appear to be appropriate options for insulin-resistant individuals. When recommending HP diets appropriate composition of dietary fat must be ensured. HC diet recommendations must include advice regarding appropriate high-fibre, low glycaemic index foods.

Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin-resistant obese women.

AIMS/HYPOTHESIS: A diet low in saturated fatty acids and rich in wholegrains, vegetables and fruit is recommended in order to reduce the risk of obesity, cardiovascular disease and type 2 diabetes mellitus. However there is widespread interest in high-fat ("Atkins Diet") and high-protein ("Zone Diet") alternatives to the conventional high-carbohydrate, high-fibre approach. We report on a randomised trial that compared these two alternative approaches with a conventional diet in overweight insulin-resistant women. METHODS: Ninety-six normoglycaemic, insulin-resistant women (BMI >27 kg/m(2)) were randomised to one of three dietary interventions: a high-carbohydrate, high-fibre (HC) diet, the high-fat (HF) Atkins Diet, or the high-protein (HP) Zone Diet. The experimental approach was designed to mimic what might be achieved in clinical practice: the recommendations involved advice concerning food choices and were not prescriptive in terms of total energy. There were supervised weight loss and weight maintenance phases (8 weeks each), but there was no contact between the research team and the participants during the final 8 weeks of the study. Outcome was assessed in terms of body composition and indicators of cardiovascular and diabetes risk. RESULTS: Body weight, waist circumference, triglycerides and insulin levels decreased with all three diets but, apart from insulin, the reductions were significantly greater in the HF and HP groups than in the HC group. These observations suggest that the popular diets reduced insulin resistance to a greater extent than the standard dietary advice did. When compared with the HC diet, the HF and HP diets were shown to produce significantly (p<0.01) greater reductions in several parameters, including weight loss (HF -2.8 kg, HP -2.7 kg), waist circumference (HF -3.5 cm, HP -2.7 cm) and triglycerides (HF -0.30 mmol/l, HP [corrected] -0.22 mmol/l). LDL cholesterol decreased in individuals on the HC and HP diets, but tended to fluctuate in those on the HF diet to the extent that overall levels were significantly lower in the HP group than in the HF group (-0.28 mmol/l, 95% CI 0.04-0.52, p=0.02). Of those on the HF diet, 25% showed a >10% increase in LDL cholesterol, whereas this occurred in only 13% of subjects on the HC diet and 3% of those on the HP diet. CONCLUSIONS/INTERPRETATION: In routine practice a reduced-carbohydrate, higher protein diet may be the most appropriate overall approach to reducing the risk of cardiovascular disease and type 2 diabetes. To achieve similar benefits on a HC diet, it may be necessary to increase fibre-rich wholegrains, legumes, vegetables and fruits, and to reduce saturated fatty acids to a greater extent than appears to be achieved by implementing current guidelines. The HF approach appears successful for weight loss in the short term, but lipid levels should be monitored. The potential deleterious effects of the diet in the long term remain a concern.