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Background Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. Methods TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. Results At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. Conclusions TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. Clinical trial information NCT02743221 (clinicaltrials.gov)

Background Sleep problems are frequent in older adults and are associated with chronic diseases. However, the association with multimorbidity patterns is still unknown. Considering the negative impacts that multimorbidity patterns can have on older adults’ life, knowledge of this association can help in the screening and early identification of older adults with sleep problems. The objective was to verify the association between sleep problems and multimorbidity patterns in older Brazilian adults. Methods This was a cross-sectional study conducted with data from 22,728 community-dwelling older adults from the 2019 National Health Survey. The exposure variable was self-reported sleep problems (yes/no). The study outcomes were: multimorbidity patterns, analyzed by self-report of the coexistence of two or more chronic diseases with similar clinical characteristics: (1) cardiopulmonary; (2) vascular-metabolic; (3) musculoskeletal; (4) coexisting patterns. Results Older adults with sleep problems had 1.34 (95%CI: 1.21; 1.48), 1.62 (95%CI: 1.15; 2.28), 1.64 (95%CI: 1.39; 1.93), and 1.88 (95%CI: 1.52; 2.33) greater odds of presenting vascular-metabolic, cardiopulmonary, musculoskeletal, and coexisting patterns, respectively. Conclusions These results suggest that public health programs aimed at preventing sleep problems in older adults are essential to reduce possible adverse health outcomes, including multimorbidity patterns and their negative consequences for older adults’ health.

Having pets in the house during the first years of life has been shown to protect against allergies. However, the result of different studies is heterogeneous. The aim of this study was to evaluate the methylation pattern in cord blood in relation to pet ownership during pregnancy. We investigated the methylation patterns of 96 cord blood samples, participants of the Epigenetic Hallmark of Maternal Atopy and Diet—ELMA project, born to mothers who either owned pets (n = 32) or did not own pets (n = 64) during their pregnancy. DNA from cord blood was analysed using the Infinium methylation EPIC. For statistical analysis, RnBeads software was applied. We found 113 differentially methylated sites (DMs) in the covariate-adjusted analysis (FDR p

Maize is a subtropical, cold-sensitive species. However, some varieties of this species have the potential to withstand long-term low temperatures, even at the seedling stage. The molecular basis of this phenomenon has not been determined. In a chromatin-level study, we compared the cold-stress reaction of seedlings of two maize inbred lines showing contrasting levels of cold sensitivity. The cold-tolerant line was selected based on field data and previous physiological and transcriptomic level studies. The first condition of gene expression—chromatin accessibility—was assessed by formaldehyde-aided isolation of regulatory elements method and DNA sequencing. Potentially expressed genes and cis-regulatory sequences open for interaction with transcription factors have been defined. The results of this study suggest that during cold stress, the tolerant maize line shifted resources from growth to defense. This shift was shown by potential hormone-level events—degradation of growth-promoting gibberellins and synthesis of jasmonic and abscisic acids. This finding is congruent with the xeromorphic morphology of seedlings of the cold-tolerant line and their ability to regrow when stress ceases. It is a common reaction of cold-tolerant maize lines. Moreover, in the cold-tolerant line, several genes from the low-temperature signaling pathways were potentially expressed. Additionally, numerous stress-response AP2/EREBP-binding cis-motifs were accessible in the cold-tolerant line. Differently in the cold-sensitive B73 line, MADS-binding cis-motifs were the most abundant. Development of the photosynthetic apparatus is crucial for the survival of maize seedlings at low temperature. Our results suggest efficient photosynthesis in seedlings of the cold-tolerant line, as was described earlier in physiological-level analyses.

Septoria tritici blotch (STB;Zymoseptoria tritici) is the most important leaf disease of wheat in Northern and Western Europe. The problem of fungicide resistance inZ. triticipopulations is challenging future control options. In order to investigate differences in azole performances against STB, 55 field trials were carried out during four seasons (2015–2018). These trials were undertaken in ten different countries across Europe covering a diversity of climatic zones and agricultural practices. During all four seasons, four single azoles (epoxiconazole, prothioconazole, tebuconazole and metconazole) were tested. Increasing variability in the performances of these azoles against STB was observed across Europe. The efficacy of the tested azoles varied considerably across the continent and between countries. The shifts in disease control from these commonly used azoles were confirmed by increasing EC50values for epoxiconazole, prothioconazole-desthio and metconazole. The sensitivity towards tebuconazole remained relatively low across the four years. The frequencies ofCYP51mutations varied substantially across Europe, with a clear pattern of significantly decreasing frequencies of D134G, V136A and S524T in the localZ. triticipopulations from west to east. In contrast, no major differences were seen forCYP51mutations V136C, A379 and I381V. The four azoles showed different levels of cross-resistance, which again depended on specificCYP51mutations. Across the four seasons, the single azoles increased the yields between 9 and 11% on average.

Purpose The aim of current systematic review was to update the body of evidence on associations between adherence to the Mediterranean diet (MedDiet) and risk of cancer mortality, site-specific cancer in the general population; all-cause, and cancer mortality as well as cancer reoccurrence among cancer survivors. Methods A literature search for randomized controlled trials (RCTs), case–control and cohort studies published up to April 2020 was performed using PubMed and Scopus. Study-specific risk estimates for the highest versus lowest adherence to the MedDiet category were pooled using random-effects meta-analyses. Certainty of evidence from cohort studies and RCTs was evaluated using the NutriGrade scoring system. Results The updated search revealed 44 studies not identified in the previous review. Altogether, 117 studies including 3,202,496 participants were enclosed for meta-analysis. The highest adherence to MedDiet was inversely associated with cancer mortality (RRcohort: 0.87, 95% CI 0.82, 0.92; N = 18 studies), all-cause mortality among cancer survivors (RRcohort: 0.75, 95% CI 0.66, 0.86; N = 8), breast (RRobservational: 0.94, 95% CI 0.90, 0.97; N = 23), colorectal (RRobservational: 0.83, 95% CI 0.76, 0.90; N = 17), head and neck (RRobservational: 0.56, 95% CI 0.44, 0.72; N = 9), respiratory (RRcohort: 0.84, 95% CI 0.76, 0.94; N = 5), gastric (RRobservational: 0.70, 95% CI 0.61, 0.80; N = 7), bladder (RRobservational: 0.87, 95% CI 0.76, 0.98; N = 4), and liver cancer (RRobservational: 0.64, 95% CI 0.54, 0.75; N = 4). Adhering to MedDiet did not modify risk of blood, esophageal, pancreatic and prostate cancer risk. Conclusion In conclusion, our results suggest that highest adherence to the MedDiet was related to lower risk of cancer mortality in the general population, and all-cause mortality among cancer survivors as well as colorectal, head and neck, respiratory, gastric, liver and bladder cancer risks. Moderate certainty of evidence from cohort studies suggest an inverse association for cancer mortality and colorectal cancer, but most of the comparisons were rated as low or very low certainty of evidence.

Computational difficulties aside, nonequilibrium Green’s functions appear ideally suited for investigating the dynamics of central nuclear reactions. Many particles actively participate in those reactions. At the two energy extremes for the collisions, the limiting cases of the Green’s function approach have been successful: the time-dependent Hartree–Fock theory at low energy and Boltzmann equation at high. The strategy for computational adaptation of the Green’s function to central reactions is discussed. The strategy involves, in particular, incremental progression from one to three dimensions to develop and assess approximations, discarding of far-away function elements, use of effective interactions and preparation of initial states for the reactions through adiabatic switching. At this stage we concentrate on inclusion of correlations in one dimension, where relatively few approximations are needed, and we carry out reference calculations that can benchmark approximations needed for more dimensions. We switch on short-range interactions generating the correlations adiabatically in the Kadanoff–Baym equations to arrive at correlated ground states for uniform matter. As the energy of the correlated matter does not quite match the expectations for nuclear matter, we add mean field to arrive at the match in energy. From there on, we move to finite systems. In switching on the correlations, we observe emergence of extended tails in momentum distributions and evolution of single particle occupations away from 1 to 0.

The weight share of the pith, nodes and internodes in the stalks of Miscanthus, as well as the types of cells in these anatomical parts, were examined. Studies have shown that the pith contains mainly parenchyma cells, nodes—short fibres and palisade parenchyma cells, while internodes contains mainly fibres, which are accompanied by a certain amount of vessels and parenchyma cells. Then the whole stalks of Miscanthus were subjected to pulping using the kraft and soda pulping methods. These studies have shown that hard, regular, soft and very soft kraft pulps can be obtained using a lower amount of active alkali, with comparable or higher screened yield of pulp than is the case of pulping of birch. Furthermore, it was found that the content of knots and shives was lower in the digester hard and regular kraft pulps from Miscanthus compared to birch kraft pulp. Of the two pulping methods studied, kraft pulping gives better results than soda pulping concerning the considerably higher yield of pulp.

The introduction of alien species can have a significant impact on the food preferences of native phytophagous insects. The moth Earias clorana L. has previously been considered to be monophagous, ingesting only plants in the genus Salix. In recent years, we have observed larval E. clorana feeding on Spiraea tomentosa L., an invasive shrub species in Central Europe that is native to North America. We hypothesised that this insect can feed on Spiraea tomentosa leaves with no negative effects on its growth and development, and that the leaves of Spiraea tomentosa as a source of food for E. clorana are equally as good as leaves of Salix viminalis L. Our results showed that despite significant differences in the chemical composition of the studied species’ leaves, including a much higher concentration of defence compounds (total soluble phenols and condensed tannins) in Spiraea tomentosa leaves than in those of Salix viminalis, feeding on a new host plant did not significantly affect the survival of larvae. The change in host plant had an unfavourable effect, however, on several parameters of growth and development for the larvae (masses of larvae and pupae, relative growth rates, and efficiency of conversion of ingested food). We conclude that, in comparison to Salix viminalis, Spiraea tomentosa is not a particularly favourable food for larval development. Perhaps, even without direct improvements in adult foraging efficiency, however, the costs of switching hosts may be minimised in larvae that develop on very abundant, invasive species, such as Spiraea tomentosa in Central Europe.

High food quality, together with adequate macro- and micronutrient intake in pregnancy, is crucial for the health status of the mother and child. Recent findings suggest that it could also be beneficial or harmful in the context of the well-being of the whole future population. According to the developmental origins of health and disease hypothesis, most conditions that occur in adulthood originate in foetal life. Moreover, some epigenetic events, modified inter alia by diet, impact more than one generation. Still, the recommendations in most countries are neither popularised nor very detailed. While it seems to be important to direct diet trends towards a healthier lifestyle, the methods of preventing specific disorders like diabetes or asthma are not yet established and require further investigation. Conclusion: In this review, we will summarise the recommendations for diet composition in pregnancy, focusing on both diet quality and quantity. What is Known • High food quality, together with adequate macro- and micronutrient intake in pregnancy, is crucial for the health status of the mother and child. What is New • Recent findings suggest that the diet could be beneficial or harmful in the context of the well-being of the whole future population. Most conditions that occur in adulthood originate in foetal life. • Moreover, some epigenetic events, modified by diet impact more than one generation.

The papermaking potential of bleached kraft pulps made from hemp stalks, hemp woody-core and hemp bast fibres was studied and compared with that of bleached birch pulp and pine kraft pulp. It has been shown that among the pulps from these raw materials, hemp stalk pulp has the most useful properties for papermaking. The disadvantages of hemp woody-core pulp and hemp bast fibre pulp as papermaking intermediates proved to be low tear resistance and low tensile strength, respectively. Results indicate that the main reasons for the low tensile strength of hemp bast fibre pulp are the low susceptibility of their fibres for internal fibrillation and low hemicellulose content. The technology used in this work for the processing of hemp bast fibres into papermaking pulp made it possible to obtain pulp with high α-cellulose content from this fibrous raw material with a high yield in a much simpler way than when such pulps are obtained from wood.

One of the adverse effects of prolonged stress in rats is impaired performance of skilled reaching and walking tasks. The mechanisms that lead to these abnormalities are incompletely understood. Therefore, we compared the effects of twice daily repeated corticosterone injections for 7 days on miniature excitatory postsynaptic currents (mEPSCs), as well as on synaptic plasticity and morphology of layers II/III and V pyramidal neurons of the primary motor cortex (M1) of male Wistar rats. Corticosterone treatment resulted in increased frequency, but not amplitude, of mEPSCs in layer II/III neurons accompanied by increased complexity of the apical part of their dendritic tree, with no changes in the density of dendritic spines. The frequency and amplitude of mEPSCs as well as the parameters characterizing the complexity of the dendritic tree were not changed in layer V cells; however, their dendritic spine density was increased. While corticosterone treatment resulted in an increase in the amplitude of field potentials evoked in intralaminar connections within layer II/III, it did not influence field responses in layer V intralaminar connections, as well as the extent of chemically induced layer V long-term potentiation (chemLTP) by the application of tetraethylammonium (TEA, 25 mM). However, chemLTP induction in layer II/III was impaired in slices prepared from corticosterone-treated animals. These data indicate that repeated 7-day administration of exogenous corticosterone induces structural and functional plasticity in the M1, which occurs mainly in layer II/III pyramidal neurons. These findings shed light on potential sites of action and mechanisms underlying stress-induced impairment of motor functions.

Isolation and detection of circulating tumor cells (CTCs) from human blood plays an important role in non- invasive screening of cancer evolution and in predictive therapeutic treatment. Here, we present the novel tool utilizing: (i) the microfluidic device with (ii) incorporated photovoltaic (PV) based SERS-active platform, and (iii) shell-isolated nanoparticles (SHINs) for simultaneous separation and label-free analysis of circulating tumour cells CTCs in the blood specimens with high specificity and sensitivity. The proposed microfluidic chip enables the efficient size – based inertial separation of circulating cancer cells from the whole blood samples. The SERS-active platform incorporated into the microfluidic device permits the label-free detection and identification of isolated cells through the insight into their molecular and biochemical structure. Additionally, the silver nanoparticles coated with an ultrathin shell of silica (Ag@SiO2) was used to improve the detection accuracy and sensitivity of analysed tumor cells via taking advantages of shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS). The empirical analysis of SHINERS spectra revealed that there are some differences among studied (HeLa), renal cell carcinoma (Caki-1), and blood cells. Unique SHINERS features and differences in bands intensities between healthy and cancer cells might be associated with the variations in the quantity and quality of molecules such as lipid, protein, and DNA or their structure during the metastasis cancer formation. To demonstrate the statistical efficiency of the developed method and improve the differentiation for circulating tumors cells detection the principal component analysis (PCA) has been performed for all SHINERS data. PCA method has been applied to recognize the most significant differences in SHINERS data among the three analyzed cells: Caki-1, HeLa, and blood cells. The proposed approach challenges the current multi-steps CTCs detection methods in the terms of simplicity, sensitivity, invasiveness, destructivity, time and cost of analysis, and also prevents the defragmentation/damage of tumor cells and thus leads to improving the accuracy of analysis. The results of this research work show the potential of developed SERS based tool for the separation of tumor cells from whole blood samples in a simple and minimally invasive manner, their detection and molecular characterization using one single technology.

Pch1 gene translocated from Aegilops ventricosa provides effective resistance to eyespot in wheat. To track the Pch1 gene introgression, we investigated 372 genotypes obtained from various breeding programs using endopeptidase EpD1b marker, sequence-tagged-site (STS) marker XustSSR2001-7DL, and the score of infection index (K-index) evaluated after in vivo inoculation test. These genotypes were divided into three groups with 136, 124 and 112 genotypes for the field test lasting three years. In 2011, the mean K-index was 0.81, while 2012 and 2013 the mean K-indexes were 1.60 and 1.46, respectively. Both marker results indicated that 18 genotypes possessed Pch1 gene. Statistical analysis of the level of K-index showed that these 18 genotypes were resistant to eyespot, which verified the proper assignment of wheat genotypes with Pch1 gene based on the marker data. Thus, the endopeptidase and XustSSR2001-7DL are useful for identifying sources of eyespot resistance gene Pch1 in wheat breeding program.

Findings on the relationship between health literacy and outcomes in HIV have been inconsistent. Health literacy has previously been operationalized as general functional literacy, but has not included content knowledge about HIV disease and treatment. Semi-structured interviews with people living with HIV in 2 U.S. cities, including questions about the etiology, pathophysiology and treatment of HIV. We compared responses to biomedical conceptions. The 32 respondents were demographically diverse. Although most understood that HIV degrades the immune system, none could explain the nature of a virus, or the mechanism of antiretroviral (ARV) drug action. Fewer than half accurately reported that it is desirable to have a high CD4+ cell count and low viral load. A minority understood the concept of drug resistance. While most believed that strict adherence to ARV regimens was important to maintain health, three believed that periodic treatment interruption was beneficial, and three believed they should not take ARVs when they used alcohol or illicit drugs. Respondents generally had very limited, and often inaccurate biomedical understanding of HIV disease. Most reported good regimen adherence but did not have any mechanistic rationale for it. The failure to find a consistent relationship between health literacy and ARV adherence may be largely because most people simply follow their doctors’ instructions, without the need for deep understanding.

Recent progress in selective breeding of maize (Zea mays L.) towards adaptation to temperate climate has allowed the production of inbred lines withstanding cold springs with temperatures below 8 °C or even close to 0 °C, indicating that despite its tropical origins maize is not inherently cold-sensitive. Here we studied the acclimatory response of three maize inbred lines of contrasting cold-sensitivity selected basing on multi-year routine field data. The field observations were confirmed in the growth chamber. Under controlled conditions the damage to the photosynthetic apparatus due to severe cold treatment was the least in the cold-tolerant line provided that it had been subjected to prior moderate chilling, i.e., acclimation. The cold-sensitive lines performed equally poorly with or without acclimation. To uncover the molecular basis of the attained cold-acclimatability we performed comparative transcriptome profiling of the response of the lines to the cold during acclimation phase by means of microarrays with a statistical and bioinformatic data analysis. The analyses indicated three mechanisms likely responsible for the cold-tolerance: acclimation-dependent modification of the photosynthetic apparatus, cell wall properties, and developmental processes. Those conclusions supported the observed acclimation of photosynthesis to severe cold at moderate chilling and were further confirmed by experimentally showing specific modification of cell wall properties and repression of selected miRNA species, general regulators of development, in the cold-tolerant line subjected to cold stress.

For analyzing anisotropic low relative-velocity correlation-functions and the associated emission sources, we propose an expansion in terms of cartesian spherical harmonics. The expansion coefficients represent angular moments of the investigated functions. The respective coefficients for the correlation and source are directly related to each other via one-dimensional integral transforms. The shape features of the source may be partly read off from the respective features of the correlation function and can be, otherwise, imaged.

We report an extension of the source imaging method for imag- ing full three-dimensional sources from three-dimensional like-pair correlations. Our technique consists of expanding the correlation data and the underlying source function in spherical harmonics and inverting the resulting system of one-dimensional integral equations. With this method of attack, we can image the source function quickly, even with the extremely large data sets common in three-dimensional analyses. We apply our method to the recently measured E859 un-Coulomb corrected data.

Starting from a discussion of the grand potential change associated with introduction of ions into water, the electrocaloric effect for the system ion–surrounding water is calculated by means of this recent statistical approach to the problem of water in a high electric field. It is concluded that this effect is essential for the hydration of ions, in particular, for the heat of solution of salts. Consistency between the present approach and recent literature results of a density functionals calculation, as well as experimental data for sequential enthalpies of hydration of doubly charged ions in the gas phase, is discussed.

The etiology of pain in anterior knee pain syndrome is a matter of controversy. The normal, articular cartilage is aneural, so defects in the surface are not thought to produce pain. Some authors have sought the origin of the pain in soft tissue structures around the knee. Knowledge of the distribution of nociceptive nerve fibers around the knee would provide insight for treating anterior knee pain syndrome. Twenty consecutive patients (28 knees), all women, with anterior knee pain syndrome (group I) participated in the study. For comparison we used two groups of patients: 20 patients with an osteoarthritic knee (group II) and 20 patients with anterior cruciate ligament rupture or meniscal lesion with no history of pain in the anterior compartment (group III). Immunohistochemical techniques using a monoclonal antibody to substance-P (SP) were employed to identify nociceptive fibers. For statistical analyses we used the one-way ANOVA test, which was corrected with the LSD test, at the level of significance P < 0.05. Results of the study demonstrate that SP-immunoreactive nerve fibers are widespread within the soft tissues around the knee. These tissues include the retinaculum, synovium, fat pad and, in some circumstances, bone. In cases of anterior knee pain, the presence of neuropeptide-containing fibers was statistically significant in the medial retinaculum (P < 0.005) and in the fat pad (P < 0.001) compared to group III, and compared to group II (P < 0.05 and P < 0.007, respectively). For lateral retinaculum this relationship was not so statistically strong (P < 0.02) and was equal in comparison between anterior knee pain patients (group I) and group II or group III. There were no statistically significant differences in the distribution of substance-P nerve fibers in the fat pad, lateral and medial retinaculum or synovium between groups II and III. The results of this study provide immunohistochemical evidence suggesting that pain may originate in the fat pad and medial retinaculum of many patients with anterior knee pain syndrome.