Summary Background The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2·0 Gy over 5 weeks, but there is a long history of non-standard regimens ...delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2·0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. Methods Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2·0 Gy over 5 weeks or 40 Gy in 15 fractions of 2·67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. Findings 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6·0 years (IQR 5·0–6·2) the rate of local-regional tumour relapse at 5 years was 2·2% (95% CI 1·3–3·1) in the 40 Gy group and 3·3% (95% CI 2·2 to 4·5) in the 50 Gy group, representing an absolute difference of −0·7% (95% CI −1·7% to 0·9%)—ie, the absolute difference in local-regional relapse could be up to 1·7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. Interpretation A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.
The evaporation of liquid solution droplets and solute crystallization can be highly complex and is an important problem, particularly in spray drying where powdered products are produced from ...sprayed liquid droplets, such as in the food or pharmaceutical industries. In this work, we study the relationship between the evaporation rates of single levitated NaNO3 droplets under varying environmental conditions and the propensity for nucleation of NaNO3 crystals. We use a combination of an electrodynamic balance to study single-droplet evaporation kinetics, SEM imaging of dried particles, and modeling of the internal solute distribution inside a drying droplet. We show that the aqueous NaNO3 droplets exhibit broad distributions in the time that crystal nucleation is observed, droplet to droplet. The distribution of nucleation time is dependent upon environmental conditions such as the drying temperature, relative humidity (RH), and solute concentration. Even when evaporating in 0% RH, some droplets do not nucleate crystals in the time taken for all water to evaporate and dry to form an amorphous particle. We believe that this interplay between crystalline or amorphous particle formation is a result of the viscosity of aqueous NaNO3 solutions, which rises by several orders of magnitude as the concentration increases. We show that for droplets with an initial radius of ∼25 μm the propensity for aqueous NaNO3 droplets to nucleate crystals upon drying increases with a decreasing RH and increases with an increasing temperature in the range 278–306 K. This work demonstrates the importance of the drying kinetics on the propensity of evaporating droplets to nucleate crystals.
We present a detailed analysis of the far-infrared (-IR) properties of the bright, lensed, z = 2.3, submillimetre-selected galaxy (SMG), SMM J2135-0102 (hereafter SMM J2135), using new observations ...with Herschel, SCUBA-2 and the Very Large Array (VLA). These data allow us to constrain the galaxy's spectral energy distribution (SED) and show that it has an intrinsic rest-frame 8-1000-μm luminosity, Lbol, of (2.3±0.2) × 1012 L⊙ and a likely star-formation rate (SFR) of ~400 M⊙ yr-1. The galaxy sits on the far-IR/radio correlation for far-IR-selected galaxies. At ⪆70 μm, the SED can be described adequately by dust components with dust temperatures, Td ~ 30 and 60 k. Using SPIRE's Fourier- transform spectrometer (FTS) we report a detection of the C ii 158 μm cooling line. If the C ii, CO and far-IR continuum arise in photo-dissociation regions (PDRs), we derive a characteristic gas density, n ~ 103 cm-3, and a far-ultraviolet (-UV) radiation field, G0, 103× stronger than the Milky Way. LCII/Lbol is significantly higher than in local ultra-luminous IR galaxies (ULIRGs) but similar to the values found in local star-forming galaxies and starburst nuclei. This is consistent with SMM J2135 being powered by starburst clumps distributed across ~2 kpc, evidence that SMGs are not simply scaled-up ULIRGs. Our results show that SPIRE's FTS has the ability to measure the redshifts of distant, obscured galaxies via the blind detection of atomic cooling lines, but it will not be competitive with ground-based CO-line searches. It will, however, allow detailed study of the integrated properties of high-redshift galaxies, as well as the chemistry of their interstellar medium (ISM), once more suitably bright candidates have been found. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.
Phyllosilicates, a class of hydrous mineral first definitively identified on Mars by the OMEGA (Observatoire pour la Mineralogie, L'Eau, les Glaces et l'Activitié) instrument, preserve a record of ...the interaction of water with rocks on Mars. Global mapping showed that phyllosilicates are widespread but are apparently restricted to ancient terrains and a relatively narrow range of mineralogy (Fe/Mg and Al smectite clays). This was interpreted to indicate that phyllosilicate formation occurred during the Noachian (the earliest geological era of Mars), and that the conditions necessary for phyllosilicate formation (moderate to high pH and high water activity) were specific to surface environments during the earliest era of Mars's history. Here we report results from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) of phyllosilicate-rich regions. We expand the diversity of phyllosilicate mineralogy with the identification of kaolinite, chlorite and illite or muscovite, and a new class of hydrated silicate (hydrated silica). We observe diverse Fe/Mg-OH phyllosilicates and find that smectites such as nontronite and saponite are the most common, but chlorites are also present in some locations. Stratigraphic relationships in the Nili Fossae region show olivine-rich materials overlying phyllosilicate-bearing units, indicating the cessation of aqueous alteration before emplacement of the olivine-bearing unit. Hundreds of detections of Fe/Mg phyllosilicate in rims, ejecta and central peaks of craters in the southern highland Noachian cratered terrain indicate excavation of altered crust from depth. We also find phyllosilicate in sedimentary deposits clearly laid by water. These results point to a rich diversity of Noachian environments conducive to habitability.
Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral ...vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines.
Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.
Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation.
Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.
UK Vaccine Task Force and National Institute for Health Research.
Drug resistance in liver flukes Fairweather, I.; Brennan, G.P.; Hanna, R.E.B. ...
International journal for parasitology -- drugs and drug resistance,
04/2020, Volume:
12
Journal Article
Peer reviewed
Open access
Liver flukes include Fasciola hepatica, Fasciola gigantica, Clonorchis sinensis, Opisthorchis spp., Fascioloides magna, Gigantocotyle explanatum and Dicrocoelium spp. The two main species, F. ...hepatica and F. gigantica, are major parasites of livestock and infections result in huge economic losses. As with C. sinensis, Opisthorchis spp. and Dicrocoelium spp., they affect millions of people worldwide, causing severe health problems. Collectively, the group is referred to as the Food-Borne Trematodes and their true significance is now being more widely recognised. However, reports of resistance to triclabendazole (TCBZ), the most widely used anti-Fasciola drug, and to other current drugs are increasing. This is a worrying scenario. In this review, progress in understanding the mechanism(s) of resistance to TCBZ is discussed, focusing on tubulin mutations, altered drug uptake and changes in drug metabolism. There is much interest in the development of new drugs and drug combinations, the re-purposing of non-flukicidal drugs, and the development of new drug formulations and delivery systems; all this work will be reviewed. Sound farm management practices also need to be put in place, with effective treatment programmes, so that drugs can be used wisely and their efficacy conserved as much as is possible. This depends on reliable advice being given by veterinarians and other advisors. Accurate diagnosis and identification of drug-resistant fluke populations is central to effective control: to determine the actual extent of the problem and to determine how well or otherwise a treatment has worked; for research on establishing the mechanism of resistance (and identifying molecular markers of resistance); for informing treatment options; and for testing the efficacy of new drug candidates. Several diagnostic methods are available, but there are no recommended guidelines or standardised protocols in place and this is an issue that needs to be addressed.
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•Liver flukes are major parasites of humans and livestock and cause severe disease.•Resistance to triclabendazole and other flukicides is becoming a serious problem.•The mechanism of resistance to triclabendazole is not clear, but may have a polygenic basis.•Possible treatment and management strategies to deal with resistance are discussed.•Several diagnostic tests are available, but no recommended guidelines are in place.
•We investigate the thermal mechanisms by which microwave heating enhances emulsion separation.•Settling times decrease with increased microwave heating duration and the addition of NaCl.•Results ...show significant water droplet coalescence, but viscosity effects cannot be decoupled.•No evidence for non-thermal microwave effects is observed.•Proposed mechanism is selective heating of the saline phase causing thermal gradients in the oil.
The separation of water-in-oil emulsions made with Azeri crude was investigated using natural gravity settling and microwave heating techniques. Separation times could be reduced by an order of magnitude compared with untreated emulsions. Increasing the salinity of the water phase leads to a 15% average decrease in the settling time for untreated emulsions compared with over 90% for microwave-heated emulsions. An image analysis technique showed that the observed increases in settling time could not be attributed to changes in viscosity alone. Significant coalescence of water droplets occurs during microwave heating, however the effects of coalescence and viscosity reduction cannot be completely decoupled. Despite this, it is clear that it is the thermal effect of microwave heating that leads to improvements in settling times, and that any advantages in microwave heating over conventional heating can be explained by selective heating of the aqueous phase rather than so-called non-thermal effects.
There is considerable need to develop tailored approaches to psychiatric treatment. Numerous researchers have proposed using functional magnetic resonance imaging (fMRI) biomarkers to predict ...therapeutic response, in particular by measuring task-evoked subgenual anterior cingulate (sgACC) and amygdala activation in mood and anxiety disorders. Translating this to the clinic relies on the assumption that blood-oxygen-level dependent (BOLD) responses in these regions are stable within individuals. To test this assumption, we scanned a group of 29 volunteers twice (mean test-retest interval=14.3 days) and calculated the within-subject reliability of the amplitude of the amygdalae and sgACC BOLD responses to emotional faces using three paradigms: emotion identification; emotion matching; and gender classification. We also calculated the reliability of activation in a control region, the right fusiform face area (FFA). All three tasks elicited robust group activations in the amygdalae and sgACC (which changed little on average over scanning sessions), but within-subject reliability was surprisingly low, despite excellent reliability in the control right FFA region. Our findings demonstrate low statistical reliability of two important putative treatment biomarkers in mood and anxiety disorders.
•Reliability of neural responses to emotional faces was measured in healthy subjects.•Robust responses were detected in the amygdalae and subgenual anterior cingulate.•Amygdala and subgenual cingulate activation were rarely reliable over time.•Responses in the fusiform face area were generally highly reliable.
Abstract Background Efficacy and safety of alirocumab were compared with ezetimibe in hypercholesterolemic patients at moderate cardiovascular risk not receiving statins or other lipid-lowering ...therapy. Methods In a Phase 3, randomized, double-blind, double-dummy study ( NCT01644474 ), patients (low-density lipoprotein cholesterol LDL-C 100–190 mg/dL, 10-year risk of fatal cardiovascular events ≥ 1%–<5% systemic coronary risk estimation) were randomized to ezetimibe 10 mg/day ( n = 51) or alirocumab 75 mg subcutaneously (via 1mL autoinjector) every 2 weeks (Q2W) ( n = 52), with dose up-titrated to 150 mg Q2W (also 1 mL) at week 12 if week 8 LDL-C was ≥ 70 mg/dL. Primary endpoint was mean LDL-C % change from baseline to 24 weeks, analyzed using all available data (intent-to-treat approach, ITT). Analyses using on-treatment LDL-C values were also conducted. Results Mean (SD) baseline LDL-C levels were 141.1 (27.1) mg/dL (alirocumab) and 138.3 (24.5) mg/dL (ezetimibe). The 24-week treatment period was completed by 85% of alirocumab and 86% of ezetimibe patients. Least squares mean (SE) LDL-C reductions were 47 (3)% with alirocumab versus 16 (3)% with ezetimibe (ITT; p < 0.0001) and 54 (2)% versus 17 (2)% (on-treatment; p < 0.0001). At week 12, before up-titration, alirocumab 75 mg Q2W reduced LDL-C by 53 (2)% (on-treatment). Injection site reactions were infrequent (< 2% and < 4% of alirocumab and ezetimibe patients, respectively). Conclusions Alirocumab demonstrated significantly greater LDL-C lowering versus ezetimibe after 24 weeks with the lower 75 mg Q2W dose sufficient to provide ≥ 50% LDL-C reduction in the majority of the patients. Adverse events were comparable between groups.
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