The Pfizer Crystal Structure Database: An essential tool for structure-based design at Pfizer.

Pfizer's Crystal Structure Database (CSDB) is a key enabling technology that allows scientists on structure-based projects rapid access to Pfizer's vast library of in-house crystal structures, as well as a significant number of structures imported from the Protein Data Bank. In addition to capturing basic information such as the asymmetric unit coordinates, reflection data, and the like, CSDB employs a variety of automated methods to first ensure a standard level of annotations and error checking, and then to add significant value for design teams by processing the structures through a sequence of algorithms that prepares the structures for use in modeling. The structures are made available, both as the original asymmetric unit as submitted, as well as the final prepared structures, through REST-based web services that are consumed by several client desktop applications. The structures can be searched by keyword, sequence, submission date, ligand substructure and similarity search, and other common queries.

On the Origins of Some Spectroscopic Properties of "Purple Iron" (the Tetraoxoferrate(VI) Ion) and Its Pourbaix Safe-Space.

In this work, the authors attempt to interpret the visible, infrared and Raman spectra of ferrate(VI) by means of theoretical physical-inorganic chemistry and historical highlights in this field of interest. In addition, the sacrificial decomposition of ferrate(VI) during water treatment will also be discussed together with a brief mention of how Rayleigh scattering caused by the decomposition of FeVIO42- may render absorbance readings erroneous. This work is not a compendium of all the instrumental methods of analysis which have been deployed to identify ferrate(VI) or to study its plethora of reactions, but mention will be made of the relevant techniques (e.g., Mössbauer Spectroscopy amongst others) which support and advance this overall discourse at appropriate junctures, without undue elaboration on the foundational physics of these techniques.

Behaviour of neonicotinoids in contrasting soils.

Neonicotinoids are widely used to control insect pests in agriculture. Their presence in the environment can affect the health of non-target insects and aquatic animals. The behaviour of four neonicotinoids, namely imidacloprid, acetamiprid, thiacloprid and thiamethoxam, has been investigated in soils with contrasting characteristics to understand their migration in soil and ecological risk. Among the study neonicotinoids, thiamethoxam and thiacloprid were found to be the least and most sorbed neonicotinoids by all the soils, respectively (up to 186 time greater adsorption of thiacloprid), and their uptake was affected by the content of organic matter in the soil. Leaching studies in columns confirmed that thiamethoxam leached out of the soils readily, pointing out to a relatively high risk of ground water contamination with possible ecological impact when thiamethoxam is used in soils with low organic matter. In soil column studies, the soil with the lowest organic matter presents the greatest residue of neonicotinoids in the sub-surface (≤5 cm). In contrast the soil richer in organic matter presented most of the contamination deeper down in the column; a factor to be considered in the remediation from soil.

A single-point modeling approach for the intercomparison and evaluation of ozone dry deposition across chemical transport models (Activity 2 of AQMEII4).

A primary sink of air pollutants and their precursors is dry deposition. Dry deposition estimates differ across chemical transport models, yet an understanding of the model spread is incomplete. Here, we introduce Activity 2 of the Air Quality Model Evaluation International Initiative Phase 4 (AQMEII4). We examine 18 dry deposition schemes from regional and global chemical transport models as well as standalone models used for impact assessments or process understanding. We configure the schemes as single-point models at eight Northern Hemisphere locations with observed ozone fluxes. Single-point models are driven by a common set of site-specific meteorological and environmental conditions. Five of eight sites have at least 3 years and up to 12 years of ozone fluxes. The interquartile range across models in multiyear mean ozone deposition velocities ranges from a factor of 1.2 to 1.9 annually across sites and tends to be highest during winter compared with summer. No model is within 50 % of observed multiyear averages across all sites and seasons, but some models perform well for some sites and seasons. For the first time, we demonstrate how contributions from depositional pathways vary across models. Models can disagree with respect to relative contributions from the pathways, even when they predict similar deposition velocities, or agree with respect to the relative contributions but predict different deposition velocities. Both stomatal and nonstomatal uptake contribute to the large model spread across sites. Our findings are the beginning of results from AQMEII4 Activity 2, which brings scientists who model air quality and dry deposition together with scientists who measure ozone fluxes to evaluate and improve dry deposition schemes in the chemical transport models used for research, planning, and regulatory purposes.

Automated Identification and Measurement Extraction of Pancreatic Cystic Lesions from Free-Text Radiology Reports Using Natural Language Processing.

Purpose: To automatically identify a cohort of patients with pancreatic cystic lesions (PCLs) and extract PCL measurements from historical CT and MRI reports using natural language processing (NLP) and a question answering system. Materials and Methods: Institutional review board approval was obtained for this retrospective Health Insurance Portability and Accountability Act-compliant study, and the requirement to obtain informed consent was waived. A cohort of free-text CT and MRI reports generated between January 1991 and July 2019 that covered the pancreatic region were identified. A PCL identification model was developed by modifying a rule-based information extraction model; measurement extraction was performed using a state-of-the-art question answering system. The system's performance was evaluated against radiologists' annotations. Results: For this study, 430 426 free-text radiology reports from 199 783 unique patients were identified. The NLP model for identifying PCL was applied to 1000 test samples. The interobserver agreement between the model and two radiologists was almost perfect (Fleiss κ = 0.951), and the false-positive rate and true-positive rate were 3.0% and 98.2%, respectively, against consensus of radiologists' annotations as ground truths. The overall accuracy and Lin concordance correlation coefficient for measurement extraction were 0.958 and 0.874, respectively, against radiologists' annotations as ground truths. Conclusion: An NLP-based system was developed that identifies patients with PCLs and extracts measurements from a large single-institution archive of free-text radiology reports. This approach may prove valuable to study the natural history and potential risks of PCLs and can be applied to many other use cases.Keywords: Informatics, Abdomen/GI, Pancreas, Cysts, Computer Applications-General (Informatics), Named Entity Recognition Supplemental material is available for this article. © RSNA, 2022See also commentary by Horii in this issue.

Using Machine Learning to Parse Chemical Mixture Descriptions.

Chemical mixtures have recently come to the attention of open standards and data structures for capturing machine-readable descriptions for informatics uses. At the present time, essentially all transmission of information about mixtures is done using short text descriptions that are readable only by trained scientists, and there are no accessible repositories of marked-up mixture data. We have designed a machine learning tool that can interpret mixture descriptions and upgrade them to the high-level Mixfile format, which can in turn be used to generate Mixtures InChI notation. The interpretation achieves a high success rate and can be used at scale to markup large catalogs and inventories, with some expert checking to catch edge cases. The training data that was accumulated during the project is made openly available, along with previously released mixture editing tools and utilities.

Prevalence of migraine headaches in patients with congenital heart disease.

The prevalence of migraine headaches (MH) is 12% in the general population and increases to 40% in patients with patent foramen ovale. This study evaluated the prevalence of MH in patients with congenital heart disease (CHD). Of 466 patients contacted from the UCLA Adult Congenital Heart Disease Center, 395 (85%) completed a questionnaire to determine the prevalence of MH. Patients were stratified by diagnosis of right-to-left, left-to-right, or no shunt. A group of 252 sex-matched patients with acquired cardiovascular disease served as controls. The prevalence of MH was 45% in adults with CHD compared to 11% in the controls (p<0.001). Of the 179 patients with MH, 143 (80%) had migraines with aura and 36 (20%) had migraines without aura versus 36% and 64% observed in the controls (p<0.001). The frequency of MH was 52% in the right-to-left shunt group, 44% in the left-to-right, and 38% in the no shunt group (p=NS). In patients with a right-to-left shunt who underwent surgical repair, 47% had complete resolution of MH, whereas 76% experienced >50% reduction in headache days per month. In conclusion, the prevalence of MH in all groups of adults with CHD is 3 to 4 times more than a sex-matched control population, with increasing prevalence of MH in patients with no shunt, left-to-right, and right-to-left shunt. The higher than expected frequency of MH in patients with CHD without an intracardiac shunt, suggests additional mechanisms to explain the significant association with MH.

Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis.

BACKGROUND: Atherosclerosis has been implicated as a cause of valvular calcification. The aim of this study was to determine whether atherosclerotic calcification in multiple vascular areas is significantly associated with aortic or mitral annular calcification independent of traditional risk factors. METHODS AND RESULTS: A total of 1242 consecutive asymptomatic patients free of clinical coronary heart disease were studied by electron-beam computed tomography for the extent of calcium due to atherosclerosis in 5 distinct vascular beds and calcium in the aortic and mitral annuli. Nearly 24% had calcium in the aortic annulus, whereas 8% were found to have mitral annular calcification. Age and a history of hypertension were the only traditional cardiovascular risk factors that were independently associated with prevalent calcification in the aortic and mitral annuli. After adjustment for age, gender, and cardiovascular disease risk factors, subjects with calcium in the thoracic aorta had the highest odds for the presence of aortic annular calcium (OR=3.9, P<0.01), whereas those with calcium in the abdominal aorta had the highest odds for mitral annular calcification (OR=5.1, P=0.01). Standardized increases in calcium in the abdominal aorta (OR=2.0, P<0.01) and iliacs (OR=1.8, P=0.01) were significantly associated with calcium in the aortic annulus after adjustment for the extent of calcium in the other vascular beds, whereas the thoracic aorta was significantly associated (OR=1.4, P=0.02) with calcium in the mitral annulus. CONCLUSIONS: This study supports the hypothesis that calcification of the mitral and aortic annuli is related to atherosclerosis in other vascular beds.

Single-door cervical laminoplasty using titanium miniplates alone.

PURPOSE: To review outcome of 29 patients who underwent single-door cervical laminoplasty for myelopathy using titanium miniplates alone. METHODS: Records of 20 men and 9 women aged 35 to 79 (mean, 64.3) years who underwent single-door cervical laminoplasty for myelopathy using titanium miniplates alone were reviewed. A total of 125 laminae were opened; 97 of them were fixed with a titanium miniplate. In 19 patients, a 20-hole titanium miniplate bent to the contour of a lamina was used and fixed into 3 laminae at alternate levels. In the remaining 10 patients, the pre-contoured ARCH Laminoplasty System was used and fixed into all laminae. In most patients, screw fixation was unicortical, and no spacer or bone graft was used. RESULTS: The mean follow-up duration was 4 (range, 2-9) years. At one-year follow-up, the mean Japanese Orthopaedic Association (JOA) score improved from 9.2 to 13.2 (p<0.001). The mean JOA recovery rate was 64%. No patient had neurological deterioration. The mean anteroposterior diameter increased from 14.3 mm to 19.7 mm; the mean increase was 6.1 mm in the plated laminae and 5.3 mm in the unplated laminae (p=0.11). Out of the 125 laminae, there were 2 hinge non-unions in the unplated laminae, and 2 screw pullouts (not associated with plate loosening). No patient had penetration into the vertebral foramen or neuroforamen. Spring-back closure occurred in 5 (18%) of the 28 unplated laminae, with a mean of <3 mm loss of the initial expansion. Two patients developed transient C5 palsy presenting as shoulder abduction weakness. One patient had a delayed dural tear due to a sharp spike at the edge of the opened C6 lamina. CONCLUSION: Single-door cervical laminoplasty using miniplates alone is a safe technique and achieves a high hinge union rate, good canal expansion, and neurological recovery.

Noninvasive image texture analysis differentiates K-ras mutation from pan-wildtype NSCLC and is prognostic.

BACKGROUND: Non-invasive characterization of a tumor's molecular features could enhance treatment management. Quantitative computed tomography (CT) based texture analysis (QTA) has been used to derive tumor heterogeneity information, and the appearance of the tumors has been shown to relate to patient outcome in non-small cell lung cancer (NSCLC) and other cancers. In this study, we examined the potential of tumoral QTA to differentiate K-ras mutant from pan-wildtype tumors and its prognostic potential using baseline pre-treatment non-contrast CT imaging in NSCLC. METHODS: Tumor DNA from patients with early-stage NSCLC was analyzed on the LungCarta Panel. Cases with a K-ras mutation or pan-wildtype for 26 oncogenes and tumor suppressor genes were selected for QTA. QTA was applied to regions of interest in the primary tumor. Non-parametric Mann Whitney test assessed the ability of the QTA, clinical and patient characteristics to differentiate between K-ras mutation from pan-wildtype. A recursive decision tree was developed to determine whether the differentiation of K-ras mutant from pan-wildtype tumors could be improved by sequential application of QTA parameters. Kaplan-Meier survival analysis assessed the ability of these markers to predict survival. RESULTS: QTA was applied to 48 cases identified, 27 had a K-ras mutation and 21 cases were pan-wildtype. Positive skewness and lower kurtosis were significantly associated with the presence of a K-ras mutation. A five node decision tree had sensitivity, specificity, and accuracy values (95% CI) of 96.3% (78.1-100), 81.0% (50.5-97.4), and 89.6% (72.9-97.0); respectively. Kurtosis was a significant predictor of OS and DFS, with a lower kurtosis value linked with poorer survival. CONCLUSIONS: Lower kurtosis and positive skewness are significantly associated with K-ras mutations. A QTA feature such as kurtosis is prognostic for OS and DFS. Non-invasive QTA can differentiate the presence of K-ras mutation from pan-wildtype NSCLC and is associated with patient survival.

Squamous Cell Carcinoma of the Lung with Metastasis to the GI Tract Associated with EGFR Exon 19 Deletion.

We describe three confirmed cases of squamous cell carcinoma (SCC) of the lung with metastasis to the gastrointestinal (GI) tract, with two having epidermal growth factor receptor (EGFR) exon 19 deletions in all available specimens. One of these patients received EGFR tyrosine kinase directed therapy for a brief period with some symptom relief. Consideration of EGFR exon 19 mutation testing in SCC of the lung, particularly for those with GI tract metastasis, may identify this potentially drug-targetable entity.

Molecular determinants of lung cancer metastasis to the central nervous system.

Lung cancer remains the leading cause of cancer-related mortality worldwide. The propensity for metastasis to the central nervous system (CNS) is a major clinical hurdle contributing to the low five-year survival rate of advanced disease. CNS metastases significantly outnumber primary brain tumors and carry a dismal prognosis in part due to the inability of therapeutic agents to cross the blood brain barrier. Standard treatment using radiation has been largely ineffective in improving mortality, suggesting the need for new agents targeting the critical metastatic drivers. The genetic and molecular events governing CNS metastasis from the lung are poorly understood at this time. This review highlights genetic events associated with CNS dissemination from the lung and molecular mechanisms associated with CNS metastasis. In vivo model systems that faithfully recapitulate escape from the lung and colonization of the CNS are described as tools for understanding the metastatic phenotype and for testing new therapeutic agents. A deeper understanding of the mechanisms of lung cancer metastasis to the CNS is needed to elucidate novel therapeutic avenues towards the improvement of the mortality associated with advanced stage lung cancer.

No miR quirk: dysregulation of microRNAs in pancreatic ductal adenocarcinoma.

MicroRNAs are post-transcriptional regulators of gene expression with tissue-specific expression profiles. Dysregulation of microRNAs has been shown to play a role in carcinogenesis. Although progress has been made in the diagnosis and treatment of many cancers, pancreatic cancer remains an intractable public health problem, causing 6.58% of cancer deaths despite making up less than 3% of cancer diagnoses in the United States. No screening, diagnostic or imaging techniques exist with the sensitivity to detect pancreatic cancer in its early, operable stages. Risk factors include numerous inherited syndromes, diabetes mellitus, and hepatitis C virus infection. Here we review the literature regarding dysregulation of microRNA expression in native pancreas, pancreatic ductal adenocarcinoma (the dominant form of pancreatic cancer), and its risk factors to illuminate the biology and progression of this disease. We explore promising evidence for the use of microRNAs as prognostic and diagnostic tools, and discuss emerging reports on microRNA therapeutics.

Femoral tunnel widening after quadrupled hamstring anterior cruciate ligament reconstruction.

PURPOSE: To evaluate the extent of femoral tunnel widening after quadrupled hamstring anterior cruciate ligament reconstruction using femoral cross pin fixation in contrast to bioabsorbable screw fixation augmented with Endopearl. METHODS: 16 patients underwent cross pin femoral fixation and the next 15 underwent bioabsorbable screw fixation augmented with Endopearl. The patients were evaluated radiographically for femoral tunnel widening. Standard posteroanterior radiographs of the knee in full extension were taken at postoperative year 2 and 5. The tunnel width was measured at the opening, the widest and the most proximal parts of the femoral tunnel. RESULTS: In the femoral cross pin and bioabsorbable screw fixations, the mean femoral tunnel sizes were 7.6 and 8.0 mm, respectively. The overall mean tunnel widening at all measured sites were 2.7 and 1.8 mm at the 2-year follow-up and were 2.5 and 1.8 mm at the 5-year follow-up, respectively. The femoral tunnel widening was greater in the cross pin than the bioabsorbable screw group, but only the difference in the most proximal part was significant (p=0.01 at year 2 and p<0.001 at year 5). CONCLUSION: Femoral tunnel widening was greater in femoral cross pin fixation, probably related to the windshield-wiper and bungee-cord effects. It usually occurred in the first 2 years after the operation and remained static thereafter.

Modeling evidence of episodic intercontinental long-range transport of lindane.

Two global atmospheric transport models for persistent toxic substances were employed to quantify the intercontinental atmospheric transport of lindane in 2005 using a recently constructed global lindane emission inventory. The focus of this numerical investigation was to identify, on an intercontinental scale, the major sources of lindane that contributed to the contamination of North America and the Arctic. Both models simulated several strong episodic trans-Pacific atmospheric transport events of lindane from its sources in Asia to the western seaboard of North America. Modeling results also detected, forthe firsttime, an important atmospheric pathway for persistent toxic substances from Western Africa/Western Europe to the Caribbean, the southern United States, and the eastern seaboard of North America. Several episodic lindane transAtlantic atmospheric transport events were found from May to October. These events were associated primarily with the easterly trade winds and the African easterly wave that extends from the subtropical eastern Atlantic to the Caribbean. This atmospheric pathway for toxic chemicals has a substantial implication for the level of toxic substances in North America. Atmospheric mechanisms contributing to these transport events are briefly discussed. Multiple modeling scenarios were studied to assess the contribution of lindane sources in Europe, Asia, and North America to its fate in the Arctic. Results show that these continental contributions are season-dependent with the highest contribution from Europe in the spring.

Health promotion and lifestyle advice in a general practice: what do patients think?

BACKGROUND/RATIONALE: Since 1990 health promotion and lifestyle advice has been integrated in general practice and has been mainly undertaken by practice nurses. However little is known about patients' views of the service provided. AIMS OF THE STUDY: To examine patients' recall and perceptions of lifestyle counselling received from practice nurses in a general practice in the North-east of England. To investigate the extent to which patients' needs are met. To assess the main sources of health information sought by patients. DESIGN/METHODS: Cross-sectional descriptive survey. A total of 512 patients were sent a postal questionnaire about current lifestyle, recall of lifestyle advice received and perceptions of the advice provided. FINDINGS: A response rate of 64% was achieved. Questionnaire analysis revealed unhealthy lifestyles among the population studied that could be addressed through health promotion, e.g. 25% were smokers; 44% exercised occasionally; 40% had a body mass index >25 kg/m2. Advice received on diet was reported by 6% of patients; on exercise by 4%; on smoking by 4% and on alcohol consumption by 2%. Patients were willing to receive more health promotion in areas such as stress, exercise and weight reduction. Magazines (67%) and TV (47%) were selected as the main sources for health promotion information. CONCLUSIONS: Health needs to be promoted. The low rate of lifestyle advice reported by the patients implies that more preventive advice should be provided in primary care settings. More effective health promotion should be planned according to the needs of the practice population.