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1.  Treatment of Active Tuberculosis in Chicago, 2008-2011: The Role of Public Health Departments 
PLoS ONE  2016;11(10):e0164162.
Objective
Evaluate differences in TB outcomes among different provider types in Chicago, IL.
Methods
We retrospectively reviewed all TB cases reported to the Chicago Department of Public Health (CDPH) from 2008 through 2011. Provider type was stratified into three groups: public, public-private, and private providers. Multivariate regression was used to evaluate treatment duration and time to sputum culture conversion. A Cox proportional hazard model was used to assess treatment completion.
Results
Of 703 cases, 203 (28.9%), 314 (44.7%), and 186 (26.5%) were treated by public, public-private and private providers, respectively. Adjusted regression showed private provider patients had a 48-day (95% CI 22.0–74.3) increase in treatment duration and a 30-day (95% C.I. 9.5–51.1) increase in time to sputum culture conversion. Cox model showed increased risk of remaining on treatment was associated with extra-pulmonary TB (aHR 0.78, 95% C.I. 0.62–0.98), being foreign-born (aHR 0.74, 95% C.I. 0.58–0.95), and any drug resistance (aHR 0.59, 95% C.I. 0.46–0.76). There were no differences in outcomes between public and public-private providers.
Conclusion
Patients treated solely in the private sector had prolonged time to sputum culture conversion and treatment duration which lead to increased cost for treatment, prolonged infectiousness, potential for transmission, and the possibility for increased medication side effects.
doi:10.1371/journal.pone.0164162
PMCID: PMC5061361  PMID: 27732650
2.  Laminin-111 Peptides Conjugated to Fibrin Hydrogels Promote Formation of Lumen Containing Parotid Gland Cell Clusters 
Biomacromolecules  2016;17(6):2293-2301.
Previous studies showed that mouse submandibular gland cells form three-dimensional structures when grown on Laminin-111 gels. The use of Laminin-111 for tissue bioengineering is complicated due to its lack of purity. By contrast, the use of synthetic peptides derived from Laminin-111 is beneficial due to their high purity and easy manipulation. Two Laminin-111 peptides have been identified for salivary cells: the A99 peptide corresponding to the α1 chain from Laminin-111 and the YIGSR peptide corresponding to the β1 chain from Laminin-111, which are important for cell adhesion and migration. We created three-dimensional salivary cell clusters using a modified fibrin hydrogel matrix containing immobilized Laminin-111 peptides. Results indicate that the YIGSR peptide improved morphology and lumen formation in rat parotid Par-C10 cells as compared to cells grown on unmodified fibrin hydrogel. Moreover, a combination of both peptides not only allowed the formation of functional three-dimensional salivary cell clusters but also increased attachment and number of cell clusters. In summary, we demonstrated that fibrin hydrogel decorated with Laminin-111 peptides supports attachment and differentiation of salivary gland cell clusters with mature lumens.
Graphical abstract
doi:10.1021/acs.biomac.6b00588
PMCID: PMC5029268  PMID: 27151393
3.  Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma  
Oncotarget  2016;7(23):35241-35256.
Purpose
The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes.
Methods
Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer–specific mortality as the primary outcome.
Results
In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer–specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14–2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer–specific mortality (HR=1.77; 95% CI, 1.18–2.66; P=0.006). Five-year lung cancer–specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer–specific survival (P<0.001 and 0.015, respectively), compared with low mPS.
Conclusion
This study validates CCP score and mPS as independent prognostic markers for lung cancer–specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone.
doi:10.18632/oncotarget.9129
PMCID: PMC5085225  PMID: 27153551
molecular prognostic score; CCP score; chemotherapy; adjuvant therapy; overall survival
4.  Midbrain dopamine neurons compute inferred and cached value prediction errors in a common framework 
eLife  null;5:e13665.
Midbrain dopamine neurons have been proposed to signal reward prediction errors as defined in temporal difference (TD) learning algorithms. While these models have been extremely powerful in interpreting dopamine activity, they typically do not use value derived through inference in computing errors. This is important because much real world behavior – and thus many opportunities for error-driven learning – is based on such predictions. Here, we show that error-signaling rat dopamine neurons respond to the inferred, model-based value of cues that have not been paired with reward and do so in the same framework as they track the putative cached value of cues previously paired with reward. This suggests that dopamine neurons access a wider variety of information than contemplated by standard TD models and that, while their firing conforms to predictions of TD models in some cases, they may not be restricted to signaling errors from TD predictions.
DOI: http://dx.doi.org/10.7554/eLife.13665.001
eLife digest
Learning is driven by discrepancies between what we think is going to happen and what actually happens. These discrepancies, or ‘prediction errors’, trigger changes in the brain that support learning. These errors are signaled by neurons in the midbrain – called dopamine neurons – that fire rapidly in response to unexpectedly good events, and thereby instruct other parts of the brain to learn about the factors that occurred before the event. These events can be rewards, such as food, or cues that have predicted rewards in the past.
Yet we often anticipate, or infer, rewards even if we have not experienced them directly in a given situation. This inference reflects our ability to mentally simulate likely outcomes or consequences of our actions in new situations based upon, but going beyond, our previous experiences. These inferred predictions of reward can alter error-based learning just like predictions based upon direct experience; but do inferred reward predictions also alter the error signals from dopamine neurons?
Sadacca et al. tested this question by exposing rats to cues while recording the activity of dopamine neurons from the rats’ midbrains. In some cases, the cues directly predicted rewards based on the rats’ previous experience; in other cases, the cues predicted rewards only indirectly and based on inference. Sadacca et al. found that the dopamine neurons fired in similar ways in response to the cues in both of these situations. This result is consistent with the proposal that dopamine neurons use both types of information to calculate errors in predictions. These findings provide a mechanism by which dopamine neurons could support a much broader and more complex range of learning than previously thought.
DOI: http://dx.doi.org/10.7554/eLife.13665.002
doi:10.7554/eLife.13665
PMCID: PMC4805544  PMID: 26949249
dopamine; prediction error; rat; single unit; Rat
5.  High-Resolution Analysis of Coronavirus Gene Expression by RNA Sequencing and Ribosome Profiling 
PLoS Pathogens  2016;12(2):e1005473.
Members of the family Coronaviridae have the largest genomes of all RNA viruses, typically in the region of 30 kilobases. Several coronaviruses, such as Severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), are of medical importance, with high mortality rates and, in the case of SARS-CoV, significant pandemic potential. Other coronaviruses, such as Porcine epidemic diarrhea virus and Avian coronavirus, are important livestock pathogens. Ribosome profiling is a technique which exploits the capacity of the translating ribosome to protect around 30 nucleotides of mRNA from ribonuclease digestion. Ribosome-protected mRNA fragments are purified, subjected to deep sequencing and mapped back to the transcriptome to give a global “snap-shot” of translation. Parallel RNA sequencing allows normalization by transcript abundance. Here we apply ribosome profiling to cells infected with Murine coronavirus, mouse hepatitis virus, strain A59 (MHV-A59), a model coronavirus in the same genus as SARS-CoV and MERS-CoV. The data obtained allowed us to study the kinetics of virus transcription and translation with exquisite precision. We studied the timecourse of positive and negative-sense genomic and subgenomic viral RNA production and the relative translation efficiencies of the different virus ORFs. Virus mRNAs were not found to be translated more efficiently than host mRNAs; rather, virus translation dominates host translation at later time points due to high levels of virus transcripts. Triplet phasing of the profiling data allowed precise determination of translated reading frames and revealed several translated short open reading frames upstream of, or embedded within, known virus protein-coding regions. Ribosome pause sites were identified in the virus replicase polyprotein pp1a ORF and investigated experimentally. Contrary to expectations, ribosomes were not found to pause at the ribosomal frameshift site. To our knowledge this is the first application of ribosome profiling to an RNA virus.
Author Summary
Ribosome profiling is emerging as a powerful technique to monitor translation in living cells at sub-codon resolution. It has particular applicability to virology, with the capacity to identify viral mRNAs that are being translated during infection and to provide new insights into virus gene expression, regulation and host-virus interactions. In this work, we carried out the first ribosome profiling analysis of an RNA virus, using as a model system the murine coronavirus strain MHV-A59, a betacoronavirus in the same genus as the medically important SARS-CoV and MERS-CoV. Parallel ribosome profiling and RNA sequencing of infected-cell time points was performed during the course of MHV replication in mouse tissue culture cells and used to determine virus gene expression kinetics and the relative translational efficiencies of virus and host mRNAs. The sensitivity and precision of the approach permitted us to uncover several unanticipated features of coronavirus translation, giving insights into ribosomal frameshifting, ribosome pausing, and the utilisation of short, potentially regulatory, upstream open reading frames. We also identified some challenges associated with the technique that are of general relevance to the ribosome profiling technique and developed bioinformatic strategies to address these.
doi:10.1371/journal.ppat.1005473
PMCID: PMC4769073  PMID: 26919232
6.  Supportive and palliative radiation oncology service: Impact of a dedicated service on palliative cancer care 
Practical radiation oncology  2013;4(4):247-253.
Purpose
The American Society of Clinical Oncology has recommended tailoring palliative cancer care (PCC) to the distinct and complex needs of advanced cancer patients. The Supportive and Palliative Radiation Oncology (SPRO) service was initiated July 2011 to provide dedicated palliative radiation oncology (RO) care to cancer patients. We used care providers’ ratings to assess SPRO’s impact on the quality of PCC and compared perceptions of PCC delivery among physicians practicing with and without a dedicated palliative RO service.
Methods and materials
An online survey was sent to 117 RO care providers working at 4 Boston-area academic centers. Physicians and nurses at the SPRO-affiliated center rated the impact of the SPRO service on 8 PCC quality measures (7-point scale, “very unfavorably” to “very favorably”). Physicians at all sites rated their department’s performance on 10 measures of PCC (7-point scale, “very poorly” to “very well”).
Results
Among 102 RO care providers who responded (response rate, 89% for physicians; 83% for nurses), large majorities believed that SPRO improved the following PCC quality measures: overall quality of care (physician/nurse, 98%/92%); communication with patients and families (95%/96%); staff experience (93%/84%); time spent on technical aspects of PCC (eg, reviewing imaging) (88%/56%); appropriateness of treatment recommendations (85%/84%); appropriateness of dose/fractionation (78%/60%); and patient follow-up (64%/68%). Compared with physicians practicing in departments without a dedicated palliative RO service, physicians at the SPRO-affiliated department rated the overall quality of their department’s PCC more highly (P = .02).
Conclusions
Clinicians indicated that SPRO improved the quality of PCC. Physicians practicing within this dedicated service rated their department’s overall PCC quality higher than physicians practicing at academic centers without a dedicated service. These findings point to dedicated palliative RO services as a promising means of improving PCC quality.
doi:10.1016/j.prro.2013.09.005
PMCID: PMC4617676  PMID: 25012833
7.  Risperidone and the 5-HT2A receptor antagonist, M100907 improve probabilistic reversal learning in BTBR T+ tf/J mice 
Lay Abstract
Restricted interests and repetitive behaviors in autism can lead to an ‘insistence on sameness’ for routines and decision-making. The ability to adapt choice patterns when external contingencies change is commonly referred to as cognitive flexibility. To date, there are limited options for treating cognitive inflexibility in autism. Risperidone, an atypical antipsychotic, is approved to treat irritability in autism, but less is known of whether it is effective in treating cognitive inflexibility. Risperidone acts at multiple receptors although only actions at a subset of these receptors may be beneficial for cognitive flexibility. 5HT2A receptor blockade represents one pharmacological action of risperidone. Rodent studies have shown that 5HT2A receptor antagonists improve attention and cognitive flexibility. The present studies investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist, improved cognitive flexibility in the BTBR mouse model of autism. The BTBR mouse compared to C57BL/6J (B6) mice exhibit a deficit in reversing learned choice patterns comparable to that in individuals with autism. The present experiments used a two-choice probabilistic reversal learning test in which the ‘correct’ choice was reinforced on 80% of trials and the ‘incorrect’ choice reinforced on 20% of trials. After initial acquisition, the contingencies were reversed. Both risperidone and M100907 improved probabilistic reversal learning performance in BTBR mice. The same treatments did not improve reversal learning in B6 mice. Because risperidone can often lead to unwanted side effects, treatment with a 5HT2A receptor antagonist may offer an alternative for improving cognitive flexibility in individuals with autism.
Scientific Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD. Risperidone, an atypical antipsychotic, is approved to treat irritability in ASD, but less is known about whether it is effective in treating ‘higher-order’ RRBs, e.g. cognitive inflexibility. Risperidone also has multiple receptor targets in which only a subset may be procognitive and others induce cognitive impairment. 5HT2A receptor blockade represents one promising and more targeted approach as various preclinical studies have shown that 5HT2A receptor antagonists improve cognition. The present studies investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist improved probabilistic reversal learning performance in the BTBR T+ tf/J (BTBR) mouse model of autism. The effects of these treatments were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, similar to one in which ASD individuals exhibit impairments, both risperidone (0.125 mg) and M100907 (0.01 and 0.1 mg) improved reversal learning in BTBR mice. Risperidone (0.125 mg) impaired reversal learning in B6 mice. Improvement in probabilistic reversal learning performance resulted from treatments enhancing the maintenance of the newly correct choice pattern. Because risperidone can lead to unwanted side effects, treatment with a specific 5HT2A receptor antagonist may improve cognitive flexibility in individuals with ASD while also minimizing unwanted side effects.
doi:10.1002/aur.1395
PMCID: PMC4230321  PMID: 24894823
autism; cognitive flexibility; BTBR; reversal learning; serotonin; risperidone
8.  Effects of learning and food form on energy intake and appetitive responses 
Physiology & behavior  2014;137:1-8.
Energy-yielding beverages reportedly contribute to positive energy balance uniquely. They are highly consumed and evoke weaker satiety signaling and dietary energy compensation than solid foods of the same energy content. This study measured the contribution of learning to appetitive sensations and adjustments of energy intake for preloads varying in energy content and food form in lean and obese adults. One-hundred seven participants received four preload trials before and after a dietary intervention in this randomized cross-over trial with the stipulation that lean and obese individuals were evenly assigned to each intervention. The study entailed monitoring appetitive sensations and daily energy intake after consumption of low and high energy beverage and solid food loads on weekly visit days. Preload testing was conducted at baseline, followed by daily ingestion of one load for 14 days and then retesting responses to the four treatments. Lean individuals compensated precisely for the high energy beverage and solid loads from the onset of the study, whereas the obese did not alter eating patterns after consuming the higher energy beverage load. The learning intervention did not have an effect on the responses to the preloads, as responses in both lean and obese participants did not differ from baseline values. Responses to personality and eating behavior questionnaires revealed differences between the lean and obese groups and weakly, but significantly, predicted challenge meal and total daily energy intake. These data suggest that lean and obese individuals respond to energy in beverage form differently, and this is not altered by purposeful daily exposure to loads varying in physical form and energy content for two weeks.
doi:10.1016/j.physbeh.2014.06.016
PMCID: PMC4184995  PMID: 24955495
Beverages; Energy; Obesity; Intervention; Intake; Conditioning
9.  Role of Radiation Therapy in Palliative Care of the Patient With Cancer 
Journal of Clinical Oncology  2014;32(26):2913-2919.
Radiotherapy is a successful, time-efficient, well-tolerated, and cost-effective intervention that is crucial for the appropriate delivery of palliative oncology care. The distinction between curative and palliative goals is blurred in many patients with cancer, requiring that treatments be chosen on the basis of factors related to the patient (ie, poor performance status, advanced age, significant weight loss, severe comorbid disease), the cancer (ie, metastatic disease, aggressive histology), or the treatment (ie, poor response to systemic therapy, previous radiotherapy). Goals may include symptom relief at the site of primary tumor or from metastatic lesions. Attention to a patient's discomfort and transportation limitations requires hypofractionated courses, when feasible. Innovative approaches include rapid response palliative care clinics as well as the formation of palliative radiotherapy specialty services in academic centers. Guidelines are providing better definitions of appropriate palliative radiotherapy interventions, and bone metastases fractionation has become the first radiotherapy quality measure accepted by the National Quality Forum. Further advances in the palliative radiation oncology subspecialty will require integration of education and training between the radiotherapy and palliative care specialties.
doi:10.1200/JCO.2014.55.1143
PMCID: PMC4152720  PMID: 25113773
10.  How Radiation Oncologists Evaluate and Incorporate Life Expectancy Estimates Into the Treatment of Palliative Cancer Patients: A Survey-Based Study 
Purpose
We surveyed how radiation oncologists think about and incorporate a palliative cancer patient’s life expectancy (LE) into their treatment recommendations.
Methods and Materials
A 41-item survey was e-mailed to 113 radiation oncology attending physicians and residents at radiation oncology centers within the Boston area. Physicians estimated how frequently they assessed the LE of their palliative cancer patients and rated the importance of 18 factors in formulating LE estimates. For 3 common palliative case scenarios, physicians estimated LE and reported whether they had an LE threshold below which they would modify their treatment recommendation. LE estimates were considered accurate when within the 95% confidence interval of median survival estimates from an established prognostic model.
Results
Among 92 respondents (81%), the majority were male (62%), from an academic practice (75%), and an attending physician (70%). Physicians reported assessing LE in 91% of their evaluations and most frequently rated performance status (92%), overall metastatic burden (90%), presence of central nervous system metastases (75%), and primary cancer site (73%) as “very important” in assessing LE. Across the 3 cases, most (88%–97%) had LE thresholds that would alter treatment recommendations. Overall, physicians’ LE estimates were 22% accurate with 67% over the range predicted by the prognostic model.
Conclusions
Physicians often incorporate LE estimates into palliative cancer care and identify important prognostic factors. Most have LE thresholds that guide their treatment recommendations. However, physicians overestimated patient survival times in most cases. Future studies focused on improving LE assessment are needed.
doi:10.1016/j.ijrobp.2013.06.2046
PMCID: PMC4435719  PMID: 24074920
11.  Leishmania tarentolae: an alternative approach to the production of monoclonal antibodies to treat emerging viral infections 
Background
Monoclonal antibody therapy has an important role to play as a post-exposure prophylactic and therapeutic for the treatment of viral infections, including emerging infections. For example, several patients of the present Ebola virus outbreak in West Africa were treated with ZMapp, a cocktail of three monoclonal antibodies which are expressed in Nicotiana benthamiana.
Discussion
The majority of monoclonal antibodies in clinical use are expressed in mammalian cell lines which offer native folding and glycosylation of the expressed antibody. Monoclonal antibody expression in vegetal systems offers advantages over expression in mammalian cell lines, including improved potential for scale up and reduced costs. In this paper, I highlight the advantages of an upcoming protozoal system for the expression of recombinant antibody formats. Leishmania tarentolae offers a robust, economical expression of proteins with mammalian glycosylation patterns expressed in stable cell lines and grown in suspension culture. Several advantages of this system make it particularly suited for use in developing contexts.
Summary
Given the potential importance of monoclonal antibody therapy in the containment of emerging viral infections, novel and alternative strategies to improve production must be explored.
Electronic supplementary material
The online version of this article (doi:10.1186/2049-9957-4-8) contains supplementary material, which is available to authorized users.
doi:10.1186/2049-9957-4-8
PMCID: PMC4506428  PMID: 26191408
Antibody; Ebola; Emerging; Expression; Infection; Leishmania; Monoclonal; Therapy
12.  Does impaired O2 delivery during exercise accentuate central and peripheral fatigue in patients with coexistent COPD-CHF? 
Impairment in oxygen (O2) delivery to the central nervous system (“brain”) and skeletal locomotor muscle during exercise has been associated with central and peripheral neuromuscular fatigue in healthy humans. From a clinical perspective, impaired tissue O2 transport is a key pathophysiological mechanism shared by cardiopulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF). In addition to arterial hypoxemic conditions in COPD, there is growing evidence that cerebral and muscle blood flow and oxygenation can be reduced during exercise in both isolated COPD and CHF. Compromised cardiac output due to impaired cardiopulmonary function/interactions and blood flow redistribution to the overloaded respiratory muscles (i.e., ↑work of breathing) may underpin these abnormalities. Unfortunately, COPD and CHF coexist in almost a third of elderly patients making these mechanisms potentially more relevant to exercise intolerance. In this context, it remains unknown whether decreased O2 delivery accentuates neuromuscular manifestations of central and peripheral fatigue in coexistent COPD-CHF. If this holds true, it is conceivable that delivering a low-density gas mixture (heliox) through non-invasive positive pressure ventilation could ameliorate cardiopulmonary function/interactions and reduce the work of breathing during exercise in these patients. The major consequence would be increased O2 delivery to the brain and active muscles with potential benefits to exercise capacity (i.e., ↓central and peripheral neuromuscular fatigue, respectively). We therefore hypothesize that patients with coexistent COPD-CHF stop exercising prematurely due to impaired central motor drive and muscle contractility as the cardiorespiratory system fails to deliver sufficient O2 to simultaneously attend the metabolic demands of the brain and the active limb muscles.
doi:10.3389/fphys.2014.00514
PMCID: PMC4285731  PMID: 25610401
chronic heart failure; chronic obstructive pulmonary disease; oxygenation; respiratory muscle; skeletal muscle
13.  Validation of a Molecular and Pathological Model for Five-Year Mortality Risk in Patients with Early Stage Lung Adenocarcinoma 
Journal of Thoracic Oncology  2014;10(1):67-73.
Introduction:
The aim of this study was to validate a molecular expression signature [cell cycle progression (CCP) score] that identifies patients with a higher risk of cancer-related death after surgical resection of early stage (I-II) lung adenocarcinoma in a large patient cohort and evaluate the effectiveness of combining CCP score and pathological stage for predicting lung cancer mortality.
Methods:
Formalin-fixed paraffin-embedded surgical tumor samples from 650 patients diagnosed with stage I and II adenocarcinoma who underwent definitive surgical treatment without adjuvant chemotherapy were analyzed for 31 proliferation genes by quantitative real-time polymerase chain reaction. The prognostic discrimination of the expression score was assessed by Cox proportional hazards analysis using 5-year lung cancer-specific death as primary outcome.
Results:
The CCP score was a significant predictor of lung cancer-specific mortality above clinical covariates [hazard ratio (HR) = 1.46 per interquartile range (95% confidence interval = 1.12–1.90; p = 0.0050)]. The prognostic score, a combination of CCP score and pathological stage, was a more significant indicator of lung cancer mortality risk than pathological stage in the full cohort (HR = 2.01; p = 2.8 × 10−11) and in stage I patients (HR = 1.67; p = 0.00027). Using the 85th percentile of the prognostic score as a threshold, there was a significant difference in lung cancer survival between low-risk and high-risk patient groups (p = 3.8 × 10−7).
Conclusions:
This study validates the CCP score and the prognostic score as independent predictors of lung cancer death in patients with early stage lung adenocarcinoma treated with surgery alone. Patients with resected stage I lung adenocarcinoma and a high prognostic score may be candidates for adjuvant therapy to reduce cancer-related mortality.
doi:10.1097/JTO.0000000000000365
PMCID: PMC4272230  PMID: 25396679
Carcinoma; Nonsmall cell lung cancer; Real-time polymerase chain reaction; Risk stratification
15.  Land Use and Land Cover Change Dynamics across the Brazilian Amazon: Insights from Extensive Time-Series Analysis of Remote Sensing Data 
PLoS ONE  2014;9(8):e104144.
Throughout the Amazon region, the age of forests regenerating on previously deforested land is determined, in part, by the periods of active land use prior to abandonment and the frequency of reclearance of regrowth, both of which can be quantified by comparing time-series of Landsat sensor data. Using these time-series of near annual data from 1973–2011 for an area north of Manaus (in Amazonas state), from 1984–2010 for south of Santarém (Pará state) and 1984–2011 near Machadinho d’Oeste (Rondônia state), the changes in the area of primary forest, non-forest and secondary forest were documented from which the age of regenerating forests, periods of active land use and the frequency of forest reclearance were derived. At Manaus, and at the end of the time-series, over 50% of regenerating forests were older than 16 years, whilst at Santarém and Machadinho d’Oeste, 57% and 41% of forests respectively were aged 6–15 years, with the remainder being mostly younger forests. These differences were attributed to the time since deforestation commenced but also the greater frequencies of reclearance of forests at the latter two sites with short periods of use in the intervening periods. The majority of clearance for agriculture was also found outside of protected areas. The study suggested that a) the history of clearance and land use should be taken into account when protecting deforested land for the purpose of restoring both tree species diversity and biomass through natural regeneration and b) a greater proportion of the forested landscape should be placed under protection, including areas of regrowth.
doi:10.1371/journal.pone.0104144
PMCID: PMC4123946  PMID: 25099362
16.  Orbitofrontal neurons acquire responses to ‘valueless’ Pavlovian cues during unblocking 
eLife  2014;3:e02653.
The orbitofrontal cortex (OFC) has been described as signaling outcome expectancies or value. Evidence for the latter comes from the studies showing that neural signals in the OFC correlate with value across features. Yet features can co-vary with value, and individual units may participate in multiple ensembles coding different features. Here we used unblocking to test whether OFC neurons would respond to a predictive cue signaling a ‘valueless’ change in outcome flavor. Neurons were recorded as the rats learned about cues that signaled either an increase in reward number or a valueless change in flavor. We found that OFC neurons acquired responses to both predictive cues. This activity exceeded that exhibited to a ‘blocked’ cue and was correlated with activity to the actual outcome. These results show that OFC neurons fire to cues with no value independent of what can be inferred through features of the predicted outcome.
DOI: http://dx.doi.org/10.7554/eLife.02653.001
eLife digest
Imagine you are at a restaurant and the waiter offers you a choice of cheesecake or fruit salad for dessert. When making your choice it is likely that you will consider the features of these desserts, such as their taste, their sweetness or how healthy they are. However, when you decide which dessert to have, you will pick the one that you judge to have the highest value for you at that moment in time. In this sense, ‘value’ is a subjective concept that varies from person to person, while ‘features’ remain relatively static.
It is generally agreed that the orbitofrontal cortex (OFC) is involved in making these sorts of decisions, but its role is still a topic of debate. According to one theory the neurons in the OFC signal the subjective value of an outcome, whereas a rival theory suggests that they signal the features of the expected outcome. However, it has proved challenging to test these theories in experiments because it is difficult to say for certain that a given decision was clearly due to the value or a feature.
Now, McDannald et al. have devised an approach that can tell the difference between neurons signaling value and neurons signaling features. They trained thirsty rats to associate different odours with either an increase in the amount of milk they were given (a change in both value and a feature), or a change in the flavor of the milk (a change in a feature without a change in value). Extensive testing showed that the rats did not value one flavor over the other.
McDannald et al. then examined how the neurons in the OFC responded. If these neurons signal only value, they should only fire when the value of the outcome changes. On the other hand, if they signal features, they should fire when a feature changes, even if the value does not. It turned out that the neurons in the OFC responded whenever the features changed, irrespective of whether or not the value changed. These findings present a challenge to popular conceptions of the role of the neurons in the OFC.
DOI: http://dx.doi.org/10.7554/eLife.02653.002
doi:10.7554/eLife.02653
PMCID: PMC4132288  PMID: 25037263
orbitofrontal; single unit; blocking; rat
17.  The TOTS Community Intervention to Prevent Overweight in American Indian Toddlers: A Feasibility and Efficacy Study 
Journal of community health  2010;35(6):667-675.
Objective
Excess weight gain in American Indian/Alaskan native (AI/AN) children is a public health concern. This study tested 1) the feasibility of delivering community-wide interventions, alone or in combination with family-based interventions, to promote breastfeeding and reduce the consumption of sugar-sweetened beverages; and 2) whether these interventions decrease Body Mass Index (BMI)-Z scores in children 18–24 months of age.
Methods
Three AI/AN tribes were randomly assigned to two active interventions; a community-wide intervention alone (tribe A; n=63 families) or community-wide intervention containing a family component (tribes B and C; n=142 families). Tribal staff and the research team designed community-tailored interventions and trained community health workers to deliver the family intervention through home visits. Feasibility and acceptability of the intervention and BMI-Z scores at 18–24 months were compared between tribe A and tribes B&C combined using a separate sample pretest, posttest design.
Results
Eighty-six percent of enrolled families completed the study. Breastfeeding initiation and 6-month duration increased 14 and 15%, respectively, in all tribes compared to national rates for American Indians. Breastfeeding at 12 months was comparable to national data. Parents expressed confidence in their ability to curtail family consumption of sugar-sweetened beverages. Compared to a pretest sample of children of a similar age two years before the study begun, BMI-Z scores increased in all tribes. However, the increase was less in tribes B &C compared to tribe A (−0.75, p=0.016).
Conclusion
Family, plus community-wide interventions to increase breastfeeding and curtail sugar-sweetened beverages attenuate BMI rise in AI/AN toddlers more than community-wide interventions alone.
doi:10.1007/s10900-010-9270-5
PMCID: PMC4058573  PMID: 20508978
Obesity prevention; infants; toddlers; breastfeeding; sugar-sweetened beverages
18.  Disruption of model-based behavior and learning by cocaine self-administration in rats 
Psychopharmacology  2013;229(3):493-501.
Rationale
Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis.
Objectives
This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment.
Methods
We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes.
Results
Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward.
Conclusions
These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.
doi:10.1007/s00213-013-3222-6
PMCID: PMC3982792  PMID: 23949256
Addiction; Cocaine; Orbitofrontal; Sensory preconditioning; Blocking
19.  Orbitofrontal Cortex Supports Behavior and Learning Using Inferred but not Cached Values 
Science (New York, N.Y.)  2012;338(6109):953-956.
Computational and learning theory models propose that behavioral control reflects value that is both cached (computed and stored during previous experience) and inferred (estimated on-the-fly based on knowledge of the causal structure of the environment). The latter is thought to depend on the orbitofrontal cortex. Yet, some accounts propose that the orbitofrontal cortex contributes to behavior by signaling “economic” value, regardless of the associative basis of the information. We found that the orbitofrontal cortex is critical for both value-based behavior and learning when value must be inferred but not when a cached value is sufficient. The orbitofrontal cortex is thus fundamental for accessing model-based representations of the environment to compute value rather than for signaling value per se.
doi:10.1126/science.1227489
PMCID: PMC3592380  PMID: 23162000
20.  Detecting pregnancy use of non-hormonal category X medications in electronic medical records 
Objectives
To determine whether a rule-based algorithm applied to an outpatient electronic medical record (EMR) can identify patients who are pregnant and prescribed medications proved to cause birth defects.
Design
A descriptive study using the University of Pennsylvania Health System outpatient EMR to simulate a prospective algorithm to identify exposures during pregnancy to category X medications, soon enough to intervene and potentially prevent the exposure. A subsequent post-hoc algorithm was also tested, working backwards from pregnancy endpoints, to search for possible exposures that should have been detected.
Measurements
Category X medications prescribed to pregnant patients.
Results
The alert simulation identified 2201 pregnancies with 16 969 pregnancy months (excluding abortions and ectopic pregnancies). Of these, 30 appeared to have an order for a non-hormone category X medication during pregnancy. However, none of the 30 ‘exposed pregnancies’ were confirmed as true exposures in medical records review. The post-hoc algorithm identified 5841 pregnancies with 64 exposed pregnancies in 52 569 risk months, only one of which was a confirmed case.
Conclusions
Category X medications may indeed be used in pregnancy, although rarely. However, most patients identified by the algorithm as exposed in pregnancy were not truly exposed. Therefore, implementing an electronic warning without evaluation would have inconvenienced prescribers, possibly hurting some patients (leading to non-use of needed drugs), with no benefit. These data demonstrate that computerized physician order entry interventions should be selected and evaluated carefully even before their use, using alert simulations such as that performed here, rather than just taken off the shelf and accepted as credible without formal evaluation.
doi:10.1136/amiajnl-2010-000057
PMCID: PMC3241158  PMID: 22071529
Category X medications; computerized physician order entry (CPOE); electronic medical records (EMR); electronic warning; improving healthcare workflow and process efficiency; informatics; measuring/improving outcomes in specific conditions and patient subgroups; measuring/improving patient safety and reducing medical errors; medications during pregnancy; monitoring the health of populations; pharmacoepidemiology; statistical computing; violence
21.  A General Organocatalyzed Michael-Michael Cascade Reaction Generates Functionalized Cyclohexenes 
The Journal of organic chemistry  2011;76(15):6309-6319.
While β-dicarbonyl compounds are regularly employed as Michael donors, intermediates arising from the Michael addition of unsaturated β-ketoesters to α,β-unsaturated aldehydes are susceptible to multiple subsequent reaction pathways. We designed cyclic unsaturated β-ketoester substrates that enabled the development of the first diphenyl prolinol silyl ether-catalyzed Michael-Michael cascade reaction initiated by a β-dicarbonyl Michael donor to form cyclohexene products. The reaction conditions we developed for this Michael-Michael cascade reaction were also amenable to a variety of linear unsaturated β-ketoester substrates, including some of the same linear unsaturated β-ketoester substrates that were previously ineffective in Michael-Michael cascade reactions. These studies thus revealed that a change in simple reaction conditions, such as solvent and additives, enables the same substrate to undergo different cascade reactions, thereby accessing different molecular scaffolds. These studies also culminated in the development of a general organocatalyzed Michael-Michael cascade reaction that generates highly functionalized cyclohexenes with up to four stereocenters, in up to 97% yield, 32:1 dr, and 99% ee, in a single step from a variety of unsaturated β-ketoesters.
doi:10.1021/jo201140a
PMCID: PMC3198797  PMID: 21714480
22.  Cocaine cues drive opposing context-dependent shifts in reward processing and emotional state 
Biological psychiatry  2011;69(11):1067-1074.
Background
Prominent neurobiological theories of addiction posit a central role for aberrant mesolimbic dopamine release, but disagree as to whether repeated drug experience blunts or enhances this system. While drug withdrawal diminishes dopamine release, drug sensitization augments mesolimbic function, and both processes have been linked to drug-seeking. One possibility is that the dopamine system can rapidly switch from dampened to enhanced release depending upon the specific drug-predictive environment. To test this, we examined dopamine release when cues signaled delayed cocaine delivery versus imminent cocaine self-administration.
Methods
Fast-scan cyclic voltammetry was used to examine real-time dopamine release while simultaneously monitoring behavioral indices of aversion as rats experienced a sweet taste cue that predicted delayed cocaine availability and during self-administration. Further, the impact of cues signaling delayed drug availability on intracranial self-stimulation (ICSS), a broad measure of reward function, was assessed.
Results
We observed decreased mesolimbic dopamine concentrations, decreased reward sensitivity, and negative affect in response to the cocaine-predictive taste cue that signaled delayed cocaine availability. Importantly, dopamine concentration rapidly switched to elevated levels to cues signaling imminent cocaine delivery in the subsequent self-administration session.
Conclusions
These findings reveal rapid, bivalent contextual control over brain reward processing, affect, and motivated behavior and have implications for mechanisms mediating substance abuse.
doi:10.1016/j.biopsych.2011.02.014
PMCID: PMC3090459  PMID: 21481843
dopamine; aversion; reward; affect; cocaine; addiction
23.  Nucleus accumbens neurons encode predicted and ongoing reward costs 
Efficient decision making requires that animals consider both the benefits and costs of potential actions, such as the amount of effort or temporal delay involved in reward seeking. The nucleus accumbens (NAc) has been implicated in the ability to choose between options with different costs and overcome high costs when necessary, but it is not clear how NAc processing contributes to this role. Here, neuronal activity in the NAc was monitored using multi-neuron electrophysiology during two cost-based decision tasks in which either reward effort or reward delay was manipulated. In each task, distinct visual cues predicted high value (low effort/immediate) and low value (high effort/delayed) rewards. After training, animals exhibited a behavioral preference for high value rewards, yet overcame high costs when necessary to obtain rewards. Electrophysiological analysis indicated that a subgroup of NAc neurons exhibited phasic increases in firing rate during cue presentations. In the effort-based decision task (but not the delay-based task), this population reflected the cost-discounted value of the future response. In contrast, other subgroups of cells were activated during response initiation or reward delivery, but activity did not differ on the basis of reward cost. Finally, another population of cells exhibited sustained changes in firing rate while animals completed high effort requirements or waited for delayed rewards. These findings are consistent with previous reports that implicate NAc function in reward prediction and behavioral allocation during reward-seeking behavior, and suggest a mechanism by which NAc activity contributes to both cost-based decisions and actual cost expenditure.
doi:10.1111/j.1460-9568.2010.07531.x
PMCID: PMC3350310  PMID: 21198983
Nucleus accumbens; decision making; reward; motivation; cost; dopamine
24.  Differences in BTBR T+ tf/J and C57BL/6J mice on probabilistic reversal learning and stereotyped behaviors 
Behavioural Brain Research  2011;227(1):64-72.
Autism spectrum disorders (ASD) represent a class of neurodevelopmental disorders characterized by impairments in social interaction, verbal and non-verbal communication, as well as restricted interests and repetitive behavior. This latter class of symptoms often includes features such as compulsive behaviors and resistance to change. The BTBR T+tf/J mouse strain has been used as an animal model to investigate the social communication and restricted interest features in ASD. Less is known about whether this mouse strain models cognitive flexibility deficits also observed in ASD. The present experiment investigated performance of BTBR T+tf/J and C57BL/6J on two different spatial reversal learning tests (100% accurate feedback and 80/20 probabilistic feedback), as well as marble burying and grooming behavior. BTBR T+tf/J and C57BL/6J mice exhibited similar performance on acquisition and reversal learning with 100% accurate feedback. BTBR T+tf/J mice were impaired in probabilistic reversal learning compared to that of C57BL/6J mice. BTBR T+tf/J mice also displayed increased stereotyped repetitive behaviors compared to that of C57BL/6J mice as shown by increased marble burying and grooming behavior. The present findings indicate that BTBR T+tf/J mice exhibit similar features related to “insistence on sameness” in ASD that include not only stereotyped repetitive behaviors, but also alterations in behavioral flexibility. Thus, BTBR T+tf/J mice can serve as a model to understand the neural mechanisms underlying alterations in behavioral flexibility, as well as to test potential treatments in alleviating these symptoms.
doi:10.1016/j.bbr.2011.10.032
PMCID: PMC3273330  PMID: 22056750
BTBR T+ tf/J; Autism; Stereotypy; Reversal Learning; Mice; Memory
25.  Influenza-Like Illness in a Community Surrounding a School-Based Outbreak of 2009 Pandemic Influenza A (H1N1) Virus–Chicago, Illinois, 2009 
In April 2009, following the first school closure due to 2009 pandemic influenza A (H1N1) (pH1N1) in Chicago, Illinois, area hospitals were inundated with patients presenting with influenza-like illness (ILI). The extent of disease spread into the surrounding community was unclear. We performed a household survey to estimate the ILI attack rate among community residents and compared reported ILI with confirmed pH1N1 cases and ILI surveillance data (ie, hospital ILI visits, influenza testing, and school absenteeism). The estimated ILI attack rate was 4.6% (95% confidence interval, 2.8%-7.4%), with cases distributed throughout the 5-week study period. In contrast, 36 (84%) of 43 confirmed pH1N1 cases were identified the week of the school closure. Trends in surveillance data peaked during the same week and rapidly decreased to near baseline. Public awareness and health care practices impact standard ILI surveillance data. Community-based surveys are a valuable tool to help assess the burden of ILI in a community.
doi:10.1093/cid/ciq025
PMCID: PMC4990819  PMID: 21342907

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