Takshan/R1 huggingface dataset:
Addition of platinum derivatives to neoadjuvant single-agent fluoropyrimidine chemoradiotherapy in patients with stage II/III rectal cancer: protocol for a systematic review and meta-analysis (PROSPERO CRD42017073064).

BACKGROUND: Neoadjuvant (chemo-)radiation has proven to improve local control compared to surgery alone, but this improvement did not translate into better overall or disease-specific survival. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy holds the potential of positively affecting survival in this context since it has been proven effective in the palliative and adjuvant setting of colorectal cancer. Thus, the objective of this systematic review is to assess the efficacy, safety, and quality of life resulting from adding a platinum derivative to neoadjuvant single-agent fluoropyrimidine-based chemoradiotherapy in patients with Union for International Cancer Control stage II and III rectal cancer. METHODS: MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials will be systematically searched to identify all randomized controlled trials comparing single-agent fluoropyrimidine-based chemoradiotherapy to combined neoadjuvant therapy including a platinum derivative. Predefined data on trial design, quality, patient characteristics, and endpoints will be extracted. Quality of included trials will be assessed according to the Cochrane Risk of Bias Tool, and the GRADE recommendations will be applied to judge the quality of the resulting evidence. The main outcome parameter will be survival, but also treatment toxicity, perioperative morbidity, and quality of life will be assessed. DISCUSSION: The findings of this systematic review and meta-analysis will provide novel insights into the efficacy and safety of combined neoadjuvant chemoradiotherapy including a platinum derivative and may form a basis for future clinical decision-making, guideline evaluation, and research prioritization. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017073064.
Alcohol and older people: A systematic review of barriers, facilitators and context of drinking in older people and implications for intervention design.

BACKGROUND: Harmful alcohol consumption in older people has increased and effective approaches to understanding and addressing this societal concern are needed. METHODS: Systematic review of qualitative studies in older populations (55+ years) to identify barriers, facilitators or context of drinking in older people. Multiple databases (MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, Social Sciences Citation Index, York Centre for Reviews and Dissemination, Cochrane database and grey literature) were searched from 2000 to February 2017 for studies in English, from OECD countries using MeSH terms and text words relating to alcohol combined with older age terms. Study quality was assessed using NICE methodology. The review is reported according to PRISMA. RESULTS: Drinking in older people is strongly linked to social engagement and there is scepticism about the health risks of alcohol. Drinking was also linked to difficulties such as social isolation, illness or bereavement. Alcohol can be related to routines and identity. However, older people often regulate their own drinking and strategies that emphasise the life experience of older people to drink wisely could be helpful. CONCLUSIONS: To be effective societal approaches need to take into account contexts of risks for harmful drinking. The evidence supports a strong social role for drinking alcohol which should be taken into account in any policy development with the potential benefits of social participation for cognitive health. Approaches to reducing alcohol use in older people need to avoid paradoxical harm, with a need for approaches that reduce harm from drinking alcohol but retain the benefit of socialising.
Addition of MRI for CT-based pancreatic tumor delineation: a feasibility study.

PURPOSE: To assess the effect of additional magnetic resonance imaging (MRI) alongside the planning computed tomography (CT) scan on target volume delineation in pancreatic cancer patients. MATERIAL AND METHODS: Eight observers (radiation oncologists) from six institutions delineated the gross tumor volume (GTV) on 3DCT, and internal GTV (iGTV) on 4DCT of four pancreatic cancer patients, while MRI was available in a second window (CT + MRI). Variations in volume, generalized conformity index (CIgen), and overall observer variation, expressed as standard deviation (SD) of the distances between delineated surfaces, were analyzed. CIgen is a measure of overlap of the delineated iGTVs (1 = full overlap, 0 = no overlap). Results were compared with those from an earlier study that assessed the interobserver variation by the same observers on the same patients on CT without MRI (CT-only). RESULTS: The maximum ratios between delineated volumes within a patient were 6.1 and 22.4 for the GTV (3DCT) and iGTV (4DCT), respectively. The average (root-mean-square) overall observer variations were SD = 0.41 cm (GTV) and SD = 0.73 cm (iGTV). The mean CIgen was 0.36 for GTV and 0.37 for iGTV. When compared to the iGTV delineated on CT-only, the mean volumes of the iGTV on CT + MRI were significantly smaller (32%, Wilcoxon signed-rank, p < .0005). The median volumes of the iGTV on CT + MRI were included for 97% and 92% in the median volumes of the iGTV on CT. Furthermore, CT + MRI showed smaller overall observer variations (root-mean-square SD = 0.59 cm) in six out of eight delineated structures compared to CT-only (root-mean-square SD = 0.72 cm). However, large local observer variations remained close to biliary stents and pathological lymph nodes, indicating issues with instructions and instruction compliance. CONCLUSIONS: The availability of MRI images during target delineation of pancreatic cancer on 3DCT and 4DCT resulted in smaller target volumes and reduced the interobserver variation in six out of eight delineated structures.
Identification of Differentially Expressed Genes during Bacillus subtilis Spore Outgrowth in High-Salinity Environments Using RNA Sequencing.

In its natural habitat, the soil bacterium Bacillus subtilis often has to cope with fluctuating osmolality and nutrient availability. Upon nutrient depletion it can form dormant spores, which can revive to form vegetative cells when nutrients become available again. While the effects of salt stress on spore germination have been analyzed previously, detailed knowledge on the salt stress response during the subsequent outgrowth phase is lacking. In this study, we investigated the changes in gene expression during B. subtilis outgrowth in the presence of 1.2 M NaCl using RNA sequencing. In total, 402 different genes were upregulated and 632 genes were downregulated during 90 min of outgrowth in the presence of salt. The salt stress response of outgrowing spores largely resembled the osmospecific response of vegetative cells exposed to sustained high salinity and included strong upregulation of genes involved in osmoprotectant uptake and compatible solute synthesis. The σ(B)-dependent general stress response typically triggered by salt shocks was not induced, whereas the σ(W) regulon appears to play an important role for osmoadaptation of outgrowing spores. Furthermore, high salinity induced many changes in the membrane protein and transporter transcriptome. Overall, salt stress seemed to slow down the complex molecular reorganization processes ("ripening") of outgrowing spores by exerting detrimental effects on vegetative functions such as amino acid metabolism.
Correlation between adrenal function, growth hormone secretion, and insulin sensitivity in children with idiopathic growth hormone deficiency.

PURPOSE: Patients with growth hormone deficiency (GHD) demonstrate an increased cortisol/cortisone ratio which could potentially explain the metabolic features of GHD, while GH treatment (GHT) could increase the cortisol metabolism. METHODS: In 35 children (27 M, mean age 10.1 years) with idiopathic GHD at baseline and after 12 months of GHT and in 25 controls, in addition to metabolic parameters, we assessed adrenal function by morning serum cortisol, its peak, and its area under the curve (AUCCOR) during insulin tolerance test (ITT). RESULTS: A cortisol peak <18 µg/dl was shown in 22 and 31% of GHD children at baseline and after GHT, respectively. At baseline, GHD children had lower fasting glucose (p < 0.001) and ISI-Matsuda (p = 0.042), with concomitant higher Homa-IR (p = 0.006) and morning cortisol (p = 0.012) than controls. Morning cortisol was negatively correlated with GH (p < 0.001), fasting glucose (p < 0.001) and ISI-Matsuda (p < 0.001) and positively with Homa-IR (p = 0.010). Both cortisol peak and AUCCOR were negatively correlated with GH (all p < 0.001) and ISI-Matsuda (p = 0.016 and p = 0.001, respectively). After 12 months of GHT, a significant increase in fasting glucose (p < 0.001), and Homa-IR (p = 0.011) was documented, with a concomitant decrease in morning cortisol (p = 0.002), AUCCOR (p = 0.038), total (p = 0.003) and LDL-cholesterol (p = 0.016). No significant correlations were found among cortisol levels and all parameters were investigated. CONCLUSIONS: Cortisol levels correlate with GH secretion and with many metabolic parameters in GHD children, while the metabolic effects during GHT are mainly due to GHT per se and less to cortisol reduction.
Barriers and Facilitators to the Uptake and Maintenance of Healthy Behaviours by People at Mid-Life: A Rapid Systematic Review.

BACKGROUND: With an ageing population, there is an increasing societal impact of ill health in later life. People who adopt healthy behaviours are more likely to age successfully. To engage people in health promotion initiatives in mid-life, a good understanding is needed of why people do not undertake healthy behaviours or engage in unhealthy ones. METHODS: Searches were conducted to identify systematic reviews and qualitative or longitudinal cohort studies that reported mid-life barriers and facilitators to healthy behaviours. Mid-life ranged from 40 to 64 years, but younger adults in disadvantaged or minority groups were also eligible to reflect potential earlier disease onset. Two reviewers independently conducted reference screening and study inclusion. Included studies were assessed for quality. Barriers and facilitators were identified and synthesised into broader themes to allow comparisons across behavioural risks. FINDINGS: From 16,426 titles reviewed, 28 qualitative studies, 11 longitudinal cohort studies and 46 systematic reviews were included. Evidence was found relating to uptake and maintenance of physical activity, diet and eating behaviours, smoking, alcohol, eye care, and other health promoting behaviours and grouped into six themes: health and quality of life, sociocultural factors, the physical environment, access, psychological factors, evidence relating to health inequalities. Most of the available evidence was from developed countries. Barriers that recur across different health behaviours include lack of time (due to family, household and occupational responsibilities), access issues (to transport, facilities and resources), financial costs, entrenched attitudes and behaviours, restrictions in the physical environment, low socioeconomic status, lack of knowledge. Facilitators include a focus on enjoyment, health benefits including healthy ageing, social support, clear messages, and integration of behaviours into lifestyle. Specific issues relating to population and culture were identified relating to health inequalities. CONCLUSIONS: The barriers and facilitators identified can inform the design of tailored interventions for people in mid-life.
Revisiting the Potential of Alternating Repetition Time Balanced Steady-State Free Precession Imaging of the Abdomen at 3 T.

OBJECTIVE: The aim was to investigate the value of optimized 3-dimensional alternating repetition time balanced steady-state free precession (ATR-SSFP), as an alternative to conventional segmented balanced steady-state free precession (bSSFP) with fat suppression prepulse (FS-bSSFP), in single breath-hold abdominal magnetic resonance imaging at 3 T. METHODS: Bloch simulations were performed to determine the optimal flip angle (FA = 1-90 degrees) and τ (1-3) with respect to signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) between abdominal organs for ATR-SSFP. These were corroborated by phantom measurements for different T1/T2 values (5-47) as well as in a healthy volunteer. In addition, fat suppression efficiency was studied using phantom and volunteer measurements. The effect of resolution on image quality was studied in a healthy volunteer. Using the optimal settings, ATR-SSFP images as well as FS-bSSFP images were obtained in 15 pancreatic cancer patients. For 10 structures of interest, the signal ratio with respect to the pancreas was computed and compared between both sequences. Finally, 10 items on image quality (fat suppression, artifacts, and sharpness) and tissue conspicuity (ducts, vessels, and duodenum) were scored by 2 abdominal radiologists for both image sequences. RESULTS: The results of simulations, phantom measurements, and volunteer measurements showed that, considering scan time, fat suppression, and clinical relevance, the ideal settings for ATR-SSFP were as follows: τ = 3; TR1 = 3.46 milliseconds; radiofrequency phase cycling 0, 180, 180, 0 degrees; and FA = 13-16 degrees (highest SNR) and 24-26 degrees (highest CNR). The optimized feasible additional settings implemented for patient scans were FA = 18 degrees and resolution = 1.4 × 1.4 × 1.4 mm. In patients, the signal ratios of both ATR-SSFP and FS-bSSFP were comparable and had a T2-like contrast behavior, although more accentuated in ATR-SSFP. The ATR-SSFP scored significantly higher than FS-bSSFP for 9 of 10 items scored. CONCLUSIONS: For single breath-hold abdominal imaging at 3 T, ATR-SSFP performs best with τ = 3 and an FA between 13 degrees (highest SNR) and 26 degrees (highest CNR). The scoring of both abdominal radiologists indicated that, at τ = 3, FA = 18 degrees, and 1.4 × 1.4 × 1.4 mm resolution, ATR-SSFP was preferred over conventional FS-bSSFP with similar settings.
Regulation of Locomotor activity in fed, fasted, and food-restricted mice lacking tissue-type plasminogen activator.

BACKGROUND: Circadian rhythms of physiology and behavior are driven by a circadian clock located in the suprachiasmatic nucleus of the hypothalamus. This clock is synchronized to environmental day/night cycles by photic input, which is dependent on the presence of mature brain-derived neurotrophic factor (BDNF) in the SCN. Mature BDNF is produced by the enzyme plasmin, which is converted from plasminogen by the enzyme tissue-type plasminogen activator (tPA). In this study, we evaluate circadian function in mice lacking functional tPA. RESULTS: tPA-/- mice have normal circadian periods, but show decreased nocturnal wheel-running activity. This difference is eliminated or reversed on the second day of a 48-h fast. Similarly, when placed on daily cycles of restricted food availability the genotypic difference in total wheel-running activity disappears, and tPA-/- mice show equivalent amounts of food anticipatory activity to wild type mice. CONCLUSIONS: These data suggest that tPA regulates nocturnal wheel-running activity, and that tPA differentially affects SCN-driven nocturnal activity rhythms and activity driven by fasting or temporal food restriction.
Minimizing the Acquisition Time for Intravoxel Incoherent Motion Magnetic Resonance Imaging Acquisitions in the Liver and Pancreas.

OBJECTIVES: The aim of this study was to determine the combination of b-values and signal averages for diffusion-weighted image acquisitions that render the minimum acquisition time necessary to obtain values of the intravoxel incoherent motion (IVIM) model parameters in vivo in the pancreas or liver with acceptable reproducibility. MATERIALS AND METHODS: For 16 volunteers, diffusion-weighted images, with 14 b-values and 9 acquisitions per b-value, were acquired in 2 scan sessions. The IVIM model was fitted to data from lesion-sized regions of interest (ROIs) (1.7 cm) as well as organ-sized ROIs in the pancreas and liver. By deleting data during analyzes, the IVIM model parameters, D and f, could be determined as a function of the number of b-values as well as the number of measurements per b-value taken along. For the IVIM model parameters, we examined the behavior reproducibility, in the form of the within-subject coefficient of variation (CVw), as a function of the amount of data taken along in the fits. Finally, we determined the minimum acquisition time required as a function of CVw. RESULT: For the lesion-sized ROI, the intersession CVws were 8%/46% and 13%/55% for D/f in the pancreas and liver, respectively, when all data were taken along. For 1.2 times larger CVws, acquisition in the pancreas could be done in 5:15 minutes using 9 acquisitions per b-value at b = 0, 30, 50, 65, 100, 375, and 500 mms and for the liver in 2:15 using 9 acquisitions per b-value at b = 0, 40, and 500 mms. CONCLUSIONS: Acquiring 7 b-values in the pancreas and 3 b-values in the liver only decreases the reproducibility by 20% compared with an acquisition with 14 b-values. The understanding of the behavior of reproducibility as a function of b-values and acquisitions per b-values scanned will help researchers select the shortest IVIM protocol.
Insights into the molecular regulation of monolignol-derived product biosynthesis in the growing hemp hypocotyl.

BACKGROUND: Lignin and lignans are both derived from the monolignol pathway. Despite the similarity of their building blocks, they fulfil different functions in planta. Lignin strengthens the tissues of the plant, while lignans are involved in plant defence and growth regulation. Their biosyntheses are tuned both spatially and temporally to suit the development of the plant (water conduction, reaction to stresses). We propose to study the general molecular events related to monolignol-derived product biosynthesis, especially lignin. It was previously shown that the growing hemp hypocotyl (between 6 and 20 days after sowing) is a valid system to study secondary growth and the molecular events accompanying lignification. The present work confirms the validity of this system, by using it to study the regulation of lignin and lignan biosynthesis. Microscopic observations, lignin analysis, proteomics, together with in situ laccase and peroxidase activity assays were carried out to understand the dynamics of lignin synthesis during the development of the hemp hypocotyl. RESULTS: Based on phylogenetic analysis and targeted gene expression, we suggest a role for the hemp dirigent and dirigent-like proteins in lignan biosynthesis. The transdisciplinary approach adopted resulted in the gene- and protein-level quantification of the main enzymes involved in the biosynthesis of monolignols and their oxidative coupling (laccases and class III peroxidases), in lignin deposition (dirigent-like proteins) and in the determination of the stereoconformation of lignans (dirigent proteins). CONCLUSIONS: Our work sheds light on how, in the growing hemp hypocotyl, the provision of the precursors needed to synthesize the aromatic biomolecules lignin and lignans is regulated at the transcriptional and proteomic level.
Scuba: scalable kernel-based gene prioritization.

BACKGROUND: The uncovering of genes linked to human diseases is a pressing challenge in molecular biology and precision medicine. This task is often hindered by the large number of candidate genes and by the heterogeneity of the available information. Computational methods for the prioritization of candidate genes can help to cope with these problems. In particular, kernel-based methods are a powerful resource for the integration of heterogeneous biological knowledge, however, their practical implementation is often precluded by their limited scalability. RESULTS: We propose Scuba, a scalable kernel-based method for gene prioritization. It implements a novel multiple kernel learning approach, based on a semi-supervised perspective and on the optimization of the margin distribution. Scuba is optimized to cope with strongly unbalanced settings where known disease genes are few and large scale predictions are required. Importantly, it is able to efficiently deal both with a large amount of candidate genes and with an arbitrary number of data sources. As a direct consequence of scalability, Scuba integrates also a new efficient strategy to select optimal kernel parameters for each data source. We performed cross-validation experiments and simulated a realistic usage setting, showing that Scuba outperforms a wide range of state-of-the-art methods. CONCLUSIONS: Scuba achieves state-of-the-art performance and has enhanced scalability compared to existing kernel-based approaches for genomic data. This method can be useful to prioritize candidate genes, particularly when their number is large or when input data is highly heterogeneous. The code is freely available at https://github.com/gzampieri/Scuba .
MI (2-methyl-4-isothiazolin-3-one) contained in detergents is not detectable in machine washed textiles.

Background: European legislation has banned the preservative methylisothiazolinone (MI) from inclusion in leave-on cosmetics. However, the risk for allergic reactions depends on exposure. The aim of this study was to determine the risk of MI in laundry detergents for household machine washing. Methods: Different formulations of laundry detergents with commercial MI levels, up to one thousand ppm were used and three different types of clothes were washed in a normal household machine setting one time and 10 times. The level of MI was measured by HPLC. Results: While MI could be retrieved in the positive control of clothes drenched with washing powder but not washed afterwards, MI could not be detected in any specimen of clothes washed under household conditions. The detection limit was 0.5 ppm. Conclusion: It is important to discuss the difference of risk and hazard. While MI clearly is a high hazard as a strong contact allergen, the risk depends on exposure. Regarding the risk of exposure levels for the consumer to MI in clothes it can be stated that the use of MI in laundry detergents is safe for the consumer if these products are used according to the instructions in the normal household setting machine wash.
A high-throughput, restriction-free cloning and screening strategy based on ccdB-gene replacement.

BACKGROUND: In high-throughput demanding fields, such as biotechnology and structural biology, molecular cloning is an essential tool in obtaining high yields of recombinant protein. Here, we address recently developed restriction-free methods in cloning, and present a more cost-efficient protocol that has been optimized to improve both cloning and clone screening. RESULTS: In our case study, three homologous β-lactamase genes were successfully cloned using these restriction-free protocols. To clone the genes, we chose a gene replacement strategy, where the recombinant genes contained overhangs that targeted a region of the expression vector including a cytotoxin-encoding ccdB-gene. CONCLUSION: We provide further evidence that gene replacement can be applied with high-throughput cloning protocols. Targeting a replacement of the ccdB-gene was found to be very successful for counterselection using these protocols. This eliminated the need for treatment with the restriction enzyme DpnI that has so far been the preferred clone selection approach. We thus present an optimized cloning protocol using a restriction-free ccdB-gene replacement strategy, which allows for parallel cloning at a high-throughput level.