bluuebunny/crossref_metadata_2025 huggingface dataset:
The use of image analysis software increases the accuracy of the periacetabular osteotomy fragment placement
Authors: Dittmer Flemig Alison J , Essilfie Anthony , Schneider Brandon , Robustelli Stacy , Sink Ernest L
Published: December 2021

The purpose of this study was to report on the use of image analysis technology to enhance accuracy of intra-operative imaging and evaluation of periacetabular osteotomy (PAO) correction. This was a retrospective study reporting on the first 25 cases of PAO performed with the use of an image analysis tool. This technology was used intra-operatively to assess the position of the supine coronal image in comparison to pre-operative standing images using a ratio of pelvic tilt (PT). Intra-operative PT, Tönnis angle, lateral center–edge angle (LCEA) and anterior wall index were compared to post-operative images. Post-operative radiographic parameters in the study group were compared with a control group of PAO cases performed prior to the implementation of the new software. The image analysis software was able to obtain intra-operative supine imaging that was equivalent to pre-operative standing imaging. When comparing the PAOs performed with the use of the software versus those without, the study group trended toward being more likely within the surgeon’s defined target range of radiographic values, which was statistically significant for LCEA. This tool can be used to assure the surgeon that the intra-operative image being used for surgical decision-making is representative of the functional radiograph. PAOs performed with the use of this technology showed enhanced accuracy of surgical correction for the parameters within our defined target ranges. This may increase the ability of the surgeon to place the acetabular fragment more precisely within his or her goal parameters for acetabular reorientation correction.
A Preliminary Study of Necrophagous Flies (Insecta: Diptera) in the Lhasa Region (Qinghai–Tibet Plateau), China
Authors: Shen Xiao , Jiang Yangshuai , Shang Yanjie , Wang Yuanxing , Guo Shaojiang , Guo Nan , Yang Junbo , Cai Jifeng , Guo Yadong , Zhang Changquan
Published: December 2021

Lhasa is located on the Qinghai–Tibet Plateau, with an altitude of 3,650 m, and a unique geography. Its climate is dry and cold all year round. Forensic entomological studies of the region are scarce. In this study, the diversity and seasonality of necrophagous flies in eight counties among Lhasa region were determined, and succession of necrophagous flies colonizing on rabbits in the Chengguan area of Lhasa was studied, so as to provide reference data for estimating postmortem interval (PMI) and location of death. In total, 22 species of necrophagous flies, belonging to six families were identified in Lhasa. Protophormia terraenovae (Robineau-Desvoidy, 1830) (Diptera: Calliphoridae) was the dominant species throughout the year, the diversity index (4.5834) indicated that the study on necrophagous flies in the Lhasa region is representative.
Collaborating With Community Scientists Across Arkansas to Update Tick Distributions and Pathogen Prevalence of Spotted Fever Group Rickettsia and Ehrlichia
Authors: Dowling Ashley P G , Young Sean G , Loftin Kelly
Published: December 2021

Tick-borne diseases (TBD) in humans have dramatically increased over recent years and although the bulk of cases are attributable to Lyme Disease in the Northeastern US, TBDs like spotted fever rickettsiosis and ehrlichiosis heavily impact other parts of the country, namely the mid-south. Understanding tick and pathogen distributions and prevalence traditionally requires active surveillance, which quickly becomes logistically and financially unrealistic as the geographic area of focus increases. We report on a community science effort to survey ticks across Arkansas to obtain updated data on tick distributions and prevalence of human tick-borne disease-causing pathogens in the most commonly encountered ticks. During a 20-mo period, Arkansans submitted 9,002 ticks from 71 of the 75 counties in the state. Amblyomma americanum was the most common tick species received, accounting for 76% of total tick submissions. Nearly 6,000 samples were screened for spotted fever group Rickettsia (SFGR) and Ehrlichia, resulting in general prevalence rates of 37.4 and 5.1%, respectively. In addition, 145 ticks (2.5%) were infected with both SFGR and Ehrlichia. Arkansas Department of Health reported 2,281 spotted fever and 380 ehrlichiosis cases during the same period as our tick collections. Since known SFGR vectors Dermacentor variabilis and Amblyomma maculatum were not the most common ticks submitted, nor did they have the highest prevalence rates of SFGR, it appears that other tick species play the primary role in infecting humans with SFGR. Our investigation demonstrated the utility of community science to efficiently and economically survey ticks and identify vector-borne disease risk in Arkansas.
The association between pill mill legislation and neonatal abstinence syndrome
Authors: Anwar Tahiya , Jayawardhana Jayani
Published: December 2021

Objectives

Neonatal abstinence syndrome (NAS) is a drug withdrawal syndrome in newborns who were primarily been exposed to drugs such as opioids in the mothers’ womb. The NAS rate in the USA has increased over the past decade. With rising opioid use and opioid overdose deaths, many states adopted various policies to combat the opioid epidemic, including the pill mill legislation. However, its effect on NAS is not evident. This study examines the association between pill mill legislation and NAS rate in the USA.

Methods

The study utilizes state-level hospital discharge data from Healthcare Cost and Utilization Project’s (HCUP) Fast Stats database from 2008 to 2018, along with state-level socio-demographic and opioid-related health policy data. Analysis was conducted using a difference-in-differences regression approach.

Key findings

The results indicate that pill mill legislation is associated with 4 additional incidents of NAS cases per 1000 newborn hospitalizations (P < 0.05), and 6.5 additional incidents of NAS cases per 1000 newborn hospitalizations among Medicaid payers (P < 0.05) in states with pill mill legislation compared with states without the legislation. Moreover, the results indicate that states with prescription drug monitoring programmes (PDMP) are experiencing lower incidents of NAS cases overall (P < 0.01), and among Medicaid and privately insured populations (P < 0.05) in comparison with states without PDMPs.

Conclusions

These findings indicate that pill mill legislation has not been effective in reducing NAS rates in the USA. A comprehensive policy approach targeting opioid use among pregnant women may be needed to effectively reduce NAS rates in the USA.
The Impact of Having a Child With Special Healthcare Needs on Length of Military Service
Authors: Perkins Elizabeth M , Sorensen Ian , Susi Apryl , Hisle-Gorman Elizabeth
Published: December 2021

Introduction

In 2010, the National Survey of Children with Special Healthcare Needs revealed that parents of children with special healthcare needs (CSHCN) report employment decisions are influenced by healthcare coverage needs. The U.S. military healthcare system arguably offers service member parents of CSHCN with the most comprehensive, inexpensive, long-term healthcare in the country—potentially increasing their incentive to remain in the military. This study explored the effect of having a CSHCN on the length of parental military service.

Materials and Methods

A retrospective cohort was formed using the Military Health System database from 2008 to 2018. Included children were <10 years in 2010 and received ≥1 year of military healthcare between 2008 and 2010. The Pediatric Medical Complexity Algorithm categorized children as having special healthcare needs via ICD 9/10 codes as having complex chronic (C-CD), non-complex chronic (NC-CD), or no chronic disease (CD). Families were classified by the child with the most complex healthcare need. Duration of military healthcare eligibility measured parental length of service (LOS). ANOVA and linear regression analysis compared LOS by category. Logistic regression determined odds of parental LOS lasting the full 8-year study length. Adjusted analyses controlled for child age and sex, and military parent sex, rank, and marital status.

Results

Over 1.45 million children in 915,584 families were categorized as per the algorithm. Of individual children included, 292,050 (20.1%) were CSHCN including those with complex chronic and non-complex chronic conditions. After grouping by family, 80,909 (8.8%) families had a child/children with C-CD (mean LOS 6.39 years), 170,787 (18.7%) families had a child/children with NC-CD (mean LOS 6.41 years), and 663,888 (72.5%) families had children with no CD (mean LOS 5.7 years). In adjusted analysis, parents of children with C-CD and NC-CD served 0.4 [0.37-0.42] and 0.33 [0.31-0.34] years longer than parents of children with no CD; odds of parents serving for the full study period were increased 33% (1.33 [1.31-1.36]) in families of children with C-CD and 27% (1.27 [1.26-1.29]) in families of children with NC-CD.

Conclusions

Findings indicate that military parents of CSHCN serve longer military careers than parents of children with no chronic conditions. Continued provision of free, high-quality healthcare coverage for dependent children may be important for service member retention. Retaining trained and experienced service members is key to ensuring a ready and lethal U.S. military.
Onboard dynamic image exposure control for the Star–Planet Activity Research CubeSat (SPARCS)
Authors: Ramiaramanantsoa Tahina , Bowman Judd D , Shkolnik Evgenya L , Loyd R O Parke , Ardila David R , Jewell April , Barman Travis , Basset Christophe , Beasley Matthew , Cheng Samuel , Gamaunt Johnathan , Gorjian Varoujan , Hennessy John , Jacobs Daniel , Jensen Logan , Knapp Mary , Llama Joe , Meadows Victoria , Nikzad Shouleh , Peacock Sarah , Scowen Paul , Swain Mark R
Published: December 2021

The Star–Planet Activity Research CubeSat (SPARCS) is a 6U CubeSat under development to monitor the flaring and chromospheric activity of M dwarfs at near-ultraviolet (NUV) and far-ultraviolet (FUV) wavelengths. The spacecraft hosts two UV-optimized delta-doped charge-coupled devices fed by a 9-cm telescope and a dichroic beam splitter. A dedicated science payload processor performs near-real-time onboard science image processing to dynamically change detector integration times and gains to reduce the occurrence of pixel saturation during strong M dwarf flaring events and provide adequate flare light-curve structure resolution while enabling the detection of low-amplitude rotational modulation. The processor independently controls the NUV and FUV detectors. For each detector, it derives control updates from the most recent completed exposure and applies them to the next exposure. The detection of a flare event in the NUV channel resets the exposure in the FUV channel with new exposure parameters. Implementation testing of the control algorithm using simulated light curves and full-frame images demonstrates a robust response to the quiescent and flaring levels expected for the stars to be monitored by the mission. The SPARCS onboard autonomous exposure control algorithm is adaptable for operation in future point source-targeting space-based and ground-based observatories geared towards the monitoring of extreme transient astrophysics phenomena.
Physical properties and real nature of massive clumps in the galaxy
Authors: Lu Zu-Jia , Pelkonen Veli-Matti , Juvela Mika , Padoan Paolo , Haugbølle Troels , Nordlund Åke
Published: December 2021

Systematic surveys of massive clumps have been carried out to study the conditions leading to the formation of massive stars. These clumps are typically at large distances and unresolved, so their physical properties cannot be reliably derived from the observations alone. Numerical simulations are needed to interpret the observations. To this end, we generate synthetic Herschel observations using our large-scale star-formation simulation, where massive stars explode as supernovae driving the interstellar-medium turbulence. From the synthetic observations, we compile a catalogue of compact sources following the exact same procedure as for the Hi-GAL compact source catalogue. We show that the sources from the simulation have observational properties with statistical distributions consistent with the observations. By relating the compact sources from the synthetic observations to their 3D counterparts in the simulation, we find that the synthetic observations overestimate the clump masses by about an order of magnitude on average due to line-of-sight projection, and projection effects are likely to be even worse for Hi-GAL Inner Galaxy sources. We also find that a large fraction of sources classified as protostellar are likely to be starless, and propose a new method to partially discriminate between true and false protostellar sources.
Infrared analysis of Valine degradation by keV electrons. Measurements and CASINO-extended model predictions
Authors: da Costa Cíntia A P , da Silveira Enio F
Published: December 2021

Degradation of L-valine by 0.06–1.0-keV electron beams is analysed in laboratory, at 10, 150, and 300 K. Valine film thicknesses are measured by profilometry, permitting band strength determination for selected valine bands. The column density evolutions during the irradiation are measured via infrared spectroscopy and destruction cross-sections are extracted; the latter range from 1–100 × 10−16 cm2. Data show that, in general, destruction cross-sections depend not only on projectile energy and sample temperature but also on sample thickness and beam fluence. In order to understand these findings, a statistical model is proposed for describing the radiolysis of organic materials. Comparing predictions with experimental results for valine, the main trends are reproduced. The quantitative disagreement indicates that it is necessary to include sputtering in the model. A major contribution of the model is to permit to simulate, layer by layer, the sample degradation rate as a function of fluence. The model assumes that the destruction cross-section of precursor molecules is proportional to the local stopping power and uses the Monte Carlo CASINO code to determine the deposited energy distribution in the bulk. As astrophysical implications, the radiolysis of valine dissolved in H2O ice and shielded by a CO2 layer is predicted, as an attempt to analyse the degradation of realistic cosmic materials by keV electrons.
Establishing clinical remission criteria and the framework of a treat-to-target algorithm for Takayasu arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour and Welfare for intractable vasculitis
Authors: Sugihara Takahiko , Nakaoka Yoshikazu , Uchida Haruhito A , Yoshifuji Hajime , Maejima Yasuhiro , Watanabe Yoshiko , Amiya Eisuke , Tanemoto Kazuo , Miyata Tetsuro , Umezawa Natsuka , Manabe Yusuke , Ishizaki Jun , Shirai Tsuyoshi , Nagafuchi Hiroko , Hasegawa Hitoshi , Miyamae Takako , Niiro Hiroaki , Ito Shuichi , Ishii Tomonori , Isobe Mitsuaki , Harigai Masayoshi
Published: December 2021

Objectives

To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK).

Methods

A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 paediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over four reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with three patients.

Results

Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0–5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including positron emission tomography–computed tomography, and two on treatment intensification.

Conclusions

We developed a T2T algorithm and proposals for standardised remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.
miR-144-3p aggravated cartilage injury in rheumatoid arthritis by regulating BMP2/PI3K/Akt axis
Authors: Mo Mei-Li , Jiang Jin-Mei , Long Xiao-Ping , Xie Li-Hu
Published: December 2021

Objectives

Present study aimed to illustrate the role of miR-144-3p in rheumatoid arthritis (RA).

Methods

N1511 chondrocytes were stimulated by interleukin (IL)-1β to mimic RA injury model in vitro. Rats were subjected to injection of type II collagen to establish an in vivo RA model, and the arthritis index score was calculated. Cell viability was determined by Cell Counting Kit-8. The expression of cartilage extracellular matrix proteins (collagen II and aggrecan) and matrix metalloproteinase protein were determined by quantitative real-time polymerase chain reaction and western blots. Cell apoptosis was measured by flow cytometry. Enzyme-linked immunosorbent assay was applied to test the secretion of pro-inflammatory cytokines (IL-1β and tumour necrosis factor-α). Tissue injury and apoptosis were detected by haematoxylin–eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling assay staining. Interaction of miR-144-3p and bone morphogenetic protein 2 (BMP2) was verified by dual-luciferase assay.

Results

miR-144-3p was dramatically increased in IL-1β-induced N1511 cells. miR-144-3p depletion elevated cell viability, suppressed apoptosis, pro-inflammatory cytokine releasing, and extracellular matrix loss in IL-1β-induced N1511 cells. Moreover, miR-144-3p targeted BMP2 to modulate its expression negatively. Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signalling compromised inhibition of BMP2 induced aggravated N1511 cell injury with IL-1β stimulation. Inhibition of miR-144-3p alleviated cartilage injury and inflammatory in RA rats.

Conclusion

Collectively, miR-144-3p could aggravate chondrocyte injury inflammatory response in RA via BMP2/PI3K/Akt axis.
Performance of recent PRINTO criteria versus current ILAR criteria for systemic juvenile idiopathic arthritis: A single-centre experience
Authors: Koker Oya , Demirkan Fatma Gul , Cakmak Figen , Aktay Ayaz Nuray
Published: December 2021

Objectives

The purpose of this study is to evaluate the performances of recently proposed Pediatric Rheumatology International Trials Organization criteria versus current International League of Associations for Rheumatology criteria for systemic juvenile idiopathic arthritis (sJIA).

Methods

The study was performed at the Department of Pediatric Rheumatology in Istanbul Faculty of Medicine with a retrospective design, covering the date range 2010–2021. Patients diagnosed with sJIA, Kawasaki disease and common autoinflammatory diseases were included. Both the International League of Associations for Rheumatology and Pediatric Rheumatology International Trials Organization classification criteria were applied to each patient and cross-checked with expert rheumatologist diagnosis.

Results

Eighty-two patients with sJIA were compared against 189 (74 Kawasaki disease, 83 familial Mediterranean fever, 16 mevalonate kinase deficiency, 10 cryopyrin-associated periodic syndromes, and 6 tumour necrosis factor receptor-associated periodic syndrome) patients. The Pediatric Rheumatology International Trials Organization criteria demonstrated higher sensitivity (62.2% vs 80.5%, P =.003) but comparable specificity (90.5% vs 91%) as regards the International League of Associations for Rheumatology criteria.

Conclusions

The revised criteria appear to enhance the ability to provide early recognition and pertinent classification of sJIA. No superiority was observed in segregating sJIA from common autoinflammatory diseases and Kawasaki disease, namely in terms of specificity.
A case of giant cell arteritis lacking typical symptoms presenting with recurrent cerebellar infarctions: A case report and case-based review
Authors: Hiyama Ryuichiro , Oiwa Hiroshi , Kanou Yukari , Nishibe Shiho , Kono Tomoyuki , Nomura Eiichi
Published: December 2021

Giant cell arteritis (GCA) occasionally presents with ischaemic stroke. Generally, symptoms related to GCA or elevated levels of inflammation markers would be a clue for the diagnosis of GCA. However, we encountered a rare case of GCA that presented with recurrent cerebellar infarctions without symptoms related to GCA (headache, fever, or jaw claudication). Furthermore, C-reactive protein levels, measured at the time of two of the stroke attacks, were within the normal range. On physical examination, the temporal arteries were prominent and weakly pulsatile. Temporal artery ultrasonography showed halo signs, and temporal artery biopsy revealed GCA. To our knowledge, this is the first case of GCA presenting with recurrent ischaemic stroke lacking GCA features but diagnosed before death. Considering this case-based review, we suggest that GCA may have been missed in elderly patients with ischaemic stroke, especially in those with posterior circulation infarction. Therefore, physical examination of the temporal arteries, temporal artery ultrasonography, and vessel wall magnetic resonance imaging may be useful in those patients.
Acute encephalitis in primary Sjögren’s syndrome: A case report and literature review
Authors: Higashida-Konishi Misako , Akiyama Mitsuhiro , Shimada Tatsuya , Hama Satoshi , Takei Hiroshi , Izumi Keisuke , Oshima Hisaji , Okano Yutaka
Published: December 2021

Acute encephalitis is an extremely rare condition in primary Sjogren’s syndrome (pSS), and its characteristics and prognosis remain unclear. Here, we report the case of pSS presented with acute encephalitis. She was admitted to our hospital for acute disturbance of consciousness. Acute encephalitis was diagnosed based on the results of the cerebrospinal fluid test (the increase of leucocyte counts, proteins, and interleukin-6 levels), magnetic resonance imaging, and single-photon emission computed tomography with 99mTc. The infectious aetiologies and underlying malignancies were excluded. Serum anti-Sjogren’s syndrome-related antigen A autoantibody was positive with extremely high titre. The biopsy specimen of her labial salivary gland revealed a focal lymphocytic sialadenitis with a score of grade 4 in the Greenspan grade. She also developed diffuse alveolar haemorrhage during the clinical course. She was diagnosed with pSS complicated with acute encephalitis followed by diffuse alveolar haemorrhage and successfully treated with pulse steroids, high dose of prednisolone and intravenous cyclophosphamide. Our present case and literature review suggest that acute encephalitis associated with pSS can be treatable with the immunosuppressive therapy, and thus early recognition and treatment initiation are important for this life-threatening condition. Thus, pSS should be included in the differential diagnosis of unexplained encephalitis. Notably, our case characteristically showed diffuse alveolar haemorrhage, adding new insights into the pathogenesis of acute encephalitis associated with pSS that capillaritis might be the underlying cause of this condition.
Canonical and novel non-canonical activities of the Holliday junction resolvase Yen1
Authors: Carreira Raquel , Aguado F Javier , Hurtado-Nieves Vanesa , Blanco Miguel G
Published: December 2021

Yen1 and GEN1 are members of the Rad2/XPG family of nucleases that were identified as the first canonical nuclear Holliday junction (HJ) resolvases in budding yeast and humans due to their ability to introduce two symmetric, coordinated incisions on opposite strands of the HJ, yielding nicked DNA products that could be readily ligated. While GEN1 has been extensively characterized in vitro, much less is known about the biochemistry of Yen1. Here, we have performed the first in-depth characterization of purified Yen1. We confirmed that Yen1 resembles GEN1 in many aspects, including range of substrates targeted, position of most incisions they produce or the increase in the first incision rate by assembly of a dimer on a HJ, despite minor differences. However, we demonstrate that Yen1 is endowed with additional nuclease activities, like a nick-specific 5′-3′ exonuclease or HJ arm-chopping that could apparently blur its classification as a canonical HJ resolvase. Despite this, we show that Yen1 fulfils the requirements of a canonical HJ resolvase and hypothesize that its wider array of nuclease activities might contribute to its function in the removal of persistent recombination or replication intermediates.
PEPATAC: an optimized pipeline for ATAC-seq data analysis with serial alignments
Authors: Smith Jason P , Corces M Ryan , Xu Jin , Reuter Vincent P , Chang Howard Y , Sheffield Nathan C
Published: December 2021

As chromatin accessibility data from ATAC-seq experiments continues to expand, there is continuing need for standardized analysis pipelines. Here, we present PEPATAC, an ATAC-seq pipeline that is easily applied to ATAC-seq projects of any size, from one-off experiments to large-scale sequencing projects. PEPATAC leverages unique features of ATAC-seq data to optimize for speed and accuracy, and it provides several unique analytical approaches. Output includes convenient quality control plots, summary statistics, and a variety of generally useful data formats to set the groundwork for subsequent project-specific data analysis. Downstream analysis is simplified by a standard definition format, modularity of components, and metadata APIs in R and Python. It is restartable, fault-tolerant, and can be run on local hardware, using any cluster resource manager, or in provided Linux containers. We also demonstrate the advantage of aligning to the mitochondrial genome serially, which improves the accuracy of alignment statistics and quality control metrics. PEPATAC is a robust and portable first step for any ATAC-seq project. BSD2-licensed code and documentation are available at https://pepatac.databio.org.
ChiTaH: a fast and accurate tool for identifying known human chimeric sequences from high-throughput sequencing data
Authors: Detroja Rajesh , Gorohovski Alessandro , Giwa Olawumi , Baum Gideon , Frenkel-Morgenstern Milana
Published: December 2021

Fusion genes or chimeras typically comprise sequences from two different genes. The chimeric RNAs of such joined sequences often serve as cancer drivers. Identifying such driver fusions in a given cancer or complex disease is important for diagnosis and treatment. The advent of next-generation sequencing technologies, such as DNA-Seq or RNA-Seq, together with the development of suitable computational tools, has made the global identification of chimeras in tumors possible. However, the testing of over 20 computational methods showed these to be limited in terms of chimera prediction sensitivity, specificity, and accurate quantification of junction reads. These shortcomings motivated us to develop the first ‘reference-based’ approach termed ChiTaH (Chimeric Transcripts from High–throughput sequencing data). ChiTaH uses 43,466 non–redundant known human chimeras as a reference database to map sequencing reads and to accurately identify chimeric reads. We benchmarked ChiTaH and four other methods to identify human chimeras, leveraging both simulated and real sequencing datasets. ChiTaH was found to be the most accurate and fastest method for identifying known human chimeras from simulated and sequencing datasets. Moreover, especially ChiTaH uncovered heterogeneity of the BCR-ABL1 chimera in both bulk and single-cells of the K-562 cell line, which was confirmed experimentally.
Advances in the diagnosis, evaluation, and management of leptomeningeal disease
Authors: Sener Ugur , Kumthekar Priya , Boire Adrienne
Published: December 2021

Leptomeningeal metastasis (LM) is a devastating complication of cancer with variable clinical presentation and limited benefit from existing treatment options. In this review, we discuss advances in LM diagnostics and therapeutics with the potential to reverse this grim course. Emerging cerebrospinal fluid circulating tumor cell and cell-free tumor DNA analysis technologies will improve diagnosis of LM, while providing crucial genetic information, capturing tumor heterogeneity, and quantifying disease burden. Circulating tumor cells and cell-free tumor DNA have utility as biomarkers to track disease progression and treatment response. Treatment options for LM include ventriculoperitoneal shunting for symptomatic relief, radiation therapy including whole-brain radiation and focal radiation for bulky leptomeningeal involvement, and systemic and intrathecal medical therapies, including targeted and immunotherapies based on tumor mutational profiling. While existing treatments for LM have limited efficacy, recent advances in liquid biopsy together with increasing availability of targeted treatments will lead to rational multimodal individualized treatments and improved patient outcomes.
Animal models of brain metastasis
Authors: Miarka Lauritz , Valiente Manuel
Published: December 2021

Modeling of metastatic disease in animal models is a critical resource to study the complexity of this multi-step process in a relevant system. Available models of metastatic disease to the brain are still far from ideal but they allow to address specific aspects of the biology or mimic clinically relevant scenarios. We not only review experimental models and their potential improvements but also discuss specific answers that could be obtained from them on unsolved aspects of clinical management.
The microenvironment of brain metastases from solid tumors
Authors: Srinivasan Ethan S , Deshpande Krutika , Neman Josh , Winkler Frank , Khasraw Mustafa
Published: December 2021

Brain metastasis (BrM) is an area of unmet medical need that poses unique therapeutic challenges and heralds a dismal prognosis. The intracranial tumor microenvironment (TME) presents several challenges, including the therapy-resistant blood–brain barrier, a unique immune milieu, distinct intercellular interactions, and specific metabolic conditions, that are responsible for treatment failures and poor clinical outcomes. There is a complex interplay between malignant cells that metastasize to the central nervous system (CNS) and the native TME. Cancer cells take advantage of vascular, neuronal, immune, and anatomical vulnerabilities to proliferate with mechanisms specific to the CNS. In this review, we discuss unique aspects of the TME in the context of brain metastases and pathways through which the TME may hold the key to the discovery of new and effective therapies for patients with BrM.
Modulation of the blood-tumor barrier to enhance drug delivery and efficacy for brain metastases
Authors: Blethen Kathryn E , Arsiwala Tasneem A , Fladeland Ross A , Sprowls Samuel A , Panchal Dhruvi M , Adkins Chris E , Kielkowski Brooke N , Earp Leland E , Glass Morgan J , Pritt Trenton A , Cabuyao Yssabela M , Aulakh Sonikpreet , Lockman Paul R
Published: December 2021

The blood-brain barrier is the selectively permeable vasculature of the brain vital for maintaining homeostasis and neurological function. Low permeability is beneficial in the presence of toxins and pathogens in the blood. However, in the presence of metastatic brain tumors, it is a challenge for drug delivery. Although the blood-tumor barrier is slightly leaky, it still is not permissive enough to allow the accumulation of therapeutic drug concentrations in brain metastases. Herein, we discuss the differences between primary brain tumors and metastatic brain tumors vasculature, effects of therapeutics on the blood-tumor barrier, and characteristics to be manipulated for more effective drug delivery.
Emergent immunotherapy approaches for brain metastases
Authors: Wang Jianbo , Tawbi Hussein A
Published: December 2021

Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients’ overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%–20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.
Itch perception is reflected by neuronal ignition in the primary somatosensory cortex
Authors: Chen Xiao-Jun , Liu Yan-He , Xu Ning-Long , Sun Yan-Gang
Published: December 2021

Multiple cortical areas including the primary somatosensory cortex (S1) are activated during itch signal processing, yet cortical representation of itch perception remains unknown. Using novel miniature two-photon microscopic imaging in free-moving mice, we investigated the coding of itch perception in S1. We found that pharmacological inactivation of S1 abolished itch-induced scratching behavior, and the itch-induced scratching behavior could be well predicted by the activity of a fraction of layer 2/3 pyramidal neurons, suggesting that a subpopulation of S1 pyramidal neurons encoded itch perception, as indicated by immediate subsequent scratching behaviors. With a newly established optogenetics-based paradigm that allows precisely controlled pruritic stimulation, we found that a small fraction of S1 neurons exhibited an ignition-like pattern at the detection threshold of itch perception. Our study revealed the neural mechanism underlying itch perceptual coding in S1, thus paving the way for the study of cortical representation of itch perception at the single-neuron level in freely moving animals.
A diagnostic conundrum in the context of a pandemic of Coronavirus Disease 2019 (COVID-19)
Authors: Abraham Deborah L , Omatseye Joyce , Gittens Jason
Published: December 2021

A 52-year-old with lung cancer and brain metastases, on a 3-month weaning regime of dexamethasone, had a coincidental finding of bilateral, patchy ground-glass opacifications of both central and peripheral lung fields on computed tomography (CT). This was reported to be a sign of Coronavirus Disease 2019 (COVID-19). On Day 13, due to poor clinical progression and multiple negative reverse transcriptase-polymerase chain reaction tests for COVID-19, an alternative diagnosis was sought. Subsequently, this led to a diagnosis of Pneumocystis jirovecii pneumonia. This case demonstrates complicating factors in the diagnosis of COVID-19 and the presence of cognitive bias during a pandemic, which may lead clinicians to overlook a diagnosis, which may otherwise be addressed earlier.
Laser additive manufacturing of metallic glasses: issues in vitrification and mechanical properties
Authors: Madge Shantanu V , Greer A Lindsay
Published: December 2021

Bulk metallic glasses (BMGs), on account of their attractive properties, have now begun to witness a few commercial applications, e.g. in coatings and micro-gears. Additive manufacturing (AM) or 3D printing, although established for crystalline alloys, has only recently been used for synthesizing BMG components. The issues arising in 3D printing of BMGs are of current relevance, and this review focuses on the key scientific aspects, namely vitrification (or crystallization) during printing, mechanical properties of printed glassy alloys and the use of AM in identifying newer BMGs. Available data on crystallization during printing of a variety of BMGs are analysed in terms of schematic time–temperature–transformation diagrams and the complex interplay between thermal cycles, the presence of quenched-in nuclei in the glass and oxygen contamination in a way that is hoped to be broadly applicable to most alloy systems. Also reviewed are three key factors influencing mechanical properties of printed BMGs, i.e. porosity, crystallinity and oxygen contamination and thereby potential strategies for improvement are suggested. The review concludes with a discussion on the use of AM for combinatorial alloy development aimed at identifying better glass-forming compositions, which may in turn facilitate greater use of AM in manufacturing glassy components with desired properties.
Water, Fish and Property in Colonial India, 1860–1890
Authors: Shankar Devika
Published: December 2021

Almost exactly a hundred years after the Permanent Settlement of 1793 revolutionized property relations in Bengal, a far less studied legislation would subtly extend the rule of property to include the province’s waters. Bengal’s Private Fisheries Protection Act 1889, which is usually regarded as having been motivated by conservationist or economic concerns, was in fact an attempt to resolve intractable legal problems surrounding the status of flowing waters and fish that had confounded judges and colonial officials in India for decades. Could water be owned like land? And could fish swimming in open waters be claimed as property? These questions would give rise to a number of important disputes in colonial India in the late nineteenth century, during a time associated with unprecedented changes in the agrarian economy. Coinciding with other legal manoeuvres that increasingly helped to render water as property in other parts of the world, the Private Fisheries Protection Act and important judgments that preceded it helped to create exceptional private rights over flowing waters in colonial India. Turning to these developments, this article examines the ways in which judges attempted to resolve contradictions generated by water’s very materiality in an economy that rested so heavily on property.
A 2-oxoglutarate-dependent dioxygenase converts dihydrofuran to furan in Salvia diterpenoids
Authors: Song Jiao-Jiao , Fang Xin , Li Chen-Yi , Jiang Yan , Li Jian-Xu , Wu Sheng , Guo Juan , Liu Yan , Fan Hang , Huang Yan-Bo , Wei Yu-Kun , Kong Yu , Zhao Qing , Xu Jing-Jing , Hu Yong-Hong , Chen Xiao-Ya , Yang Lei
Published: December 2021

Tanshinone ⅡA (TⅡA), a diterpene quinone with a furan ring, is a bioactive compound found in the medicinal herb redroot sage (Salvia miltiorrhiza Bunge), in which both furan and dihydrofuran analogs are present in abundance. Progress has been made recently in elucidating the tanshinone biosynthetic pathway, including heterocyclization of the dihydrofuran D-ring by cytochrome P450s; however, dehydrogenation of dihydrofuran to furan, a key step of furan ring formation, remains uncharacterized. Here, by differential transcriptome mining, we identified six 2-oxoglutarate-dependent dioxygenase (2-ODD) genes whose expressions corresponded to tanshinone biosynthesis. We showed that Sm2-ODD14 acts as a dehydrogenase catalyzing the furan ring aromatization. In vitro Sm2-ODD14 converted cryptotanshinone to TⅡA and thus was designated TⅡA synthase (SmTⅡAS). Furthermore, SmTⅡAS showed a strict substrate specificity, and repression of SmTⅡAS expression in hairy root by RNAi led to increased accumulation of total dihydrofuran-tanshinones and decreased production of furan-tanshinones. We conclude that SmTⅡAS controls the metabolite flux from dihydrofuran- to furan-tanshinones, which influences medicinal properties of S. miltiorrhiza.
Suppression of chloroplast triose phosphate isomerase evokes inorganic phosphate-limited photosynthesis in rice
Authors: Suzuki Yuji , Ishiyama Keiki , Yoon Dong-Kyung , Takegahara-Tamakawa Yuki , Kondo Eri , Suganami Mao , Wada Shinya , Miyake Chikahiro , Makino Amane
Published: December 2021

The availability of inorganic phosphate (Pi) for ATP synthesis is thought to limit photosynthesis at elevated [CO2] when Pi regeneration via sucrose or starch synthesis is limited. We report here another mechanism for the occurrence of Pi-limited photosynthesis caused by insufficient capacity of chloroplast triose phosphate isomerase (cpTPI). In cpTPI-antisense transgenic rice (Oryza sativa) plants with 55%–86% reductions in cpTPI content, CO2 sensitivity of the rate of CO2 assimilation (A) decreased and even reversed at elevated [CO2]. The pool sizes of the Calvin–Benson cycle metabolites from pentose phosphates to 3-phosphoglycerate increased at elevated [CO2], whereas those of ATP decreased. These phenomena are similar to the typical symptoms of Pi-limited photosynthesis, suggesting sufficient capacity of cpTPI is necessary to prevent the occurrence of Pi-limited photosynthesis and that cpTPI content moderately affects photosynthetic capacity at elevated [CO2]. As there tended to be slight variations in the amounts of total leaf-N depending on the genotypes, relationships between A and the amounts of cpTPI were examined after these parameters were expressed per unit amount of total leaf-N (A/N and cpTPI/N, respectively). A/N at elevated [CO2] decreased linearly as cpTPI/N decreased before A/N sharply decreased, owing to further decreases in cpTPI/N. Within this linear range, decreases in cpTPI/N by 80% led to decreases up to 27% in A/N at elevated [CO2]. Thus, cpTPI function is crucial for photosynthesis at elevated [CO2].
Old Boys’ Clubs and Upward Mobility Among the Educational Elite
Authors: Michelman Valerie , Price Joseph , Zimmerman Seth D
Published: December 2021

This article studies how exclusive social groups shape upward mobility and whether interactions between low- and high-status peers can integrate the top rungs of the economic and social ladders. Our setting is Harvard University in the 1920s and 1930s, where new groups of students arriving on campus encountered a social system centered on exclusive old boys’ clubs. Combining archival and census records, we first show that students from prestigious private feeder schools are overrepresented in old boys’ clubs, while academic high achievers and ethnic minorities are almost completely absent. Club members earn $32\%$ more than other students and are more likely to work in finance and join country clubs, both characteristic of the era’s elite. We use random variation in room assignment to show that exposure to high-status peers expands gaps in college club membership, adult social club membership, and finance careers by high school type, with large positive effects for private school students and zero or negative effects for others. To conclude, we turn to more recent cohorts. We show that the link between exclusive college clubs and finance careers persists across the twentieth century even as Harvard diversifies, and that elite university students from the highest-income families continue to outearn their peers.
Off-farm income and direct payments—an indispensable diversification strategy of Swiss farmers
Authors: El Benni Nadja , Schmid Dierk
Published: December 2021

Following the theory of a farm household model, the relations between farm and farmer characteristics, including two different kinds of direct payments, and their effects on the off-farm labour allocation decisions of farm operators were analysed. Swiss farm accountancy data network (FADN) data of the years 2017, 2018, and 2019 for the whole sample and two different income groups were used to model both off-farm labour participation and supply decisions. The results show that diversification into off-farm employment is a highly relevant strategy of Swiss farmers and that direct payments are a complementary income source. Above a certain level, biodiversity payments show a substitution effect, meaning that off-farm participation is reduced. Off-farm labour supply is related not to direct payments but to production type and technology, with dairy and organic farmers having spent fewer days engaging in off-farm employment. Education positively correlates to off-farm labour participation. Even though off-farm income and direct payments are an indispensable income source for Swiss farmers, income-related policy goals cannot be considered achieved in terms of either farm or household income. Whether public money would be better spent on education than on unprofitable farm businesses should be analysed in future studies.
Clinical presentation and treatment response in patients with polymyalgia rheumatica and giant cell arteritis during a 40-week follow-up
Authors: Emamifar Amir , Hess Søren , Ellingsen Torkell , Gerke Oke , Ahangarani Farahani Ziba , Syrak Hansen Per , Jensen Hansen Inger Marie , Thye-Rønn Peter
Published: December 2021

Objectives

The aim was to study the clinical features of PMR/GCA and clinical predictors of treatment response during a 40-week follow-up period.

Methods

Clinical data on 77 patients with newly diagnosed PMR/GCA who were treated with oral glucocorticoids were gathered at baseline and during a 40-week follow-up period. A unilateral temporal artery biopsy (TAB) and 18F-fluorodeoxyglucose (18F-FDG) PET/CT were undertaken at diagnosis. In total, each patient was seen on five occasions (i.e. baseline and weeks 4, 16, 28 and 40). Treatment response was assessed by considering clinical evaluations and results of inflammatory markers.

Results

Of 77 patients [49 (63.6%) female; mean age 71.8 (8.0) years], 64 (83.1%) patients had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. The patients reported that clinical symptoms, apart from scalp pain and duration of morning stiffness, improved significantly at week 4 and remained lower at week 40 compared with the relative frequencies at baseline. Besides, all components of physical examination showed significant improvement and remained lower at week 40 compared with the baseline. A complete response was seen in 68.7, 62.9, 44.1 and 33.3% of patients at weeks 4, 16, 28 and 40, respectively. Several clinical features, including female biological sex, younger age, fewer relapses and a lower level of baseline ESR, were significantly associated with a better treatment response. Treatment response during the follow-up period was independent of TAB results and fluorodeoxyglucose uptakes on 18F-FDG PET/CT at diagnosis.

Conclusion

Obtaining valid disease-specific outcome measures for evaluating treatment efficacy in PMR and GCA that can be applied universally is clearly an unmet clinical need.

Trial registration

ClinicalTrials.gov, https://clinicaltrials.gov, NCT02985424.