bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Biomarkers of Insulin and the Insulin-like Growth Factor Axis, and Risk of Colorectal Adenoma and Serrated Polyp
Authors: Hang Dong , He Xiaosheng , Kværner Ane Sørlie , Chan Andrew T , Wu Kana , Ogino Shuji , Hu Zhibin , Shen Hongbing , Pollak Michael N , Giovannucci Edward L , Song Mingyang
Published: August 2019

Background

Hyperinsulinemia, high insulin-like growth factor 1 (IGF1) levels, and low IGF binding protein 1 (IGFBP1) levels have been implicated in the relationship between obesity and increased risk of colorectal cancer (CRC). However, it remains inconclusive whether circulating biomarkers of insulin and the IGF axis are associated with conventional adenoma and serrated polyp, the two distinct groups of CRC precursors.

Methods

We prospectively examined the associations of plasma C-peptide, IGF1, IGFBP1, IGFBP3, and IGF1 to IGFBP3 ratio with conventional adenoma and serrated polyp among 11 072 women from the Nurses’ Health Studies. Multivariable logistic regression was used to calculate the odds ratio (OR) per 1-SD increase in each biomarker for overall risk of conventional adenoma and serrated polyp and according to polyp feature.

Results

During 20 years of follow-up, we documented 1234 conventional adenomas and 914 serrated polyps. After adjusting for various lifestyle factors (including body mass index), higher concentrations of IGFBP1 were associated with lower risk of serrated polyp (OR = 0.84, 95% confidence interval = 0.75 to 0.95, P = .005). The association was particularly strong for large serrated polyp (≥10 mm) located in the distal colon and rectum (OR = 0.59, 95% confidence interval = 0.39 to 0.87, P = .01). In contrast, we did not find any statistically significant association between the biomarkers and conventional adenoma.

Conclusions

A higher plasma level of IGFBP1 was associated with lower risk of serrated polyp. Our findings support a potential role of IGFBP1 in the serrated pathway of CRC in women.
Access to Clinical Trials for Adolescents and Young Adults With Cancer: A Meta-Research Analysis
Authors: de Rojas Teresa , Neven Anouk , Terada Mitsumi , García-Abós Miriam , Moreno Lucas , Gaspar Nathalie , Péron Julien
Published: August 2019

Background

The 18-year-old age limit for inclusion in clinical trials constitutes a hurdle for adolescents and young adults (AYAs) with cancer. We analyzed the impact of this age barrier on the access of AYAs to cancer trials and novel therapies.

Methods

ClinicalTrials.gov was searched to identify all the trials including patients with 10 malignancies relevant for AYAs (January 2007 to July 2018). The trials were categorized as pediatric (patients <18 y), adult (≥18 y), and transitional (including adult and pediatric patients). Transitional trials with a lower limit between 12 and 18 years and an upper limit younger than 40 years were considered AYA-specific.

Results

Of 2764 identified trials, 2176 were included: 79% adult, 19% transitional, 2% pediatric. Five trials were AYA-specific. The proportion of academic trials was higher for transitional (69%; 288 of 421) than for adult trials (48%; 832 of 1718) (P < .0001). The total number of new trials increased over the years (156 in 2007; 228 in 2017); however, the number of transitional trials remained stable. The availability of trials increased with age, with a major increase at age 18 years: at age 17 years, 20% (442 of 2176) of trials were potentially accessible vs 95% (2075 of 2176) at 18 years. For trials investigating targeted therapies, this increase was 460% (197 trials available at age 17 years; 901 at 18 years) and for immunotherapies, 1200% (55 at age 17 years; 658 at 18 years).

Conclusions

AYAs have limited access to cancer trials and innovative therapies, with no improvement over the last decade. The 18-years-old age limit continues to be a major hurdle. Our findings are consistent with the internationally supported idea that age inclusion criteria in oncological trials should be changed.
Assessing Clinical Equivalence in Oncology Biosimilar Trials With Time-to-Event Outcomes
Authors: Uno Hajime , Schrag Deborah , Kim Dae Hyun , Tang Dejun , Tian Lu , Rugo Hope S , Wei Lee-Jen
Published: August 2019

A typical biosimilar study in oncology uses the overall response evaluated at a specific time point as the primary endpoint, which is generally acceptable regulatorily, to assess clinical equivalence between a biosimilar and its reference product. The standard primary endpoint for evaluating an anticancer therapy, progression-free or overall survival would be a secondary endpoint in a biosimilar trial. With a conventional analytic procedure via, for example, hazard ratio to quantify the group difference, it is difficult and challenging to assess clinical equivalence with respect to progression-free or overall survival because the study generally has a limited number of clinical events observed in the study. In this article, we show that an alternative procedure based on the restricted mean survival time, which has been discussed extensively for design and analysis of a general equivalence study, is readily applicable to a biosimilar trial. Unlike the hazard ratio, this procedure provides a clinically interpretable estimate for assessing equivalence. Using the restricted mean survival time as a summary measure of the survival curve will enhance better treatment decision making in adopting a biosimilar product over the reference product.
Is Health Insurance Literacy Associated With Financial Hardship Among Cancer Survivors? Findings From a National Sample in the United States
Authors: Zhao Jingxuan , Han Xuesong , Zheng Zhiyuan , Banegas Matthew P , Ekwueme Donatus U , Yabroff K Robin
Published: August 2019

Little is known about the association between health insurance literacy and financial hardship among cancer survivors. Using the 2016 Medical Expenditure Panel Survey Experiences with Cancer self-administered questionnaire, we evaluated the associations between health insurance literacy and medical financial hardship and nonmedical financial sacrifices among adult cancer survivors in the United States. Of the survivors, 18.9% aged 18–64 years and 14.6% aged 65 years and older reported health insurance literacy problems. In both age groups (18–64 and ≥65 years), from multivariable logistic regressions, survivors with health insurance literacy problems were more likely to report any material (adjusted odds ratio [AOR] = 3.02, 95% confidence interval [CI] = 1.53 to 5.96; AOR = 3.33, 95% CI = 1.69 to 6.57, respectively) or psychological (AOR = 5.53, 95% CI = 2.35 to 13.01; AOR = 8.79, 95% CI = 4.55 to 16.97, respectively) hardship, as well as all types of nonmedical financial sacrifices than those without these problems. Future longitudinal studies are warranted to test causality and assess whether improving health insurance literacy can mitigate financial hardship.
PTHrP, A Biomarker for CNS Metastasis in Triple-Negative Breast Cancer and Selection for Adjuvant Chemotherapy in Node-Negative Disease
Authors: Assaker Gloria , Camirand Anne , Abdulkarim Bassam , Omeroglu Atilla , Deschenes Jean , Joseph Kurian , Noman Abu Shadat Mohammod , Ramana Kumar Agnihotram V , Kremer Richard , Sabri Siham
Published: August 2019

Background

Triple-negative breast cancer (TNBC) is characterized by poor prognosis and lack of targeted therapies and biomarkers to guide decisions on adjuvant chemotherapy. Parathyroid hormone-related protein (PTHrP) is frequently overexpressed in breast cancer and involved in proliferation and metastasis, two hallmarks of poor prognosis for node-negative breast cancer. We investigated the prognostic value of PTHrP with respect to organ-specific metastasis and nodal status in TNBC.

Methods

We assessed PTHrP expression using immunohistochemistry in a clinically annotated tissue microarray for a population-based study of 314 patients newly diagnosed with TNBC, then analyzed its correlation to progression and survival using Kaplan-Meier and Cox regression analyses. The Cancer Genome Atlas (TCGA) validation analysis was performed through Bioconductor. All statistical tests were two-sided.

Results

PTHrP overexpression (160 of 290 scorable cases, 55.2%) was statistically significantly associated in univariate analysis with decreased overall survival (OS) in our cohort (P = .0055) and The Cancer Genome Atlas (P = .0018) and decreased central nervous system (CNS)-progression-free survival (P = .0029). In multivariate analysis, PTHrP was a statistically significant independent prognostic factor for CNS-progression-free survival in TNBC (hazard ratio [HR] = 5.014, 95% confidence interval [CI] = 1.421 to 17.692, P = .0122) and for OS selectively in node-negative TNBC (HR = 2.423, 95% CI = 1.129 to 5.197, P = .0231). Strikingly, PTHrP emerged as the only statistically significant prognostic factor (HR = 2.576, 95% CI = 1.019 to 6.513, P = .0456) for OS of low-clinical risk node-negative patients who did not receive adjuvant chemotherapy.

Conclusions

PTHrP is a novel independent prognostic factor for CNS metastasis and adjuvant chemotherapy selection of low-clinical risk node-negative TNBC. Its predictive value needs to be prospectively assessed in clinical trials.
Neonatal Toxic Shock Syndrome–Like Exanthematous Disease in North America
Authors: Freeman Megan Culler , Mitchell Stephanie , Ibrahim John , Williams John V
Published: August 2019

Neonatal toxic shock syndrome (TSS)-like exanthematous disease (NTED) is a syndrome first reported in Japan. Neonates develop systemic exanthema, thrombocytopenia, and fever usually during the first week of life. The disease is distinguished from frank TSS because affected infants are not severely ill and do not meet TSS criteria. Most infants are confirmed to be colonized with TSST-1 producing strains of S. aureus. Suggested diagnostic criteria for NTED include a skin rash with generalized macular erythema and one of the following symptoms: fever >38.0°C, thrombocytopenia <150 x103uL, or low positive C-reactive protein (1-5 mg/dL) in the absence of another known disease process. NTED is common in Japanese NICUs, but outside Japan, only one case has been reported in France. We describe the first case of NTED reported in North America.
Limiting Vancomycin Exposure in Pediatric Oncology Patients With Febrile Neutropenia May Be Associated With Decreased Vancomycin-Resistant Enterococcus Incidence
Authors: Karandikar Manjiree V , Milliren Carly E , Zaboulian Robin , Peiris Poornima , Sharma Tanvi , Place Andrew E , Sandora Thomas J
Published: August 2019

Background

Limited data exists regarding the effects of empiric antibiotic use in pediatric oncology patients with febrile neutropenia (FN) on the development of antibiotic resistance. We evaluated the impact of a change in our empiric FN guideline limiting vancomycin exposure on the development of vancomycin-resistant Enterococcus in pediatric oncology patients.

Methods

Retrospective, quasi-experimental, single-center study using interrupted timeseries analysis in oncology patients aged ≤18 years with at least 1 admission for FN between 2009 and 2015. Risk strata incorporated diagnosis, chemotherapy phase, Down syndrome, septic shock, and typhlitis. Microbiologic data and inpatient antibiotic use were obtained by chart review. Segmented Poisson regression was used to compare VRE incidence and antibiotic days of therapy (DOT) before and after the intervention.

Results

We identified 285 patients with 697 FN episodes pre-intervention and 309 patients with 691 FN episodes postintervention. The proportion of high-risk episodes was similar in both periods (49% vs 48%). Empiric vancomycin DOT/1000 FN days decreased from 315 pre-intervention to 164 post-intervention (P < .01) in high-risk episodes and from 199 to 115 in standard risk episodes (P < .01). Incidence of VRE/1000 patient-days decreased significantly from 2.53 pre-intervention to 0.90 post-intervention (incidence rate ratio, 0.14; 95% confidence interval, 0.04–0.47; P = .002).

Conclusions

A FN guideline limiting empiric vancomycin exposure was associated with a decreased incidence of VRE among pediatric oncology patients. Antimicrobial stewardship interventions are feasible in immunocompromised patients and can impact antibiotic resistance.
The End of Sodomy: Law, Prosecution Patterns, and the Evanescent Will to Knowledge in Belgium, France, and the Netherlands, 1770–1830
Authors: Hofman Elwin
Published: August 2019

This article analyses discourses concerning male same-sex sexuality produced in the context of law and policing in Belgium, France, and the Netherlands between 1770 and 1830. Intervening in the debate over the making of “the homosexual” and the change from homosexual “acts” to “identities,” I argue that shifts in sexual discourses were not linear. In the late eighteenth century, the courts and the police displayed a strong “will to knowledge” in same-sex sexual matters, collecting, requesting, and recording discourses on inclination and, in some regions, even innateness. This will to knowledge all but disappeared in the early nineteenth century, when in the aftermath of the official decriminalization of sodomy, same-sex sexual acts became mostly devoid of further meaning in legal and police records. The emergence of sexual discourses was therefore uneven.
Access to the Trade: Monopoly and Mobility in European Craft Guilds in the Seventeenth and Eighteenth Centuries
Authors: Prak Maarten , Crowston Clare Haru , De Munck Bert , Kissane Christopher , Minns Chris , Schalk Ruben , Wallis Patrick
Published: August 2019

One of the standard objections against guilds in the premodern world has been their exclusiveness. Guilds have been portrayed as providing unfair advantages to the children of established masters and locals, over immigrants and other outsiders. Privileged access to certain professions and industries is seen as a source of inequality and a disincentive for technological progress. In this paper, we examine this assumption by studying the composition of guild masters and apprentices from a large sample of European towns and cities from 1600 to 1800, focusing on the share who were children of masters or locals. These data offer an indirect measurement of the strength of guild barriers and, by implication, of their monopolies. We find very wide variation between guilds in practice, but most guild masters and apprentices were immigrants or unrelated locals: openness was much more common than closure, especially in larger centers. Our understanding of guild “monopolies” and exclusivity is in need of serious revision.
To “Labour with a Greater Sense of Safety”: First Aid, Civic Duty, and Risk Management in the British Working Class, 1870–1914
Authors: Isaac Esther , Bajramovic Alisa , Miller Isabel , Pan Chelsea , Ratté Emily , Vicente Kliot Anton
Published: August 2019

Much has been written about British ideals of citizenship in the face of heightened social discord, particularly in times of war. There is a lack of analysis, however, relating notions of civic duty to the risks faced by British people in their everyday lives. Further, most scholarship on civic duty as it relates to the perception and management of risk focuses on the twentieth century and, in particular, the World Wars. This article seeks to examine civic participation in an earlier time period—from 1870 to 1914—through the lens of the civilian first-aid movement. We argue that first aid presented working-class men with a way to manage novel forms of risk introduced by new and dangerous technologies in the workplace and in their daily lives. Applying first-aid training provided these men with a way to participate in a burgeoning working-class culture of self-reliance, altruism, and civic duty. This article contributes to the discussion surrounding expressions of citizenship in the civilian realm and presents a new perspective on the significance of the British first-aid movement.
The First Peronists: Indigenous Leaders, Populism, and the Argentine Nation-State
Authors: Mathias Christine
Published: August 2019

This article examines indigenous contributions to nation-state formation in Argentina during the first and second presidencies of Juan Perón (1946–55). Perón recognized indigenous people as Argentine citizens and attempted to reorganize the state institutions responsible for their welfare, but he did not institute special policies to improve their dismal living conditions. Moreover, state agents continued to use violence against indigenous communities, sometimes with terrifying results. Nonetheless, many indigenous leaders, known as caciques, embraced both the rhetoric of Peronism and the principles of populism. Their political engagement had mixed results, but its symbolic impact was profound. Peronist caciques made national politics relevant to indigenous communities, expanded their horizons of possibility, and helped to integrate them into the Argentine nation-state. Focusing on such understudied intermediaries helps explain populism’s enduring, paradoxical appeal in the Argentine interior.
A bayesian-like approach to derive chemical abundances in type-2 active galactic nuclei based on photoionization models
Authors: Pérez-Montero E , Dors O L , Vílchez J M , García-Benito R , Cardaci M V , Hägele G F
Published: August 2019

We present a new methodology for the analysis of the emission lines of the interstellar medium in the narrow-line regions around type-2 active galactic nuclei. Our aim is to provide a recipe that can be used for large samples of objects in a consistent way using different sets of optical emission lines that takes into the account possible variations from the O/H–N/O relation to use [N ii] lines. Our approach consists of a bayesian-like comparison between certain observed emission-line ratios sensitive to total oxygen abundance, nitrogen-to-oxygen ratio, and ionization parameter with the predictions from a large grid of photoionization models calculated under the most usual conditions in this environment. We applied our method to a sample of Seyfert 2 galaxies with optical emission-line fluxes and determinations of their chemical properties from detailed models in the literature. Our results agree within the errors with other results and confirm the high metallicity of the objects of the sample, with N/O values consistent with a large secondary production of N, but with a large dispersion. The obtained ionization parameters for this sample are much larger than those for star-forming object at the same metallicity.
Dusty clumps in circumbinary discs
Authors: Poblete Pedro P , Cuello Nicolás , Cuadra Jorge
Published: August 2019

Recent observations have revealed that protoplanetary discs often exhibit cavities and azimuthal asymmetries such as dust traps and clumps. The presence of a stellar binary system in the inner disc regions has been proposed to explain the formation of these structures. Here, we study the dust and gas dynamics in circumbinary discs around eccentric and inclined binaries. This is done through two-fluid simulations of circumbinary discs, considering different values of the binary eccentricity and inclination. We find that two kinds of dust structures can form in the disc: a single horseshoe-shaped clump, on top of a similar gaseous over-density; or numerous clumps, distributed along the inner disc rim. The latter features form through the complex interplay between the dust particles and the gaseous spirals caused by the binary. All these clumps survive between one and several tens of orbital periods at the feature location. We show that their evolution strongly depends on the gas–dust coupling and the binary parameters. Interestingly, these asymmetric features could in principle be used to infer or constrain the orbital parameters of a stellar companion – potentially unseen – inside the inner disc cavity. Finally, we apply our findings to the disc around AB Aurigae.
Kinematic signatures of cluster formation from cool collapse in the Lagoon Nebula cluster NGC 6530
Authors: Wright Nicholas J , Parker Richard J
Published: August 2019

We examine the mass dependence of the velocity dispersion of stars in the young cluster NGC 6530 to better understand how it formed. Using a large sample of members we find that the proper motion velocity dispersion increases with stellar mass. While this trend is the opposite of that predicted if the cluster were developing energy equipartition, it is in agreement with recent N-body simulations that find such a trend develops because of the Spitzer instability. In these simulations the massive stars sink to the centre of the cluster and form a self-gravitating system with a higher velocity dispersion. If the cluster has formed by the cool collapse of an initially substructured distribution, then this occurs within 1–2 Myr, in agreement with our observations of NGC 6530. We therefore conclude that NGC 6530 formed from much more extended initial conditions and has since collapsed to form the cluster we see now. This cluster formation model is inconsistent with the idea that all stars form in dense, compact clusters and provides the first dynamical evidence that star clusters can form by hierarchical mergers between subclusters.
Tachyglossus aculeatus (Monotremata: Tachyglossidae)
Authors: Rismiller Peggy D , Grutzner Frank
Published: August 2019

Tachyglossus aculeatus (Shaw, 1792) is a monotreme commonly called the short-beaked echidna. Although considered Australia’s most common native mammal because of its continent-wide distribution, its population numbers everywhere are low. It is easily distinguished from all other native Australian mammals because of its spine-covered body, hairless beak, and unique “rolling” gait. The five subspecies, one of which is found in Papua New Guinea, show variations in fur density, spine diameter, length, and number of grooming claws. The Kangaroo Island short-beaked echidna Tachyglossus aculeatus multiaculeatus is listed as “Endangered” but all other Tachyglossus are listed as “Least Concern” in the 2016 International Union for Conservation of Nature and Natural Resources Red List.
Polymerase synthesis of four-base DNA from two stable dimeric nucleotides
Authors: Mohsen Michael G , Ji Debin , Kool Eric T
Published: August 2019

We document the preparation and properties of dimerized pentaphosphate-bridged deoxynucleotides (dicaptides) that contain reactive components of two different nucleotides simultaneously. Importantly, dicaptides are found to be considerably more stable to hydrolysis than standard dNTPs. Steady-state kinetics studies show that the dimers exhibit reasonably good efficiency with the Klenow fragment of DNA polymerase I, and we identify thermostable enzymes that process them efficiently at high temperature. Experiments show that the dAp5dT dimer successfully acts as a combination of dATP and dTTP in primer extension reactions, and the dGp5dC dimer as a combination of dGTP and dCTP. The two dimers in combination promote successful 4-base primer extension. The final byproduct of the reaction, triphosphate, is shown to be less inhibitory to primer extension than pyrophosphate, the canonical byproduct. Finally, we document PCR amplification of DNA with two dimeric nucleotides, and show that the dimers can promote amplification under extended conditions when PCR with normal dNTPs fails. These dimeric nucleotides represent a novel and simple approach for increasing stability of nucleotides and avoiding inhibition from pyrophosphate.
Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas
Authors: Surun Aurore , Varlet Pascale , Brugières Laurence , Lacour Brigitte , Faure-Conter Cécile , Leblond Pierre , Bertozzi-Salomon Anne-Isabelle , Berger Claire , André Nicolas , Sariban Eric , Raimbault Sandra , Prieur Fabienne , Desseigne Françoise , Zattara Hélène , Guimbaud Rosine , Polivka Marc , Delisle Marie-Bernadette , Vasiljevic Alexandre , Maurage Claude-Alain , Figarella-Branger Dominique , Coulet Florence , Guerrini-Rousseau Léa , Alapetite Claire , Dufour Christelle , Colas Chrystelle , Doz François , Bourdeaut Franck
Published: August 2019

Background

Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description.

Methods

We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae.

Results

Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1–28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series.

Conclusions

Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.
Potential role of strike-slip faults in opening up the South China Sea
Authors: Huang Chi-Yue , Wang Pinxian , Yu Mengming , You Chen-Feng , Liu Char-Shine , Zhao Xixi , Shao Lei , Zhong Guangfa , Yumul Graciano P
Published: August 2019

Radiometric dates of key rock units indicate that a remnant Late Mesozoic ocean of the Huatung Basin is still preserved today east of the South China Sea (SCS). We integrate regional geology with a Cretaceous oceanic basement in the vicinity of the Huatung Basin to reconstruct the Huatung Plate east of the Eurasian continent. Results of geophysical investigations, four expeditions of deep-sea drilling and a renaissance of regional geology allow us to propose a hypothesis that the mechanism responsible for the SCS opening was raised from strike-slip fault on the east. The hypothesis suggests that the SCS opening could highly relate to the strike-slip faults inherited from Late Mesozoic structures onshore–offshore the SE Cathaysia Block to develop rhombic-shaped extensional basins en echelon on the thinned Eurasian continental crust in the Early Cenozoic. It was followed by sinistral strike-slip movements along the boundary between the Eurasian Plate and the Huatung Plate driven by oblique subduction of the Huatung Plate to the northwest coupled with slab-pull force by southward subduction of the Proto-SCS to open up the triangle-shaped oceanic East Sub-basin in the Early Oligocene (33/34 Ma). The spreading ridge then propagated southwestward in the step-over segment between the Zhongnan-Lile and the Red River strike-slip fault systems to open the triangle-shaped oceanic Southwest Sub-basin by 23 Ma. The plate boundary fault was subsequently converted into the Manila Trench when the Eocene Sierra Madre arc of the Huatung Plate had moved from the south to its present latitude by the Middle Miocene.
Postsynthetic functionalization of covalent organic frameworks
Authors: Yusran Yusran , Guan Xinyu , Li Hui , Fang Qianrong , Qiu Shilun
Published: August 2019

Covalent organic frameworks (COFs) have been at the forefront of porous-material research in recent years. With predictable structural compositions and controllable functionalities, the structures and properties of COFs could be controlled to achieve targeted materials. On the other hand, the predesigned structure of COFs allows fruitful postsynthetic modifications to introduce new properties and functions. In this review, the postsynthetic functionalizations of COFs are discussed and their impacts towards structural qualities and performances are comparatively elaborated on. The functionalization involves the formation of specific interactions (covalent or coordination/ionic bonds) and chemical reactions (oxidation/reduction reaction) with pendant groups, skeleton and reactive linkages of COFs. The chemical stability and performance of COFs including catalytic activity, storage, sorption and opto-electronic properties might be enhanced by specific postsynthetic functionalization. The generality of these strategies in terms of chemical reactions and the range of suitable COFs places them as a pivotal role for the development of COF-based smart materials.
Effects of 6-Week Use of Very Low Nicotine Content Cigarettes in Smokers With Serious Mental Illness
Authors: Tidey Jennifer W , Colby Suzanne M , Denlinger-Apte Rachel L , Goodwin Christine , Cioe Patricia A , Cassidy Rachel N , Swift Robert M , Lindgren Bruce R , Rubin Nathan , Murphy Sharon E , Hecht Stephen S , Hatsukami Dorothy K , Donny Eric C
Published: August 2019

Introduction

The US Food and Drug Administration is considering implementing a reduced-nicotine standard for cigarettes. Given the high rate of smoking among people with serious mental illness (SMI), it is important to examine the responses of these smokers to very low nicotine content (VLNC) cigarettes.

Methods

This trial compared the effects of VLNC (0.4 mg nicotine/g tobacco) and normal nicotine content cigarettes (15.8 mg/g) over a 6-week period in non-treatment-seeking smokers with schizophrenia, schizoaffective disorder, or bipolar disorder (n = 58). Linear regression was used to examine the effects of cigarette condition on cigarettes per day, subjective responses, nicotine and tobacco toxicant exposure, craving, withdrawal symptoms, and psychiatric symptoms.

Results

At week 6, participants in the VLNC condition smoked fewer cigarettes per day, had lower breath carbon monoxide levels, lower craving scores, and rated their study cigarettes lower in satisfaction, reward, enjoyment, and craving reduction than those in the normal nicotine content condition (ps < .05). Week 6 psychiatric and extrapyramidal symptoms did not differ by condition, except for scores on a measure of parkinsonism, which were lower in the VLNC condition (p < .05). There were no differences across conditions on total nicotine exposure, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, withdrawal symptoms, or responses to abstinence.

Conclusions

These results suggest that a reduced-nicotine standard for cigarettes would reduce smoking among smokers with SMI. However, the lack of effect on total nicotine exposure indicates VLNC noncompliance, suggesting that smokers with SMI may respond to a reduced-nicotine standard by substituting alternative forms of nicotine.

Implications

Results from this trial suggest that a reduced-nicotine standard for cigarettes would reduce smoking rates and smoke exposure in smokers with SMI, without increasing psychiatric symptoms. However, noncompliance with VLNC cigarettes was observed, suggesting that these smokers might respond to a reduced-nicotine standard by substituting alternative forms of nicotine.
Examining Age as a Potential Moderator of Response to Reduced Nicotine Content Cigarettes in Vulnerable Populations
Authors: Davis Danielle R , Parker Maria A , Villanti Andrea C , Streck Joanna M , Priest Jeff S , Tidey Jennifer W , Gaalema Diann E , Sigmon Stacey C , Heil Sarah H , Higgins Stephen T
Published: August 2019

Introduction

Young adults (aged 18–24 years) have a higher smoking prevalence than younger and older age groups and young adulthood is an important developmental period during which long-term behavior patterns like cigarette smoking are established. The aim of the current study was to examine how young adult smokers with additional vulnerabilities to smoking respond to reduced nicotine content cigarettes.

Methods

This is a secondary analysis of a double-blind, within-subject experiment conducted with 169 cigarette smokers recruited from populations with comorbid psychiatric conditions or socioeconomic disadvantage assessing acute effects of research cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg/g). Participants were dichotomized by chronological age (18–24 vs. ≥25 years). Across 14 laboratory sessions effects of nicotine content were examined on measures of relative reinforcing efficacy (Cigarette Purchase Task [CPT] and Concurrent Choice testing), subjective effects, craving/withdrawal, and smoking topography. Repeated measures analysis of variances were used to examine potential moderating effects of age.

Results

Young adults exhibited lower demand for reduced nicotine content cigarettes than older adults across three of five CPT indices (ps < .05). No differences by age were observed on other measures of reinforcing efficacy, subjective effects, craving/withdrawal, or smoking topography where effects generally decreased as an orderly function of decreasing nicotine content (ps <.05).

Conclusion

Overall, these findings suggest that reducing the nicotine content of cigarettes would decrease the addiction potential of cigarette smoking in young adult smokers as much or perhaps more than older adult smokers from populations at increased vulnerability to smoking, addiction, and smoking-related health consequences.

Implications

Reducing the nicotine content in cigarettes to lower addiction potential of smoking has been proposed as a means to improve overall population health. It is imperative to examine how young adults may respond to a nicotine reduction policy. We saw minimal evidence that age moderates acute response and where there was evidence it was in the direction of reduced nicotine content cigarettes having less addictive potential among young versus older adults (eg, steeper decreases in demand for very low nicotine content cigarettes among young versus older adults). Overall, a nicotine reduction policy has the potential to reduce smoking across age groups.
Increasing Quit Attempts by Transitioning to Very Low Nicotine Content Cigarettes Versus Reducing Number of Cigarettes Per Day: A Secondary Analysis of an Exploratory Randomized Trial
Authors: Klemperer Elias M , Hughes John R , Callas Peter W
Published: August 2019

Introduction

The Food and Drug Administration (FDA) has proposed reducing nicotine with very low nicotine content (VLNC) cigarettes. In contrast, reducing nicotine by reducing number of cigarettes per day (CPD) is common. Our prior findings demonstrate that VLNC cigarettes decreased dependence more and were more acceptable than reducing CPD. This secondary analysis explored which reduction strategy increased quit attempts (QA), self-efficacy, or intention to quit more.

Methods

This is a secondary analysis of 68 adult daily smokers not ready to quit randomized to smoke VLNC cigarettes versus reduce CPD over 5 weeks. All participants smoked study cigarettes with nicotine yield similar to most commercial cigarettes ad lib for 1 week (baseline). Participants were then randomized to gradually reduce to 70%, 35%, 15%, and 3% of baseline nicotine over 4 weeks by either (1) transitioning to lower nicotine VLNC cigarettes or (2) reducing the number of full nicotine CPD. All participants received nicotine patches to aid reduction. We assessed (1) QAs using nightly and weekly self-reports, (2) Velicer’s Self-Efficacy to Quit measure weekly, and (3) the Intention-to-Quit Ladder nightly.

Results

More CPD (41%) than VLNC (17%) participants made any QA (odds ratio = 3.4, 95% confidence interval = 1.1, 10.5). There was no difference in QAs ≥24 h. Self-efficacy increased for VLNC but not CPD participants (interaction: F = 3.7, p < .01). The condition by time interaction for intention-to-quit was not significant.

Conclusions

Reducing number of CPD increased QAs more than reducing nicotine via switching to VLNC cigarettes. The lack of difference in longer QAs suggests replication tests are needed.

Implications

Reducing the frequency of smoking behavior (ie, CPD) could be a more effective strategy to increase QAs than reducing the magnitude of nicotine in each cigarette (ie, VLNC) per se.
Emergent Polymyxin Resistance: End of an Era?
Authors: Li Zekun , Cao Yuping , Yi Lingxian , Liu Jian-Hua , Yang Qiwen
Published: August 2019

Until recently, the polymyxin antibiotics were used sparingly due to dose limiting toxicities. However, the lack of therapeutic alternatives for infections caused by highly resistant Gram-negative bacteria has led to the increased use of the polymyxins. Unfortunately, the world has witnessed increased rates of polymyxin resistance in the last decade, which is likely in part due to its irrational use in human and veterinary medicine. The spread of polymyxin resistance has been aided by the dissemination of the transferable polymyxin-resistance gene, mcr, in humans and the environment. The mortality of colistin-resistant bacteria (CoRB) infections varies in different reports. However, poor clinical outcome was associated with prior colistin treatment, illness severity, complications, and multidrug resistance. Detection of polymyxin resistance in the clinic is possible through multiple robust and practical tests, including broth microdilution susceptibility testing, chromogenic agar testing, and molecular biology assays. There are multiple risk factors that increase a person’s risk for infection with a polymyxin-resistant bacteria, including age, prior colistin treatment, hospitalization, and ventilator support. For patients that are determined to be infected by polymyxin-resistant bacteria, various antibiotic treatment options currently exist. The rising trend of polymyxin resistance threatens patient care and warrants effective control.
Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model
Authors: Chesdachai Supavit , Rajasingham Radha , Nicol Melanie R , Meya David B , Bongomin Felix , Abassi Mahsa , Skipper Caleb , Kwizera Richard , Rhein Joshua , Boulware David R
Published: August 2019

Background

Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100 mg to 2000 mg/day have been used. Prevalence of fluconazole nonsusceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentrations and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy.

Method

We conducted a systematic review using the MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Then, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg/day coupled with fluconazole’s known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100 mg to 2000 mg via linear regression. The fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review.

Results

We summarized 21 studies with 11 049 clinical Cryptococcus isolates. Minimum inihibitory concentrations were normally distributed with a geometric mean of 3.4 µg/mL, median (MIC50) of 4 µg/mL, and 90th percentile (MIC90) of 16 µg/mL. The median MIC50 trended upwards from 4 µg/mL in 2000–2012 to 8 µg/mL in 2014–2018. Predicted subtherapeutic fluconazole concentrations (below MIC) would occur in 40% with 100 mg, 21% with 200 mg, and 9% with 400 mg. The AUC:MIC ratio >100 would occur in 53% for 400 mg, 74% for 800 mg, 83% for 1200 mg, and 88% for 1600 mg.

Conclusions

Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.
Ceftriaxone+Sulbactam+Disodium EDTA Versus Meropenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: PLEA, a Double-Blind, Randomized Noninferiority Trial
Authors: Mir Mohd Amin , Chaudhary Saransh , Payasi Anurag , Sood Rajeev , Mavuduru Ravimohan S , Shameem Mohd
Published: August 2019

Background

CSE is a novel combination of ceftriaxone, sulbactam, and disodium ethylenediaminetetraacetic acid (EDTA) with activity against multidrug-resistant Gram-negative pathogens.

Methods

Adult patients aged ≥18 years with a diagnosis of complicated urinary tract infections (cUTIs), including acute pyelonephritis (AP), were randomized 1:1 to receive either intravenous CSE (1000 mg ceftriaxone/500 mg sulbactam/37 mg disodium EDTA) every 12 hours or intravenous meropenem (1000 mg) every 8 hours for up to 14 days. The primary objective was to show the noninferiority of CSE to meropenem at the test-of-cure visit (8–12 days after the end of therapy), with a noninferiority margin of 10%.

Results

Of 230 randomized patients, 74 of 143 and 69 of 143 were treated with CSE and meropenem, respectively. Of these, 98% were ceftriaxone nonsusceptible and 83% were ESBL-positive at baseline. Noninferiority of CSE to meropenem was demonstrated for both the US Food and Drug Administration-defined coprimary endpoints of (1) symptomatic resolution at test-of-cure (71 of 74 [95.9%] patients vs 62 of 69 [89.9%]; treatment difference, 6%; 95% confidence interval [CI] −2.6% to 16%) and (2) symptomatic resolution as well as microbiological eradication at test-of-cure (70 of 74 [94.6%] vs 60 of 69 [87.0%]; treatment difference, 7.6%; 95% CI, −2.0% to 18.4%). Microbiological eradication at test-of-cure (European Medical Agency’s primary endpoint) was observed in 70 of 74 (94.6%) vs 61 of 69 (88.4%) (treatment difference, 6.2%; 95% CI, −3.2% to 16.6%) patients treated with CSE and meropenem, respectively. Safety profile of CSE was consistent with that of ceftriaxone alone.

Conclusions

The results support the use of CSE as a carbapenem-sparing treatment for patients suffering from cUTI/AP caused by resistant Gram-negative pathogens.
Resistance in Patients Failing Integrase Strand Transfer Inhibitors: A Call to Replace Raltegravir With Dolutegravir in Third-Line Treatment in South Africa
Authors: Steegen Kim , Van Zyl Gert , Letsoalo Esrom , Claassen Mathilda , Hans Lucia , Carmona Sergio
Published: August 2019

Data on integrase resistance patterns in low- and middle-income countries (LMICs) is scarce. We assessed genotypic drug resistance in 43 patients with virological failure on integrase strand transfer inhibitors (INSTIs) containing regimens as part of the third-line treatment program in South Africa. Of the raltegravir (RAL)-exposed patients 20 of 34 (59%) had ≥1 major INSTI mutation, including 2 (6%) with dolutegravir (DTG) cross-resistance. Dolutegravir resistance was detected in 1 of 4 DTG-exposed patients. Replacing RAL with DTG may reduce the risk of INSTI mutations. We recommend DTG drug resistance monitoring when DTG is introduced at a larger scale in LMICs.
The Changing Partisanship of the South and Its Impact on National Politics
Authors: Bullock Charles S. , MacManus Susan A. , Mayer Jeremy D. , Rozell Mark J.
Published: August 2019

For generations many assumed that Democratic hegemony in the South would last forever. Civil rights and the national Democratic Party’s move to the left reconfigured partisan competition in the South. By the 1970s, the South became a crucial battleground in the election of the president and Republican gains in the region started to trickle down to statewide elections and eventually to local offices. The realignment of the southern electorate looked complete by the 2000s with near GOP control of the region, but recent elections have shown some swing back to the Democrats in several Growth States.
New York Sybarite Conquers the South
Authors: Bullock Charles S. , MacManus Susan A. , Mayer Jeremy D. , Rozell Mark J.
Published: August 2019

Donald Trump, the thrice married and publicly philandering Manhattan resident who had recently been pro-choice and pro-gun control, won the Republican nomination and the presidency in 2016 in part through his very strong showing among Southern white voters. How he managed to do that is the story of this chapter. Trump appealed to Southern white racial resentment, as well as to the anti-immigration fervor particularly evident in the low growth “stagnant” Southern states such as Alabama and Mississippi. But what was really remarkable is how he won the GOP nomination by doing well in all regions. The Republican Party has become unified around a largely Southern conception of conservatism: deeply religious, pro-military, and less concerned with free trade. In the general election, by contrast, regional polarization intensified in 2016. In both elections, Trump’s path to victory required him to do well among Southern whites, which he ably did.
An Epistemological Critique
Authors: Spannaus Nathan
Published: August 2019

The main premise of Qursawi’s reformism is that any action or belief must be based on the most certain sources of religious knowledge—Qur’an and sound hadith—to the exclusion of anything not conforming to them. He took aim at taqlid, the widespread reliance upon which obscured any position’s basis and obliged adherence to ulama’s interpretations rather than scripture. The “scaffolding” of postclassical scholarship limited scholars’ autonomy to engage directly with scripture in order to preclude divergent and incorrect positions, but Qursawi saw it as allowing error to spread unchecked, and he criticized ulama for failing as religious interpreters and guides for the community. Since they could not be relied upon necessarily, he argued therefore that any position must be verified through tahqiq to ensure scriptural and logical correctness.
Prior Record and the Risk of Recidivism
Authors: Frase Richard S. , Roberts Julian V.
Published: August 2019

It is generally assumed that prior convictions provide a useful proxy for the offender’s risk of committing further crimes, and as a general proposition that assumption is well supported by research. But as this chapter shows, there is much less research on how well particular prior record formulas predict recidivism risk. This chapter identifies the elements of guidelines criminal history scores that appear to be designed to measure risk, reviews the limited research assessing the accuracy of criminal history scores and score components as predictors of subsequent offending, and examines the closeness of fit between predicted increases in risk, as the criminal history score rises, and the increments in sentence severity that are prescribed by grid-based guidelines systems. The chapter also argues against the use of rigid prior record enhancement formulas, and in favor of giving judges power to adjust sentences to take into account case-specific variations in recidivism risk.
The Effects of Prior Convictions on Sentence Severity
Authors: Frase Richard S. , Roberts Julian V. , Hester Rhys
Published: August 2019

This chapter explores the degree to which a higher criminal history score increases the severity of recommended and imposed sentences in U.S. guidelines systems. The impact of criminal history on sentence severity is measured in several ways. One set of measures assesses the extent to which a high criminal history score translates into increased sentencing severity—by causing the offender to be recommended for immediate commitment to prison, and/or by increasing the duration of the recommended prison or other custodial sentence. Other measures of prior record enhancement magnitude relate to the criminal history formula itself—the components of the score and the way in which each component is weighted. These rules determine how quickly offenders acquire a high score, triggering the most severe impacts, and they also determine which offenders are most likely to receive high scores. The chapter concludes with proposals for regulating the magnitude of prior record enhancements.