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This study was to understand the impacts of three key demographic variables, age, gender, and race, on the adverse outcome of all-cause hospitalization or all-cause mortality in patients with COVID-19, using a deep neural network (DNN) analysis. We created a cohort of Veterans who were tested positive for COVID-19, extracted data on age, gender, and race, and clinical characteristics from their electronic health records, and trained a DNN model for predicting the adverse outcome. Then, we analyzed the association of the demographic variables with the risks of the adverse outcome using the impact scores and interaction scores for explaining DNN models. The results showed that, on average, older age and African American race were associated with higher risks while female gender was associated with lower risks. However, individual-level impact scores of age showed that age was a more impactful risk factor in younger patients and in older patients with fewer comorbidities. The individual-level impact scores of gender and race variables had a wide span covering both positive and negative values. The interaction scores between the demographic variables showed that the interaction effects were minimal compared to the impact scores associated with them. In conclusion, the DNN model is able to capture the non-linear relationship between the risk factors and the adverse outcome, and the impact scores and interaction scores can help explain the complicated non-linear effects between the demographic variables and the risk of the outcome., Competing Interests: Conflict of interestThe authors declare no competing interests., (© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021.)

Mercury (Hg) is a toxic pollutant, widespread in northeastern US ecosystems. Resource managers' efforts to develop fish consumption advisories for humans and to focus conservation efforts for fish-eating wildlife are hampered by spatial variability. Dragonfly larvae can serve as biosentinels for Hg given that they are widespread in freshwaters, long-lived, exhibit site fidelity, and bioaccumulate relatively high mercury concentrations, mostly as methylmercury (88% ± 11% MeHg in this study). We sampled lake water and dragonfly larvae in 74 northeastern US lakes that are part of the US EPA Long-Term Monitoring Network, including 45 lakes in New York, 43 of which are in the Adirondacks. Aqueous dissolved organic carbon (DOC) and total Hg (THg) were strongly related to MeHg in lake water. Dragonfly larvae total mercury ranged from 0.016-0.918 μg/g, dw across the study area; Adirondack lakes had the minimum and maximum concentrations. Aqueous MeHg and dragonfly THg were similar between the Adirondack and Northeast regions, but a majority of lakes within the highest quartile of dragonfly THg were in the Adirondacks. Using landscape, lake chemistry, and lake morphometry data, we evaluated relationships with MeHg in lake water and THg in dragonfly larvae. Lakewater DOC and lake volume were strong predictors for MeHg in water. Dragonfly THg Bioaccumulation Factors (BAFs, calculated as [dragonfly THg]:[aqueous MeHg]) increased as lake volume increased, suggesting that lake size influences Hg bioaccumulation or biomagnification. BAFs declined with increasing DOC, supporting a potential limiting effect for MeHg bioavailability with higher DOC.

The vernal transition represents the seasonal transition to spring, occurring as temperatures rise at the end of winter. With rapid snowmelt, microbial community turnover, and accelerated nutrient cycling, this is a critical but relatively under-studied period of ecosystem function. We conducted a study over two consecutive winters (2015-2016) at the Bear Brook Watershed in Maine to examine how changing winter conditions (warming winters, reduced snow accumulation) altered soil nitrogen availability and stream N export during winter and the vernal transition, and how these patterns were influenced by ecosystem N status (N-enriched vs. N-limited). Of the two study years, 2016 had a warmer winter with substantially less snow accumulation and a discontinuous snowpack-and as a result, had a longer vernal transition and a snowpack that thawed before the vernal transition began. Across both years, snowmelt triggered a transition, signaled by increased ammonium concentrations in soil, decreased soil nitrate concentrations due to flushing by meltwater, and increased stream nitrate exports. Despite the contrasting winter conditions, both years showed similar patterns in N availability and export, differing only in the timing of these transitions. The vernal transition has conventionally been considered a critical period for biogeochemical cycling, because the associated snowmelt event triggers physicochemical and biochemical changes in soil systems. This was consistent with our results in 2015, but our data for 2016 show that this may not always hold true, and instead, that warmer, low-snow winters may demonstrate a temporal asynchrony between snowmelt and the vernal transition. We also show that ecosystem N status is a strong driver of the seasonal N pattern, and the interaction of N status and changing climate must be further investigated to understand ecosystem function under our current predicted trajectory of warming winters, declining snowfall, and winter thaw events.

The failure behavior and mechanical properties of soft tissue can be characterized by conducting uniaxial tensile tests on small sectioned specimens, called test coupons. An ideal coupon geometry for tensile testing is a dumbbell shape (dog-bone), yet the cost and time required to fabricate custom steel punches to cut dumbbell-shaped coupons has hindered their universal application in biomechanics research. In this study, we developed an economical and reliable cutting device that can extract dumbbell-shaped coupons from soft biological tissue. The novel device, called Print-A-Punch, uses three-dimensional (3D) printed components in combination with standard fasteners and replaceable flexible razors. We identified design factors that influence the dimensional accuracy and symmetry of elastomer coupons extracted using this cutting device, and demonstrated its use on bovine meniscus. Advantages of this 3D printed device include a fast fabrication time, low material cost, good accuracy, replaceable blades, and an ability to scale coupon dimensions for specific tissues and experiments. By reducing the cost and time to cut accurate dumbbell-shaped coupons, this technology can facilitate the broad adoption of standard test methods that improve the quality and reproducibility of tensile tests in soft biological tissue. Researchers can freely download a set of STL files from this study to build their own Print-A-Punch device (https://boisestate.edu/coen-ntm/technology/print-a-punch)., Competing Interests: Declaration of Competing Interest All authors (SN, JC, MW, TL) are co-inventors on a patent submitted by Boise State University for the cutting device described in this study. The authors have no other affiliations with or involvement in any other entity with any financial interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Differentiating treatment-induced injury from recurrent high-grade glioma is an ongoing challenge in neuro-oncology, in part due to lesion heterogeneity. This study aimed to determine whether different MR features were relevant for distinguishing recurrent tumor from the effects of treatment in contrast-enhancing lesions (CEL) and non-enhancing lesions (NEL)., Methods: This prospective study analyzed 291 tissue samples (222 recurrent tumor, 69 treatment-effect) with known coordinates on imaging from 139 patients who underwent preoperative 3T MRI and surgery for a suspected recurrence. 8 MR parameter values were tested from perfusion-weighted, diffusion-weighted, and MR spectroscopic imaging at each tissue sample location for association with histopathological outcome using generalized estimating equation models for CEL and NEL tissue samples. Individual cutoff values were evaluated using receiver operating characteristic curve analysis with 5-fold cross-validation., Results: In tissue samples obtained from CEL, elevated relative cerebral blood volume (rCBV) was associated with the presence of recurrent tumor pathology (P < 0.03), while increases in normalized choline (nCho) and choline-to-NAA index (CNI) were associated with the presence of recurrent tumor pathology in NEL tissue samples (P < 0.008). A mean CNI cutoff value of 2.7 had the highest performance, resulting in mean sensitivity and specificity of 0.61 and 0.81 for distinguishing treatment-effect from recurrent tumor within the NEL., Conclusion: Although our results support prior work that underscores the utility of rCBV in distinguishing the effects of treatment from recurrent tumor within the contrast enhancing lesion, we found that metabolic parameters may be better at differentiating recurrent tumor from treatment-related changes in the NEL of high-grade gliomas., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We conducted a national-scale assessment of mercury (Hg) bioaccumulation in aquatic ecosystems, using dragonfly larvae as biosentinels, by developing a citizen-science network to facilitate biological sampling. Implementing a carefully designed sampling methodology for citizen scientists, we developed an effective framework for a landscape-level inquiry that might otherwise be resource limited. We assessed the variation in dragonfly Hg concentrations across >450 sites spanning 100 United States National Park Service units and examined intrinsic and extrinsic factors associated with the variation in Hg concentrations. Mercury concentrations ranged between 10.4 and 1411 ng/g dry weight across sites and varied among habitat types. Dragonfly total Hg (THg) concentrations were up to 1.8-fold higher in lotic habitats than in lentic habitats and 37% higher in waterbodies with abundant wetlands along their margins than those without wetlands. Mercury concentrations in dragonflies differed among families but were correlated (r 2 > 0.80) with each other, enabling adjustment to a consistent family to facilitate spatial comparisons among sampling units. Dragonfly THg concentrations were positively correlated with THg concentrations in both fish and amphibians from the same locations, indicating that dragonfly larvae are effective indicators of Hg bioavailability in aquatic food webs. We used these relationships to develop an integrated impairment index of Hg risk to aquatic ecosytems and found that 12% of site-years exceeded high or severe benchmarks of fish, wildlife, or human health risk. Collectively, this continental-scale study demonstrates the utility of dragonfly larvae for estimating the potential mercury risk to fish and wildlife in aquatic ecosystems and provides a framework for engaging citizen science as a component of landscape Hg monitoring programs.

In 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However, total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area., (Copyright © 2020 Winchell, Mishra, Phuah, Saqib, Nelson, Maiello, Causgrove, Ameel, Stein, Borish, White, Klein, Zimmerman, Dartois, Lin, Sassetti and Flynn.)

Objective: To compare the largest set of bipolar disorder pharmacotherapies to date (102 drugs and drug combinations) for risk of diabetes mellitus (DM)., Methods: The IBM MarketScan® database was used to retrospectively analyze data on 565,253 adults with bipolar disorder without prior glucose metabolism-related diagnoses. The pharmacotherapies compared were lithium, mood-stabilizing anticonvulsants, antipsychotics, and antidepressants (monotherapy and multi-class polypharmacy). Cox regression modeling included fixed pre-treatment covariates and time-varying drug exposure covariates to estimate the hazard ratio (HR) of each treatment versus "No drug"., Results: The annual incidence of new-onset diabetes during the exposure period was 3.09 % (22,951 patients). The HR of drug-dependent DM ranged from 0.79 to 2.37. One-third of the studied pharmacotherapies, including most of the antipsychotic-containing regimens, had a significantly higher risk of DM compared to "No drug". A significantly lower DM risk was associated with lithium, lamotrigine, oxcarbazepine and bupropion monotherapies, selective serotonin reuptake inhibitors (SSRI) mono-class therapy and several drug combinations containing bupropion and an SSRI. As additional drugs were combined in more complex polypharmacy, higher HRs were consistently observed., Conclusions: There is an increased risk of diabetes mellitus associated with antipsychotic and psychotropic polypharmacy use in bipolar disorder. The evidence of a lower-than-baseline risk of DM with lamotrigine, oxcarbazepine, lithium, and bupropion monotherapy should be further investigated., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The LocalControl R package implements novel approaches to address biases and confounding when comparing treatments or exposures in observational studies of outcomes. While designed and appropriate for use in comparative safety and effectiveness research involving medicine and the life sciences, the package can be used in other situations involving outcomes with multiple confounders. LocalControl is an open-source tool for researchers whose aim is to generate high quality evidence using observational data. The package implements a family of methods for non-parametric bias correction when comparing treatments in observational studies, including survival analysis settings, where competing risks and/or censoring may be present. The approach extends to bias-corrected personalized predictions of treatment outcome differences, and analysis of heterogeneity of treatment effect-sizes across patient subgroups.

Objective: We aimed to impute uncoded self-harm in administrative claims data of individuals with major mental illness (MMI), characterize self-harm incidence, and identify factors associated with coding bias., Materials and Methods: The IBM MarketScan database (2003-2016) was used to analyze visit-level self-harm in 10 120 030 patients with ≥2 MMI codes. Five machine learning (ML) classifiers were tested on a balanced data subset, with XGBoost selected for the full dataset. Classification performance was validated via random data mislabeling and comparison with a clinician-derived "gold standard." The incidence of coded and imputed self-harm was characterized by year, patient age, sex, U.S. state, and MMI diagnosis., Results: Imputation identified 1 592 703 self-harm events vs 83 113 coded events, with areas under the curve >0.99 for the balanced and full datasets, and 83.5% agreement with the gold standard. The overall coded and imputed self-harm incidence were 0.28% and 5.34%, respectively, varied considerably by age and sex, and was highest in individuals with multiple MMI diagnoses. Self-harm undercoding was higher in male than in female individuals and increased with age. Substance abuse, injuries, poisoning, asphyxiation, brain disorders, harmful thoughts, and psychotherapy were the main features used by ML to classify visits., Discussion: Only 1 of 19 self-harm events was coded for individuals with MMI. ML demonstrated excellent performance in recovering self-harm visits. Male individuals and seniors with MMI are particularly vulnerable to self-harm undercoding and may be at risk of not getting appropriate psychiatric care., Conclusions: ML can effectively recover unrecorded self-harm in claims data and inform psychiatric epidemiological and observational studies., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations., Competing Interests: The authors have declared that no competing interests exist.

Artificial intelligence (AI), the computerized capability of doing tasks, which until recently was thought to be the exclusive domain of human intelligence, has demonstrated great strides in the past decade. The abilities to play games, provide piloting for an automobile, and respond to spoken language are remarkable successes. How are the challenges and opportunities of medicine different from these challenges and how can we best apply these data-driven techniques to patient care and outcomes? A New England Journal of Medicine paper published in 1980 suggested that more well-defined "specialized" tasks of medical care were more amenable to computer assistance, while the breadth of approach required for defining a problem and narrowing down the problem space was less so, and perhaps, unachievable. On the other hand, one can argue that the modern version of AI, which uses data-driven approaches, will be the most useful in tackling tasks such as outcome prediction that are often difficult for clinicians and patients. The ability today to collect large volumes of data about a single individual (eg, through a wearable device) and the accumulation of large datasets about multiple persons receiving medical care has the potential to apply to the care of individuals. As these techniques of analysis, enumeration, aggregation, and presentation are brought to bear in medicine, the question arises as to their utility and applicability in that domain. Early efforts in decision support were found to be helpful; as the systems proliferated, later experiences have shown difficulties such as alert fatigue and physician burnout becoming more prevalent. Will something similar arise from data-driven predictions? Will empowering patients by equipping them with information gained from data analysis help? Patients, providers, technology, and policymakers each have a role to play in the development and utilization of AI in medicine. Some of the challenges, opportunities, and tradeoffs implicit here are presented as a dialog between a clinician (SJN) and an informatician (QZT)., (©Qing Zeng-Treitler, Stuart J Nelson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 27.11.2019.)

Winter is an understudied but key period for the socioecological systems of northeastern North American forests. A growing awareness of the importance of the winter season to forest ecosystems and surrounding communities has inspired several decades of research, both across the northern forest and at other mid- and high-latitude ecosystems around the globe. Despite these efforts, we lack a synthetic understanding of how winter climate change may impact hydrological and biogeochemical processes and the social and economic activities they support. Here, we take advantage of 100 years of meteorological observations across the northern forest region of the northeastern United States and eastern Canada to develop a suite of indicators that enable a cross-cutting understanding of (1) how winter temperatures and snow cover have been changing and (2) how these shifts may impact both ecosystems and surrounding human communities. We show that cold and snow covered conditions have generally decreased over the past 100 years. These trends suggest positive outcomes for tree health as related to reduced fine root mortality and nutrient loss associated with winter frost but negative outcomes as related to the northward advancement and proliferation of forest insect pests. In addition to effects on vegetation, reductions in cold temperatures and snow cover are likely to have negative impacts on the ecology of the northern forest through impacts on water, soils, and wildlife. The overall loss of coldness and snow cover may also have negative consequences for logging and forest products, vector-borne diseases, and human health, recreation, and tourism, and cultural practices, which together represent important social and economic dimensions for the northern forest region. These findings advance our understanding of how our changing winters may transform the socioecological system of a region that has been defined by the contrasting rhythm of the seasons. Our research also identifies a trajectory of change that informs our expectations for the future as the climate continues to warm., (© 2019 The Authors. Ecological Applications published by Wiley Periodicals, Inc. on behalf of Ecological Society of America.)

Purpose: To compare the performance of an 8-channel surface coil/clamshell transmitter and 32-channel head array coil/birdcage transmitter for hyperpolarized 13 C brain metabolic imaging., Methods: To determine the field homogeneity of the radiofrequency transmitters, B 1 + mapping was performed on an ethylene glycol head phantom and evaluated by means of the double angle method. Using a 3D echo-planar imaging sequence, coil sensitivity and noise-only phantom data were acquired with the 8- and 32-channel receiver arrays, and compared against data from the birdcage in transceiver mode. Multislice frequency-specific 13 C dynamic echo-planar imaging was performed on a patient with a brain tumor for each hardware configuration following injection of hyperpolarized [1- 13 C]pyruvate. Signal-to-noise ratio (SNR) was evaluated from pre-whitened phantom and temporally summed patient data after coil combination based on optimal weights., Results: The birdcage transmitter produced more uniform B 1 + compared with the clamshell: 0.07 versus 0.12 (fractional error). Phantom experiments conducted with matched lateral housing separation demonstrated 8- versus 32-channel mean transceiver-normalized SNR performance: 0.91 versus 0.97 at the head center; 6.67 versus 2.08 on the sides; 0.66 versus 2.73 at the anterior; and 0.67 versus 3.17 on the posterior aspect. While the 8-channel receiver array showed SNR benefits along lateral aspects, the 32-channel array exhibited greater coverage and a more uniform coil-combined profile. Temporally summed, parameter-normalized patient data showed SNR mean,slice ratios (8-channel/32-channel) ranging 0.5-2.00 from apical to central brain. White matter lactate-to-pyruvate ratios were conserved across hardware: 0.45 ± 0.12 (8-channel) versus 0.43 ± 0.14 (32-channel)., Conclusion: The 8- and 32-channel hardware configurations each have advantages in particular brain anatomy., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: The purpose of this study was to compare C-13 imaging parameters with hyperpolarized [1- 13 C]pyruvate with conventional gadolinium (Gd)-based perfusion weighted imaging using an orthotopic xenograft model of human glioblastoma multiforme (GBM)., Procedures: C-13 3D magnetic resonance spectroscopic imaging (MRSI) data were obtained from 14 tumor-bearing rats after the injection of hyperpolarized [1- 13 C]pyruvate at a 3T scanner. Dynamic susceptibility contrast (DSC) perfusion-weighted MR images were obtained following intravenous administration of Gd-DTPA. Normalized lactate, pyruvate, total carbon, and lactate to pyruvate ratio from C-13 MRSI data were compared with normalized peak height and percent recovery of ΔR2* curve from the DSC images in the voxels containing tumor using a Pearson's linear correlation., Results: Normalized peak height from DSC imaging showed substantial correlations with normalized lactate (r = 0.6, p = 0.02) and total carbon (r = 0.6, p = 0.02) from hyperpolarized C-13 MRSI data., Conclusions: Since the peak height in the ΔR2* curve from DSC data is related to the extent of blood volume, these hyperpolarized C-13 imaging parameters may be used to assess blood volume in rodent intracranial xenograft models of GBM.

Proton MRS ( 1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B 0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use., (© 2019 International Society for Magnetic Resonance in Medicine.)

Background: Stem cell injections are being offered to patients as a nonoperative treatment for osteoarthritis of the hip and knee. To our knowledge, no peer-reviewed data exist to document the usage frequency of these injections nor to quantify the public interest in these injections. We sought to use Google Trends to provide a quantitative analysis of interest in hip and knee stem cell injections at the population level., Methods: Google Trends search parameters were set to obtain query data from January 2010 through December 2017. 'Arthritis,' 'osteoarthritis,' 'stem cell,' 'injection,' 'knee,' and 'hip' were entered in various combinations to obtain the highest yield search volume. Trend analyses were performed., Results: Six linear models were generated to show trends in the volume of searches for the United States and the World. Model fit was good, and regression analysis showed significant trends over time for all searches. Use of search terms increased significantly over time (all models P < .001). Adjusted R-square values ranged from 54.4% to 78.1%. All trends showed an upward trajectory for the entirety of the study time period., Conclusion: There has been a marked and statistically significant rise in search query volume related to stem cells and osteoarthritis of the hip and knee since 2010. Online interest in stem cell injections may suggest increased utilization of these procedures. Well-designed clinical studies are required to keep pace with the rising popularity and public interest in this intervention for hip and knee arthritis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: This study compared the largest set of bipolar disorder pharmacotherapies to date (71 drugs and drug combinations) for risk of kidney disorders (KDs)., Methods: This retrospective observational study used the IBM MarketScan® database to analyze data on 591,052 adults with bipolar disorder without prior nephropathy, for onset of KDs (of "moderate" or "high" severity) following psychopharmacotherapy (lithium, mood stabilizing anticonvulsants [MSAs], antipsychotics, antidepressants), or "No drug". Cox regression models included fixed pre-treatment covariates and time-varying drug exposure covariates to estimate the hazard ratio (HR) of each treatment versus "No drug"., Results: Newly observed KD occurred in 14,713 patients. No regimen had significantly lower risk of KDs than "No drug". The HR estimates ranged 0.86-2.66 for "all" KDs and 0.87-5.30 for "severe" KDs. As additional drugs were combined to compare more complex polypharmacies, higher HRs were consistently observed. Most regimens containing lithium, MSAs, or antipsychotics had a higher risk than "No drug" (p < 0.05). The risk for "all" and "severe" KDs was highest respectively on monoamine oxidase inhibitors (MAOIs) (HR = 2.66, p = 5.73 × 10 -5 ), and a lithium-containing four-class combination (HR = 5.30, p = 2.46 × 10 - 9 ). The HR for lithium monotherapy was 1.82 (p = 4.73 × 10 -17 ) for "severe" KDs., Limitations: The limitations inherent for an observational study were non-randomized assignment of patients to treatment groups, non-standardization of diagnostic decisions, and non-uniform quality of data collection. No correction was made for medication dosage., Conclusions: The findings support literature concerns about lithium nephrotoxicity and highlight the potential risks of MAOIs, MSAs, antipsychotics and psychotropic polypharmacy., (Copyright © 2019. Published by Elsevier B.V.)

Little is known about the regional extent and variability of nitrate from atmospheric deposition that is transported to streams without biological processing in forests. We measured water chemistry and isotopic tracers (δ 18 O and δ 15 N) of nitrate sources across the Northern Forest Region of the U.S. and Canada and reanalyzed data from other studies to determine when, where, and how unprocessed atmospheric nitrate was transported in catchments. These inputs were more widespread and numerous than commonly recognized, but with high spatial and temporal variability. Only 6 of 32 streams had high fractions (>20%) of unprocessed atmospheric nitrate during baseflow. Seventeen had high fractions during stormflow or snowmelt, which corresponded to large fractions in near-surface soil waters or groundwaters, but not deep groundwater. The remaining 10 streams occasionally had some (<20%) unprocessed atmospheric nitrate during stormflow or baseflow. Large, sporadic events may continue to be cryptic due to atmospheric deposition variation among storms and a near complete lack of monitoring for these events. A general lack of observance may bias perceptions of occurrence; sustained monitoring of chronic nitrogen pollution effects on forests with nitrate source apportionments may offer insights needed to advance the science as well as assess regulatory and management schemes.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13 C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13 C MRI in 2011, preclinical studies involving [1- 13 C]pyruvate as well a number of other 13 C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1- 13 C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13 C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Upon inhibition of respiration, which occurs in hypoxic or nitric oxide-containing host microenvironments, Mycobacterium tuberculosis (Mtb) adopts a non-replicating "quiescent" state and becomes relatively unresponsive to antibiotic treatment. We used comprehensive mutant fitness analysis to identify regulatory and metabolic pathways that are essential for the survival of quiescent Mtb. This genetic study identified a protein acetyltransferase (Mt-Pat/Rv0998) that promoted survival and altered the flux of carbon from oxidative to reductive tricarboxylic acid (TCA) reactions. Reductive TCA requires malate dehydrogenase (MDH) and maintains the redox state of the NAD+/NADH pool. Genetic or chemical inhibition of MDH resulted in rapid cell death in both hypoxic cultures and in murine lung. These phenotypic data, in conjunction with significant structural differences between human and mycobacterial MDH enzymes that could be exploited for drug development, suggest a new strategy for eradicating quiescent bacteria., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Two efficient recombination systems were combined to produce a versatile method for chromosomal engineering that obviates the need to prepare double-stranded DNA (dsDNA) recombination substrates. A synthetic "targeting oligonucleotide" is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annealase. This oligonucleotide contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a "payload plasmid" that contains a cognate recombination site and a selectable marker. The targeting oligonucleotide and payload plasmid are cotransformed into a RecT- and Int-expressing strain, and drug-resistant homologous recombinants are selected in a single step. A library of reusable target-independent payload plasmids is available to generate gene knockouts, promoter replacements, or C-terminal tags. This new system is called ORBIT (for " o ligonucleotide-mediated r ecombineering followed by B xb1 i ntegrase t argeting") and is ideally suited for the creation of libraries consisting of large numbers of deletions, insertions, or fusions in a bacterial chromosome. We demonstrate the utility of this "drag and drop" strategy by the construction of insertions or deletions in over 100 genes in Mycobacterium tuberculosis and M. smegmatis IMPORTANCE We sought to develop a system that could increase the usefulness of oligonucleotide-mediated recombineering of bacterial chromosomes by expanding the types of modifications generated by an oligonucleotide (i.e., insertions and deletions) and by making recombinant formation a selectable event. This paper describes such a system for use in M. smegmatis and M. tuberculosis By incorporating a single-stranded DNA (ssDNA) version of the phage Bxb1 attP site into the oligonucleotide and coelectroporating it with a nonreplicative plasmid that carries an attB site and a drug selection marker, we show both formation of a chromosomal attP site and integration of the plasmid in a single transformation. No target-specific dsDNA substrates are required. This system will allow investigators studying mycobacterial diseases, including tuberculosis, to easily generate multiple mutants for analysis of virulence factors, identification of new drug targets, and development of new vaccines., (Copyright © 2018 Murphy et al.)

Background: To identify potential participants for clinical trials, electronic health records (EHRs) are searched at potential sites. As an alternative, we investigated using medical devices used for real-time diagnostic decisions for trial enrollment., Methods: To project cohorts for a trial in acute coronary syndromes (ACS), we used electrocardiograph-based algorithms that identify ACS or ST elevation myocardial infarction (STEMI) that prompt clinicians to offer patients trial enrollment. We searched six hospitals' electrocardiograph systems for electrocardiograms (ECGs) meeting the planned trial's enrollment criterion: ECGs with STEMI or > 75% probability of ACS by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI). We revised the ACI-TIPI regression to require only data directly from the electrocardiograph, the e-ACI-TIPI using the same data used for the original ACI-TIPI (development set n = 3,453; test set n = 2,315). We also tested both on data from emergency department electrocardiographs from across the US ( n = 8,556). We then used ACI-TIPI and e-ACI-TIPI to identify potential cohorts for the ACS trial and compared performance to cohorts from EHR data at the hospitals., Results: Receiver-operating characteristic (ROC) curve areas on the test set were excellent, 0.89 for ACI-TIPI and 0.84 for the e-ACI-TIPI, as was calibration. On the national electrocardiographic database, ROC areas were 0.78 and 0.69, respectively, and with very good calibration. When tested for detection of patients with > 75% ACS probability, both electrocardiograph-based methods identified eligible patients well, and better than did EHRs., Conclusion: Using data from medical devices such as electrocardiographs may provide accurate projections of available cohorts for clinical trials.

Objectives: This study compared 29 drugs for risk of psychiatric hospitalization in bipolar disorders, addressing the evidence gap on the >50 drugs used by US patients for treatment., Methods: The Truven Health Analytics MarketScan ® database was used to identify 190 894 individuals with bipolar or schizoaffective disorder who filled a prescription for one of 29 drugs of interest: lithium, first- or second-generation antipsychotics, mood-stabilizing anticonvulsants, and antidepressants. Competing risks regression survival analysis was used to compare drugs for risk of psychiatric hospitalization, adjusting for patient age, sex, comorbidities, and pretreatment medications. Other competing risks were ending monotherapy and non-psychiatric hospitalization., Results: Three drugs were associated with significantly lower risk of psychiatric hospitalization than lithium: valproate (relative risk [RR] = 0.80, P = 3.20 × 10 -4 ), aripiprazole (RR = 0.80, P = 3.50 × 10 -4 ), and bupropion (RR = 0.80, P = 2.80 × 10 -4 ). Eight drugs were associated with significantly higher risk of psychiatric hospitalization: haloperidol (RR = 1.57, P = 9.40 × 10 -4 ), clozapine (RR = 1.52, P = .017), fluoxetine (RR = 1.17, P = 3.70 × 10 -3 ), sertraline (RR = 1.17, P = 3.20 × 10 -3 ), citalopram (RR = 1.14, P = .013), duloxetine (RR = 1.24, P = 5.10 × 10 -4 ), venlafaxine (RR = 1.33; P = 1.00 × 10 -6 ), and ziprasidone (RR = 1.25; P = 6.20 × 10 -3 )., Conclusions: This largest reported retrospective observational study on bipolar disorders pharmacotherapy to date demonstrates that the majority of patients end monotherapy within 2 months after treatment start. The risk of psychiatric hospitalization varied almost two-fold across individual medications. The data add to the evidence favoring lithium and mood stabilizer use in short-term bipolar disorder management. The findings that the dopaminergic drugs aripiprazole and bupropion had better outcomes than other members of their respective classes and that antidepressant outcomes may vary by baseline mood polarity merit further investigation., (© 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.)

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7-10.2 mCi 68Ga-citrate and were imaged with PET/MR 123-307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.

MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1- 13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, k PL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in k PL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B 1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate k PL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless k PL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1- 13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1- 13 C]pyruvate parameters (SNR, k PL , bolus characteristics) in the human prostate., (© 2018 John Wiley & Sons, Ltd.)

Purpose: The purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1- 13 C]pyruvate to [1- 13 C]lactate with whole gland coverage at high spatial and temporal resolution., Methods: A 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1- 13 C]pyruvate. 3D dynamic 13 C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm 3 , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time., Results: Through preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP 13 C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1- 13 C]pyruvate to [1- 13 C]lactate in a biopsy-proven prostate cancer patient with full gland coverage., Conclusion: The results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure k PL , the kinetic rate constant of [1- 13 C]pyruvate to [1- 13 C]lactate conversion., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background: In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS)., Methods: Data from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS., Results: A log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status., Conclusion: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

The goal of this research was to elucidate the relationship between WHO 2016 molecular classifications of newly diagnosed, nonenhancing lower grade gliomas (LrGG), tissue sample histopathology, and magnetic resonance (MR) parameters derived from diffusion, perfusion, and 1 H spectroscopic imaging from the tissue sample locations and the entire tumor. A total of 135 patients were scanned prior to initial surgery, with tumor cellularity scores obtained from 88 image-guided tissue samples. MR parameters were obtained from corresponding sample locations, and histograms of normalized MR parameters within the T2 fluid-attenuated inversion recovery lesion were analyzed in order to evaluate differences between subgroups. For tissue samples, higher tumor scores were related to increased normalized apparent diffusion coefficient (nADC), lower fractional anisotropy (nFA), lower cerebral blood volume (nCBV), higher choline (nCho), and lower N-acetylaspartate (nNAA). Within the T2 lesion, higher tumor grade was associated with higher nADC, lower nFA, and higher Cho to NAA index. Pathological analysis confirmed that diffusion and metabolic parameters increased and perfusion decreased with tumor cellularity. This information can be used to select targets for tissue sampling and to aid in making decisions about treating residual disease., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

This paper describes a record of air and soil temperature collected from 2001 to 2016 in temperate forests at the Bear Brook Watershed in Maine (BBWM). BBWM is a long-term research site established to study the response of forest ecosystem function to various environmental disturbances, including chronic acidic deposition. Replicate HOBO data loggers were deployed in BBWM's two forest types (coniferous and deciduous), to record temperatures at four positions: (1) air temperature, 100 cm above the forest floor; (2) surface organic soil, 2 cm below the forest floor surface; (3) mineral soil, 10 cm below the organic-mineral horizon interface; and (4) mineral soil, 25 cm below the organic-mineral horizon interface. Data were recorded every three hours, and these raw data were used to compute daily maximum, daily minimum, daily average, and monthly average values. This fifteen-year record represents one of the few readily-available soil temperature datasets in the region, and provides information on long-term changes in climatology, and seasonal and episodic weather patterns.

The USA has set aside over 400 national parks and other protected areas to be managed by the National Park Service (NPS). Collectively, these sites attract over 300 million visits per year which makes the NPS one of the largest informal education institutions in the country. Because the NPS supports and facilitates scientific studies in parks, the national park system provides abundant opportunity for biologists and other scientists to engage global audiences in learning, exploring, and even conducting science. Those opportunities are best pursued through collaborations among scientists and the professional communication staff (interpreters, educators, media specialists, etc.) of parks and their partner organizations. This article describes unique opportunities and rationale for such collaborations, presents several examples that highlight the range of activities and lessons drawn from them, and invites scientists to conduct studies in parks and bring their science into the public eye.

Background: Rare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution., Methods: In this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions., Results: One patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second., Conclusions: Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

Study Design: Retrospective cohort comparison study., Objective: To compare perioperative outcomes between navigated and conventional single-level instrumented posterior lumbar fusions in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database., Summary of Background Data: Although multiple studies have investigated the accuracy of pedicle screw placement and radiation exposure with navigation, no study has compared perioperative complications between navigated and conventional posterior lumbar fusion. The potential benefits of navigation include improved accuracy of screw placement and reduced surgeon radiation exposure, but this is balanced by potential operative time and surgical site contamination/infection related to this bulky technology., Methods: Patients who underwent navigated or conventional single-level posterior instrumented lumbar fusions were identified in the 2010-2015 NSQIP database. The usage of navigation was characterized. Patient characteristics and comorbidities were compared between the two treatment groups. Propensity score matching was done and comparisons were made for operative time, hospital length of stay, postoperative complications, and 30-day readmissions between the two cohorts., Results: The percentage of navigated cases tended to increase over years studied to approximately 10%. After propensity matching to control potential confounding factors, statistical analysis revealed no significant difference in operative time and for most adverse events including wound infection, return to the operating room, and readmission. There were significantly lower blood transfusions in the navigated cohort (2.84% vs. 7.15%, P < 0.001). Patients who underwent navigated surgery also had a shorter mean hospital length of stay (0.2 day difference, P = 0.016)., Conclusion: The reduced blood loss and mildly reduced hospital length of stay identified for the navigated cases are probably markers of more minimally invasive surgery in the navigated cohort. The current study could not identify other differences in operative time, wound infection, or return to the operating room/readmission between navigated and conventional single level posterior instrumented lumbar cases., Level of Evidence: 3.

Study Design: This is a retrospective study., Objective: To study the differences in definition of "inpatient" and "outpatient" [stated status vs. actual length of stay (LOS)], and the effect of defining populations based on the different definitions, for anterior cervical discectomy and fusion (ACDF) and lumbar discectomy procedures in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database., Summary of Background Data: There has been an overall trend toward performing ACDF and lumbar discectomy in the outpatient setting. However, with the possibility of patients who underwent outpatient surgery staying overnight or longer at the hospital under "observation" status, the distinction of "inpatient" and "outpatient" is not clear., Materials and Methods: Patients who underwent ACDF or lumbar discectomy in the 2005-2014 ACS-NSQIP database were identified. Outpatient procedures were defined in 1 of 2 ways: either as being termed "outpatient" or hospital LOS=0. Differences in definitions were studied. Further, to evaluate the effect of the different definitions, 30-day outcomes were compared between "inpatient" and "outpatient" and between LOS>0 and LOS=0 for ACDF patients., Results: Of the 4123 "outpatient" ACDF patients, 919 had LOS=0, whereas 3204 had LOS>0. Of the 13,210 "inpatient" ACDF patients, 337 had LOS=0, whereas 12,873 had LOS>0. Of the 15,166 "outpatient" lumbar discectomy patients, 8968 had LOS=0, whereas 6198 had LOS>0. Of the 12,705 "inpatient" lumbar discectomy patients, 814 had LOS=0, whereas 11,891 had LOS>0. On multivariate analysis of ACDF patients, when comparing "inpatient" with "outpatient" and "LOS>0" with "LOS=0" there were differences in risks for adverse outcomes based on the definition of outpatient status., Conclusions: When evaluating the ACS-NSQIP population, ACDF and lumbar discectomy procedures recorded as "outpatient" can be misleading and often did not correlate with same day discharge. These findings have significant impact on the interpretation of existing studies and define an area that needs clarification for future studies., Level of Evidence: Level 3.

Purpose: To implement a fully automated atlas-based method for prescribing 3D PRESS MR spectroscopic imaging (MRSI)., Methods: The PRESS selected volume and outer-volume suppression bands were predefined on the MNI152 standard template image. The template image was aligned to the subject T 1 -weighted image during a scan, and the resulting transformation was then applied to the predefined prescription. To evaluate the method, H-1 MRSI data were obtained in repeat scan sessions from 20 healthy volunteers. In each session, datasets were acquired twice without repositioning. The overlap ratio of the prescribed volume in the two sessions was calculated and the reproducibility of inter- and intrasession metabolite peak height and area ratios was measured by the coefficient of variation (CoV). The CoVs from intra- and intersession were compared by a paired t-test., Results: The average overlap ratio of the automatically prescribed selection volumes between two sessions was 97.8%. The average voxel-based intersession CoVs were less than 0.124 and 0.163 for peak height and area ratios, respectively. Paired t-test showed no significant difference between the intra- and intersession CoVs., Conclusion: The proposed method provides a time efficient method to prescribe 3D PRESS MRSI with reproducible imaging positioning and metabolite measurements. Magn Reson Med 79:636-642, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) is a powerful non-invasive tool for characterizing spatial variations in metabolic profiles for patients with glioma. Metabolic parameters obtained using this technique have been shown to predict treatment response, disease progression, and transformation to a more malignant phenotype. The availability of ultra-high-field MR systems has the potential to improve the characterization of metabolites. The purpose of this study was to compare the metabolite profiles acquired with conventional long echo time (TE) MRSI at 3T with those obtained with short TE MRSI at 3T and 7T in patients with glioma. The data acquisition parameters were optimized separately for each echo time and field strength to obtain volumetric coverage within clinically feasible data acquisition times of 5-10 min. While a higher field strength did provide better detection of metabolites with overlapping peaks, spatial coverage was reduced and the use of inversion recovery to reduce lipid precluded the detection of lipid in regions of necrosis. For serial evaluation of large, heterogeneous lesions, the use of 3T short TE MRSI may thus be preferred. Despite the limited number of metabolites that it is able to detect, the use of 3T long TE MRSI gives the best contrast in choline/N-acetyl aspartate between normal appearing brain and tumor and also allows the separate detection of lactate and lipid. It may therefore be preferred for serial evaluation of patients with high-grade glioma and for detection of malignant transformation in patients with low-grade glioma.

Purpose: The purpose of the current study was to use the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) to determine whether there were differences in 30-day perioperative complications between open arthrotomy and arthroscopy for the treatment of septic knees in a large national sample., Methods: Patients who were diagnosed with a septic knee and underwent open arthrotomy or arthroscopy were identified in the 2005-2014 NSQIP data sets. Patient demographics and perioperative complications were characterized and compared between the 2 procedures., Results: In total, 168 patients undergoing knee arthrotomy and 216 patients undergoing knee arthroscopy for septic knee were identified. There were no statistically significant differences in demographic variables between the 2 groups. On univariate analysis, the rate of minor adverse events (MAEs; 15.48% vs 8.80%, P = .043) was higher in the open arthrotomy treatment group, while the rate of serious adverse events (SAEs; 37.50% vs 26.19%, P = .019) was higher in the arthroscopic surgery treatment group. On multivariate analysis, which controlled for patient characteristics/comorbidities and used the Bonferroni correction for multiple comparisons, there were no statistically significant differences in risk of any adverse events (relative risk [RR] = 0.851; 99% confidence interval [CI], 0.598-1.211; P = .240), MAE (RR = 1.653; 99% CI, 0.818-3.341; P = .066), SAE (RR = 0.706; 99% CI, 0.471-1.058; P = .027), return to the operating room (RR = 0.810; 99% CI, 0.433-1.516; P = .387), or readmission (RR = 1.022; 99% CI, 0.456-2.294; P = .944) between open compared with arthroscopic surgery., Conclusions: Univariate analysis revealed a lower rate of MAE but a higher rate of SAE in the arthroscopic surgery treatment group. However, on multivariate analysis, similar perioperative complications, rate of return to the operating room, and rate of readmission were found after open and arthroscopic debridement for septic knees. Based on the lack of demonstrated superiority of either of these 2 treatment modalities for this given diagnosis, and the expectation that most differences in perioperative complications for this diagnosis would have declared themselves within the first 30 days, deciding between the studied treatment modalities may be based more on other factors not included in this study., Level of Evidence: Retrospective comparative study, Level III., (Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Although uncommon, stroke can be a catastrophic inpatient complication for patients with hip fractures. The current study determines the incidence of inpatient stroke after hip fractures in elderly patients, identifies risk factors associated with such strokes, and determines the association of stroke with short-term inpatient outcomes. A retrospective review of all patients aged 65 years or older with isolated hip fractures in the 2011 and 2012 National Trauma Data Bank was conducted. A total of 37,584 patients met inclusion criteria. Of these patients, 162 (0.4%) experienced a stroke during their hospitalization for the hip fracture. In multivariate analysis, a history of prior stroke (odds ratio [OR], 13.24), coronary artery disease (OR, 2.05), systolic blood pressure 180 mm Hg or higher (OR, 1.66), and bleeding disorders (OR, 1.65) were associated with inpatient stroke. Inpatient stroke was associated with increased mortality (OR, 7.17) and inpatient serious adverse events (OR, 6.52). These findings highlight the need for vigilant care of high-risk patients, such as those with a history of prior stoke, and for an understanding that patients who experience an inpatient stroke after a hip fracture are at significantly increased risk of mortality and inpatient serious adverse events. [Orthopedics. 2018; 41(1):e27-e32.]., (Copyright 2017, SLACK Incorporated.)

Background: Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population., Methods: Fifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [K ps ] for vascular permeability) measured during treatment. The primary endpoint was progression-free survival at 6 months (PFS-6) in patients with WHO II disease at enrollment., Results: For patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P < .001 for an improvement from the historical rate of 17%). Evidence of PI3K/mTOR activation by immunohistochemistry for phosphorylated ribosomal S6 Ser240/244 (p-S6 Ser240/244 ) was associated with worse progression-free survival (PFS; hazard ratio [HR], 3.03; P = .004) and overall survival (HR, 12.7; P = .01). Tumor perfusion decreased after 6 months (median decrease in fBV, 15%; P = .03; median decrease in K ps , 12%; P = .09), with greater decreases associated with improved PFS (HR for each 10% fBV decrease, 0.71; P = .01; HR for each 10% K ps decrease, 0.82; P = .04)., Conclusions: Patients with recurrent LGGs demonstrated a high degree of disease stability during treatment with everolimus. PI3K/mTOR activation, as measured by immunohistochemistry for p-S6, was associated with a worse prognosis. Tumor vascular changes were observed that were consistent with the antiangiogenic effects of mTOR inhibitors. These results support further study of everolimus for LGGs. Cancer 2017;123:4631-4639. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Although the contrast-enhancing (CE) lesion on T 1 -weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T 2 -weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden., Methods: Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy., Results: The Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data., Conclusions: The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding the factors that affect water quality and the ecological services provided by freshwater ecosystems is an urgent global environmental issue. Predicting how water quality will respond to global changes not only requires water quality data, but also information about the ecological context of individual water bodies across broad spatial extents. Because lake water quality is usually sampled in limited geographic regions, often for limited time periods, assessing the environmental controls of water quality requires compilation of many data sets across broad regions and across time into an integrated database. LAGOS-NE accomplishes this goal for lakes in the northeastern-most 17 US states.LAGOS-NE contains data for 51 101 lakes and reservoirs larger than 4 ha in 17 lake-rich US states. The database includes 3 data modules for: lake location and physical characteristics for all lakes; ecological context (i.e., the land use, geologic, climatic, and hydrologic setting of lakes) for all lakes; and in situ measurements of lake water quality for a subset of the lakes from the past 3 decades for approximately 2600-12 000 lakes depending on the variable. The database contains approximately 150 000 measures of total phosphorus, 200 000 measures of chlorophyll, and 900 000 measures of Secchi depth. The water quality data were compiled from 87 lake water quality data sets from federal, state, tribal, and non-profit agencies, university researchers, and citizen scientists. This database is one of the largest and most comprehensive databases of its type because it includes both in situ measurements and ecological context data. Because ecological context can be used to study a variety of other questions about lakes, streams, and wetlands, this database can also be used as the foundation for other studies of freshwaters at broad spatial and ecological scales., (© The Author 2017. Published by Oxford University Press.)

Objectives: As part of a series of Patient-Centered Outcomes Research Institute-funded large-scale retrospective observational studies on bipolar disorder (BD) treatments and outcomes, we sought the input of patients with BD and their family members to develop research questions. We aimed to identify systemic root causes of patient-reported challenges with BD management in order to guide subsequent studies and initiatives., Methods: Three focus groups were conducted where patients and their family members (total n = 34) formulated questions around the central theme, "What do you wish you had known in advance or over the course of treatment for BD?" In an affinity mapping exercise, participants clustered their questions and ranked the resulting categories by importance. The research team and members of our patient partner advisory council further rated the questions by expected impact on patients. Using a Theory of Constraints systems thinking approach, several causal models of BD management challenges and their potential solution were developed with patients using the focus group data., Results: A total of 369 research questions were mapped to 33 categories revealing 10 broad themes. The top priorities for patient stakeholders involved pharmacotherapy and treatment alternatives. Analysis of causal relationships underlying 47 patient concerns revealed two core conflicts: for patients, whether or not to take pharmacotherapy, and for mental health services, the dilemma of care quality vs quantity., Conclusions: To alleviate the core conflicts identified, BD management requires a coordinated multidisciplinary approach including: improved access to mental health services, objective diagnostics, sufficient provider visit time, evidence-based individualized treatment, and psychosocial support., (© 2017 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.)

Therapeutic intent, the reason behind the choice of a therapy and the context in which a given approach should be used, is an important aspect of medical practice. There are unmet needs with respect to current electronic mapping of drug indications. For example, the active ingredient sildenafil has 2 distinct indications, which differ solely on dosage strength. In progressing toward a practice of precision medicine, there is a need to capture and structure therapeutic intent for computational reuse, thus enabling more sophisticated decision-support tools and a possible mechanism for computer-aided drug repurposing. The indications for drugs, such as those expressed in the Structured Product Labels approved by the US Food and Drug Administration, appears to be a tractable area for developing an application ontology of therapeutic intent., (© The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

The uneven representation of frugivorous mammals and birds across tropical regions - high in the New World, low in Madagascar and intermediate in Africa and Asia - represents a long-standing enigma in ecology. Several hypotheses have been proposed to explain these differences but the ultimate drivers remain unclear. Here, we tested the hypothesis that fruits in Madagascar contain insufficient nitrogen to meet primate metabolic requirements, thus constraining the evolution of frugivory. We performed a global analysis of nitrogen in fruits consumed by primates, as collated from 79 studies. Our results showed that average frugivory among lemur communities was lower compared to New World and Asian-African primate communities. Fruits in Madagascar contain lower average nitrogen than those in the New World and Old World. Nitrogen content in the overall diets of primate species did not differ significantly between major taxonomic radiations. There is no relationship between fruit protein and the degree of frugivory among primates either globally or within regions, with the exception of Madagascar. This suggests that low protein availability in fruits influences current lemur communities to select for protein from other sources, whereas in the New World and Old World other factors are more significant in shaping primate communities.

Purpose: To evaluate spectral acquisition processes important for obtaining reliable and reproducible γ-aminobutyric acid (GABA) signals from volunteers in brain regions that are frequently used for neuroimaging studies [anterior cingulate cortex (ACC), superior temporal gyrus, and caudate] at ultra-high field. Methods: Ten healthy volunteers were studied using a single-voxel Point-RESolved Spectrosocpy (PRESS) sequence with band selective inversion with gradient dephasing pulses (BASING). The editing pulse was designed to be symmetrically placed at 2.0 and 1.4 ppm in the two cycles to reduce the co-editing of macro-molecules (MM). Spectral data were obtained with phase encoding matrix 8 × 8 × 1 and two editing cycles or 1 × 1 × 1 and 64 editing/64 non-editing. The total acquisition time was approximately 4.5 min for each acquisition. An automated MRS prescription method was utilized for the placement of the GABA scan location in 5/10 subjects. Three regions of interest were predefined in the MNI152 space and then registered and transformed to subject space. These volunteers also had repeat scans to examine between-session reproducibility. Results: The placement of editing pulses symmetrically at 1.7 ppm reduced the effect of MM contributions and provided more accurate GABA estimation. Chemical shift misregistration errors caused by classic PRESS localization sequence are more significant at ultra-high field strength. Therefore, a large over-excitation factor was needed to reduce this error. Furthermore, the inefficiency of saturation bands and unspoiled coherence could also interfere with the quality of the data. Reliable recovery of metabolite signals resulted from the implementation of 8 × 8 × 1 phase encoding that successfully removed artifacts and errors, without compromising the total acquisition time. Between successive scans on the same subject, dice overlap ratios of the excited spectral volume between the two scans were in the range of 92-95%. Within subject variability of metabolites between two repeat scans was smaller in the ACC and left superior temporal gyrus when compared to that in the right caudate, with averaged coefficients of variation being 3.6, 6.0, and 16.9%, respectively. Conclusion: This study demonstrated the feasibility of obtaining reliable and reproducible GABA measurements at ultra-high field.

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions., Competing Interests: The authors declare no conflict of interest.

Background: This study uses the American College of Surgeons National Trauma Data Bank (NTDB) to update the field on the demographics, injury mechanisms, and concurrent injuries among a national sample of patients admitted to the hospital department with calcaneus fractures., Methods: Patients with calcaneus fractures in the NTDB during 2011-2012 were identified and assessed., Results: A total of 14 516 patients with calcaneus fractures were included. The most common comorbidity was hypertension (18%), and more than 90% of fractures occurred via traffic accident (49%) or fall (43%). A total of 11 137 patients had concurrent injuries. Associated lower extremity fractures had the highest incidence and occurred in 61% of patients (of which the most common were other foot and ankle fractures). Concurrent spine fractures occurred in 23% of patients (of which the most common were lumbar spine fractures). Concurrent nonorthopaedic injuries included head injuries in 18% of patients and thoracic organ injuries in 15% of patients., Conclusion: This national sample indicates that associated injuries occur in more than three quarters calcaneus fracture patients. The most common associated fractures are in close proximity to the calcaneus. Although the well-defined association of calcaneus fractures with lumbar spine fractures was identified, the data presented highlight additional strong associations of calcaneus fractures with other orthopaedic and nonorthopaedic injuries., Levels of Evidence: Prognostic, Level III: Retrospective review of a prospectively collected cohort.

Background: Advances in surgical techniques and anesthesia have made performing unicompartmental knee arthroplasty (UKA) in the outpatient setting a possibility. The touted benefits of outpatient surgery include higher patient satisfaction and reduced costs. However, detailed information on the perioperative outcomes of outpatient compared with inpatient UKA in a large, national patient population in the United States has never been reported. The present study compares perioperative complications between outpatient and inpatient UKAs in the National Surgical Quality Improvement Program database., Methods: Patients who underwent UKA were identified in the 2005-2015 National Surgical Quality Improvement Program database. Outpatient procedures were defined as those with length of hospital stay = 0 days, whereas inpatient procedures were defined as those with length of hospital stay = 1-4 days. Patients' characteristics and comorbidities were compared between the two groups. Propensity score matched comparisons were performed for 30-day perioperative complications and readmissions between the two cohorts., Results: This study included 568 outpatient and 5312 inpatient UKA cases. After propensity matching to control potential confounding factors, statistical analysis revealed no significant difference in any perioperative complications or any postdischarge complications between the outpatient and inpatient cohorts. Notably, the rate of 30-day readmissions between the two cohorts was not statistically different., Conclusion: Based on the perioperative outcome measures assessed in this study, outpatient UKA can be appropriately considered in carefully selected patients based on the lack of differences in rates of 30-day perioperative complications and readmissions between the outpatient and matched inpatient groups., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Despite the longstanding role of radiation in cancer treatment and the presence of advanced, high-resolution imaging techniques, delineation of voxels at-risk for progression remains purely a geometric expansion of anatomic images, missing subclinical disease at risk for recurrence while treating potentially uninvolved tissue and increasing toxicity. This remains despite the modern ability to precisely shape radiation fields. A striking example of this is the treatment of glioblastoma, a highly infiltrative tumor that may benefit from accurate identification of subclinical disease. In this study, we hypothesize that parameters from physiologic and metabolic magnetic resonance imaging (MRI) at diagnosis could predict the likelihood of voxel progression at radiographic recurrence in glioblastoma by identifying voxel characteristics that indicate subclinical disease. Integrating dosimetry can reveal its effect on voxel outcome, enabling risk-adapted voxel dosing. As a system example, 24 patients with glioblastoma treated with radiotherapy, temozolomide and an anti-angiogenic agent were analyzed. Pretreatment median apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative cerebral blood volume (rCBV), vessel leakage (percentage recovery), choline-to-NAA index (CNI) and dose of voxels in the T2 nonenhancing lesion (NEL), T1 post-contrast enhancing lesion (CEL) or normal-appearing volume (NAV) of brain, were calculated for voxels that progressed [NAV→NEL, CEL (N = 8,765)] and compared against those that remained stable [NAV→NAV (N = 98,665)]. Voxels that progressed (NAV→NEL) had significantly different (P < 0.01) ADC (860), FA (0.36) and CNI (0.67) versus stable voxels (804, 0.43 and 0.05, respectively), indicating increased cell turnover, edema and decreased directionality, consistent with subclinical disease. NAV→CEL voxels were more abnormal (1,014, 0.28, 2.67, respectively) and leakier (percentage recovery = 70). A predictive model identified areas of recurrence, demonstrating that elevated CNI potentiates abnormal diffusion, even far (>2 cm) from the tumor and dose escalation >45 Gy has diminishing benefits. Integrating advanced MRI with dosimetry can identify at voxels at risk for progression and may allow voxel-level risk-adapted dose escalation to subclinical disease while sparing normal tissue. When combined with modern planning software, this technique may enable risk-adapted radiotherapy in any disease site with multimodal imaging.