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Background: The provision of palliative care is increasing, with many people dying in community-based settings. It is essential that communication is effective if and when patients transition from hospice to community palliative care. Past research has indicated that communication issues are prevalent during hospital discharges, but little is known about hospice discharges., Methods: An explanatory sequential mixed methods study consisting of a retrospective review of hospice discharge letters, followed by hospice focus groups, to explore patterns in communication of palliative care needs of discharged patients and describe why these patients were being discharged. Discharge letters were extracted for key content information using a standardised form. Letters were then examined for language patterns using a linguistic methodology termed corpus linguistics. Thematic analysis was used to analyse the focus group transcripts. Findings were triangulated to develop an explanatory understanding of discharge communication from hospice care., Results: We sampled 250 discharge letters from five UK hospices whereby patients had been discharged to primary care. Twenty-five staff took part in focus groups. The main reasons for discharge extracted from the letters were symptoms "managed/resolved" (75.2%), and/or the "patient wishes to die/for care at home" (37.2%). Most patients had some form of physical needs documented on the letters (98.4%) but spiritual needs were rarely documented (2.4%). Psychological/emotional needs and social needs were documented in 46.4 and 35.6% of letters respectively. There was sometimes ambiguity in "who" will be following up "what" in the discharge letters, and whether described patients' needs were resolved or ongoing for managing in the community setting. The extent to which patients received a copy of their discharge letter varied. Focus groups conveyed a lack of consensus on what constitutes "complexity" and "complex pain"., Conclusions: The content and structure of discharge letters varied between hospices, although generally focused on physical needs. Our study provides insights into patterns associated with those discharged from hospice, and how policy and guidance in this area may be improved, such as greater consistency of sharing letters with patients. A patient-centred set of hospice-specific discharge letter principles could help improve future practice., (© 2022. The Author(s).)

Background: With advancing therapeutics, lung cancer (LC) survivors are rapidly increasing in number. Although mounting evidence suggests LC survivors have high risk of second primary lung cancer (SPLC), there is no validated prediction model available for clinical use to identify high-risk LC survivors for SPLC., Methods: Using data from 6325 ever-smokers in the Multiethnic Cohort (MEC) study diagnosed with initial primary lung cancer (IPLC) in 1993-2017, we developed a prediction model for 10-year SPLC risk after IPLC diagnosis using cause-specific Cox regression. We evaluated the model's clinical utility using decision curve analysis and externally validated it using 2 population-based data-Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and National Lung Screening Trial (NLST)-that included 2963 and 2844 IPLC (101 and 93 SPLC cases), respectively., Results: Over 14 063 person-years, 145 (2.3%) ever-smoking IPLC patients developed SPLC in MEC. Our prediction model demonstrated a high predictive accuracy (Brier score = 2.9, 95% confidence interval [CI] = 2.4 to 3.3) and discrimination (area under the receiver operating characteristics [AUC] = 81.9%, 95% CI = 78.2% to 85.5%) based on bootstrap validation in MEC. Stratification by the estimated risk quartiles showed that the observed SPLC incidence was statistically significantly higher in the 4th vs 1st quartile (9.5% vs 0.2%; P < .001). Decision curve analysis indicated that in a wide range of 10-year risk thresholds from 1% to 20%, the model yielded a larger net-benefit vs hypothetical all-screening or no-screening scenarios. External validation using PLCO and NLST showed an AUC of 78.8% (95% CI = 74.6% to 82.9%) and 72.7% (95% CI = 67.7% to 77.7%), respectively., Conclusions: We developed and validated a SPLC prediction model based on large population-based cohorts. The proposed prediction model can help identify high-risk LC patients for SPLC and can be incorporated into clinical decision making for SPLC surveillance and screening., (© The Author(s) 2021. Published by Oxford University Press.)

Evaluating gene by environment (G × E) interaction under an additive risk model (i.e., additive interaction) has gained wider attention. Recently, statistical tests have been proposed for detecting additive interaction, utilizing an assumption on gene-environment (G-E) independence to boost power, that do not rely on restrictive genetic models such as dominant or recessive models. However, a major limitation of these methods is a sharp increase in type I error when this assumption is violated. Our goal was to develop a robust test for additive G × E interaction under the trend effect of genotype, applying an empirical Bayes-type shrinkage estimator of the relative excess risk due to interaction. The proposed method uses a set of constraints to impose the trend effect of genotype and builds an estimator that data-adaptively shrinks an estimator of relative excess risk due to interaction obtained under a general model for G-E dependence using a retrospective likelihood framework. Numerical study under varying levels of departures from G-E independence shows that the proposed method is robust against the violation of the independence assumption while providing an adequate balance between bias and efficiency compared with existing methods. We applied the proposed method to the genetic data of Alzheimer disease and lung cancer., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Several statistical methods have been proposed for testing gene-environment (G-E) interactions under additive risk models using data from genome-wide association studies. However, these approaches have strong assumptions from underlying genetic models, such as dominant or recessive effects that are known to be less robust when the true genetic model is unknown. We aimed to develop a robust trend test employing a likelihood ratio test for detecting G-E interaction under an additive risk model, while incorporating the G-E independence assumption to increase power. We used a constrained likelihood to impose 2 sets of constraints for: 1) the linear trend effect of genotype and 2) the additive joint effects of gene and environment. To incorporate the G-E independence assumption, a retrospective likelihood was used versus a standard prospective likelihood. Numerical investigation suggests that the proposed tests are more powerful than tests assuming dominant, recessive, or general models under various parameter settings and under both likelihoods. Incorporation of the independence assumption enhances efficiency by 2.5-fold. We applied the proposed methods to examine the gene-smoking interaction for lung cancer and gene-apolipoprotein E $\varepsilon$4 interaction for Alzheimer disease, which identified 2 interactions between apolipoprotein E $\varepsilon$4 and loci membrane-spanning 4-domains subfamily A (MS4A) and bridging integrator 1 (BIN1) genes at genome-wide significance that were replicated using independent data., (© Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Motivation: Multiple marker analysis of the genome-wide association study (GWAS) data has gained ample attention in recent years. However, because of the ultra high-dimensionality of GWAS data, such analysis is challenging. Frequently used penalized regression methods often lead to large number of false positives, whereas Bayesian methods are computationally very expensive. Motivated to ameliorate these issues simultaneously, we consider the novel approach of using non-local priors in an iterative variable selection framework., Results: We develop a variable selection method, named, iterative non-local prior based selection for GWAS, or GWASinlps, that combines, in an iterative variable selection framework, the computational efficiency of the screen-and-select approach based on some association learning and the parsimonious uncertainty quantification provided by the use of non-local priors. The hallmark of our method is the introduction of 'structured screen-and-select' strategy, that considers hierarchical screening, which is not only based on response-predictor associations, but also based on response-response associations and concatenates variable selection within that hierarchy. Extensive simulation studies with single nucleotide polymorphisms having realistic linkage disequilibrium structures demonstrate the advantages of our computationally efficient method compared to several frequentist and Bayesian variable selection methods, in terms of true positive rate, false discovery rate, mean squared error and effect size estimation error. Further, we provide empirical power analysis useful for study design. Finally, a real GWAS data application was considered with human height as phenotype., Availability and Implementation: An R-package for implementing the GWASinlps method is available at https://cran.r-project.org/web/packages/GWASinlps/index.html., Supplementary Information: Supplementary data are available at Bioinformatics online.

Discovering genetic variants associated with human brain structures is an on-going effort. The ENIGMA consortium conducted genome-wide association studies (GWAS) with standard multi-study analytical methodology and identified several significant single nucleotide polymorphisms (SNPs). Here we employ a novel analytical approach that incorporates functional genome annotations (e.g., exon or 5'UTR), total linkage disequilibrium (LD) scores and heterozygosity to construct enrichment scores for improved identification of relevant SNPs. The method provides increased power to detect associated SNPs by estimating stratum-specific false discovery rate (FDR), where strata are classified according to enrichment scores. Applying this approach to the GWAS summary statistics of putamen volume in the ENIGMA cohort, a total of 15 independent significant SNPs were identified (conditional FDR < 0.05). In contrast, 4 SNPs were found based on standard GWAS analysis (P < 5 × 10 -8 ). These 11 novel loci include GATAD2B, ASCC3, DSCAML1, and HELZ, which are previously implicated in various neural related phenotypes. The current findings demonstrate the boost in power with the annotation-informed FDR method, and provide insight into the genetic architecture of the putamen.

Neuroticism reflects emotional instability, and is related to various mental and physical health issues. However, the majority of genetic variants associated with neuroticism remain unclear. Inconsistent genetic variants identified by different genome-wide association studies (GWAS) may be attributable to low statistical power. We proposed a novel framework to improve the power for gene discovery by incorporating prior information of single nucleotide polymorphisms (SNPs) and combining two relevant existing tools, relative enrichment score (RES) and conditional false discovery rate (FDR). Here, SNP's conditional FDR was estimated given its RES based on SNP prior information including linkage disequilibrium (LD)-weighted genic annotation scores, total LD scores and heterozygosity. A known significant locus in chromosome 8p was excluded before estimating FDR due to long-range LD structure. Only one significant LD-independent SNP was detected by analyses of unconditional FDR and traditional GWAS in the discovery sample (N = 59 225), and notably four additional SNPs by conditional FDR. Three of the five SNPs, all identified by conditional FDR, were replicated (P < 0.05) in an independent sample (N = 170 911). These three SNPs are located in intronic regions of CADM2, LINGO2 and EP300 which have been reported to be associated with autism, Parkinson's disease and schizophrenia, respectively. Our approach using a combination of RES and conditional FDR improved power of traditional GWAS for gene discovery providing a useful framework for the analysis of GWAS summary statistics by utilizing SNP prior information, and helping to elucidate the links between neuroticism and complex diseases from a genetic perspective., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Present investigation was carried out using two commercial products Raft (oxadiargyl 6% EC) and Topstar (oxadiargyl 80% WP) of Oxadiargyl {5-tert-butyl-3[2,4-dichloro-5-(prop-2-ynyloxy)phenyl]-1,3,4-oxadiazol-2 (3H)-one} to investigate the persistence behavior and metabolism of the herbicide in various aqueous system under different pH condition. Half-life values revealed that alkaline hydrolysis played a dominant role in hydrolytic degradation of this compound. Q-ToF micromass study with the alkaline fractions of oxadiargyl indicated the formation of five metabolites, which was further characterized from their mass fragmentation data. The nature of metabolites formed indicated that heterocyclic oxadiazoline ring cleavage was found to be the main pathway of hydrolytic transformation of oxadiargyl.

Proline dehydrogenase (PRODH) and Δ(1)-pyrroline-5-carboxylate (P5C) dehydrogenase (P5CDH) catalyze the four-electron oxidation of proline to glutamate via the intermediates P5C and l-glutamate-γ-semialdehyde (GSA). In Gram-negative bacteria, PRODH and P5CDH are fused together in the bifunctional enzyme proline utilization A (PutA) whereas in other organisms PRODH and P5CDH are expressed as separate monofunctional enzymes. Substrate channeling has previously been shown for bifunctional PutAs, but whether the monofunctional enzymes utilize an analogous channeling mechanism has not been examined. Here, we report the first evidence of substrate channeling in a PRODH-P5CDH two-enzyme pair. Kinetic data for the coupled reaction of PRODH and P5CDH from Thermus thermophilus are consistent with a substrate channeling mechanism, as the approach to steady-state formation of NADH does not fit a non-channeling two-enzyme model. Furthermore, inactive P5CDH and PRODH mutants inhibit NADH production and increase trapping of the P5C intermediate in coupled assays of wild-type PRODH-P5CDH enzyme pairs, indicating that the mutants disrupt PRODH-P5CDH channeling interactions. A dissociation constant of 3 μm was estimated for a putative PRODH-P5CDH complex by surface plasmon resonance (SPR). Interestingly, P5CDH binding to PRODH was only observed when PRODH was immobilized with the top face of its (βα)8 barrel exposed. Using the known x-ray crystal structures of PRODH and P5CDH from T. thermophilus, a model was built for a proposed PRODH-P5CDH enzyme channeling complex. The structural model predicts that the core channeling pathway of bifunctional PutA enzymes is conserved in monofunctional PRODH-P5CDH enzyme pairs., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: An endeavour to probe into the psychological profile of infertile women in a comparative stance with the fertile women is not very common. This study is an attempt to explore the possible non-apparent personality factors which contribute to the unexplained pain of infertility., Methods: The main objectives of the present study were (a) to examine whether infertile women are different from fertile women in terms of selected psychological variables- narcissistic components, dimensions of attachment style and uses of defensive manoeuvres; and (b) whether the primary infertile women (n=18) are different from the secondary infertile women (n=12) with respect to those variables. A total of 60 individuals (30 infertile women and 30 matched fertile women) were assessed through Attachment Style Questionnaire (ASQ), Narcissistic Personality Inventory (NPI) and Defense Style Questionnaire (DSQ-40). General Health Questionnaire (GHQ) was administered on to the fertile women to rule out the psychiatric morbidity., Results: Findings revealed that infertile women group differed from fertile women group with respect to narcissism, dimensions of attachment style and uses of defense mechanism. The primary infertile group also showed marked difference from the secondary infertile group with respect to those variables., Conclusions: This study endeavours to enrich the knowledge regarding the personality dynamics of infertile women to design psychotherapeutic programme to aid their well-being, help them to cherish the flavour of parenthood and improve their quality of life.

PutA (proline utilization A) is a large bifunctional flavoenzyme with proline dehydrogenase (PRODH) and Δ(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH) domains that catalyze the oxidation of l-proline to l-glutamate in two successive reactions. In the PRODH active site, proline undergoes a two-electron oxidation to Δ(1)-pyrroline-5-carboxlylate, and the FAD cofactor is reduced. In the P5CDH active site, l-glutamate-γ-semialdehyde (the hydrolyzed form of Δ(1)-pyrroline-5-carboxylate) undergoes a two-electron oxidation in which a hydride is transferred to NAD(+)-producing NADH and glutamate. Here we report the first kinetic model for the overall PRODH-P5CDH reaction of a PutA enzyme. Global analysis of steady-state and transient kinetic data for the PRODH, P5CDH, and coupled PRODH-P5CDH reactions was used to test various models describing the conversion of proline to glutamate by Escherichia coli PutA. The coupled PRODH-P5CDH activity of PutA is best described by a mechanism in which the intermediate is not released into the bulk medium, i.e., substrate channeling. Unexpectedly, single-turnover kinetic experiments of the coupled PRODH-P5CDH reaction revealed that the rate of NADH formation is 20-fold slower than the steady-state turnover number for the overall reaction, implying that catalytic cycling speeds up throughput. We show that the limiting rate constant observed for NADH formation in the first turnover increases by almost 40-fold after multiple turnovers, achieving half of the steady-state value after 15 turnovers. These results suggest that EcPutA achieves an activated channeling state during the approach to steady state and is thus a new example of a hysteretic enzyme. Potential underlying causes of activation of channeling are discussed.

The bifunctional proline catabolic flavoenzyme, proline utilization A (PutA), catalyzes the oxidation of proline to glutamate via the sequential activities of FAD-dependent proline dehydrogenase (PRODH) and NAD(+)-dependent Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH) domains. Although structures for some of the domains of PutA are known, a structure for the full-length protein has not previously been solved. Here we report the 2.1 A resolution crystal structure of PutA from Bradyrhizobium japonicum, along with data from small-angle x-ray scattering, analytical ultracentrifugation, and steady-state and rapid-reaction kinetics. PutA forms a ring-shaped tetramer in solution having a diameter of 150 A. Within each protomer, the PRODH and P5CDH active sites face each other at a distance of 41 A and are connected by a large, irregularly shaped cavity. Kinetics measurements show that glutamate production occurs without a lag phase, suggesting that the intermediate, Delta(1)-pyrroline-5-carboxylate, is preferably transferred to the P5CDH domain rather than released into the bulk medium. The structural and kinetic data imply that the cavity serves both as a microscopic vessel for the hydrolysis of Delta(1)-pyrroline-5-carboxylate to glutamate semialdehyde and a protected conduit for the transport of glutamate semialdehyde to the P5CDH active site.

Glycal-based bolaforms serve as synthetically flexible components of molecular self-assembly. The compounds are prepared in good yield by a Ferrier reaction between triacetylglucal or -galactal or diacetylxylal and a long chain alpha,omega-diol, followed by deacetylation under Zemplen conditions. The reactions are stereoselective and preferentially afford the alpha-diastereomer. The bolaforms undergo self-assembly in water or water/dioxane solution to give a variety of nanostructures. In solution, bolaforms with C8 or C10 chains between glucal headgroups form nanoscale vesicles. In contrast, bolaforms with C12 chains exhibit lower solubility and a dynamic self-assembly, forming several different nanoscale structures. However, the solid-state structures of C12 bolaform isomers adopt shapes very similar to those of bolaforms possessing more extensive hydrogen-bonding networks, indicating that multiple hydrogen bonds in solution are important to formation of stable, discrete nanostructures but that only a few key intermolecular interactions between bolaform headgroups are necessary to determine the structure in the solid state. The diversity and differentiation of the functional groups present in glycal-based bolaforms suggest that they could be useful probes of the various noncovalent forces controlling the structure of new nanomaterials.

Intensive agriculture is spectacularly successful since last couple of decades due to the inputs viz; fertilizers and pesticides along with high yielding varieties. The mandate for agriculture development was to feed and adequate nutrition supply to the expanding population by side the agriculture would be entering to into new area of commercial and export orientation. The attention of public health and proper utilization natural resources are also the main issues related with agriculture development. Concern for pesticide contamination in the environment in the current context of pesticide use has assumed great importance [1]. The fate of the pesticides in the soil environment in respect of pest control efficacy, non-target organism exposure and offsite mobility has been given due consideration [2]. Kinetics and pathways of degradation depend on abiotic and biotic factors [6], which are specific to a particular pesticide and therefore find preference. Adverse effect of pesticidal chemicals on soil microorganisms [3], may affect soil fertility [4] becomes a foreign chemicals major issue. Soil microorganisms show an early warning about soil disturbances by foreign chemicals than any other parameters.But the fate and behavior of these chemicals in soil ecosystem is very important since they are degraded by various factors and have the potential to be in the soil, water etc. So it is indispensable to monitor the persistence, degradation of pesticides in soil and is also necessary to study the effect of pesticide on the soil quality or soil health by in depth studies on soil microbial activity.The removal of metabolites or degraded products should be removed from soil and it has now a day's primary concern to the environmentalist. Toxicity or the contamination of pesticides can be reduced by the bioremediation process which involves the uses of microbes or plants. Either they degrade or use the pesticides by various co metabolic processes.

Two sulfonylurea herbicides, metsulfuron methyl (Ally 20 WP) and chlorimuron ethyl (Classic 25 WP) were evaluated for their dissipation behaviour in alluvial, coastal saline and laterite soils under laboratory incubated condition at 60% water holding capacity of soils and 30 degrees C temperature was maintained. In field study herbicides were applied twice for the control of grasses, annual and perennials broad leaves weeds and sedges in rice, wheat and soybean to find out the residual fate of both the herbicides on different matrices of respective crops after harvest. Extraction and clean up methodologies for the herbicides were standardized and subsequently analyzed by HPLC. The study revealed that the half-lives of metsulfuron methyl and chlorimuron ethyl ranged from 10.75 to 13.94 d irrespective of soils and doses applied. Field trials with rice, wheat and soybean also revealed that these two herbicides could safely be recommended for application as no residues were detected in the harvest samples.

In continuation with work regarding the evaluation of the energy of association of various RNA bases with various base pairs, the results of the computations of the electrostatic interaction energy of A-U base pair with four RNA bases viz. Adenine, Uracil, Guanine and Cytosine have been reported. Non bonded induced polarization and dispersion potentials are not taken into account. Electrostatic hard sphere model of Nash and Bradley has been employed. Computations have been performed to find out the minimum energy configuration out of the various possible complex configurations. Results have been discussed with reference to similar calculations with G-C base pair performed by the authors.

The purpose of this work is to show that the selectivity of the nucleotide bases in RNA transcription c an be inferred, in principle, from the DNA base pair - RNA base interaction. The catalytic role of enzymes in this process is, therefore, only to form the sugar - phosphate backbone. A systematic study for the evaluation of the interaction energy of the DNA base pair with the enterant RNA bases have been undertaken to elucidate the aforesaid mechanism. Electrostatic hard sphere approximation of Nash and Bradley 1 has been employed. Non bonded induced dipole and London dispersion forces are not taken into account. The present communication gives the results of computations of the interaction energy of the four RNA bases. The results have been discussed with reference to Stent's and Zubay's schemes of RNA transcription.