ABSTRACT: Structural genomics (SG) programs have developed during the last decade many novel methodologies for faster and more accurate structure determination. These new tools and approaches led to the determination of thousands of protein structures. The generation of enormous amounts of experimental data resulted in significant improvements in the understanding of many biological processes at molecular levels. However, the amount of data collected so far is so large that traditional analysis methods are limiting the rate of extraction of biological and biochemical information from 3D models. This situation has prompted us to review the challenges that remain unmet by SG, as well as the areas in which the potential impact of SG could exceed what has been achieved so far.
Project description:While three dimensional structures have long been used to search for new drug targets, only a fraction of new drugs coming to the market has been developed with the use of a structure-based drug discovery approach. However, the recent years have brought not only an avalanche of new macromolecular structures, but also significant advances in the protein structure determination methodology only now making their way into structure-based drug discovery. In this paper, we review recent developments resulting from the Structural Genomics (SG) programs, focusing on the methods and results most likely to improve our understanding of the molecular foundation of human diseases. SG programs have been around for almost a decade, and in that time, have contributed a significant part of the structural coverage of both the genomes of pathogens causing infectious diseases and structurally uncharacterized biological processes in general. Perhaps most importantly, SG programs have developed new methodology at all steps of the structure determination process, not only to determine new structures highly efficiently, but also to screen protein/ligand interactions. We describe the methodologies, experience and technologies developed by SG, which range from improvements to cloning protocols to improved procedures for crystallographic structure solution that may be applied in "traditional" structural biology laboratories particularly those performing drug discovery. We also discuss the conditions that must be met to convert the present high-throughput structure determination pipeline into a high-output structure-based drug discovery system.
Project description:Background:Documentary evidence points to high unmet need for family planning across sub-Saharan Africa. Modern contraceptive use has been staggering over decades with unacceptable marginal increases given that one in three women still report unmet need in Ghana. This study sought to re-examine through a further analysis on the prevalence and determinants of unmet need for family planning in Ghana using married women extracted from the recent 2014 Ghana Demographic and Health Survey. Method:Data was analyzed using univariate, bivariate, logistic and multinomial logistic regression models. Results:Of the 4527 women, more than a third (35.17%) experienced unmet need of which 20.19% had unmet need for spacing while 14.98% reported unmet need for limiting. The logistic results showed that older aged women, being employed and women with higher ideal number of children were less likely to experience unmet need. However, women who did not know the couples' preferred number of children, women who had more than one union and those with higher number of living biological children were more likely to report unmet need. From the multinomial model, an increase in age, residing in a rural area, and being employed were associated with lower risk of unmet need for spacing. Additionally, Women who did not know the couples' ideal number of children, women who had higher age when they got married, and women with higher number of biological children were more likely to report unmet need for spacing. Women who had a higher number of ideal children, women who had secondary or higher education, women from higher socio-economic households, were less likely to report unmet need for limiting. . Conclusions:We recommend the strengthening of contraception services in order to address the various age specific needs and women within the different socio-demographic sects so as to reduce unmet need. Addressing the needs of women with increasing number of living biological children is equally paramount.
Project description:The explosion of the size of the universe of known protein sequences has stimulated two complementary approaches to structural mapping of these sequences: theoretical structure prediction and experimental determination by structural genomics (SG). In this work, we assess the accuracy of structure prediction by two automated template-based structure prediction metaservers (genesilico.pl and bioinfo.pl) by measuring the structural similarity of the predicted models to corresponding experimental models determined a posteriori. Of 199 targets chosen from SG programs, the metaservers predicted the structures of about a fourth of them "correctly." (In this case, "correct" was defined as placing more than 70 % of the alpha carbon atoms in the model within 2 Å of the experimentally determined positions.) Almost all of the targets that could be modeled to this accuracy were those with an available template in the Protein Data Bank (PDB) with more than 25 % sequence identity. The majority of those SG targets with lower sequence identity to structures in the PDB were not predicted by the metaservers with this accuracy. We also compared metaserver results to CASP8 results, finding that the models obtained by participants in the CASP competition were significantly better than those produced by the metaservers.
Project description:Tea is among the world's most widely consumed non-alcoholic beverages and possesses enormous economic, health, and cultural values. It is produced from the cured leaves of tea plants, which are important evergreen crops globally cultivated in over 50?countries. Along with recent innovations and advances in biotechnologies, great progress in tea plant genomics and genetics has been achieved, which has facilitated our understanding of the molecular mechanisms of tea quality and the evolution of the tea plant genome. In this review, we briefly summarize the achievements of the past two decades, which primarily include diverse genome and transcriptome sequencing projects, gene discovery and regulation studies, investigation of the epigenetics and noncoding RNAs, origin and domestication, phylogenetics and germplasm utilization of tea plant as well as newly developed tools/platforms. We also present perspectives and possible challenges for future functional genomic studies that will contribute to the acceleration of breeding programs in tea plants.
Project description:BACKGROUND:Non-compliance to, or drop-out from treatment for childhood ADHD, result in suboptimal outcome. Non-compliance and drop-out may be due to mismatches between patients' care needs and treatments provided. This study investigated unmet care needs in ADHD patients. Unmet needs were assessed in two different treatment settings (general outpatient setting versus youth-ACT). Youth-ACT treatment is an intensive outreach-oriented treatment for patients with severe psychiatric and psychosocial problems. Comparison of a general outpatient sample with a youth-ACT sample enabled us to assess the influence of severity of psychiatric and psychosocial problems on perceived care needs. METHODS:Self-reported unmet care needs were assessed among 105 ADHD patients between 6 and 17 years of age in a general outpatient (n = 52) and a youth-ACT setting (n = 53). RESULTS:ADHD patients most frequently reported unmet needs regarding mental health problems, information on diagnosis/treatment, and future prospects. Outpatients differed from youth-ACT patients with respect to 30% of the unmet care needs that were investigated. Outpatients perceived more unmet needs regarding information on diagnosis/treatment (p = 0.014). Youth-ACT patients perceived more unmet needs concerning medication side effects (p = 0.038), quality and/or quantity of food (p = 0.016), self-care abilities (p = 0.016), regular/suitable school or other daytime activities (p = 0.013), making and/or keeping friends (p = 0.049), and future prospects (p = 0.045). CONCLUSIONS:Focusing treatment of ADHD patients on unmet needs may reduce non-compliance and drop-out. In clinical practice, systematic assessment of unmet care needs in all ADHD patients may be warranted, e.g. using the CANSAS questionnaire during the screening/intake phase.
Project description:BACKGROUND:The assessment of unmet need is one way to gauge inequities in access to healthcare services. While there are multiple reasons for unmet need, financial barriers are a major reason particularly in low- and middle-income countries where healthcare systems do not offer financial protection. Moreover, accessibility and affordability are paramount in achieving universal health coverage. This study examines the extent of unmet need in Kenya due to financial barriers, the associated determinants, and the influence of regional variations. METHODS:We use data from the 2013 Kenya household health expenditure and utilization (KHHEUS) cross sectional survey. Self-reported unmet need due to lack of money and high costs of care is used to compute the outcome of interest. A multilevel regression model is employed to assess the determinants of cost-related unmet need, confounding for the effect of variations at the regional level. RESULTS:Cost-related barriers are the main cause of unmet need for outpatient and inpatient services, with wide variations across the counties. A positive association between county poverty rates and cost-related unmet is noted. Results reveal a higher intraclass correlation coefficient (ICC) of 0.359(35.9%) for inpatient services relative to 0.091(9.1%) for outpatient services. Overall, differences between counties accounted for 9.4% (ICC?~?0.094) of the total variance in cost-related unmet need. Factors that positively influence cost-related unmet need include older household heads, inpatient services, and urban residence. Education of household head, good self-rated health, larger household size, insured households, and higher wealth quintiles are negatively associated with cost-related unmet need. CONCLUSION:The findings underscore the important role of cost in enabling access to healthcare services. The county level is seen to have a significant influence on cost-related unmet need. The variations noted in cost-related unmet need across the counties signify the existence of wide disparities within and between counties. Scaling up of health financing mechanisms would fundamentally require a multi-layered approach with a focus on the relatively poor counties to address the variations in access. Further segmentation of the population for better targeting of health financing policies is paramount, to address equity in access for the most vulnerable and marginalized populations.
Project description:This study aimed to analyze the factors affecting the unmet medical needs of patients with benign prostate enlargement (BPE) based on Andersen's behavioral model. The data were taken from the 2009-2016 Korea Health Panel Study and 3003 participants were used for analysis. "Unmet medical needs" was used as a dependent variable. Independent variables were predisposing variables: age, educational attainment, and marital status; enabling factors: income, job type, and insurance type; and need factors: lying in a sickbed, activity limitation, subjective health status, and having chronic diseases. Results showed that younger patients experienced a higher probability of unmet medical needs. Those with higher educational attainment had a lower chance of experiencing unmet medical needs. Patients with national health insurance were less likely to experience unmet medical needs. In addition, patients who experienced lying in a sickbed had a higher probability of experiencing unmet medical needs. Therefore, in order to reduce the unmet medical needs of patients with BPE, it is necessary to allow patients to be treated early and give them accurate information about the disease. In addition, access to medical care should be strengthened through continuous care focused on primary care.
Project description:BACKGROUND:Dental health is an important component of general health. Socioeconomic inequalities in unmet dental care needs have been identified in the literature, but some knowledge gaps persist. This paper tries to identify the determinants of income-related inequality in unmet need for dental care and the reasons for its recent evolution in Spain, and it inquires about the traces left by the Great Recession. METHODS:Data from the EU-SILC forming a decade (2007-2017) were used. Income-related inequalities for three years were measured by calculating corrected concentration indices (CCI), which were further decomposed in order to compute the contribution of different factors to inequality. An Oaxaca-type decomposition approach was also used to analyze the origin of changes over time. Men and women were analyzed separately. RESULTS:Pro-rich inequality in unmet dental care needs significantly increased over time (CCI 2007: -?0.0272 and?-?0.0334 for males and females, respectively; CCI 2017: -?0.0704 and?-?0.0776; p <?0.001). Inequality showed a clear "pro-cycle" pattern, growing during the Great Recession and starting to decrease just after the economic recovery began. Gender differences only were significant for 2009 (p =?0.004) and 2014 (p =?0.063). Income was the main determinant of inequality and of its variation along time -particularly for women-, followed by far by unemployment -particularly for men-; the contributions of both were mainly due to changes in elasticites. CONCLUSIONS:The Great Recession left its trace in form of a higher inequality in the access to dental care. Also, unmet need for dental care, as well as its inequality, became more sensitive to the ability to pay and to unemployment along recent years. To broaden public coverage of dental care for vulnerable groups, such as low-income/unemployed people with high oral health needs, would help to prevent further growth of inequality.
Project description:For the majority of patients with newly diagnosed follicular lymphoma (FL), current treatments, while not curative, allow for long remission durations. However, several important needs remain unaddressed. Studies have consistently shown that ?20% of patients with FL experience disease progression within 2?years of first-line treatment, and consequently have a 50% risk of death in 5?years. Better characterization of this group of patients at diagnosis may provide insight into those in need of alternate or intensive therapies, facilitate a precision approach to inform clinical trials, and allow for improved patient counseling. Prognostic methods to date have employed clinical parameters, genomic methods, and a wide assortment of biological and biochemical markers, but none so far has been able to adequately identify this high-risk population. Advances in the first-line treatment of FL with chemoimmunotherapy have led to a median progression-free survival (PFS) of approximately 7?years; creating a challenge in the development of clinical trials where PFS is a primary end point. A surrogate end point that accurately predicts PFS would allow for new treatments to reach patients with FL sooner, or lessen toxicity, time, and expense to those patients requiring little to no therapy. Quality of response to treatment may predict PFS and overall survival in FL; as such complete response rates, either alone or in conjunction with PET imaging or minimal residual disease negativity, are being studied as surrogates, with complete response at 30?months after induction providing the strongest surrogacy evidence to date. A better understanding of how to optimize quality of life in the context of this chronic illness is another important focus deserving of further study. Ongoing efforts to address these important unmet needs are herein discussed.
Project description:OBJECTIVES:To synthesise evidence on longer term unmet needs perceived by stroke survivors, and psychometric properties of the tools used to evaluate unmet care needs after stroke. DESIGN:Systematic review. SETTING:Community or patients' home. PARTICIPANTS:Stroke survivors. METHODS:We searched PubMed, PsycINFO, CINAHL, EMBASE from inception to 31 March 2018 to identify survey studies that evaluated unmet needs perceived by stroke survivors after hospital discharge. Reported unmet needs were categorised under three domains: body functioning, activity/participation and environmental factors. Ranges of prevalence rates of unmet needs reported in studies were presented. RESULTS:We included 19 eligible studies, with considerable heterogeneity in patients, survey methods and results. Psychometric properties of two stroke-specific tools were formally evaluated, indicating their moderate reliability and content/concurrent validity. The median number of reported unmet needs per stroke survivor was from two to five, and the proportion of stroke survivors with at least one unmet needs was on average 73.8% (range 19.8%- 91.7%). Unmet needs perceived by stroke survivors included 55 records of unmet body functioning needs, 47 records of unmet activities/participatory needs and 101 records of unmet environmental needs. Common unmet service needs were unmet information needs (3.1%- 65.0%), transport (5.4%-53.0%), home help/personal care (4.7%-39.3%) and therapy (2.0%-35.7%). CONCLUSIONS:The prevalence of unmet long-term needs is high among stroke survivors, and there is considerable heterogeneity in type and frequency of specific unmet needs. More research is required to link regular assessment of long-term unmet needs of stroke survivors with the provision of cost-effective patient-centred health and social care services.