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OBJECTIVE: This study assessed patterns of psychopharmacological treatment for bipolar disorder. METHOD: Intake treatment data were examined for the first 500 patients in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1998 to 1999). Diagnoses were assessed by using the Structured Clinical Interview for DSM-IV mood modules. Data on treatments were obtained by interviewing patients during the initial psychiatric examination. RESULTS: Of the 500 participants, 73.6 percent had bipolar I disorder, 23.0 percent had bipolar II disorder, and 3.4 percent had bipolar disorder not otherwise specified. Upon examination, 63.4 percent were euthymic, 24.6 percent were depressed, and 12.0 percent were experiencing manic, hypomanic, or mixed states. Standard mood stabilizers (lithium, valproate, or carbamazepine) were the most commonly prescribed class of drugs that participants were taking at intake (71.9 percent). The next most common class of agents was antidepressants (40.6 percent), followed by novel anticonvulsants (31.8 percent), second-generation neuroleptics (27.2 percent), and benzodiazepines (25.0 percent). Eleven percent of patients were treated with standard mood stabilizer monotherapy. These prescribing patterns were further analyzed by subtype of illness and compared with patterns in other clinical and community settings. CONCLUSION: In a large, well-characterized cross-sectional analysis of prescription patterns in the U.S. psychiatric academic setting, patients with bipolar disorder were primarily treated with standard mood stabilizers, followed by moderate use of antidepressants, novel anticonvulsants, and second-generation neuroleptics. Results can be useful in understanding the current clinical standard of care, as well as in guiding research studies toward areas in which there is a relative absence of evidence to inform clinical practice. Studies of longitudinal prescribing patterns in bipolar disorder are also needed. [ABSTRACT FROM AUTHOR]

The i-motif is a pH-responsive cytosine-rich oligonucleotide sequence that forms, under acidic conditions, a quadruplex structure. This tunable structural switching has made the i-motif a useful platform for designing pH-responsive nanomaterials. Despite the widespread application of i-motif DNA constructs as biomolecular switches, the mechanism of i-motif folding on the atomic scale has yet to be established. We investigate the early folding structural dynamics of i-motif oligonucleotides with laser-pulse-induced pH-jump time-resolved X-ray solution scattering. Following the pH-jump, we observe that the initial random coil ensemble converts into a contracted intermediate state within 113 ns followed by further folding on the 10 ms time scale. We reveal the representative structures of these transient species, hitherto unknown, with molecular dynamics simulations and ensemble fitting. These results pave the way for understanding metastable conformations of i-motif folding and for benchmarking emerging theoretical models for simulating noncanonical nucleic acid structures.

The unfolding dynamics of ubiquitin were studied using a combination of x-ray solution scattering (XSS) and molecular dynamics (MD) simulations. The kinetic analysis of the XSS ubiquitin signals showed that the protein unfolds through a two-state process, independent of the presence of destabilizing salts. In order to characterize the ensemble of unfolded states in atomic detail, the experimental XSS results were used as a constraint in the MD simulations through the incorporation of x-ray scattering derived potential to drive the folded ubiquitin structure toward sampling unfolded states consistent with the XSS signals. We detail how biased MD simulations provide insight into unfolded states that are otherwise difficult to resolve and underscore how experimental XSS data can be combined with MD to efficiently sample structures away from the native state. Our results indicate that ubiquitin samples unfolded in states with a high degree of loss in secondary structure yet without a collapse to a molten globule or fully solvated extended chain. Finally, we propose how using biased-MD can significantly decrease the computational time and resources required to sample experimentally relevant nonequilibrium states., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N 6 -threonylcarbamoyladenosine (t 6 A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t 6 A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t 6 A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t 6 A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In this issue of Molecular Cell, Yang et al. 1 find that arginine-to-cysteine substitutants are enriched in a subset of lung cancer proteomes, potentiated by arginine deprivation, and promote resistance to chemotherapy., Competing Interests: Declaration of interests S.F.T. is a co-founder, shareholder, and member of the scientific advisory board of Inspirna., (Copyright © 2024. Published by Elsevier Inc.)

Photoexcited molecular trajectories on potential energy surfaces (PESs) prior to thermalization are intimately connected to the photochemical reaction outcome. The excited-state trajectories of a diplatinum complex featuring photo-activated metal-metal σ-bond formation and associated Pt-Pt stretching motions were detected in real time using femtosecond wide-angle X-ray solution scattering. The observed motions correspond well with coherent vibrational wavepacket motions detected by femtosecond optical transient absorption. Two key coordinates for intersystem crossing have been identified, the Pt-Pt bond length and the orientation of the ligands coordinated with the platinum centers, along which the excited-state trajectories can be projected onto the calculated PESs of the excited states. This investigation has gleaned novel insight into electronic transitions occurring on the time scales of vibrational motions measured in real time, revealing ultrafast nonadiabatic or non-equilibrium processes along excited-state trajectories involving multiple excited-state PESs., (© 2023 The Authors. Published by Wiley-VCH GmbH.)

A critical step in structure-based drug discovery is predicting whether and how a candidate molecule binds to a model of a therapeutic target. However, substantial protein side chain movements prevent current screening methods, such as docking, from accurately predicting the ligand conformations and require expensive refinements to produce viable candidates. We present the development of a high-throughput and flexible ligand pose refinement workflow, called "tinyIFD". The main features of the workflow include the use of specialized high-throughput, small-system MD simulation code mdgx.cuda and an actively learning model zoo approach. We show the application of this workflow on a large test set of diverse protein targets, achieving 66% and 76% success rates for finding a crystal-like pose within the top-2 and top-5 poses, respectively. We also applied this workflow to the SARS-CoV-2 main protease (M pro ) inhibitors, where we demonstrate the benefit of the active learning aspect in this workflow.

The Trp-cage miniprotein is one of the smallest systems to exhibit a stable secondary structure and fast-folding dynamics, serving as an apt model system to study transient intermediates with both experimental and computational analyses. Previous spectroscopic characterizations that have been done on Trp-cage have inferred a single stable intermediate on a pathway from folded to unfolded basins. We aim to bridge the understanding of Trp-cage structural folding dynamics on microsecond-time scales, by utilizing time-resolved X-ray solution scattering to probe the temperature-induced unfolding pathway. Our results indicate the formation of a conformationally extended intermediate on the time scale of 1 μs, which undergoes complete unfolding within 5 μs. We further investigated the atomistic structural details of the unfolding pathway using a genetic algorithm to generate ensemble model fits to the scattering profiles. This analysis paves the way for direct benchmarking of theoretical models of protein folding ensembles produced with molecular dynamics simulations.

Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation-a feature of tumor microenvironments-is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon-containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons-reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.

Inhibition of the SARS-CoV-2 main protease (M pro ) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M pro . Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC 50 values around 1 μM were found. Interestingly, despite the large search space, the isoquinolone motif was conserved in each of these four strongest binders. Room-temperature X-ray structures of co-crystallized protein-inhibitor complexes were determined up to 1.9 Å resolution for two of these compounds as well as one of the stronger inhibitors in the original isoquinoline series, revealing essential interactions with the binding site and water molecules. Molecular dynamics simulations and quantum chemical calculations further elucidate the binding interactions as well as electrostatic effects on ligand binding. The results help explain the strength of this new non-covalent scaffold for M pro inhibition and inform lead optimization efforts for this series, while demonstrating the effectiveness of a high-throughput computational approach to expanding a pharmacophore library., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

In photosynthetic systems employing multiple transition metal centers, the properties of charge-transfer states are tuned by the coupling between metal centers. Here, we use ultrafast optical and X-ray spectroscopies to elucidate the effects of metal-metal interactions in a bimetallic tetrapyridophenazine-bridged Os(ii)/Cu(i) complex. Despite having an appropriate driving force for Os-to-Cu hole transfer in the Os(ii) moiety excited state, no such charge transfer was observed. However, excited-state coupling between the metal centers is present, evidenced by variations in the Os MLCT lifetime depending on the identity of the opposite metal center. This coupling results in concerted coherent vibrations appearing in the relaxation kinetics of the MLCT states for both Cu and Os centers. These vibrations are dominated by metal-ligand contraction at the Cu/Os centers, which are in-phase and linked through the conjugated bridging ligand. This study shows how vibronic coupling between transition metal centers affects the ultrafast dynamics in bridged, multi-metallic systems from the earliest times after photoexcitation to excited-state decay, presenting avenues for tuning charge-transfer states through judicious choice of metal/ligand groups., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Therapeutic combinations of VEGFR tyrosine kinase inhibitor plus immune checkpoint blockade now represent a standard in the first-line management of patients with advanced renal cell carcinoma. Tumor molecular profiling has shown notable heterogeneity when it comes to activation states of relevant pathways, and it is not clear that concurrent pursuit of two mechanisms of action is needed in all patients. Here, we applied an in silico drug model to simulate combination therapy by integrating previously reported findings from individual monotherapy studies. Clinical data was collected from prospective clinical trials of axitinib, cabozantinib, pembrolizumab and nivolumab. Efficacy of two-drug combination regimens (cabozantinib plus nivolumab, and axitinib plus pembrolizumab) was then modeled assuming independent effects of each partner. Reduction in target lesions, objective response rates (ORR), and progression-free survival (PFS) were projected based on previously reported activity of each agent, randomly pairing efficacy data from two source trials for individual patients and including only the superior effect of each pair in the model. In silico results were then contextualized to register phase III studies of these combinations with similar ORR, PFS, and best tumor response. As increasingly complex therapeutic strategies emerge, computational tools like this could help define benchmarks for trial designs and precision medicine efforts. Summary statement: In silico drug modeling provides meaningful insights into the effects of combination immunotherapy for patients with advanced kidney cancer., Competing Interests: Competing interests: RRK reports advisory board consultation for Eisai and reports receiving institutional research funding from Pfizer and Takeda. MHV reports receiving commercial research support from Bristol-Myers Squibb, Pfizer and Genentech/Roche; honoraria from Novartis and Bristol-Myers Squibb; travel/accommodation from Astra Zeneca, Eisai, Novartis and Takeda; consultant/advisory board member for Aveo, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Merck, Onquality Pharmaceuticals, Novartis and Pfizer. C-HL reports consulting fees from Amgen, Bristol Myers Squibb, Exelixis, Pfizer, Eisai, Merck and EMD Serono; honoraria from AiCME, Intellisphere, and Research to Practice; institutional research support from Bristol Myers Squibb, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer. The remaining authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Proteins have been found to inhabit a diverse set of three-dimensional structures. The dynamics that govern protein interconversion between structures happen over a wide range of time scales─picoseconds to seconds. Our understanding of protein functions and dynamics is largely reliant upon our ability to elucidate physically populated structures. From an experimental structural characterization perspective, we are often limited to measuring the ensemble-averaged structure both in the steady-state and time-resolved regimes. Generating kinetic models and understanding protein structure-function relationships require atomistic knowledge of the populated states in the ensemble. In this Perspective, we present ensemble refinement methodologies that integrate time-resolved experimental signals with molecular dynamics models. We first discuss integration of experimental structural restraints to molecular models in disordered protein systems that adhere to the principle of maximum entropy for creating a complete set of ensemble structures. We then propose strategies to find kinetic pathways between the refined structures, using time-resolved inputs to guide molecular dynamics trajectories and the use of inference to generate tailored stimuli to prepare a desired ensemble of protein states.

The protein folding process often proceeds through partially folded transient states. Therefore, a structural understanding of these disordered states is crucial for developing mechanistic models of the folding process. Characterization of unfolded states remains challenging due to their disordered nature, and incorporating multiple methods is necessary. Combining the time-resolved x-ray solution scattering (TRXSS) signal with molecular dynamics (MD), we are able to characterize transient partially folded states of bovine α-lactalbumin, a model system widely used for investigation of molten globule states, during its unfolding triggered by a temperature jump. We track the unfolding process between 20 µs and 70 ms and demonstrate that it passes through three distinct kinetic states. The scattering signals associated with these transient species are then analyzed with TRXSS constrained MD simulations to produce protein structures that are compatible with the input signals. Without utilizing any experimentally extracted kinetic information, the constrained MD simulation successfully drove the protein to an intermediate molten globule state; signals for two later disordered states are refined to terminal unfolded states. From our examination of the structural characteristics of these disordered states, we discuss the implications disordered states have on the folding process, especially on the folding pathway. Finally, we discuss the potential applications and limitations of this method.

In the past few decades, prediction of macromolecular structures beyond the native conformation has been aided by the development of molecular dynamics (MD) protocols aimed at exploration of the energetic landscape of proteins. Yet, the computed structures do not always agree with experimental observables, calling for further development of the MD strategies to bring the computations and experiments closer together. Here, we report a scalable, efficient MD simulation approach that incorporates an x-ray solution scattering signal as a driving force for the conformational search of stable structural configurations outside of the native basin. We further demonstrate the importance of inclusion of the hydration layer effect for a precise description of the processes involving large changes in the solvent exposed area, such as unfolding. Utilization of the graphics processing unit allows for an efficient all-atom calculation of scattering patterns on-the-fly, even for large biomolecules, resulting in a speed-up of the calculation of the associated driving force. The utility of the methodology is demonstrated on two model protein systems, the structural transition of lysine-, arginine-, ornithine-binding protein and the folding of deca-alanine. We discuss how the present approach will aid in the interpretation of dynamical scattering experiments on protein folding and association.

Cytochrome c (cyt c ) has long been utilized as a model system to study metalloprotein folding dynamics and the interplay between active site ligation and tertiary structure. However, recent reports regarding the weakness of the native Fe(ii)-S bond (Fe-Met80) call into question the role of the active site ligation in the protein folding process. In order to investigate the interplay between protein conformation and active site structures, we directly tracked the evolution of both during a photolysis-induced folding reaction using X-ray transient absorption spectroscopy and time-resolved X-ray solution scattering techniques. We observe an intermediate Fe-Met80 species appearing on ∼2 μs timescale, which should not be sustained without stabilization from the folded protein structure. We also observe the appearance of a new active site intermediate: a weakly interacting Fe-H 2 O state. As both intermediates require stabilization of weak metal-ligand interactions, we surmise the existence of a local structure within the unfolded protein that protects and limits the movement of the ligands, similar to the entatic state found in the native cyt c fold. Furthermore, we observe that in some of the unfolded ensemble, the local stabilizing structure is lost, leading to expansion of the unfolded protein structure and misligation to His26/His33 residues., (This journal is © The Royal Society of Chemistry 2019.)

The semiconductor plants on the top of high-tech industrial chain hire many packaging workers to carry out miscellaneous packing tasks for various product orders from different companies and countries. Under tremendous workload the quality of life (QoL) of such packaging workers need to be concerned. The aim of this study was to explore factors influencing their QoL. This study recruited 247 packing workers (162 male and 85 female; mean age: 35.6 years old) in 2015 and 2016 from a semiconductor plant in Taiwan by convenience sampling. The questionnaire comprised four parts: demographics, the World Health Organization Quality of Life (WHOQOL-BREF), an occupational burnout inventory and the Nordic Musculoskeletal Questionnaire. The four domains of the WHOQOL-BREF were defined as outcome variables. Predictive factors included gender (reference: male), age (reference: ≤ 35), BMI (reference: ≤ 25), educational level (reference: below university), marital/partner status (reference: married/cohabiting), years of work (reference: ≤ 5), work shift (reference: day shift), personal burnout, work-related burnout, over-commitment to work and the number of body parts with discomfort (0-9). The findings showed that physical QoL was negatively correlated with night -shift work, personal burnout, and number of body parts with discomfort. Psychological QoL was negatively correlated with night shift work and personal burnout. Environment QoL was negatively correlated with being male, night shift work and personal burnout. The results showed that the QoL among the packaging workers could be improved by reducing musculoskeletal discomfort, personal burnout and by improving work schedules., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Many biomaterials can adapt to changes in the local biological environment (such as pH, temperature, or ionic composition) in order to regulate function or deliver a payload. Such adaptation to environmental perturbation is typically a hierarchical process that begins with a response at a local structural level and then propagates to supramolecular and macromolecular scales. Understanding fast structural dynamics that occur upon perturbation is important for rational design of functional biomaterials. However, few nanosecond time-resolved methods can probe both intra- and intermolecular scales simultaneously with a high structural resolution. Here, we utilize time-resolved X-ray scattering to probe nanosecond to microsecond structural dynamics of poly-l-glutamic acid undergoing protonation via a pH jump initiated by photoexcitation of a photoacid. Our results provide insights into the protonation-induced hierarchical changes in packing of peptide chains, formation of a helical structure, and the associated collapse of the peptide chain.

The structural dynamics of insulin hexamer dissociation were studied by the photoinduced temperature jump technique and monitored by time-resolved X-ray scattering. The process of hexamer dissociation was found to involve several transient intermediates, including an expanded hexamer and an unstable tetramer. Our findings provide insights into the mechanisms of protien-protein association.

Direct tracking of protein structural dynamics during folding-unfolding processes is important for understanding the roles of hierarchic structural factors in the formation of functional proteins. Using cytochrome c (cyt c) as a platform, we investigated its structural dynamics during folding processes triggered by local environmental changes (i.e., pH or heme iron center oxidation/spin/ligation states) with time-resolved X-ray solution scattering measurements. Starting from partially unfolded cyt c, a sudden pH drop initiated by light excitation of a photoacid caused a structural contraction in microseconds, followed by active site restructuring and unfolding in milliseconds. In contrast, the reduction of iron in the heme via photoinduced electron transfer did not affect conformational stability at short timescales (<1 ms), despite active site coordination geometry changes. These results demonstrate how different environmental perturbations can change the nature of interaction between the active site and protein conformation, even within the same metalloprotein, which will subsequently affect the folding structural dynamics.

Exposure to lead-containing dusts is a global public health concern. This work addresses an important issue of whether eco-friendly water-based paints reduce the exposure potential of auto-repainting workers to metals. With this aim, metal levels in automobile paints and worker metal exposure were measured using both solvent- and water-based paints. The levels of metals, and particularly Pb, Cr (total), Fe, and Cu, in solvent-based paints varied greatly among colors and brands. Lead concentrations ranged from below the detection limit (~0.25 &mu;g/g) to 107,928 &mu;g/g (dry film) across all samples. In water-based paints, the concentrations of Pb and Cr (total) were generally two to three orders of magnitude lower, but the concentrations of Al and Cu exceeded those in some solvent-based paints. The personal short-term exposure of workers who applied water-based paints of popular colors, such as black and white, were generally low, with Pb levels of less than <4 &micro;g/m³ and Cr (total) levels of less than 1 &micro;g/m³. Conversely, mean short-term exposure to Pb during the painting of a yellow cab using solvent-based paints were 2028 &micro;g/m³, which was ~14 times the Taiwan short-term permissible exposure limit, while the mean level of exposure to Cr (total) was 290 &micro;g/m³, which was well below the exposure limit. This study demonstrates that water-based paints reduce the exposure potential to lead, and highlights the importance of source control in limiting the toxic metals in paints.

Rationale: Opioid abuse is increasing, but its impact on critical care resources in the United States is unknown., Objectives: We hypothesized that there would be a rising need for critical care among opioid-associated overdoses in the United States., Methods: We analyzed all adult admissions, using a retrospective cohort study from 162 hospitals in 44 states, discharged between January 1, 2009, and September 31, 2015 to describe the incidence of intensive care unit (ICU) admissions for opioid overdose during this time. Admissions were identified using the Clinical Database/Resource Manager of Vizient, the successor to the University Health System Consortium., Results: Our primary outcome was opioid-associated overdose admissions to the ICU. The outcome was defined on the basis of previously validated ICD-9 codes. Our secondary outcomes were in-hospital death and markers of ICU resources. The final cohort included 22,783,628 admissions; 4,145,068 required ICU care. There were 52.4 ICU admissions for overdose per 10,000 ICU admissions over the entire study (95% confidence interval [CI], 51.8-53.0 per 10,000 ICU admissions). During this time period, opioid overdose admissions requiring intensive care increased 34%, from 44 per 10,000 (95% CI, 43-46 per 10,000) to 59 per 10,000 ICU admissions (95% CI, 57-61 per 10,000; P < 0.0001). The mortality rate of patients with ICU admissions with overdoses averaged 7% (95% CI, 7.0-7.6%) but increased to 10% in 2015 (95% CI, 8.8-10.8%)., Conclusions: The number of deaths of ICU patients with opioid overdoses increased substantially in the 7 years of our study, reflecting increases in both the incidence and mortality of this condition. Our findings raise the need for a national approach to developing safe strategies to care for patients with overdose in the ICU, to providing coordinated resources in the hospital for patients and families, and to helping survivors maintain sobriety on discharge.

Biological functions frequently require protein-protein interactions that involve secondary and tertiary structural perturbation. Here we study protein-protein dissociation and reassociation dynamics in insulin, a model system for protein oligomerization. Insulin dimer dissociation into monomers was induced by a nanosecond temperature-jump (T-jump) of ∼8 °C in aqueous solution, and the resulting protein and solvent dynamics were tracked by time-resolved X-ray solution scattering (TRXSS) on time scales of 10 ns to 100 ms. The protein scattering signals revealed the formation of five distinguishable transient species during the association process that deviate from simple two-state kinetics. Our results show that the combination of T-jump pump coupled to TRXSS probe allows for direct tracking of structural dynamics in nonphotoactive proteins.

Background and Aims: The full burden of the opioid epidemic on US hospitals has not been described. We aimed to estimate how heroin (HOD) and prescription opioid (POD) overdose-associated admissions, costs, outcomes and patient characteristics have changed from 2001 to 2012., Design: Retrospective cohort study of hospital admissions from the National Inpatient Sample (NIS)., Setting: United States of America., Participants: Hospital admissions in patients aged 18 years or older admitted with a diagnosis of HOD or POD. The NIS sample included 94 492 438 admissions from 2001 to 2012. The final unweighted study sample included 138 610 admissions (POD: 122 147 and HOD: 16 463)., Measurements: Primary outcomes were rates of admissions per 100 000 people using US Census Bureau annual estimates. Other outcomes included in-patient mortality, hospital length-of-stay, cumulative and mean hospital costs and patient demographics. All analyses were weighted to provide national estimates., Findings: Between 2001 and 2012, an estimated 663 715 POD and HOD admissions occurred nation-wide. HOD admissions increased 0.11 per 100 000 people per year [95% confidence interval (CI) = 0.04, 0.17], while POD admissions increased 1.25 per 100 000 people per year (95% CI = 1.15, 1.34). Total in-patient costs increased by $4.1 million dollars per year (95% CI = 2.7, 5.5) for HOD admissions and by $46.0 million dollars per year (95% CI = 43.1, 48.9) for POD admissions, with an associated increase in hospitalization costs to more than $700 million annually. The adjusted odds of death in the POD group declined modestly per year [odds ratio (OR) = 0.98, 95% CI = 0.97, 0.99], with no difference in HOD mortality or length-of-stay. Patients with POD were older, more likely to be female and more likely to be white compared with HOD patients., Conclusions: Rates and costs of heroin and prescription opioid overdose related admissions in the United States increased substantially from 2001 to 2012. The rapid and ongoing rise in both numbers of hospitalizations and their costs suggests that the burden of POD may threaten the infrastructure and finances of US hospitals., (© 2017 Society for the Study of Addiction.)

Background: This investigation examines the extraction of metals from animal bones into broth, and assesses whether bone broths are good sources of essential metals and the risks associated with the consumption of toxic metals. Method: Three sets of controlled experiments were performed to study the factors (cooking time, acidity, bone type and animal species) that influence metal extractions. Three types of animal bone broth-based foods were also tested. Results: Reducing the broth pH from 8.38 to 5.32 significantly ( p < 0.05) increased Ca and Mg extraction by factors of 17.4 and 15.3, respectively. A long cooking time, > 8 h, yielded significantly higher ( p < 0.05) Ca and Mg extraction than shorter cooking times. The extraction characteristics of metals, particularly Ca, Mg, Cu and Al, from the leg and rib bones differed. The between-species variations in extraction were larger than those of within-species. Conclusions: The Ca and Mg levels in home-made or commercial broth/soup were found not to exceed low tenths of milligram per serving, or <5% of the daily recommended levels. The risks that are associated with the ingestion of heavy metals such as Pb and Cd in broth are minimal because the levels were in the ranges of a few μg per serving.

Background: Health policy debate commonly focuses on frequently hospitalized patients, but less research has examined trends in long-stay patients, despite their high cost, effect on availability of hospital beds, and physical and financial implications for patients and hospitals., Methods: Using the National Inpatient Sample, a nationally representative sample of acute care hospitalizations in the US, we examined trends in long-stay hospitalizations from 2001-2012. We defined long stays as those 21 days or longer and evaluated characteristics and outcomes of those hospitalizations, including discharge disposition and length of stay and trends in hospital characteristics. We excluded patients under 18 years of age and those with primary psychiatry, obstetric, or rehabilitation diagnoses, and weighted estimates to the US population., Results: Prolonged hospitalizations represented only 2% of hospitalizations, but approximately 14% of hospital days and incurred estimated charges of over $20 billion dollars annually. Over time, patients with prolonged hospitalizations were increasingly younger, male, and of minority status, and these hospitalizations occurred more frequently in urban, academic hospitals. In-hospital mortality for patients with prolonged stays progressively decreased over the 10-year period from 14.5% to 11.6% (P <.001 for trend in grouped years), even accounting for changes in demographics and comorbidity., Conclusions: The profile of patients with prolonged hospitalizations in the US has changed, although their impact remains large, as they continue to represent 1 of every 7 hospital days. Their large number of hospital days and expense increasingly falls upon urban academic medical centers, which will need to adapt to this vulnerable patient population., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for influenza-related morbidity and mortality. Influenza vaccination is known to decrease influenza incidence, severity, hospitalizations, and mortality. Identification of barriers to influenza vaccination among patients with COPD may aid in efforts to increase vaccination rates. This study aims to identify predictors of influenza vaccination in COPD patients., Methods: This study used data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS). Participants with self-reported COPD and receiving an influenza vaccination in the prior 12 months were identified. Independent predictors of the exposure were identified by estimating a parsimonious logistic regression model of influenza vaccination. All analyses were performed using weighted data., Results: The final study sample consisted of 36,811 COPD participants, with 48.5% of COPD patients reporting having been vaccinated and 51.5% reporting being unvaccinated. A total of 15 independent predictors of influenza vaccination in COPD patients were identified. Negative predictors included predisposing factors (younger age, male gender, household children, black or non-white/non-Hispanic/non-black race/ethnicity, lower education level, heavy alcohol use, current tobacco use) and enabling factors that reflect access to medical care (insurance status, ability to afford care, having a recent check-up). Positive predictors of influenza vaccination included need factors (chronic comorbidities), being a military veteran, or being a former smoker., Conclusions: This analysis identifies multiple predictors of influenza vaccination in persons with COPD. Identification of at risk-groups provides the foundation for development of focused efforts to improve influenza vaccination rates in patients with COPD.

Background: Indwelling arterial catheters (IACs) are used extensively in the ICU for hemodynamic monitoring and for blood gas analysis. IAC use also poses potentially serious risks, including bloodstream infections and vascular complications. The purpose of this study was to assess whether IAC use was associated with mortality in patients who are mechanically ventilated and do not require vasopressor support., Methods: This study used the Multiparameter Intelligent Monitoring in Intensive Care II database, consisting of > 24,000 patients admitted to the Beth Israel Deaconess Medical Center ICU between 2001 and 2008. Patients requiring mechanical ventilation who did not require vasopressors or have a diagnosis of sepsis were identified, and the primary outcome was 28-day mortality. A model based on patient demographics, comorbidities, vital signs, and laboratory results was developed to estimate the propensity for IAC placement. Patients were then propensity matched, and McNemar test was used to evaluate the association of IAC with 28-day mortality., Results: We identified 1,776 patients who were mechanically ventilated who met inclusion criteria. There were no differences in the covariates included in the final propensity model between the IAC and non-IAC propensity-matched groups. For the matched cohort, there was no difference in 28-day mortality between the IAC group and the non-IAC group (14.7% vs 15.2%; OR, 0.96; 95% CI, 0.62-1.47)., Conclusions: In hemodynamically stable patients who are mechanically ventilated, the presence of an IAC is not associated with a difference in 28-day mortality. Validation in other datasets, as well as further analyses in other subgroups, is warranted.

The National Institute of Health invests US $30.9 billion annually in medical research. However, the subsequent impact of this research output on society and the economy is amplified dramatically as a result of the actual medical treatments, biomedical innovations, and various commercial enterprises that emanate from and depend on these findings. It is therefore a great concern to discover that much of published research is unreliable. We propose extending the open data concept to the culture of the scientific research community. By dialing down unproductive features of secrecy and competition, while ramping up cooperation and transparency, we make a case that what is published would then be less susceptible to the sometimes corrupting and confounding pressures to be first or journalistically attractive, which can compromise the more fundamental need to be robustly correct.

Unlabelled: RNAi is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We used a functional "Sensor" assay to establish a library of potent siRNAs against RAS pathway genes and to show that they efficiently suppress their targets at low dose. This reduces off-target effects and enables combination gene knockdown. We administered Sensor siRNAs in vitro and in vivo and validated the delivery of KRAS siRNA alone and siRNA targeting the complete RAF effector node (A/B/CRAF) as promising strategies to treat KRAS-mutant colorectal cancer. We further demonstrate that improved therapeutic efficacy is achieved by formulating siRNA payloads that combine both single-gene siRNA and node-targeted siRNAs (KRAS + PIK3CA/B). The customizable nature of Sensor siRNA payloads offers a universal platform for the combination target identification and development of RNAi therapeutics., Significance: To advance RNAi therapy for KRAS-mutant cancer, we developed a validated siRNA library against RAS pathway genes that enables combination gene silencing. Using an in vivo model for real-time siRNA delivery tracking, we show that siRNA-mediated inhibition of KRAS as well as RAF or PI3K combinations can impair KRAS-mutant colorectal cancer in xenograft models., (©2014 American Association for Cancer Research.)

Background: Betel quid chewing is common in Taiwan. The work of betel quid preparers is characterized by long hours of static work, awkward working posture and highly repetitive hand/wrist motion. However, the musculoskeletal health of betel quid preparers receives very little attention., Methods: The Chinese version of the Standardized Nordic Musculoskeletal Questionnaire (NMQ) was administered, and electrogoniometers and electromyography were used in this cross-sectional study to characterize the hand/wrist motion of the subjects. Physical examinations on the thumbs and wrists of the subjects were conducted by means of Phalen's test and Finkelstein's test, respectively., Results: Among the 225 participants, more than 95% attributed their musculoskeletal complaints to their work, and shoulder, neck, hand/wrist, and lower back discomfort were most frequently reported. More than 70% of the preparers did not seek medical treatment for their musculoskeletal problems. Based on the physical examination, 24% of the participants had suspected symptom of either carpal tunnel syndrome (CTS) or DeQuervain's tenosynovitis. The instrumental measurements indicated that betel quid preparation is characterized by extreme angle ranges and moderate repetition of wrist motion as well as low forceful exertion., Conclusions: This study concludes that betel quid preparers are a high risk group of developing musculoskeletal disorders (MSDs). Future studies by electrogoniometers and detailed physical examination on betel quid preparers are needed to determine the predisposing factors for CTS. Some intervention measures to prevent MSDs and to lessen psychological stress for this group of workers are strongly suggested., (© 2014 Wiley Periodicals, Inc.)

Background: Professional cleaning has emerged as a new industry in Taiwan in the past few years. However, information about the workload and prevalence of musculoskeletal disorders (MSDs) among these workers is still limited. This study investigated the prevalence of musculoskeletal discomforts and the characteristics of musculoskeletal activities of cleaning workers in Taiwan., Methods: Face-to-face interviews to collect basic information and to administer the Chinese version of the Standardized Nordic Musculoskeletal Questionnaire were conducted on 180 cleaners. Biaxial electrogoniometers and electromyography were used to characterize the motion and forceful exertion of 56 cleaners during work., Results: Nearly 90% of the participants reported musculoskeletal discomfort in at least one body part due to work. Of the nine body parts examined, hand/wrist (41.7%), shoulder (41.1%), low back (37.8%), and elbow (33.3%) were most frequently reported to exhibit discomfort. Additionally, time pressure as a psychosocial risk factor was found to be associated with discomfort in several body parts. Measurements of electrogoniometry showed that wrists of many cleaners were frequently held in extreme angles of ulnar/radial deviation, leading to an increased risk of developing carpal tunnel syndrome. Motion repetitiveness and force output during mopping and sweeping tasks were considered less influential in developing hand/wrist discomfort., Conclusions: Cleaners in Taiwan are a high-risk group for developing MSDs, and solutions are needed to avoid extreme motion angles of the wrists when performing cleaning tasks. Moreover, both psychosocial stress and the welfare of this group of workers deserve immediate attention from management and the government., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Oyster shucking is characterized by long hours of static work, awkward working posture, and highly repetitive hand/wrist motion. The objectives of this study were to investigate the prevalence of musculoskeletal discomfort and kyphosis in oyster shuckers in Taiwan as well as the biomechanical features of oyster shucking., Methods: The Chinese version of the Standardized Nordic Musculoskeletal Questionnaire was successfully collected from 234 oyster shuckers. The characteristics of workstation, hand/wrist motion angles, and muscular exertion in shucking oysters were recorded. Measurements to identify kyphosis were also taken from the subjects and a control group., Results: Among the participated oyster shuckers, low back (75.2%), hand/wrist (60.3%), shoulder (44.0%), and elbow (27.8%) discomfort were reported most frequently. The prevalence of low back discomfort in oyster shuckers was higher than various groups of workers who need long hours of seated position. Those who worked on tables had fewer musculoskeletal complaints in shoulder and elbow (P < 0.05) than those not. Additionally, oyster shuckers were more prone to kyphosis than the general population (P < 0.001)., Conclusions: Oyster shuckers are observed to have high prevalence of musculoskeletal discomfort and kyphosis. Introduction of ergonomic design to oyster shucking workshops is strongly suggested., (Copyright © 2011 Wiley Periodicals, Inc.)

The present study was set out to characterize nanoparticle exposures in three selected workplaces of the packaging, warehouse, and pelletizing in a carbon black manufacturing plant using a newly developed modified electrical aerosol detector (MEAD). For confirmation purposes, the MEAD results were compared with those simultaneously obtained from a nanoparticle surface area monitor (NSAM) and a scanning mobility particle sizer (SMPS). We found that workplace background nanoparticle concentrations were mainly coming from the outdoor environment. Size distributions of nanoparticles for the three selected process areas during the work hours were consistently in the form of bimodel. Unlike nanoparticles of the second mode (simply contributed by the process emissions), particles of the first mode could be also contributed by the forklift exhaust or fugitive emissions of heaters. The percents of nanoparticles deposited on the alveolar (A) region were much higher than the other two regions of the head airway (H), tracheobronchial (TB) for all selected workplaces in both number and surface area concentrations. However, significant differences were found in percents of nanoparticles deposited on each of the three regions while different exposure metrics were adopted. Both NSAM and MEAD obtained quite comparable results. No significant difference can be found between the results obtained from SMPS and MEAD after being normalized. Considering the MEAD is less expensive, less bulky, and easy to use, our results further support the suitability of using MEAD in the field for nanoparticle exposure assessments.

The degradation and oxidation of quercetin, as affected by cholesterol during heating at 150 °C, was kinetically studied using non-linear regression models. Both TLC and HPLC were used to monitor the changes of quercetin, cholesterol and cholesterol oxidation products (COPs) during heating. The formation of COPs, including triol, 7-keto, 7α-OH and 7β-OH, was completely inhibited during the initial 30 minute heating period in the presence of 0.02% quercetin, accompanied by reduction in cholesterol peroxidation and degradation. However, the quercetin degradation or oxidation proceeded fast, with the rate constants (h(-1)) in the presence of nitrogen, oxygen and the combination of oxygen and cholesterol being 0.253, 0.868 and 7.17, respectively. When cholesterol and quercetin were heated together, the rate constants (h(-1)) of cholesterol peroxidation, epoxidation and degradation were 1.8 × 10(-4), 0.016 and 0.19, respectively. The correlation coefficients (r(2)) for all the oxidative and degradation reactions ranged from 0.82-0.99. The kinetic models developed in this study may be used to predict the degradation and oxidation of quercetin as affected by cholesterol during heating.

Introduction: To identify factors associated with timely initiation of antibiotic therapy for patients hospitalized with pneumonia., Design: Secondary analysis of a cluster-randomized, controlled trial., Setting: Thirty- two emergency departments (EDs) in Pennsylvania and Connecticut., Subjects: Patients with a clinical and radiographic diagnosis of community-acquired pneumonia., Interventions: From January to December 2001, EDs were randomly allocated to guideline implementation strategies of low (n = 8), moderate (n = 12), and high intensity (n = 12) to improve the initial site of treatment and the performance of evidence-based processes of care. Our primary outcome was antibiotic initiation within 4 hours of presentation, which at that time was the recommended process of care for inpatients., Results: Of the 2076 inpatients enrolled, 1632 (78.6%) received antibiotic therapy within 4 hours of presentation. Antibiotic timeliness ranged from 55.6% to 100% (P < 0.001) by ED and from 77.0% to 79.7% (P = 0.2) across the 3 guideline implementation arms. In multivariable analysis, heart rate > or =125 per minute (OR = 1.6, 95% CI 1.1-2.3), respiratory rate > or =30 per minute (OR = 2.3, 95% CI 1.6-3.4), and aspiration pneumonia (OR = 3.7, 95% CI 1.1-12.7) were positively associated with timely initiation of antibiotic therapy, whereas a hematocrit <30% (OR = 0.6, 95% CI 0.4-1.0) was negatively associated with this outcome., Conclusions: Timely initiation of antibiotic therapy is associated primarily with patient-related factors that reflect severity of illness at presentation. Although this study demonstrates an opportunity to improve performance on this quality measure in nearly one quarter of inpatients with pneumonia, we failed to identify any modifiable patient, provider, or hospital level factors to target in such quality improvement efforts.

This study used a full scale mockup of a concrete drilling simulator to simulate drilling processes in an exposure chamber. Six drilling conditions were selected with rotating speeds and drill bit sizes varied from 265 to 587 rpm and 16 to 32 mm, respectively. For each drilling condition, the emitted noise power spectrums were measured and dust exposure concentrations of the fractions of the total (C(tot)), inhalable (C(inh)), thoracic (C(tho)), and respirable (C(res)) were estimated. We find that neither the resultant dust exposure levels nor the noise levels can be explained simply by the involved drilling mechanical energy. By dividing the emitted noise power spectrums into the high and low frequency noise (i.e., W(H) and W(L)), we find that 86.3%, 85.6%, 81.5%, and 77.6% variations of C(tot), C(inh), C(tho), and C(res) could be explained by the combination of W(H) and W(L), respectively. We also find that the emissions of coarse particles and W(L) were possibly contributed by two mechanisms of the impact wear and brittle fracture wear, whereas fine particles and W(H) could be contributed by the mechanism of abrasive wear. Although the predictive models obtained from this study could not be directly used in other dust emission sources, the developed methodology would be beneficial to industries in the future for aerosol exposure assessment, particularly when conducting conventional personal aerosol samplings is not possible in the field.

The objective of this study is to investigate whether work fatigue and physiological symptoms that high-elevation construction workers experience would be affected by the occupations. Questionnaires of demographic data and subjective fatigue symptoms as well as some physiological measurements were carried out, pre- and post-shift, on scaffolders, steel fixers, formworkers, electrician-plumbers, concreters and miscellaneous workers at a high-rise building construction site. This study found that some subjective fatigue symptoms coincide with the life style of some workers and that the extent of fatigue symptoms and physiological strains varies among different occupations of construction workers. Scaffolders, steel fixers and formworkers are categorized as physically demanding fatigue type of workers, while concreters, electrician-plumbers and miscellaneous workers as general type. The prevalence and occurrence of subjective fatigue symptoms indicate high-elevation workers have more complaints of "projection of physical impairment" than "drowsiness and dullness" and "difficulty in concentration". Some unexpected changes (i.e., post-shift measurements are greater than pre-shift ones) in some strength tests in scaffolders and concreters were consistent with the observations of how they exercised their bodies during work shift. Considerable variation of average heart rate among occupations was found, with scaffolders the highest and concreters the lowest. This study concludes that questionnaires of subjective fatigue symptoms and some physiological measurements can be used as indicators to predict the extent of strains or hazards which construction workers encounter. In terms of management program of safety and health, more attention should be paid to those physically demanding workers, such as scaffolders, workers with lower sense of safety and health, such as miscellaneous workers, and workers with older age, such as concreters.

Unlabelled: This study investigated the passenger exposure to particulate matter (PM) in long-distance buses in Taiwan. PM and CO(2) were measured in thirty buses traveling between Taipei and Tainan. The results indicated that average in-cabin PM levels were below the guidelines or standards suggested by Taiwan and other countries. Cigarette smoking revealed no effect on in-cabin PM2.5 level. However, since only one cigarette was lit per journey, the effect might be different if more cigarettes were lit in bus cabins. Opening windows was found to affect in-cabin PM2.5 and PM2.5/PM10 ratios may be elevated. Moreover, the PM10 level from air monitoring stations did not reflect the true passenger exposure to PM10. This study concludes that PM levels in long-distance buses is lower than those in other studies of urban buses, as a result of faster driving speed, non-stop driving pattern, and highway surroundings. Keeping windows closed on long-distance buses can minimize passenger exposure to PM2.5. Conversely, high in-cabin CO(2) levels may occur if opening window is minimized when air change rate is low. This study suggests that long-distance buses should increase their air exchange rates to reduce CO(2) levels and install particle filters with high removal efficiency to lower in-cabin PM levels., Practical Implications: The PM levels in the long-distance buses running on highways are lower than those observed in city buses. Opening window in the long-distance buses would result in higher in-cabin PM levels but may effectively reduce in-cabin CO(2) levels, which accumulate over the journey of long hours. Increase of air exchange rate and installation of filters with high PM removal efficiency in ventilation system are suggested to improve air quality in the cabin of long-distance buses.

Previous studies have demonstrated that Polarization Sensitive Optical Coherence Tomography (PS-OCT) can be used to image the remineralization of early artificial caries lesion on smooth enamel surfaces of human and bovine teeth. However, most new dental decay is found in the pits and fissures of the occlusal surfaces of posterior dentition and it is in these high risk areas where the performance of new caries imaging devices need to be investigated. The purpose of this study was to demonstrate that PS-OCT can be used to measure the subsequent remineralization of artificial lesions produced in the pits and fissures of extracted 3(rd) molars. A PS-OCT system operating at 1310-nm was used to acquire polarization resolved images of occlusal surfaces exposed to a demineralizing solution at pH-4.5 followed by a fluoride containing remineralizing solution at pH-7.0 containing 2-ppm fluoride. The integrated reflectivity was calculated to a depth of 200-μm in the entire lesion area using an automated image processing algorithm. Although a well-defined surface zone was clearly resolved in only a few of the samples that underwent remineralization, the PS-OCT measurements indicated a significant (p<0.05) reduction in the integrated reflectivity between the severity of the lesions that were exposed to the remineralization solution and those that were not. The lesion depth and mineral loss were also measured with polarized light microscopy and transverse microradiography after sectioning the teeth. These results show that PS-OCT can be used to non-destructively monitor the remineralization potential of anti-caries agents in the important pits and fissures of the occlusal surface.

Studies have shown that lasers can be used to modify the chemical composition of tooth enamel to render it less soluble. The purpose of this study was to determine if polarization-sensitive optical coherence tomography (PS-OCT) can be used to nondestructively assess the inhibition of demineralization after CO2 laser irradiation. Human and bovine enamel specimens were irradiated by a microsecond pulsed CO2 laser operating at a wavelength of 9.3 microm. Some specimen areas were also treated with topical fluoride to create six treatment groups on each sample, including protected surface (no demineralization), protected +laser, laser, fluoride, laser+fluoride, and unprotected surface. Samples were placed in an artificial demineralization solution to create lesions approximately 100-200 microm in depth and were subsequently scanned with a PS-OCT system to assess lesion severity before sectioning for analysis by polarized light microscopy and transverse microradiography for comparison. PS-OCT was able to measure a significant reduction in the integrated reflectivity due to inhibition by the laser on both human and bovine enamel even though the laser modification of the enamel surface did cause an increase in reflectivity and decrease in optical penetration. This study shows that the PS-OCT is well suited for the clinical assessment of caries inhibition after laser treatments.

Several studies have shown that lasers can be used to modify the surface morphology and chemical composition of tooth enamel to render it less soluble. Other studies have shown that Polarization Sensitive Optical Coherence Tomography (PS-OCT) can be used to non-destructively measure the efficacy of fluoride in inhibiting the development of artificial caries lesions. The purpose of this study was to determine if PS-OCT can be used to measure inhibition of enamel demineralization after CO(2) laser irradiation. Polarized light microscopy and microradiography were used to measure lesion severity on histological thin sections for comparison. PS-OCT was able to measure a significant reduction in the integrated reflectivity due to inhibition by the laser even though the laser modification of the enamel surface caused a slight increase in reflectivity. This study shows that the PS-OCT is well-suited for in vivo measurements of caries inhibition after laser treatments.

Objective: The authors examined long-term effectiveness and study retention during open-label quetiapine treatment for rapid cycling bipolar disorder., Methods: An open-label, nonrandomized trial was conducted in 41 patients with rapid-cycling bipolar disorder (type I=33, type II=7, NOS=1) who received flexibly dosed quetiapine monotherapy (n=19) or add-on therapy (n=22) for up to one year. Linear growth curves were calculated to assess longitudinal changes in depression and mania., Results: Linear growth curves demonstrated highly significant reductions in manic (p<.0001) and depressive (p<.0001) symptoms. Effect sizes were large against manic symptoms (add-on therapy: Cohen's d=0.66; monotherapy: Cohen's d=0.75) but small-to-moderate against depression (monotherapy: d=0.29; add-on therapy: d=0.40). Most patients (68%) prematurely terminated the protocol (mean duration: 18.0+/-16.9 weeks, mean dose: 195.6+/-196.1 mg/day), most often because of the need for additional psychotropic treatments., Limitations: The study protocol involved an open label design with no placebo or active comparator group. The sample size provided adequate statistical power to detect large but not medium or small within-group effects. Premature dropout during the first six months precluded inferences about longer-term treatment outcome., Conclusions: These observational findings provisionally suggest some benefit with quetiapine for both manic and depressive symptoms in rapid cycling bipolar disorder, at dosages somewhat lower than previously described either for mania or bipolar depression. The relatively high dropout rate underscores the complexity of rapid cycling bipolar disorder and likely necessity for pharmacotherapy adjustments over time.

This study reports a method for constructing a head model with a continuous airway passage beginning from the nostrils and continuing through the second generation of bronchi, using computerized tomographic (CT) images of facial features and airway passages from a healthy Taiwanese male adult. When combined with a manikin torso and connected to a cyclic breathing machine, the Taiwanese head model can simulate human breathing movement. This model enables investigation of important parameters of deposition efficiency without the inter- and intrasubject variability that often occurs in human studies. Being an assembly of numerous polymethyl methacrylate (PMMA) plastic slabs, the head model can be applied to study particle deposition at specified respiratory regions. The nasal geometry obtained in this study was compared with those obtained in other studies, which demonstrated this head model to be 36% smaller in nostril cross-sectional area than for European Americans. Additionally, this Taiwanese head model was found to be shorter in nasal cavity length, and the minimum cross-sectional area was only 50% compared to that of European Americans. This study also measured the nasal inhalation efficiency and deposition for particles ranging from 1.5 to 15 microm under various ventilation levels to test the feasibility of this head model. Future particle deposition studies using this Taiwanese head model can be compared with the currently available data, which are primarily based on Caucasian cast models or human subjects.

Objective: To examine, in a real-world clinical setting, the risk of extrapyramidal symptoms (EPS) with atypical neuroleptics in bipolar patients., Methods: The authors assessed 51 individual patient trials of atypical neuroleptic agents (17 risperidone, 13 olanzapine, 11 quetiapine, 8 ziprasidone, and 2 aripiprazole) in 37 bipolar patients (type I or type II). Risk of EPS was assessed using the Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, and the Simpson-Angus Scale. Mean duration of treatment was 25.5 weeks (range 3-107 weeks) and 60.8% of patients were female., Results: 62.7% of trials resulted in moderate to severe EPS. EPS and discontinuation frequencies were similar between specific neuroleptic agents or between high potency (risperidone/ziprasidone/aripiprazole; 52.9%, 27/51 trials) and low potency (quetiapine/olanzapine; 47.1%, 24/51 trials) agents. In a multiple regression model adjusted for confounders, akathisia was less common with low potency agents. Younger age was associated with more akathisia. 31.4% (11/35) of trials discontinued due to side effects. 7.8% (4/51) of trials led to mild de novo tardive dyskinesia., Conclusions: Over one-half of bipolar patients experienced EPS in this real world clinical setting. This rate is much higher than the 5-15% range reported in clinical trials, suggesting potential problems with clinical trial generalizability.

Inhibition of the heat-induced cholesterol oxidation at 150 degrees C by incorporation of quercetin was kinetically studied. Results showed that without quercetin, the cholesterol oxidation products (COPs) concentration increased with increasing heating time. A low amount (0.002%, w/w) of quercetin was effective in inhibiting the formation of COPs during the initial heating period (< or =30 min) at 150 degrees C. However, after prolonged heating (30-120 min), a low antioxidant activity was observed because of the degradation of quercetin. When using nonlinear regression models for kinetic study of cholesterol oxidation in the absence of quercetin, the epoxidation showed the highest rate constant (h(-1) = 683.1), followed by free radical chain reaction (h(-1) = 453.5), reduction (h(-1) = 290.3), dehydration (h(-1) = 155.5), triol dehydrogenation (h(-1) = 5.35), dehydrogenation (h(-1) = 0.68), thermal degradation (h(-1) = 0.66), and triol formation (h(-1) = 0.38). However, in the presence of quercetin, the reaction rate constants (h(-1)) for epoxidation (551.4), free radical chain reaction (111.7), and thermal degradation (0.28) were reduced greatly. The kinetic model developed in this study can be used to predict the inhibition of COPs by quercetin during the heating of cholesterol.

This study investigates the indoor air quality of typical photocopy centers in Taiwan to evaluate the human health risk following inhalation exposure. Both personal and area samplings were conducted at seven photocopy centers in the Tainan area from July 2002 to March 2003, which covered both summer and winter seasons in Taiwan. The benzene, toluene, ethylbenzene, xylenes, and styrene (BTEXS) measurements indicated no difference between personal and area samplings (P>0.05) and found that air conditioning improves indoor air quality. The additive factor at each photocopy center was significantly below 1.0, based on the current BTEXS permissible exposure limits in Taiwan. However, the mean benzene and styrene levels in the current study were 138 and 18 times, respectively, higher than those in another study conducted in the United States. Comparison of mass ratios of BTEXS with those of several chamber studies revealed that the photocopier is not the only volatile organic compound (VOC) source in photocopy centers. The lifetime cancer and noncancer risks for workers exposed to VOCs were also assessed. Results show that all seven centers in this study had a lifetime cancer risk exceeding 1x10(-6) (ranging from 2.5x10(-3) to 8.5x10(-5)). Regarding noncancer risk, levels of toluene, ethylbenzene, xylenes, and styrene were below the reference levels in all photocopy centers; however, the hazard indices for all still exceeded 1.0 (range 26.2-1.8) because of the high level of benzene in the photocopy centers.