bluuebunny/crossref_metadata_2025_split huggingface dataset:
Introduction
Authors: Miller Michael M. , Peppin John F. 
Published: November 2020

Abstract
At the same time that it became apparent that overdose toxicity and adverse effects limited the utility of barbiturates to treat anxiety and insomnia, a new class of drugs emerged in the 1950s and 1960s: benzodiazepines. With a rapid onset of action, these new drugs were highly effective in reducing anxiety and promoting sleep when used short term. Rapidly becoming some of the most prescribed drugs in the world, benzodiazepines brought with them a Pandora’s box of potential risks that weren’t at first fully appreciated. Although rarely fatal when taken alone, benzodiazepines have been shown to be correlated with polydrug overdose mortality. With prolonged exposure these drugs can lead to tolerance, physical dependence, and addiction. They can also launch a vicious cycle of rebound after initially relieving anxiety, they can lead to a state of tolerance with the need for increasing doses to achieve the same effect, resulting in more subjectively experienced anxiety. Rebound insomnia is a well-known feature of the long-term use of these agents. Despite these risks, these drugs were extremely popular upon their introduction into the medical marketplace and they became among the most frequently prescribed pharmaceuticals in America, with a variety of agents in this class of drugs being introduced. There then emerged the so-called Z-drugs (e.g., zolpidem and zaleplon), which were marketed as effective sleep aids and “not a benzodiazepine,” with the implication from sales representatives that, without having the molecular structure of benzodiazepines, they would not present the same rebound or adverse effects as benzodiazepines. However, the “Z-drug” agents are indeed benzodiazepine receptor agonists and are associated with the same downsides as agents in the true benzodiazepine drug class.
Benzodiazepine Withdrawal
Authors: Wright Steven L. 
Published: November 2020

Abstract
Benzodiazepines and related compounds (benzodiazepine receptor agonists [BzRAs]) cause a wide range of adverse reactions, including withdrawal symptoms, even when normal or low dosages are used. Deprescribing is recommended when there is loss of efficacy, major side effects, or use longer than four weeks. The withdrawal syndrome is due to physiologic dependence based on various receptor adaptations. Psychological, neurophysiologic, and somatic complaints can be misdiagnosed as psychiatric, psychosomatic, or substance use disorder. These symptoms may be severe and prolonged. The discontinuation process should include careful planning, support, and the use of cognitive behavioral therapy. Tapering, perhaps after substituting with a long-acting BzRA, should be patient-led and proceed slowly, anticipating completion over 12 to 18 months or even longer. In a proportion of patients, symptoms may continue months or years after complete BzRA cessation, requiring ongoing medical care.
Benzodiazepines and Pain Management
Authors: Peppin John F. , Wright Steven L. 
Published: November 2020

Abstract
Chronic pain is widespread and the use of opioids for chronic pain is also common. Frequently benzodiazepines are concomitantly prescribed in these patients, for anxiety, sleep disorders, and muscle pain and spasm. In the United States, Canada, and the European Union, increases in benzodiazepine prescribing has been seen, in some cases over 16% over the last decade. Unfortunately, the combination of opioids and benzodiazepines is correlated with overdose and overdose death. Few data exist to support the use of benzos for sleep, muscle spasm, or the long-term treatment of anxiety in the context of pain. It has been further shown that the use of benzodiazepines carries other adverse events and issues. It is estimated that the elimination of benzodiazepines would decrease overdoses by over 15%. The deprescribing of benzodiazepines should become common practice in the professional pain community and their use drastically limited. The authors suggest an approach to the discontinuation of benzodiazepines that includes extensive patient involvement. Other options for anxiety, sleep disturbances, and muscle relaxation are available and should be considered. For those already on these agents (legacy patients), tapering with the goal of discontinuation in a safe and person-centered process should be undertaken.
The Regulatory History of Benzodiazepines in the Age of the Dark Web and Other Threats
Authors: Coleman John J. 
Published: November 2020

Abstract
The US Congress enacted a tiered structure for controlling drugs based on relative abuse potential, which is commonly known as the Controlled Substances Act (CSA). The CSA codifies five levels, or schedules, to classify such problematic drugs, ranging from those that have no accepted medical utility (Schedule I) to those with known medical utility but having relative abuse potential ranging from low (Schedule V) to high (Schedule II). Unfortunately, the process that regulatory agencies use to assess the abuse potential of street drugs does not work as well or as reliably for medicinal substances. This chapter discusses these issues and summarizes the history of efforts by a variety of worldwide regulatory agencies to properly characterize the benzodiazepines and related drugs with regard to legitimate therapeutic use versus the public health risks posed by drugs with misuse/abuse potential. The inadequacy of some of the general approaches and some specific attempts are discussed. Also discussed are some of the unintended consequences resulting from uninformed, misguided, or misdirected efforts. New complications include the influx of counterfeit drugs from domestic and foreign sources, and the existence of the Dark Web.
A Two-Locus System with Strong Epistasis Underlies Rapid Parasite-Mediated Evolution of Host Resistance
Authors: Ameline Camille , Bourgeois Yann , Vögtli Felix , Savola Eevi , Andras Jason , Engelstädter Jan , Ebert Dieter 
Published: November 2020

Abstract
Parasites are a major evolutionary force, driving adaptive responses in host populations. Although the link between phenotypic response to parasite-mediated natural selection and the underlying genetic architecture often remains obscure, this link is crucial for understanding the evolution of resistance and predicting associated allele frequency changes in the population. To close this gap, we monitored the response to selection during epidemics of a virulent bacterial pathogen, Pasteuria ramosa, in a natural host population of Daphnia magna. Across two epidemics, we observed a strong increase in the proportion of resistant phenotypes as the epidemics progressed. Field and laboratory experiments confirmed that this increase in resistance was caused by selection from the local parasite. Using a genome-wide association study, we built a genetic model in which two genomic regions with dominance and epistasis control resistance polymorphism in the host. We verified this model by selfing host genotypes with different resistance phenotypes and scoring their F1 for segregation of resistance and associated genetic markers. Such epistatic effects with strong fitness consequences in host–parasite coevolution are believed to be crucial in the Red Queen model for the evolution of genetic recombination.
TRANSMISSION COEFFICIENT OF POWER DENSITY INTO SKIN TISSUE BETWEEN 6 AND 300 GHZ
Authors: Christ Andreas , Samaras Theodoros , Neufeld Esra , Kuster Niels 
Published: November 2020

Abstract
The latest electromagnetic safety guidelines define transmitted or epithelial power density as the basic restriction above 6 GHz. In this note, we derive an approximation for a conservative transmission coefficient for quasi plane wave incidence as a function of the frequency for the normal component of the Poynting vector with respect to the evaluation plane or tissue surface |Sz inc| and for its modulus ||Sinc||. The maximum transmission coefficient for the normal component of the Poynting vector ${\boldsymbol{T}}_{\mathbf{z}}^{\mathbf{max}}$ is 1 independent of tissue composition and frequency. Approximations of ${\boldsymbol{T}}_{\mathbf{total}}^{\mathbf{max}}$ normalized to ||Sinc|| for thin and thick stratum corneum are provided allowing higher exposures. These approximations allow to conservatively demonstrate compliance with basic restrictions when quasi plane-wave conditions are locally satisfied and enhancement effects of standing waves between source and body can be neglected. The reported results are important to regulators and standardization bodies regarding revisions of compliance requirements and safety guidelines.
Ovulation is Inhibited by an Environmentally Relevant Phthalate Mixture in Mouse Antral Follicles In Vitro
Authors: Land Katie L , Lane Madison E , Fugate Ava C , Hannon Patrick R 
Published: November 2020

Abstract
Phthalates are solvents and plasticizers found in consumer products including cosmetics, food/beverage containers, housing materials, etc. Phthalates are known endocrine-disrupting chemicals that can directly target the ovary, potentially causing defects in ovulation and fertility. Women are exposed to multiple different phthalates daily, therefore this study investigated the effects of an environmentally relevant phthalate mixture (PHTmix) on ovulation. Ovulation is initiated by the luteinizing hormone (LH) surge, which induces prostaglandin (PG) production, progesterone (P4)/progesterone receptor (PGR) signaling, and extracellular matrix (ECM) remodeling. We hypothesized that the PHTmix would directly inhibit ovulation by altering the levels of PGs, P4/PGR, and enzymes involved in ECM remodeling. Antral follicles from CD-1 mice were treated with vehicle control alone (dimethylsulfoxide, DMSO), hCG alone (LH analog), and hCG+PHTmix (1–500μg/ml), and samples were collected across the ovulatory period. The PHTmix decreased ovulation rates at all doses tested in a dose-dependent manner when compared to hCG. PG levels were decreased by the PHTmix when compared to hCG, which was potentially mediated by altered levels of PG synthesis (Ptgs2) and transport (Slco2a1) genes. The PHTmix altered P4 and Pgr levels when compared to hCG, leading to decreases in downstream PGR-mediated genes (Edn2, Il6, Adamts1). ECM remodeling was potentially dysregulated by altered levels of ovulatory mediators belonging to the matrix metalloproteases and plasminogen activator families. These data suggest that phthalate exposure inhibits ovulation by altering PG levels, P4/PGR action, and ECM remodeling.
Divergent RNA viruses in Macrophomina phaseolina exhibit potential as virocontrol agents
Authors: Wang Jing , Ni Yunxia , Liu Xintao , Zhao Hui , Xiao Yannong , Xiao Xueqiong , Li Shujun , Liu Hongyan 
Published: November 2020

Abstract
Macrophomina phaseolina is an important necrotrophic phytopathogenic fungus and cause extensive damage in many oilseed crops. Twelve M.phaseolina isolates with diverse biological phenotypes were selected for a high-throughput sequencing-based metatranscriptomic and bioinformatics analysis to identify viruses infecting M.phaseolina. The analysis identified 40 partial or nearly complete viral genome segments, 31 of which were novel viruses. Among these viral sequences, 43% of the viral genomes were double-stranded RNA (dsRNA), 47% were positive single-stranded RNA (ssRNA+), and the remaining 10% were negative sense-stranded RNA (ssRNA−). The 40 viruses showed affinity to 13 distinct viral lineages, including Bunyavirales (four viruses), Totiviridae (three viruses), Chrysoviridae (five viruses), Partitiviridae (four viruses), Hypoviridae (one virus), Endornaviridae (two viruses), Tombusviridae (three viruses), Narnaviridae (one virus), Potyviridae (one virus), Bromoviridae (one virus), Virgaviridae (six viruses), ‘Fusagraviridae’ (five viruses), and Ourmiavirus (four viruses). Two viruses are closely related to two families, Potyviridae and Bromoviridae, which previously contained no mycovirus species. Moreover, nine novel viruses associated with M.phaseolina were identified in the family Totiviridae, Endornaviridae, and Partitiviridae. Coinfection with multiple viruses is prevalent in M.phaseolina, with each isolate harboring different numbers of viruses, ranging from three to eighteen. Furthermore, the effects of the viruses on the fungal host were analyzed according to the biological characteristics of each isolate. The results suggested that M.phaseolina hypovirus 2, M.phaseolina fusagravirus virus 1-5 (MpFV1-5), M.phaseolina endornavirus 1-2 (MpEV1-2), M.phaseolina ourmia-like virus 1-3 (MpOLV1-3), M.phaseolina mitovirus 4 (MpMV4), and M.phaseolina mycobunyavirus 1-4 (MpMBV1-4) were only detected in hypovirulent isolates. Those viruses associated with hypovirulence might be used as biological control agents as an environmentally friendly alternative to chemical fungicides. These findings considerably expand our understanding of mycoviruses in M.phaseolina and unvailed the presence of a huge difference among viruses in isolates from different hosts in distant geographical regions. Together, the present study provides new knowledge about viral evolution and fungus-virus coevolution.
Outcomes of Patients With Nonunion After Open Tibial Shaft Fractures With or Without Soft Tissue Coverage Procedures
Authors: Egol Kenneth A. , Littlefield Connor P. , Walden Timothy , Leucht Philipp , Levine Jaime , Konda Sanjit 
Published: November 2020

Objectives:
To evaluate the outcomes of patients who underwent soft tissue flap coverage during treatment of a tibia fracture nonunion.

Design:
Retrospective analysis on prospectively collected data.

Setting:
Academic medical center.

Patients/Participants:
One hundred fifty-seven patients were treated for a fracture nonunion after a tibia fracture over a 15-year period. Sixty-six patients had sustained an open tibial fracture initially and 25 of these patients underwent soft tissue flaps for their open tibia fracture nonunion.

Intervention:
Manipulation of soft tissue flaps, either placement or elevation for graft placement in ununited previously open tibial fractures.

Main Outcome Measurements:
Bony healing, time to union, ultimate soft tissue status, postoperative complications, and functional outcome scores using the Short Musculoskeletal Functional Assessment (SMFA). This group was compared with a group of open tibial fracture nonunions that did not undergo soft tissue transfer.

Results:
Bony healing was achieved in 24 of 25 patients (96.0%) who received flaps at a mean time to union of 8.7 ± 3.3 months compared with 39 of 41 patients (95.1%) at a mean 7.5 ± 3.2 months (P > 0.05) in the noncoverage group. Healing rate and time to union did not differ between groups. At latest follow-up, the flap coverage group reported a mean SMFA index of 17.1 compared with an SMFA index of 27.7 for the noncoverage group (P = 0.037).

Conclusions:
Utilization of soft tissue flaps in the setting of open tibia shaft nonunion repair surgery are associated with a high union rate (>90%). Coverage with or manipulation of soft tissue flaps did not result in improved bony healing rate or time to union compared with those who did not require flaps. However, soft tissue flap coverage was associated with higher functional scores at long-term follow-up.

Level of Evidence:
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Clinical Characteristics and Treatment Response With Checkpoint Inhibitors in Malignant Melanoma of the Vulva and Vagina
Authors: Wohlmuth Christoph , Wohlmuth-Wieser Iris , Laframboise Stéphane 
Published: November 2020

Objectives
The aims of the study were to assess the clinical and histopathological characteristics of a comprehensive cohort of women with vulvovaginal melanoma (VVM) treated at our institution and to study the treatment response of checkpoint inhibitors in this patient cohort.

Materials and Methods
This is a retrospective study of women with invasive VVM treated at the Princess Margaret Cancer Centre in Toronto, Ontario, Canada, over a period of 15 years. Clinical and histopathological characteristics, treatment, as well as treatment-related outcome were analyzed in 32 women. Treatment response was evaluated retrospectively using the “response criteria for use in trials testing immunotherapeutics” (iRECIST). The objective response rate was defined as the proportion of patients with complete or partial response based on the best overall response.

Results
At a median follow-up of 37.8 months (5.8–110.4), 26 women (81.3%) had disease progression and 16 (50%) died. Thirteen patients with locally unresectable or metastatic melanoma were treated with immune checkpoint inhibitors. Ten additional cases were identified from previously published reports. The best objective response rate for immune checkpoint inhibitors was 30.4% (95% CI = 11.6%–49.2%) and the clinical benefit rate was 52.2% (95% CI = 31.8%–72.6%). The clinical benefit rate was significantly better for programmed cell death protein 1 inhibitors (or a combination) compared with ipilimumab alone (Fisher exact, p = .023). Grade 3/4 adverse events were observed in 3 (13.0%) of the 23 patients.

Conclusions
Women with VVM constitute a high-risk group with poor overall prognosis. Immune checkpoint inhibitors are effective in the treatment of metastatic melanoma in this patient cohort.
Heart Valve Abnormalities in Systemic Sclerosis Patients
Authors: Colaci Michele , Schinocca Claudia , Bosco Ylenia Dal , Ronsivalle Giuseppe , Guggino Giuliana , de Andres Ilenia , Russo Alessandra A. , Sambataro Domenico , Sambataro Gianluca , Malatino Lorenzo 
Published: November 2020

Background
Systemic sclerosis (SSc) is a chronic autoimmune disease that is characterized by vasculopathy and fibrosis of the skin and visceral organs. Heart valve diseases are poorly described and generally not considered typical of SSc. We aimed to describe valvular abnormalities in a multicenter cohort of SSc patients and to investigate their correlation with SSc features.

Methods
We recruited 118 consecutive SSc patients (male/female, 14/104; mean age, 55.2 ± 12.1 years) in 3 rheumatology centers in Sicily, Italy, from January to October 2019.

Results
Mitral and tricuspid valve insufficiency was found in 85% and 91% of patients, respectively; regurgitations were generally mild and never severe. Mitral stenosis was rare (2%), and tricuspid stenosis was not observed. Sclerosis and calcification were present in 30% of mitral valves and in only 4% of tricuspid valves. The aortic valve was affected in 25% of cases, and it generally presented as regurgitation or sclerosis, whereas stenosis was rare (3%). Finally, 11% of SSc patients showed regurgitation of the pulmonary valve. No specific associations between SSc features and valve alterations were found.

Conclusions
Valvular diseases are frequently observed in SSc patients, with a predominant pattern of valvular regurgitations. Therefore, echocardiography should be routinely performed during SSc patient follow-up, considering the potential influence of additional cardiac involvement in the prognosis of these patients.
Dendrochronological dates confirm a Late Prehistoric population decline in the American Southwest derived from radiocarbon dates
Authors: Robinson Erick , Bocinsky R. Kyle , Bird Darcy , Freeman Jacob , Kelly Robert L. 
Published: November 2020

The northern American Southwest provides one of the most well-documented cases of human population growth and decline in the world. The geographic extent of this decline in North America is unknown owing to the lack of high-resolution palaeodemographic data from regions across and beyond the greater Southwest, where archaeological radiocarbon data are often the only available proxy for investigating these palaeodemographic processes. Radiocarbon time series across and beyond the greater Southwest suggest widespread population collapses from AD 1300 to 1600. However, radiocarbon data have potential biases caused by variable radiocarbon sample preservation, sample collection and the nonlinearity of the radiocarbon calibration curve. In order to be confident in the wider trends seen in radiocarbon time series across and beyond the greater Southwest, here we focus on regions that have multiple palaeodemographic proxies and compare those proxies to radiocarbon time series. We develop a new method for time series analysis and comparison between dendrochronological data and radiocarbon data. Results confirm a multiple proxy decline in human populations across the Upland US Southwest, Central Mesa Verde and Northern Rio Grande from AD 1300 to 1600. These results lend confidence to single proxy radiocarbon-based reconstructions of palaeodemography outside the Southwest that suggest post-AD 1300 population declines in many parts of North America.
This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.
Sometimes hidden but always there: the assumptions underlying genetic inference of demographic histories
Authors: Loog Liisa 
Published: November 2020

Demographic processes directly affect patterns of genetic variation within contemporary populations as well as future generations, allowing for demographic inference from patterns of both present-day and past genetic variation. Advances in laboratory procedures, sequencing and genotyping technologies in the past decades have resulted in massive increases in high-quality genome-wide genetic data from present-day populations and allowed retrieval of genetic data from archaeological material, also known as ancient DNA. This has resulted in an explosion of work exploring past changes in population size, structure, continuity and movement. However, as genetic processes are highly stochastic, patterns of genetic variation only indirectly reflect demographic histories. As a result, past demographic processes need to be reconstructed using an inferential approach. This usually involves comparing observed patterns of variation with model expectations from theoretical population genetics. A large number of approaches have been developed based on different population genetic models that each come with assumptions about the data and underlying demography. In this article I review some of the key models and assumptions underlying the most commonly used approaches for past demographic inference and their consequences for our ability to link the inferred demographic processes to the archaeological and climate records.This article is part of the theme issue ‘Cross-disciplinary approaches to prehistoric demography’.