Adaptive clinical trials incorporating treatment selection and evaluation: methodology and application in progressive multiple sclerosis

In progressive multiple sclerosis (MS) irreversible disability often takes many years to accumulate as a result prolonged trials are required to assess the benefits of therapies. There is a need to understand the relationship between short-term outcome measures such as MRI endpoints and long-term clinical outcomes in progression to determine the evolution of the disease early on. Thus, the common phase I-II-III paradigm for clinical trial design with separate trials for each phase may not be appropriate

Increased susceptibility to repeated freeze-thaw cycles in Escherichia coli following long-term evolution in a benign environment

BACKGROUND: In order to study the dynamics of evolutionary change, 12 populations of E. coli B were serially propagated for 20,000 generations in minimal glucose medium at constant 37°C. Correlated changes in various other traits have been previously associated with the improvement in competitive fitness in the selective environment. This study examines whether these evolved lines changed in their ability to tolerate the stresses of prolonged freezing and repeated freeze-thaw cycles during adaptation to a benign environment. RESULTS: All 12 lines that evolved in the benign environment for 20,000 generations are more sensitive to freeze-thaw cycles than their ancestor. The evolved lines have an average mortality rate of 54% per daily cycle, compared to the ancestral rate of 34%. By contrast, there was no significant difference between the evolved lines and their ancestor in mortality during prolonged freezing. There was also some variability among the evolved lines in susceptibility to repeated freeze-thaw cycles. Those lines that had evolved higher competitive fitness in the minimal glucose medium at 37°C also had higher mortality during freeze-thaw cycles. This variability was not associated, however, with differences among lines in DNA repair functionality and mutability. CONCLUSION: The consistency of the evolutionary declines in freeze-thaw tolerance, the correlation between fitness in glucose medium at 37°C and mortality during freeze-thaw cycles, and the absence of greater declines in freeze-thaw survival among the hypermutable lines all indicate a trade-off between performance in minimal glucose medium at 37°C and the capacity to tolerate this stress. Analyses of the mutations that enhance fitness at 37°C may shed light on the physiological basis of this trade-off

Structure and Composition of Molecular Clouds with CN Zeeman Detections I: W3OH

We have carried out a multi-species study of a region which has had previous measurements of strong magnetic fields through the CN Zeeman effect in order to to explore the relationship between CN and N$_2$H$^+$, both of which have evidence that they remain in the gas phase at densities of 10$^5$ - 10$^6$ cm$^{-3}$. To achieve this we map the 1 arcmin$^2$ region around the UCHII region of W3(OH) using the Combined Array for Millimeter-wave Astronomy (CARMA). Approximately 105 hours of data were collected in multiple array configurations to produce maps with an effective resolution of $\sim$ 2.5\arcsec at high signal-to-noise in CN, C$^{18}$O, HCN, HCO$^+$, N$_2$H$^+$, and two continuum bands (91.2 GHz and 112 GHz). These data allow us to compare tracer molecules associated with both low and high density regions to infer gas properties. We determine that CARMA resolves out approximately 35% of the CN emission around W3(OH) when compared with spectra obtained from the IRAM-30 meter telescope. The presence of strong absorption lines towards the continuum source in three of the molecular transitions infers the presence of a cold, dark, optically thick region in front of the continuum source. In addition, the presence of high-velocity emission lines near the continuum source shows the presence of hot clumpy emission behind the continuum source. These data determine that future high-resolution interferometric CN Zeeman measurements which cannot currently be performed (due to technical limitations of current telescopes) are feasible. We confirm that CN is indeed a good tracer for high density regions; with certain objects such as W3(OH) it appears to be a more accurate tracer than N$_2$H$^+$.Comment: 33 pages, 16 figures. Accepted by Ap

The Gravitational Lens Candidate FBQ 1633+3134

We present our ground-based optical imaging, spectral analysis, and high resolution radio mapping of the gravitational lens candidate FBQ 1633+3134. This z=1.52, B=17.7 quasar appears double on CCD images with an image separation of 0.66 arcseconds and a flux ratio of ~3:1 across BVRI filters. A single 0.27 mJy radio source is detected at 8.46 GHz, coincident to within an arcsecond of both optical components, but no companion at radio wavelengths is detected down to a flux level of 0.1 mJy (3 sigma). Spectral observations reveal a rich metal-line absorption system consisting of a strong Mg II doublet and associated Fe I and Fe II absorption features, all at an intervening redshift of z=0.684, suggestive of a lensing galaxy. Point spread function subtraction however shows no obvious signs of a third object between the two quasar images, and places a detection limit of I > 23.0 if such an object exists. Although the possibility that FBQ 1633+3134 is a binary quasar cannot be ruled out, the evidence is consistent with it being a single quasar lensed by a faint, metal-rich galaxy.Comment: 24 pages, 5 figures. Accepted by AJ. A calibration error affecting B and V band apparent magnitudes has been corrected. The conclusions of the paper are not change

Validation of a clinical and genetic model for predicting severe COVID-19

Using nested case-control data from the Lifelines COVID-19 cohort, we undertook a validation study of a clinical and genetic model to predict the risk of severe COVID-19 in people with confirmed COVID-19 and in people with confirmed or self-reported COVID-19. The model performed well in terms of discrimination of cases and controls for all ages (area under the receiver operating characteristic curve (AUC) = 0.680 for confirmed COVID-19 and AUC = 0.689 for confirmed and self-reported COVID-19) and in the age group in which the model was developed (50 years and older; AUC = 0.658 for confirmed COVID-19 and AUC = 0.651 for confirmed and self-reported COVID-19). There was no evidence of over- or under-dispersion of risk scores but there was evidence of overall over-estimation of risk in all analyses (all P < 0.0001). In the light of large numbers of people worldwide remaining unvaccinated and continuing uncertainty regarding vaccine efficacy over time and against variants of concern, identification of people at high risk of severe COVID-19 may encourage the uptake of vaccinations (including boosters) and the use of non-pharmaceutical inventions

Invisible water, visible impact: How unsustainable groundwater use challenges sustainability of Indian agriculture under climate change

India is one of the world’s largest food producers, making the sustainability of its agricultural system of global significance. Groundwater irrigation underpins India’s agriculture, currently boosting crop production by enough to feed 170 million people. Groundwater overexploitation has led to drastic declines in groundwater levels, threatening to push this vital resource out of reach for millions of small-scale farmers who are the backbone of India’s food security. Historically, losing access to groundwater has decreased agricultural production and increased poverty. We take a multidisciplinary approach to assess climate change challenges facing India’s agricultural system, and to assess the effectiveness of large-scale water infrastructure projects designed to meet these challenges. We find that even in areas that experience climate change induced precipitation increases, expansion of irrigated agriculture will require increasing amounts of unsustainable groundwater. The large proposed national river linking project has limited capacity to alleviate groundwater stress. Thus, without intervention, poverty and food insecurity in rural India is likely to worsen

Evidence That Aberrant Protein Metabolism Contributes To Chemoresistance In Multiple Myeloma Cells

Multiple myeloma (MM) is an incurable B lymphocyte cancer. To date, a comparative analysis of global protein metabolism for the MM cell line CCL-155 (RPMI-8226) and the non-cancerous B lymphocyte cell line CCL-156 (RPMI-1788) has not been published. Here, we report that both global protein synthesis and degradation occur at a higher rate in MM cells and demonstrate that alkylating agents can reduce global protein degradation in both cell lines, but the effect is greater in CCL-156 cells. Treatment with melphalan plus the proteasome inhibitor MG132 reduced global protein degradation for MM cells to roughly 60% of that seen without drugs,, but the reduction was approximately three times greater for CCL-156 cells. This drug combination was growth inhibitory for both cell lines, but CCL-156 inhibition was 2-fold greater than that of the MM cell line. Additionally, treatment with melphalan plus the lysosomal inhibitor chloroquine did not affect growth of MM cells more than melphalan alone, whereas this combination drastically inhibited growth of CCL-156 cells despite protein degradation being maintained at 60% level for both cell lines. This suggests that a lysosomal function other than protein degradation is required for recovery from alkylation damage in CCL-156 cells. In general, CCL-156 cells were affected to a greater extent for both protein degradation and growth inhibition with most drug combinations tested. Statistical analysis of our data (P=0.066) provides evidence that aberrant proteasome-mediated protein degradation correlates with chemoresistance in MM cells, but that lysosome-mediated protein degradation does not