Gravi-Sensitivity of Mosses and Their Gravity-Dependent Ontogenetic Adaptations.

Gravi-morphoses affect the variability of plants and are the morphogenetic adaptation to different environmental conditions. Gravity-dependent phenotypic plasticity of gametophytes as well as gravi-sensitivity of moss protonemata in microgravity and simulated microgravity conditions are discussed. The moss protonema, a filamentous multicellular system, representing a juvenile stage of moss development, develops as a result of the elongation and division of the apical cell. This apical cell of the protonema is a unique object for research on moss gravi-sensitivity, as graviperception and gravitropic growth occur within the same single cell. Attention is focused on the influence of gravity on bryophyte ontogenesis, including the gravitropic reactivity of moss protonemata, gravi-sensitivity at the stage of leafy shoot development and sporogonium formation, gravity-influenced morphogenesis of apical cell budding, and gravity-dependent spiral growth patterns. The role of gravireceptors in the growth processes of mosses at the cellular level under microgravity conditions are being discussed, as well as the involvement of auxin transport, Ca2+-induced gravitropism and the cytoskeleton in gravitropic reactions.

Hippocampal Neuroimaging-Informed Clinical Trial Enrichment Tool for Amnestic Mild Cognitive Impairment Using Open Data.

Our goal was to assess the enrichment utility of hippocampal volume (HV) as an enrichment biomarker in amnestic mild cognitive impairment (aMCI) clinical trials, and, hence, develop an HV neuroimaging-informed clinical trial enrichment tool. Modeling of integrated longitudinal patient-level data came from open-access natural history studies in patients diagnosed with aMCI-the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2-and indicated that a decrease of 1 cm3 with respect to the analysis dataset median baseline intracranial volume-adjusted HV (ICV-HV; ~ 5 cm3 ) is associated with > 50% increase in disease progression rate as measured by the Clinical Dementia Rating Scale-Sum of Boxes. Clinical trial simulations showed that the inclusion of aMCI subjects with baseline ICV-HV below the 84th or 50th percentile allowed an approximate reduction in trial size of at least 26% and 55%, respectively. This clinical trial enrichment tool can help design more efficient and informative clinical trials.

PubChem chemical structure standardization.

BACKGROUND: PubChem is a chemical information repository, consisting of three primary databases: Substance, Compound, and BioAssay. When individual data contributors submit chemical substance descriptions to Substance, the unique chemical structures are extracted and stored into Compound through an automated process called structure standardization. The present study describes the PubChem standardization approaches and analyzes them for their success rates, reasons that cause structures to be rejected, and modifications applied to structures during the standardization process. Furthermore, the PubChem standardization is compared to the structure normalization of the IUPAC International Chemical Identifier (InChI) software, as manifested by conversion of the InChI back into a chemical structure. RESULTS: The observed rejection rate for substances processed by PubChem standardization was 0.36%, which is predominantly attributed to structures with invalid atom valences that cannot be readily corrected without additional information from contributors. Of all structures that pass standardization, 44% are modified in the process, reducing the count of unique structures from 53,574,724 in substance to 45,808,881 in compound as identified by de-aromatized canonical isomeric SMILES. Even though the processing time is very low on average (only 0.4% of structures have individual standardization time above 0.1 s), total standardization time is completely dominated by edge cases: 90% of the time to standardize all structures in PubChem substance is spent on the 2.05% of structures with the highest individual standardization time. It is worth noting that 60% of the structures obtained from PubChem structure standardization are not identical to the chemical structure resulting from the InChI (primarily due to preferences for a different tautomeric form). CONCLUSIONS: Standardization of chemical structures is complicated by the diversity of chemical information and their representations approaches. The PubChem standardization is an effective and efficient tool to account for molecular diversity and to eliminate invalid/incomplete structures. Further development will concentrate on improved tautomer consideration and an expanded stereocenter definition. Modifications are difficult to thoroughly validate, with slight changes often affecting many thousands of structures and various edge cases. The PubChem structure standardization service is accessible as a public resource ( https://pubchem.ncbi.nlm.nih.gov/standardize ), and via programmatic interfaces.

Regulatory-accepted drug development tools are needed to accelerate innovative CNS disease treatments.

Central Nervous System (CNS) diseases represent one of the most challenging therapeutic areas for successful drug approvals. Developing quantitative biomarkers as Drug Development Tools (DDTs) can catalyze the path to innovative treatments, and improve the chances of drug approvals. Drug development and healthcare management requires sensitive, reliable, validated, and regulatory accepted biomarkers and endpoints. This review highlights the regulatory paths and considerations for developing DDTs required to advance biomarker and endpoint use in clinical development (e.g., consensus CDISC [Clinical Data Interchange Standards Consortium] data standards, precompetitive sharing of anonymized patient-level data, and continual alignment with regulators). Summarized is the current landscape of biomarkers in a range of CNS diseases including Alzheimer disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorders, Depression, Huntington's disease, Multiple Sclerosis and Traumatic Brain Injury. Advancing DDTs for these devastating diseases that are both validated and qualified will require an integrated, cross-consortium approach to accelerate the delivery of innovative CNS therapeutics.

Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size.

Process Evaluation of a Blended Web-Based Intervention on Return to Work for Sick-Listed Employees with Common Mental Health Problems in the Occupational Health Setting.

Purpose A blended web-based intervention, "eHealth module embedded in collaborative occupational health care" (ECO), aimed at return to work, was developed and found effective in sick-listed employees with common mental disorders. In order to establish the feasibility of ECO, a process evaluation was conducted. Methods Seven process components were investigated: recruitment, reach, dose delivered, dose received, fidelity, satisfaction and context. Quantitative and qualitative methods were used to collect data: an online questionnaire for the employees, website data, telephonic interviews with occupational physicians (OPs) and observations of the researchers. Results Recruitment was uncomplicated for the employees, but required several steps for the OPs. Reach was 100 % at the OP level and 76.3 % at the employee level. Dose delivered and received for OPs: 91.6 % received minimally one email message. Dose delivered and received for the employees: finishing of the different modules of ECO varied between 13 and 90 %. Fidelity: the support of the OP to the employee in ECO was lower than anticipated. Satisfaction: both employees and OPs were satisfied with the intervention. However, employees reported a need for more support in ECO. The context showed that OPs had limited time to support the employees and it was impossible for the employee to contact the OP outside their regular contacts. Conclusion Feasibility of ECO and satisfaction of employees and OPs with ECO were good. Fidelity of OPs was limited. For further implementation in the occupational health setting, especially contextual barriers regarding time limitation and accessibility of OPs for employees should be addressed.

Validation of the Patient Health Questionnaire-9 for Major Depressive Disorder in the Occupational Health Setting.

Purpose Because of the increased risk of long-term sickness leave for employees with a major depressive disorder (MDD), it is important for occupational health professionals to recognize depression in a timely manner. The Patient Health Questionnaire-9 (PHQ-9) has proven to be a reliable and valid instrument for screening MDD, but has not been validated in the occupational health setting. The aim of this study was to validate the PHQ-9 for MDD within a population of employees on sickness leave by using the MINI-International Neuropsychiatric Interview (MINI) as a gold standard. Methods Participants were recruited in collaboration with the occupational health service. The study sample consisted of 170 employees on sickness leave between 4 and 26 weeks who completed the PHQ-9 and were evaluated with the MINI by telephone. Sensitivity, specificity, positive and negative predictive value, efficiency and 95 % confidence intervals (95 % CIs) were calculated for all possible cut-off values. A receiver operator characteristics (ROC) analysis was computed for PHQ-9 score versus the MINI. Results The optimal cut-off value of the PHQ-9 was 10. This resulted in a sensitivity of 86.1 % [95 % CI (69.7-94.8)] and a specificity of 78.4 % [95 % CI (70.2-84.8)]. Based on the ROC analysis, the area under the curve for the PHQ-9 was 0.90 [SE = 0.02; 95 % CI (0.85-0.94)]. Conclusion The PHQ-9 shows good sensitivity and specificity as a screener for MDD within a population of employees on sickness leave.

PubChem atom environments.

BACKGROUND: Atom environments and fragments find wide-spread use in chemical information and cheminformatics. They are the basis of prediction models, an integral part in similarity searching, and employed in structure search techniques. Most of these methods were developed and evaluated on the relatively small sets of chemical structures available at the time. An analysis of fragment distributions representative of most known chemical structures was published in the 1970s using the Chemical Abstracts Service data system. More recently, advances in automated synthesis of chemicals allow millions of chemicals to be synthesized by a single organization. In addition, open chemical databases are readily available containing tens of millions of chemical structures from a multitude of data sources, including chemical vendors, patents, and the scientific literature, making it possible for scientists to readily access most known chemical structures. With this availability of information, one can now address interesting questions, such as: what chemical fragments are known today? How do these fragments compare to earlier studies? How unique are chemical fragments found in chemical structures? RESULTS: For our analysis, after hydrogen suppression, atoms were characterized by atomic number, formal charge, implicit hydrogen count, explicit degree (number of neighbors), valence (bond order sum), and aromaticity. Bonds were differentiated as single, double, triple or aromatic bonds. Atom environments were created in a circular manner focused on a central atom with radii from 0 (atom types) up to 3 (representative of ECFP_6 fragments). In total, combining atom types and atom environments that include up to three spheres of nearest neighbors, our investigation identified 28,462,319 unique fragments in the 46 million structures found in the PubChem Compound database as of January 2013. We could identify several factors inflating the number of environments involving transition metals, with many seemingly due to erroneous interpretation of structures from patent data. Compared to fragmentation statistics published 40 years ago, the exponential growth in chemistry is mirrored in a nearly eightfold increase in the number of unique chemical fragments; however, this result is clearly an upper bound estimate as earlier studies employed structure sampling approaches and this study shows that a relatively high rate of atom fragments are found in only a single chemical structure (singletons). In addition, the percentage of singletons grows as the size of the chemical fragment is increased. CONCLUSIONS: The observed growth of the numbers of unique fragments over time suggests that many chemically possible connections of atom types to larger fragments have yet to be explored by chemists. A dramatic drop in the relative rate of increase of atom environments from smaller to larger fragments shows that larger fragments mainly consist of diverse combinations of a limited subset of smaller fragments. This is further supported by the observed concomitant increase of singleton atom environments. Combined, these findings suggest that there is considerable opportunity for chemists to combine known fragments to novel chemical compounds. The comparison of PubChem to an older study of known chemical structures shows noticeable differences. The changes suggest advances in synthetic capabilities of chemists to combine atoms in new patterns. Log-log plots of fragment incidence show small numbers of fragments are found in many structures and that large numbers of fragments are found in very few structures, with nearly half being novel using the methods in this work. The relative decrease in the count of new fragments as a function of size further suggests considerable opportunity for more novel chemicals exists. Lastly, the differences in atom environment diversity between PubChem Substance and Compound showcase the effect of PubChem standardization protocols, but also indicate that a normalization procedure for atom types, functional groups, and tautomeric/resonance forms based on atom environments is possible. The complete sets of atom types and atom environments are supplied as supporting information.

PubChem structure-activity relationship (SAR) clusters.

BACKGROUND: Developing structure-activity relationships (SARs) of molecules is an important approach in facilitating hit exploration in the early stage of drug discovery. Although information on millions of compounds and their bioactivities is freely available to the public, it is very challenging to infer a meaningful and novel SAR from that information. RESULTS: Research discussed in the present paper employed a bioactivity-centered clustering approach to group 843,845 non-inactive compounds stored in PubChem according to both structural similarity and bioactivity similarity, with the aim of mining bioactivity data in PubChem for useful SAR information. The compounds were clustered in three bioactivity similarity contexts: (1) non-inactive in a given bioassay, (2) non-inactive against a given protein, and (3) non-inactive against proteins involved in a given pathway. In each context, these small molecules were clustered according to their two-dimensional (2-D) and three-dimensional (3-D) structural similarities. The resulting 18 million clusters, named "PubChem SAR clusters", were delivered in such a way that each cluster contains a group of small molecules similar to each other in both structure and bioactivity. CONCLUSIONS: The PubChem SAR clusters, pre-computed using publicly available bioactivity information, make it possible to quickly navigate and narrow down the compounds of interest. Each SAR cluster can be a useful resource in developing a meaningful SAR or enable one to design or expand compound libraries from the cluster. It can also help to predict the potential therapeutic effects and pharmacological actions of less-known compounds from those of well-known compounds (i.e., drugs) in the same cluster.

Return-to-Work Self-Efficacy and Actual Return to Work Among Long-Term Sick-Listed Employees.

OBJECTIVE: Considering the costs incurred by sickness absence and the implications for the workers' quality of life, a fast return to work (RTW) is important. Self-efficacy (SE) seems to be an important predictor of RTW for employees with mental health problems. The predictive value of return-to-work self-efficacy (RTW-SE) has not been examined in employees on long-term sickness absence due to any cause. The aim of this study is to investigate whether RTW-SE is a predictor of time to RTW in long-term sick-listed employees with all-cause sickness absence. Furthermore, the relative contribution of RTW-SE in predicting RTW will be examined compared to health-related, job-related and personal factors. METHODS: In a longitudinal study, sick-listed employees who were currently on sick leave for more than 4 weeks filled out a self-report questionnaire. Demographics, health-related, personal, and job-related factors, and RTW-SE were measured. Employees were followed for 2 years to determine the duration until full RTW. Cox proportional hazards regression analyses were used to identify factors associated with time to RTW. RESULTS: Data were collected from 493 sick-listed employees. RTW-SE was a significant predictor of RTW. In a multivariate model, low RTW-SE, the thought of not being able to work while having symptoms (illness behaviour) and having chronic medical conditions were predictors of a longer duration until RTW. CONCLUSION: When guiding long-term sick-listed employees, it is important to focus on factors such as SE and illness behaviour, instead of just focusing on the symptoms of the sick-listed employee.

Gravitropic moss cells default to spiral growth on the clinostat and in microgravity during spaceflight.

In addition to shoots and roots, the gravity (g)-vector orients the growth of specialized cells such as the apical cell of dark-grown moss protonemata. Each apical cell of the moss Ceratodon purpureus senses the g-vector and adjusts polar growth accordingly producing entire cultures of upright protonemata (negative gravitropism). The effect of withdrawing a constant gravity stimulus on moss growth was studied on two NASA Space Shuttle (STS) missions as well as during clinostat rotation on earth. Cultures grown in microgravity (spaceflight) on the STS-87 mission exhibited two successive phases of non-random growth and patterning, a radial outgrowth followed by the formation of net clockwise spiral growth. Also, cultures pre-aligned by unilateral light developed clockwise hooks during the subsequent dark period. The second spaceflight experiment flew on STS-107 which disintegrated during its descent on 1 February 2003. However, most of the moss experimental hardware was recovered on the ground, and most cultures, which had been chemically fixed during spaceflight, were retrieved. Almost all intact STS-107 cultures displayed strong spiral growth. Non-random culture growth including clockwise spiral growth was also observed after clinostat rotation. Together these data demonstrate the existence of default non-random growth patterns that develop at a population level in microgravity, a response that must normally be overridden and masked by a constant g-vector on earth.

Oncology nurses' experiences with requests for assisted dying from terminally ill patients with cancer.

PURPOSE/OBJECTIVES: To explore oncology nurses' experiences with receiving requests for assisted dying from terminally ill patients with cancer. DESIGN: Descriptive, naturalistic. SETTING: RNs who identified themselves as direct care providers or clinical nurse specialist members of the Oncology Nursing Society. SAMPLE: 40 oncology nurses who responded to a randomized, sequential direct mailing submitted 48 stories for analysis. METHODS: Anonymously submitted written stories analyzed using Denzin's process of interpretive interactionism. MAIN RESEARCH VARIABLE: The experience of receiving a request for assisted dying. FINDINGS: Four main themes emerged from the thematic analysis: Control, Conflict, Covert Communication, and the Enduring Influence. Eleven subthemes included the Cry for Help, Hastening the Process, What if, Managing the Morphine, Countering With Palliative Care, Collision of Values, Sense of Distress, Dialogue Around the Request, Silent Knowing, the Unforgettable, and Reflections on Lessons Learned. CONCLUSIONS: Experiences included a mixture of direct-patient and family requests for pain relief, anticipatory fear of future pain, desire to end life before unacceptable deterioration, family requests to hasten the dying trajectory, and others. Stories reflected the larger societal struggle with desires to control life, health, and the dying process. IMPLICATIONS FOR NURSING PRACTICE: Nurses should be prepared to respond to such requests in a compassionate and helpful way that is respectful of both the patient's and the nurse's personal values. Diversity of individual values and priorities may trigger some patients to seek assistance in controlling the timing and circumstances of death. Thus, continued study of nurse, patient, and family member experiences with this ethical dilemma is warranted.

Carcinogenesis: application to clinical practice.

The evolution of cancer is an intricate, multistage process involving the interplay of numerous variables that both inhibit and enhance the growth and spread of disease. An understanding of the process of carcinogenesis is vital to successful care of patients with cancer. Nurses play a key role in translating information to patients about prevention and health promotion, diagnostic testing, treatment approaches and side effects, and the need for frequent and long-term follow-up. Many patients and their families are well aware of the continual, often exciting, advances in prevention, detection, and treatment of malignancies. Understandably, they look to oncology nurses and other healthcare professionals for guidance and understanding of how these changes might affect their healthcare decisions.

Oral buprenorphine is anti-inflammatory and modulates the pathogenesis of streptococcal cell wall polymer-induced arthritis in the Lew/SSN rat.

This study was carried out to determine an effective regimen for pain management in streptococcal cell wall (SCW)-induced arthritis in female Lew/SSN rats. Forty weanling rats lin 2 groups) were trained to accept disks of jelly as part of their dietary regimen. At 8 weeks of age weighing 150 g, SCW arthritis was induced and sublingual buprenorphine tablets were incorporated into the jelly disks to alleviate the pain of acute arthritis, which developed 24 h post-induction. Group A rats received buprenorphine at a rate of 1 mg/kg 12 hourly. Group B rats received buprenorphine at a rate of 2 mg/kg 12 hourly. Both groups of rats were monitored for symptoms of distress using an adaptation of the Morton and Griffin scale of adverse reactions. Group A rats with severe arthritis required additional subcutaneous (s.c.) injections of buprenorphine to alleviate the adverse effects of arthritis. Group B rats, with twice the dose of buprenorphine did not require additional s.c. injections of buprenorphine. Histological sections of rat hocks indicated that the inflammation was suppressed in Group B rats. We concluded that oral administration of buprenorphine is an effective method of pain management in the pathogenesis of SCW-induced arthritis in Lew/SSN rats. In this model of arthritis, oral buprenorphine has a significant anti-inflammatory effect and appears to modulate the destructive arthritic phase in joints in this animal model of arthritis.

Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis.

OBJECTIVE: To determine the efficacy of fish oil derived (n-3) fatty acid supplementation (3-6 capsules/day) in subjects with rheumatoid arthritis (RA) whose (n-6) fatty acid intake in the background diet was < 10 g/day, compared to olive/corn oil capsule supplement over a 15 week period. METHODS: A placebo controlled, double blind, randomized 15 week study to determine the effect of supplementation on clinical variables in 50 subjects with RA whose background diet was naturally low in (n-6) fatty acids. Fish oil containing 60% (n-3) fatty acids was supplemented at a rate of 40 mg/kg body weight. RESULTS: Analysis of 9 clinical variables indicated there was a significant difference (p < 0.02) between control and treatment groups. Five subjects in the treatment group and 3 in the control group met the American College of Rheumatology 20% improvement criteria. Dietary supplementation resulted in a significant increase in eicosapentaenoic acid in plasma and monocyte lipids in the supplemented group. CONCLUSION: The findings suggest that fish oil supplementation that delivers (n-3) fatty acids at a dose of 40 mg/kg body weight/day, with dietary (n-6) fatty acid intake < 10 g/day in the background diet, results in substantial cellular incorporation of (n-3) fatty acids and improvements in clinical status in patients with RA.

The eicosapentaenoic to docosahexaenoic acid ratio of diets affects the pathogenesis of arthritis in Lew/SSN rats.

Dietary-induced changes in tissue levels of polyunsaturated fatty acids modify inflammatory reactions through changes in the synthesis of lipid and peptide mediators of inflammation. Four semipurified 20% fat diets, based on beef tallow (BT), safflower oil (SFO), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were provided. The DHA and EPA ratios of the (n-3) fatty acid-based diets were 1.1 and 3.4, respectively. The effect of prefeeding diets differing in EPA to DHA ratios prior to the induction of streptococcal cell wall (SCW) arthritis in female Lew/SSN rats was examined. Weanling rats were fed diets for 5 wk before arthritis induction and 5 wk post-arthritis induction. Footpad thickness, hock circumference, plasma and macrophage fatty acids and histological assessment were compared. There were no differences in food intake and final body weights among the groups. Footpad inflammation, reported as percentage change (adjusted for growth) was greatest for rats fed the BT-based diet, intermediate in those fed the SFO-based diet and least for the rats fed the EPA- and DHA-based diets (P < 0.05). Macrophage phospholipids revealed cellular incorporation of EPA and DHA from the fish-oil based diets which modified lipid and peptide mediators of inflammation. Histological sections of rat hocks ranked by severity of arthritis-related changes suggested that the SFO- and EPA-based diets were more successful in ameliorating the destructive arthritic phase in hock joints than the BT- and DHA-based diets (P = 0.09) in this model of arthritis. The course of SCW-induced arthritis can be altered by diet-induced changes in macrophage fatty acid composition. The EPA-based diet is more effective in suppression of inflammation than the DHA-based diet.

Fever of unknown origin.

Despite substantial advances in antimicrobial therapy, infection remains a major cause of morbidity and mortality in immunocompromised cancer patients. As more intensive, curative antineoplastic treatment regimens are established, the risk for fatal infectious complications will continue to rise. Signs and symptoms of infection in this compromised population may be subtle; yet, an undetected and untreated infection can quickly evolve into septic shock and death. Typically, fever is considered to be a clinical hallmark of infection. Yet, most patients initially present to the clinical setting with a fever of unknown origin. Given the lethal nature of infections in immunocompromised patients, one must assume that the febrile patient is infected until proven otherwise.