bluuebunny/crossref_metadata_2025_split huggingface dataset:
The tumor microenvironment in renal cell cancer
Authors: Mier James W. 
Published: April 2019

Purpose of review
In addition to the provision of nutrients and growth factors that facilitate tumor cell proliferation and metastasis, the tumor microenvironment (MEV) restricts immune surveillance of tumor-associated antigens and limits the efficacy of immune checkpoint inhibitors, tumor vaccines, and other immune therapies. This review will focus on the immunosuppressive mechanisms operative within the tumor MVE of renal cell carcinoma.

Recent findings
Several of the immunosuppressive mechanisms within the tumor MEV have been identified and are potentially druggable. Clinical trials with agents that target several of these inhibitory pathways are currently underway.

Summary
Although renal cell carcinoma is one of several tumor types responsive to immune checkpoint inhibitors, the effectiveness of these agents is likely to be limited by the various tumor-infiltrating bone marrow-derived myeloid cells that comprise the MEV. Several strategies to combat the recruitment of these cells into tumor tissue or to neutralize their immunosuppressive function have shown encouraging results in animal tumor models and clinical trials.
A Machine Learning Strategy for Autism Screening in Toddlers
Authors: Achenie Luke E. K. , Scarpa Angela , Factor Reina S. , Wang Tao , Robins Diana L. , McCrickard D. Scott 
Published: April 2019

ABSTRACT:

Objective:
Autism spectrum disorder (ASD) screening can improve prognosis via early diagnosis and intervention, but lack of time and training can deter pediatric screening. The Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) is a widely used screener but requires follow-up questions and error-prone human scoring and interpretation. We consider an automated machine learning (ML) method for overcoming barriers to ASD screening, specifically using the feedforward neural network (fNN).

Methods:
The fNN technique was applied using archival M-CHAT-R data of 14,995 toddlers (age 16–30 months, 46.51% male). The 20 M-CHAT-R items were inputs, and ASD diagnosis after follow-up and diagnostic evaluation (i.e., ASD or not ASD) was the output. The sample was divided into subgroups by race (i.e., white and black), sex (i.e., boys and girls), and maternal education (i.e., below and above 15 years of education completed) to examine subgroup differences. Each subgroup was evaluated for best-performing fNN models.

Results:
For the total sample, best results yielded 99.72% correct classification using 18 items. Best results yielded 99.92% correct classification using 14 items for white toddlers and 99.79% correct classification using 18 items for black toddlers. In boys, best results yielded 99.64% correct classification using 18 items, whereas best results yielded 99.95% correct classification using 18 items in girls. For the case when maternal education is 15 years or less (i.e., associate degree and below), best results were 99.75% correct classification when using 16 items. Results were essentially the same when maternal education was 16 years or more (i.e., above associate degree); that is, 99.70% correct classification was obtained using 16 items.

Conclusion:
The ML method was comparable to the M-CHAT-R with follow-up items in accuracy of ASD diagnosis while using fewer items. Therefore, ML may be a beneficial tool in implementing automatic, efficient scoring that negates the need for labor-intensive follow-up and circumvents human error, providing an advantage over previous screening methods.
Epidemiology of Incarceration
Authors: Camplain Ricky , Warren Meghan , Baldwin Julie A. , Camplain Carolyn , Fofanov Viacheslav Y. , Trotter Robert T. 
Published: April 2019

Background:
Each year, 9 million individuals cycle in and out of jails. The under-characterization of incarceration as an exposure poses substantial challenges to understanding how varying levels of exposure to jail may affect health. Thus, we characterized levels of jail incarceration including recidivism, number of incarcerations, total and average number of days incarcerated, and time to reincarceration.

Methods:
We created a cohort of 75,203 individuals incarcerated at the Coconino County Detention Facility in Flagstaff, Arizona, from 2001 to 2018 from jail intake and release records.

Results:
The median number of incarcerations during the study period was one (interquartile range [IQR] = 1–2). Forty percent of individuals had >1 incarceration. The median length of stay for first observed incarcerations was 1 day (IQR = 0–5). The median total days incarcerated was 3 (IQR = 1–23). Average length of stay increased by number of incarcerations. By 18 months, 27% of our sample had been reincarcerated.

Conclusion:
Characteristics of jail incarceration have been largely left out of public health research. A better understanding of jail incarcerations can help design analyses to assess health outcomes of individuals incarcerated in jail. Our study is an early step in shaping an understanding of jail incarceration as an exposure for future epidemiologic research. See video abstract at, http://links.lww.com/EDE/B536.
Estimating the Human Papillomavirus Genotype Attribution in Screen-detected High-grade Cervical Lesions
Authors: Lissenberg-Witte Birgit I. , Bogaards Johannes A. , Quint Wim G. V. , Berkhof Johannes 
Published: April 2019

Background:
Genotype attribution in high-grade cervical lesions (CIN3+) can be calculated by the hierarchical or proportional method, but these do not account for the genotype distribution in the general population and cannot assess the number of genotype-specific high-grade cervical lesions (CIN3+).

Methods:
We present a statistical method for estimating genotype-specific CIN3+ risks and genotype attribution in CIN3+ from cervical screening samples. A key assumption is that genotype-specific infections in women with multiple infections have independent progression risks. We applied the method to 512 human papillomavirus (HPV)-positive women referred for colposcopy and validated it by laser-capture microscopy-polymerase chain reaction. We also compared performance by simulation.

Results:
For endpoint CIN3+, the summed deviation of attributable fractions between the estimated genotype-specific attributable fractions and laser-capture microscopy polymerase chain reaction-based attributable fractions was similar for the three methods: 0.17 for the new method (95% confidence interval [CI] = 0.091, 0.28), 0.19 (95% CI = 0.11, 0.33) for the hierarchical method and 0.15 (95% CI = 0.085, 0.26) for the proportional method. Simulations indicated that the new method outperformed the other methods for endpoint CIN3+ when the number of HPV-positive women was large. Exclusion of HPV16-positive women had only a small effect on the estimated genotype-specific risks, supporting the independence assumption.

Conclusions:
Genotype-specific attribution in CIN3+ can be accurately predicted by a model that assumes independence between genotypes with respect to disease progression. The method can be used to monitor HPV vaccine effectiveness for prevention of genotype-specific CIN3+ and to assess disease risk after vaccination.
Association between blood lead level and subsequent Alzheimer’s disease mortality
Authors: Horton Christelene Jack , Weng Hsin-Yi , Wells Ellen M. 
Published: April 2019

Background:
Previous studies suggest that cumulative lead exposure is associated with cognitive decline, but its relation with Alzheimer’s disease (AD) remains unclear. Therefore, this study investigated the longitudinal association between blood lead level (BLL) and AD mortality.

Methods:
This study included 8,080 elders (60 years or older) with BLL data from the 1999 to 2008 US National Health and Nutrition Examination Survey. Mortality was determined from linked 1999–2014 National Death Index data. A causal diagram presented causal assumptions and identified a sufficient set of confounders: age, sex, poverty, race/ethnicity, and smoking. Cox proportional hazard models were used to determine the association between BLL and subsequent AD mortality. Impacts of competing risks and design effect were also assessed. Adjusted hazard rate ratio (HRR) and 95% confidence interval (CI) were reported.

Results:
Follow-up ranged from <1 to 152 months (median, 74). Eighty-one participants died from AD over 632,075 total person-months at risk. An increase in BLL was associated with an increase in AD mortality after adjusting for identified confounders. We estimated that those with BLL of 1.5 and 5 μg/dl had 1.2 (95% CI = 0.70, 2.1) and 1.4 (95% CI = 0.54, 3.8) times the rate of AD mortality compared to those with BLL of 0.3 μg/dl, respectively, after accounting for competing risks. Adjusted HRRs were 1.5 (95% CI = 0.81, 2.9) and 2.1 (95% CI = 0.70, 6.3), respectively, after considering design effect.

Conclusions:
This longitudinal study demonstrated a positive, albeit not statistically significant, association between BLL and AD mortality after adjustment for competing risks or design effect.
Relative toxicities of major particulate matter constituents on birthweight in Massachusetts
Authors: Fong Kelvin C. , Di Qian , Kloog Itai , Laden Francine , Coull Brent A. , Koutrakis Petros , Schwartz Joel D. 
Published: April 2019

Background:
Maternal exposure to fine particulate air pollution (PM2.5) during pregnancy has been linked to lower newborn birthweight, making it a toxic exposure because lower birthweight is a risk factor for chronic disease and mortality. However, the toxicity of major constituents of PM2.5 and how they compare to each other remain uncertain.

Methods:
We assigned address-specific exposure to PM2.5, elemental carbon (EC), organic carbon (OC), nitrate, and sulfate averaged over the entire period of pregnancy for each birth in Massachusetts from 2001 to 2012 using a high-resolution exposure model. Using multivariate regression adjusted for total PM2.5, we estimated the relative toxicity of each constituent on continuous birthweight.

Results:
EC was more toxic per interquartile range increase compared with remaining PM2.5 in single constituent models that estimated the effect of a constituent with adjustment for PM2.5. OC, nitrate, and sulfate were each less toxic than their respective remaining PM2.5 per interquartile range increase. When all constituents and total PM2.5 were included in the same model, EC was most toxic, followed by nitrate, then OC and sulfate with similar toxicities. Sensitivity analyses using term low birth weight and small for gestational age also showed that EC was most detrimental as did averaging exposures over the third trimester of pregnancy. Scaling to unit mass increases also showed EC to be most toxic.

Conclusion:
Four major constituents of PM2.5 had different relative toxicities on continuous birthweight. Our findings suggest that EC was most toxic, followed by nitrate, OC, and sulfate.
Interlaboratory Analysis of Isavuconazole Plasma Concentration Assays Among European Laboratories
Authors: Pea Federico , Krause Robert , Müller Carsten , Hennart Benjamin , Richardson Malcolm , Meinitzer Andreas , Wiesen Martin H. J. , Wiktorowicz Tatiana , Spickermann Jochen , Henriksen Anne S. 
Published: April 2019

Background:
Under certain circumstances, clinicians treating patients with isavuconazole for invasive aspergillosis or mucormycosis may use therapeutic drug monitoring. However, the accuracy and reproducibility of the various assays used by different laboratories for the quantification of isavuconazole plasma concentrations have yet to be determined.

Methods:
Human plasma samples spiked with known concentrations of isavuconazole were provided to 27 European laboratories that took part in a “round-robin” test (an interlaboratory test performed independently at least 2 times; 2 rounds performed in the current study). Assay methods included liquid chromatography–tandem mass spectrometry (LC-MS/MS), LC with ultraviolet detection (LC-UV), LC with fluorescence detection (LC-FL), and bioassay. The accuracy and reproducibility compared with the known concentrations for each sample in each round were compared overall, between assays, and between laboratories.

Results:
Twenty-seven laboratories participated in the study (LC-MS/MS, n = 15; LC-UV; n = 9; LC-FL, n = 1; bioassay, n = 2). In round 1, for nominal concentrations of 1000, 1700, 2500, and 4000 ng/mL, the mean (SD) determined concentrations were 1007 (183), 1710 (323), 2528 (540), and 3898 (842) ng/mL, respectively. In round 2, for nominal concentrations of 1200, 1800, 2400, and 4000 ng/mL, the mean (SD) determined concentrations were 1411 (303), 2111 (409), 2789 (511), and 4723 (798) ng/mL, respectively. Over both rounds, determined concentrations were consistently within 15% of the nominal concentrations for 10 laboratories (LC-MS/MS, n = 4; LC-UV, n = 5; bioassay, n = 1) and consistently exceeded the upper 15% margin for 7 laboratories (LC-MS/MS and LC-UV, n = 3 each; LC-FL, n = 1).

Conclusions:
Alignment of methodologies among laboratories may be warranted to improve the accuracy and reproducibility of therapeutic drug measurements.
Simultaneous Quantification of Free Adalimumab and Infliximab in Human Plasma Using a Target-Based Sample Purification and Liquid Chromatography–Tandem Mass Spectrometry
Authors: El Amrani Mohsin , Bosman Sabine M. , Egas Annelies C. , Hack C. Erik , Huitema Alwin D. R. , van Maarseveen Erik M. 
Published: April 2019

Background:
Therapeutic drug monitoring of tumor necrosis factor alpha (TNF-α) inhibitors such as adalimumab (ADM) and infliximab (IFX) is considered of added value for patients with systemic inflammatory diseases. In contrast to enzyme-linked immunosorbent assay methods, liquid chromatography–tandem mass spectrometry methods allow for simultaneous quantification of multiple target antibodies in 1 run and thus providing a higher sample throughput. We describe a fast sample work-up strategy for the absolute and simultaneous quantification of ADM and IFX therapeutic monoclonal antibodies in human plasma samples using a target-specific sample purification in combination with liquid chromatography–tandem mass spectrometry.

Methods:
The sample purification was based on the selective capture of ADM and IFX in human plasma or serum using biotinylated TNF-α (b-TNF-α), which was coated on a streptavidin 96-well plate. After elution, analytes were heat denatured and trypsin digested to obtain signature peptides for quantification. Stable isotopically labeled ADM and IFX were introduced as internal standard before sample purification.

Results:
The method was successfully validated following current European medicines agency guidelines. The linear dynamic rage for both analytes were 1–32 mcg/mL with an excellent mean coefficient of determination, R2 = 0.9994 for ADM and 0.9996 for IFX. Within-run and between-run imprecision and accuracy were within acceptance criteria. Cross-validation against enzyme-linked immunosorbent assay method showed a high between-method correlation R2 = 0.962 for ADM and R2 = 0.982 for IFX.

Conclusions:
This method provides an easy, efficient, and cost-effective workflow for therapeutic drug monitoring patients treated with ADM or IFX.
Impact of Cachexia and Opioid Analgesic Cotreatment on Pregabalin Pharmacokinetics and Central Nervous System Symptoms in Cancer Patients
Authors: Yoshikawa Nozomi , Naito Takafumi , Yagi Tatsuya , Kawakami Junichi 
Published: April 2019

Background:
Patients with cancer receiving pregabalin potentially have a high incidence of central nervous system (CNS) symptoms. The purpose of this study was to explore clinical factors influencing the incidence of CNS symptoms, including plasma pregabalin exposure, cancer cachexia, and opioid analgesic cotreatment.

Methods:
Sixty-eight patients with cancer receiving twice-daily pregabalin were enrolled. Plasma concentrations of pregabalin, clinical laboratory data, opioid analgesic cotreatment, and the Glasgow Prognostic Score, which is an inflammation-based cachexia score, were considered as clinical factors. The incidence of CNS symptoms was collected from the patients' medical records. The predose plasma concentrations of pregabalin at steady state were determined by ultra-high-performance liquid chromatography.

Results:
The steady-state trough plasma pregabalin concentrations showed a large variability with an interquartile range of 0.43–1.2 mg/L per mg/kg and were negatively correlated with an estimated glomerular filtration rate (eGFR). C-reactive protein (standardized partial regression coefficient, β = 0.31) and opioid analgesic cotreatment (β = 0.24) were also identified in addition to eGFR (β = −0.60) in the multiple regression analysis. The incidence of CNS symptoms was significantly increased with opioid analgesic cotreatment and a higher Glasgow Prognostic Score but not with the absolute value of plasma pregabalin concentrations, eGFR, or other clinical laboratory data.

Conclusions:
In patients with cancer, steady-state trough plasma pregabalin concentrations were altered with renal function, systemic inflammation, and opioid analgesic cotreatment. However, a higher incidence of CNS symptoms observed in patients with cancer on pregabalin was more related to cachexia and opioid analgesic cotreatment than to altered pregabalin concentrations.
Multiple Facets of the Poisson Distribution Applicable to Health Physics Measurements
Authors: Justus Alan L. 
Published: April 2019

Abstract
This paper discusses several ways to view the standard Poisson distribution as applied to health physics scaler counts. The intent is not so much to present calculational details but rather to present some underlying concepts. Examples are provided that illustrate the various concepts for several types of specific measurements. The concepts presented involve purely Poisson-based contributions to variance; extra-Poisson variance is presently ignored, and any counting system would be presumed to function properly and without counting loss.
Design of a Do-It-Yourself Geiger-Muller Counter With Smartphone Mapping Application
Authors: Xiao Jeffery B. , Seekamp James M. , Chung Long Kiu , El-Amir Issa N. , Schiefer Kai C. , Trimas David J. , Tuey Regina , Kearfott Kimberlee J. 
Published: April 2019

Abstract
Legacy Geiger-Muller (GM) survey meters recovered from fallout shelters have been used by several nuclear scientific societies as part of high school outreach programs. A donated antique instrument helps teachers demonstrate radiological principles, but fails to develop student's electronics skills, generate excitement for nuclear careers, or provide individuals with their own devices to explore the radioactive planet. A simple, affordable GM survey meter built by each student would increase direct engagement while providing hands-on experience with circuit-building, soldering, and computer programming. The inclusion of an affordable single-board computer as a component in the survey meter would enable students to tackle more various computer science and electronics projects, thereby potentially recruiting more students into technology and engineering. This paper details the challenges faced by an interdisciplinary undergraduate team designing an easy-to-assemble smart GM survey meter. Their iterative research, design, and testing process included modification to a basic circuit to enable use of different tube types, component cost reduction, application development, and data communication. The ultimate product of the team's efforts, a survey meter with affordable components and a smartphone application capable of creating radiation maps, is detailed in full.
Towards a New Concept of Low Dose
Authors: Mothersill Carmel , Rusin Andrej , Seymour Colin 
Published: April 2019

Abstract
When people discuss the risks associated with low doses of ionizing radiation, central to the discussion is the definition of a low dose and the nature of harm. Standard answers such as “doses below 0.1 Gy are low” or “cancer is the most sensitive measure of harm” obscure the complexity within these seemingly simple questions. This paper will discuss some of the complex issues involved in determining risks to human and nonhuman species from low-dose exposures. Central to this discussion will be the role of communicable responses to all stressors (often referred to as bystander responses), which include recently discovered epigenetic and nontargeted mechanisms. There is a growing consensus that low-dose exposure to radiation is but one of many stressors to impact populations. Many of these stressors trigger responses that are generic and not unique to radiation. The lack of a unique radiation signature makes absolute definition of radiation risk difficult. This paper examines a possible new way of defining low dose based on the systemic response to the radiation. Many factors will influence this systemic response and, because it is inherently variable, it is difficult to predict and so makes low-dose responses very uncertain. Rather than seeking to reduce uncertainty, it might be valuable to accept the variability in outcomes, which arise from the complexity and multifactorial nature of responses to stressors.
A Monte Carlo t Test to Evaluate Mesothelioma and Radiation in the US Transuranium and Uranium Registries
Authors: Zhou Joey Y. , McComish Stacey L. , Tolmachev Sergei Y. 
Published: April 2019

Abstract
A cluster of nine mesothelioma cases was observed among 341 registrants’ deaths in the US Transuranium and Uranium Registries. Descriptive analysis showed that mesothelioma cases had the highest average cumulative external radiation dose compared with lung cancer, other cancer, and noncancer deaths. Further analysis indicated that the mesothelioma cluster was very different demographically from lung cancer, other cancer, and noncancer deaths. Therefore, an internally matched case-control approach was applied to evaluate the differences in an average cumulative external radiation dose between mesothelioma deaths and other causes of death. A Monte Carlo t test was used to examine the statistical significance of the differences. The results showed that there were no significant statistical differences in an average cumulative external radiation dose between mesothelioma and lung cancer, other cancers, or noncancers for the internally matched cases and controls.
SARILUMAB FOR RECALCITRANT CYSTOID MACULAR EDEMA IN NON-PARANEOPLASTIC AUTOIMMUNE RETINOPATHY
Authors: Grewal Dilraj S. , Jaffe Glenn J. , Keenan Robert T. 
Published: April 2019

Purpose:
To demonstrate a rapid improvement of recalcitrant cystoid macular edema (CME) and perivascular leakage, in a patient with non-paraneoplastic autoimmune retinopathy and autoimmune optic neuropathy after treatment with sarilumab, a human anti-interleukin-6 (IL-6) receptor antibody.

Methods:
Observational case report.

Results:
A 29-year-old woman was diagnosed with non-paraneoplastic autoimmune retinopathy and autoimmune optic neuropathy and followed over 1.5 years. She had recalcitrant CME despite local corticosteroid and immunosuppressive therapy that included azathioprine and adalimumab. Subcutaneous sarilumab was initiated at a dose of 200 mg every 2 weeks. Cystoid macular edema significantly decreased after two injections and resolved after four injections with associated improvement in visual acuity and significant improvement in perivascular leakage on fluorescein angiography. There was a sustained visual and anatomical improvement at 6 months along with mild improvement in electroretinogram responses. The patient tolerated the medication with no side effects.

Conclusion:
Management of CME in non-paraneoplastic autoimmune retinopathy is challenging, and long-term immunosuppression is often employed with varying degrees of success. The improvement in refractory CME and perivascular leakage in this case supports the potential role of an IL-6 inhibitor to treat CME associated with non-paraneoplastic autoimmune retinopathy suggesting the role.