bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Case Study of the Use of Real-World Evidence to Support the Registration of an Osteoporosis Product in China
Authors: Storm Neal E. , Chang Wen , Lin Tzu-Chieh , Lange Jeff L. , Bradbury Brian , Critchlow Cathy W. , Galson Steven K.
Published: October 2021

On June 23, 2020, Prolia® (denosumab) was approved by the National Medical Products Administration (NMPA) in the People’s Republic of China as the first monoclonal antibody for the treatment of postmenopausal women with osteoporosis at high risk of fractures. Its brand name in Chinese is 普罗力, a transliteration from the English name “Prolia”, which has an implied meaning of “to give strength to everyone”— a suitable name for a potent anti-resorptive therapy. The approval was supported by a novel marketing authorization application (MAA) that included data from Prolia’s global clinical trial program establishing favorable efficacy and safety, augmented by results from a real-world evidence (RWE) study confirming the effectiveness and safety of Prolia in clinical practice within Taiwan and Hong Kong. Key constructs for this registration-quality RWE study included the fit-for-purpose assessment of data quality, methodology and quantitative assessment of potential biases, good practices of study conduct, and reproducibility of results. Using data from clinical practice in Taiwan and Hong Kong to evaluate the benefits versus risks of Prolia treatment in ethnic Chinese women with postmenopausal osteoporosis, the RWE study results for effectiveness were comparable to efficacy demonstrated in the global clinical trial program and results for safety were consistent with the incidence observed in global post-marketing safety studies. While RWE is often used to monitor postmarket safety of drug products, support health insurance coverage decisions, and inform clinicians on real-world use of medicines, it has not been widely used to support regulatory approval for new medicines in lieu of clinical bridging studies in countries where such studies are required. Well-conducted registrational RWE studies can play a pivotal role in complementing the totality of evidence presented in an MAA. The benefits of such an approach include avoiding the collection of additional placebo-controlled trial data in populations where adequate ethnic characterization of efficacy, effectiveness, and safety may already exist from postmarketing sources, and accelerate access for patients to innovative medicines in important regions. Here, we describe a regulatory case study of a novel MAA incorporating RWE that provided important evidence to confirm the benefit:risk of a new drug and facilitated a label expansion to a new patient population.
Synthesis of conical Co–Fe alloys structures obtained with crystal modifier in superimposed magnetic field
Authors: Skibińska Katarzyna , Kutyła Dawid , Kołczyk-Siedlecka Karolina , Marzec Mateusz M. , Żabiński Piotr , Kowalik Remigiusz
Published: October 2021

The addition of crystal modifier to electrolyte used during electrodeposition of metals and alloys allows obtaining conical structures without using any template. This method is fast and ensures covering large areas during one single electrodeposition process. In this work, Co–Fe cones were obtained by one-step method with ammonium chloride as a crystal modifier. The influence of electrodeposition parameters and electrolyte compositions were investigated. Electrodeposition conditions (duration, electrolyte temperature, and addition of NH4Cl), which allow obtaining the most uniform conical structures, were applied during sample fabrication in the magnetic field. The influence of its value and direction on the quality and compositions of obtained alloys was investigated using Scanning Electron Microscope (SEM) photos. To check if there is any change in the sample crystal system, the X-Ray Diffraction (XRD) analysis was performed. To confirm the synthesis of Co–Fe cones, they were analyzed using the X-ray photoelectron Spectroscopy (XPS) method.
Rehabilitation and Remediation of Internationally Adopted Children
Authors: Gindis Boris
Published: October 2021

This book presents specific methods for the physical rehabilitation, mental health restoration, and academic remediation of post-institutionalized international adoptees. The focus of the book is on the neurological, psychological, and educational consequences of complex childhood trauma in the context of a fundamental change in the social situation of development of former orphanage residents. A discussion of after-adoption traumatic experiences includes a critique of certain “conventional” approaches to the treatment of mental health issues and different disabilities in international adoptees. Using his 30-year background in research and clinical practice, the author expertly describes and analyses a range of methodologies in order to provide an integrated and practical system of “scaffolding” and “compensation” for the successful rehabilitation and remediation of children with ongoing traumatic experiences. This is essential reading for researchers and practicing clinicians concerned with childhood trauma, remedial education, and issues of international adoption.
Community Disaster Recovery
Authors: Crow Deserai A. , Albright Elizabeth A.
Published: October 2021

Disasters can serve as focusing events that increase agenda attention related to issues of disaster response, recovery, and preparedness. Increased agenda attention can lead to policy changes and organisational learning. The degree and type of learning that occurs within a government organization after a disaster may matter to policy outcomes related to individual, household, and community-level risks and resilience. Local governments are the first line of disaster response but also bear the burden of performing long-term disaster recovery and planning for future events. Crow and Albright present the first framework for understanding if, how, and to what effect communities and local governments learn after a disaster strikes. Drawing from analyses conducted over a five-year period following extreme flooding in Colorado, USA, Community Disaster Recovery: Moving from Vulnerability to Resilience presents a framework of community-level learning after disaster and the factors that catalyse policy change towards resilience.
The Unfinished History of the Iran-Iraq War
Authors: Tracy Samuel Annie
Published: October 2021

The Islamic Revolutionary Guard Corps (IRGC), founded after the Iranian revolution in 1979, is one of the most powerful and prominent but least understood organizations in Iran. In this book, Annie Tracy Samuel presents an innovative and compelling history of this organization and, by using the Iran-Iraq War as a focal point, analyzes the links between war and revolution. Tracy Samuel provides an internal view of the IRGC by examining how the Revolutionary Guards have recorded and assessed the history of the war in the massive volume of Persian language publications produced by the organization's top members and units. This not only enhances our comprehension of the IRGC's roles and power in contemporary Iran, but also demonstrates how the history of the Iran-Iraq War has immense bearing on the Islamic Republic's present and future. In doing so, the book reveals how analyzing Iran's history provides the critical tools for understanding its actions today.
Wisdom
Authors: Sternberg Robert J. , Glück Judith
Published: October 2021

The world is simultaneously facing many crises that humanity is failing to solve. Yet, at the same time, humans are smarter (with IQs on average thirty points higher than a century ago) and more knowledgeable (with the world's knowledge base at our fingertips), and scientific advances are accelerating. However, intelligence and knowledge are not enough: wisdom harnesses these strengths to serve the common good. Education is focused on acquiring knowledge, but schools would do better also to teach and test for the development of wisdom. To a lot of people, wisdom is an abstraction, but there is a growing body of scientific research into what wisdom is and how it works. This introduction sets out why wisdom is so important. Drawing on insights from psychology, philosophy, science, and common sense, this book provides a complete account of wisdom and how we can develop it throughout our lives.
International Law and the European Union
Authors: Odermatt Jed
Published: October 2021

The European Union plays a significant role in international affairs. International Law and the European Union examines the impact this has had on public international law by integrating perspectives from both EU law and international law. Its analysis focuses on fields of public international law where the EU has had an influence, including customary international law, the law of treaties, international organizations, international dispute settlement, and international responsibility. International Law and the European Union shows how the EU has had a subtle but significant impact on the development of international law and how the international legal order has developed and adjusted to accommodate the EU as a distinct legal actor. In doing so, it contributes to our understanding of how international law addresses legal subjects other than States.
The Spread of Print in Colonial India
Authors: Gupta Abhijit
Published: October 2021

This study focuses on the spread of print in colonial India towards the middle and end of the nineteenth century. Till the first half of the century, much of the print production in the subcontinent emanated from presidency cities such as Calcutta, Bombay and Madras, along with centres of missionary production such as Serampore. But with the growing socialization of print and the entry of local entrepreneurs into the field, print began to spread from the metropole to the provinces, from large cities to mofussil towns. This Element will look at this phenomenon in eastern India, and survey how printing spread from Calcutta to centres such as Hooghly-Chinsurah, Murshidabad, Burdwan, Rangpur etc. The study will particularly consider the rise of periodicals and newspapers in the mofussil, and asses their contribution to a nascent public sphere.
When Does Migration Law Discriminate Against Women?
Authors: Briddick Catherine
Published: October 2021

It is possible to identify gendered disadvantage at almost every point in a migrant woman's journey, physical and legal, from country of origin to country of destination, from admission to naturalization. Rules which explicitly distribute migration opportunities differently on the grounds of sex/gender, such as prohibitions on certain women's emigration, may produce such disadvantage. Women may also, however, be disadvantaged by facially gender-neutral rules. Examples of indirectly disadvantageous provisions include those which classify certain forms of labor as either “low-” or “high-” skilled, using this categorization to distribute migration opportunities differentially. Such rules may disproportionately affect the mostly female workers whose labor in certain fields is considered “low-skilled” in comparison to that undertaken by their predominantly male, “high-skilled” counterparts. Scholars have identified the diverse ways in which states’ immigration and nationality laws continue to involve gendered and racialized exclusion, subordination, and violence. Migration control practices, including those concerned with deterrence, detention, and deportation, have also been impugned on these bases. This essay draws on this literature to examine whether rules that produce gendered disadvantage are open to challenge under the international legal regime charged with eradicating discrimination against women, the Convention on the Elimination of all Forms of Discrimination Against Women (CEDAW).
Uncertainty quantification and reduction using Jacobian and Hessian information
Authors: Sánchez Josefina , Otto Kevin
Published: October 2021

Robust design methods have expanded from experimental techniques to include sampling methods, sensitivity analysis and probabilistic optimisation. Such methods typically require many evaluations. We study design and noise variable cross-term second derivatives of a response to quickly identify design variables that reduce response variability. We first compute the response uncertainty and variance decomposition to determine contributing noise variables of an initial design. Then we compute the Hessian second-derivative matrix cross-terms between the variance-contributing noise variables and proposed design change variables. Design variable with large Hessian terms are those that can reduce response variability. We relate the Hessian coefficients to reduction in Sobol indices and response variance change. Next, the first derivative Jacobian terms indicate which design variable can shift the mean to maintain a desired nominal target value. Thereby, design changes can be proposed to reduce variability while maintaining a targeted nominal value. This workflow finds changes that improve robustness with a minimal four runs per design change. We also explore further computation reductions achieved through compounding variables. An example is shown on a Stirling engine where the top four variance-contributing tolerances and design changes identified through 16 Hessian terms generated a design with 20% less variance.
Governing Fake News: The Regulation of Social Media and the Right to Freedom of Expression in the Era of Emergency
Authors: Vese Donato
Published: October 2021

Governments around the world are strictly regulating information on social media in the interests of addressing fake news. There is, however, a risk that the uncontrolled spread of information could increase the adverse effects of the COVID-19 health emergency through the influence of false and misleading news. Yet governments may well use health emergency regulation as a pretext for implementing draconian restrictions on the right to freedom of expression, as well as increasing social media censorship (ie chilling effects). This article seeks to challenge the stringent legislative and administrative measures governments have recently put in place in order to analyse their negative implications for the right to freedom of expression and to suggest different regulatory approaches in the context of public law. These controversial government policies are discussed in order to clarify why freedom of expression cannot be allowed to be jeopardised in the process of trying to manage fake news. Firstly, an analysis of the legal definition of fake news in academia is presented in order to establish the essential characteristics of the phenomenon (Section II). Secondly, the legislative and administrative measures implemented by governments at both international (Section III) and European Union (EU) levels (Section IV) are assessed, showing how they may undermine a core human right by curtailing freedom of expression. Then, starting from the premise of social media as a “watchdog” of democracy and moving on to the contention that fake news is a phenomenon of “mature” democracy, the article argues that public law already protects freedom of expression and ensures its effectiveness at the international and EU levels through some fundamental rules (Section V). There follows a discussion of the key regulatory approaches, and, as alternatives to government intervention, self-regulation and especially empowering users are proposed as strategies to effectively manage fake news by mitigating the risks of undue interference by regulators in the right to freedom of expression (Section VI). The article concludes by offering some remarks on the proposed solution and in particular by recommending the implementation of reliability ratings on social media platforms (Section VII).
Psychiatric court reports and diversion outcomes in a remand prison over three years
Authors: Tong Kezanne , Smith Damian , Mohan Christopher , Hickey Philip , Taylor Enda , McLoughlin Lisa , Kennedy Harry G. , O’Neill Conor
Published: October 2021

Objectives:

There has been a notable increase in requests for psychiatric reports from District Courts for persons remanded to Ireland’s main remand prison, Cloverhill. We aimed to identify if reports were prepared for persons with severe mental illness and if they led to therapeutic benefits such as diversion to healthcare. Measures of equitability between Cloverhill and other District Courts were explored.

Methods:

For District Court-requested reports completed by the Prison Inreach and Court Liaison Service (PICLS) at Cloverhill Prison from 2015 to 2017, we recorded clinical variables and therapeutic outcomes such as diversion to inpatient psychiatric settings.

Results:

Of 236 cases, over half were diverted to inpatient or outpatient psychiatric care. One-third of remand episodes were admitted to a psychiatric hospital, mainly in non-forensic settings. Nearly two-thirds had major mental illness, mainly schizophrenia and related conditions. Almost half had active psychosis. Cases in Cloverhill District Court and other District Courts were similarly likely to have active psychosis (47% overall) and hospital admission (33% overall). Voluntary reports were more likely to identify active psychosis, with over 90% diverted to inpatient or outpatient community treatment settings.

Conclusions:

This is the first large scale study of diversion outcomes following requests for psychiatric advice from District Courts in Ireland. Requests were mainly appropriate. Over half led to diversion from the criminal justice system to healthcare settings. There is a need for a complementary network of diversion initiatives at every stage of the criminal justice system to effectively divert mentally ill individuals to appropriate settings at the earliest possible stage.
A Perpetuity of Lesser Emptiness: The Social Space of the Postcolonial Small Town and Vinod Kumar Shukla’s Naukar kī kamīz
Authors: Sperner Philipp
Published: October 2021

The article provides an analysis of the spatial configuration of the Hindi novel Naukar kī kamīz by Vinod Kumar Shukla (translated into English as The Servant’s Shirt). In highlighting the argumentative and structural similarities between the content of the novel and various concepts of social space and literary spatiality developed by Catherine Régulier, Henri Lefebrve, Edward Soja, Mikhail Bakhtin, and others, the article proposes to read the novel not only as a rare example of a detailed engagement with the social space of a postcolonial small town, but also as a text that provides a useful method and indeed a theory for the analysis of such a small town and its literary representation.
Unmitigated negative nasopharyngeal pressure is associated with attic retraction pocket formation: LaPlace's law in action
Authors: Mahajan Nilesh H , Vijayendra H , Vijayendra Vinay Kumar , Redleaf Miriam
Published: October 2021

Background

Decades of clinical observation have led our subspecialty team to suspect that negative nasopharyngeal pressure is associated with attic retraction pocket formation. Furthermore, LaPlace's law, which states that the pressure within a sphere varies with the inverse of the radius, provides the dynamic explanation for why the attic area of the tympanic membrane tends to retract more frequently than the pars tensa.

Methods

The attic retraction pockets of 154 patients were classified into grades of severity (grades I–V). Impedance audiometry of middle-ear pressure was measured in the resting state, and after sniffing, swallowing and the Valsalva manoeuvre.

Results

Negative nasopharyngeal pressure (sniffing) caused a diminution of middle-ear pressure of −5 daPa on average in normal ears, and of −24 daPa to −45 daPa for tympanic membranes with attic retraction pockets of grade I to grade V.

Conclusion

Attic retraction pockets are associated with greater collapse of middle-ear volume when negative pressure is created in the nasopharynx. LaPlace's law, and the composition of the pars flaccida, suggests an explanation for why the attic region retracts more than the pars tensa.
Thermal Tides in the Upper Cloud Layer of Venus as Deduced From the Emission Angle Dependence of the Brightness Temperature by Akatsuki/LIR
Authors: Akiba Masahiro , Taguchi Makoto , Fukuhara Tetsuya , Imamura Takeshi , Kouyama Toru , Sato Takao M.
Published: October 2021

The brightness temperature of the Venus disk obtained by Longwave Infrared Camera (LIR) on board Akatsuki shows clear limb darkening at low and middle latitudes. The profile of limb brightness reflects the vertical distributions of atmospheric temperature and the optical thickness of the cloud particles. Horizontal distributions of brightness temperature obtained by LIR during ∼5.8 Venusian years were analyzed to investigate the vertical structure of the brightness temperature distribution above the cloud tops based on the emission angle dependence of the sensing altitude. Emission angles were converted to sensing altitudes by a radiative transfer calculation with nominal temperature and cloud particle distributions based on past observations. We show a local time‐altitude cross section of the brightness temperature deviation above the cloud tops for three latitudinal zones. The derived vertical amplitude distribution of the diurnal and semidiurnal tides above ∼68 km is mostly explained by the classical theory of thermal tides. A semidiurnal tide in which the phase shifts upstream with altitude is clearly seen in the equatorial region. By applying the dispersion relation of the internal gravity wave to the observed wave structure, it was found that the zonally averaged zonal wind velocity at altitudes of 66–71 km was approximately the same as the known superrotation velocity. By comparing the observed and simulated vertical phase structures, it is suggested that the tidal wave structure seen in the equatorial cloud tops is an aspect of upward propagation of a gravity wave generated in the upper cloud layer by solar heating.
Climate as the Great Equalizer of Continental‐Scale Erosion
Authors: Jepson Gilby , Carrapa Barbara , Gillespie Jack , Feng Ran , DeCelles Peter G. , Kapp Paul , Tabor Clay R. , Zhu Jiang
Published: October 2021

Central Asia hosts the most extensive and highest topography on Earth, which is the result of the feedbacks among rock uplift, atmospheric circulation and moisture transport, and erosion. Here, we analyze 2,511 published low‐temperature thermochronometric ages as a proxy of the regional‐scale erosion of Central Asia. We compare these ages to tectonic and climate proxies, and state‐of‐the‐art paleoclimate simulations to constrain the inﬂuences of climate and tectonics on the topographic architecture of Central Asia. We observe a ﬁrst‐order relationship between younger cooling ages in areas of high precipitation and older ages (Mesozoic) in areas that have been sheltered from precipitation, despite high strain rates. Thus, we suggest that climate enhances erosion in areas where rock uplift produces signiﬁcant orographic gradients, whereas in the continental interior, areas which are tectonically active but have been sheltered from signiﬁcant precipitation record older ages and a longer erosional history.
Ionospheric Response to Sudden Stratospheric Warming Events Across Longitudes During Solar Cycle 24
Authors: Gupta Sumedha , Upadhayaya A. K. , Siingh Devendraa
Published: October 2021

Solar cycle 24 from December 2008 to December 2019 had an unusual progression and was the weakest cycle in a century, providing an ideal scenario to study perceivable effect of wave forcing from lower atmosphere. This study examines the ionospheric response to meteorological phenomenon of sudden stratospheric warming (SSW) during solar cycle 24 (Arctic winter 2008/2009 to 2018/2019) using Global Positioning System‐derived total electron content (VTEC) and its deviation from monthly median (ΔVTEC) for four longitudinal chains. Each chain comprises eight stations, covering varied latitudes in both hemispheres. A longitude‐ and latitude‐dependent response of VTEC is observed within ∼3 weeks of peak polar stratospheric temperature anomaly (ΔTmax), with maximum variations seen for low‐latitude stations at American and Australian‐East Asian sectors. It is seen that variations during minor warming events are comparable or at times even larger than during major warming events. These responses increase with an increase in solar activity, with major SSW events primarily seen during moderate and low solar activity periods and minor SSW during high solar activity period. Under similar ionizing conditions, a quite similar ionospheric response is observed irrespective of ΔTmax and of SSW type (major or minor); however, under similar SSW strength, no prominent pattern in ionospheric response is observed. Latitude‐dependent semidiurnal ionospheric behavior is observed for only a few events. This vertical coupling between lower and upper atmosphere during SSW is predominantly influenced by 13–16 days periodicities in VTEC, along with other periodicities of 9, 7, 5, and 3 days.
Ripples, Transverse Aeolian Ridges, and Dark‐Toned Sand Dunes on Mars: A Case Study in Terra Sabaea
Authors: Lu Y. , Edgett K. S. , Wu Y. Z.
Published: October 2021

Ripples, transverse aeolian ridges (TARs), and dark‐toned sand sheets and dunes are common aeolian bedforms on the Martian surface. They are important for understanding the nature of present‐day Martian sediments and regional aeolian processes. Here we present a case study investigation of ripples, TARs, a dark‐toned sand sheet, and dunes in an unnamed—but well‐covered by remote sensing datasets—crater in Terra Sabaea, Mars, to consider their nature and possible origin scenarios. Repeat high‐spatial resolution images show only minor albedo changes among the dark‐toned sand dunes but no obvious changes in the ripples and TARs. Visible and infrared spectra show that the megaripples and TARs are pyroxene‐bearing, while the dark‐toned sheet and dunes are olivine‐bearing. Thousands of TARs are superimposed on the crater walls, and they have a similar composition as the bedrock exposed around the central pit, suggesting that some percentage of the sediment composing the TARs may be locally derived. Megaripples have a similar composition as TARs, suggesting they may share a similar origin. Dark‐toned sand sheets and sand dunes show a different composition from the substrate of the crater, plus bedform orientations indicative of a dominant, north‐northwest wind, indicating that some of these dark sands might have been blown in from outside of the crater. Alternatively, the sand in the megaripples, TARs, sand sheets, and dunes could share a common source, and some or even all of them could be recycled from the weathering and erosion of the sand‐bearing clastic rocks exposed in the crater walls.
MYH9 is crucial for stem cell-like properties in non-small cell lung cancer by activating mTOR signaling
Authors: Chen Meng , Sun Li-Xin , Yu Long , Liu Jun , Sun Li-Chao , Yang Zhi-Hua , Shu Xiong , Ran Yu-Liang
Published: October 2021

The fatality rate of non-small cell lung cancer (NSCLC) has been high due to the existence of cancer stem cells (CSCs). Non-muscle myosin heavy chain 9 (MYH9) can promote the progression of various tumors, but its effect on the stem cell-like characteristics of lung cancer cells (LCCs) has not been clarified. Our research found that the stemness characteristics of LCCs were significantly enhanced by the overexpression of MYH9, and the knockout of MYH9 had the opposite effects. The in vivo with inhibitor blebbistatin further confirmed the effect of MYH9 on the stem cell-like behavior of LCCs. Furthermore, western blotting showed that the expression level of CSCs markers (CD44, SOX2, Nanog, CD133, and OCT4) was also regulated by MYH9. Mechanistic studies have shown that MYH9 regulates stem cell-like features of LCCs by regulating the mTOR signaling pathway, which was supported by sphere formation experiments after LCCs were treated with inhibitors Rapamycin and CHIR-99021. Importantly, high expression of MYH9 in lung cancer is positively correlated with poor clinical prognosis and is an independent risk factor for patients with NSCLC.
MdWRKY75e enhances resistance to Alternaria alternata in Malus domestica
Authors: Hou Yingjun , Yu Xinyi , Chen Weiping , Zhuang Weibing , Wang Sanhong , Sun Chao , Cao Lifang , Zhou Tingting , Qu Shenchun
Published: October 2021

TheAlternaria alternataapple pathotype adversely affects apple (Malus domesticaBorkh.) cultivation. However, the molecular mechanisms underlying enhanced resistance to this pathogen in apple remain poorly understood. We have previously reported thatMdWRKY75expression is upregulated byA. alternatainfection in ‘Sushuai’ apples. In this study, we discovered that overexpression ofMdWRKY75eincreased the resistance of transgenic apple lines toA. alternatainfection, whereas silencing this gene enhanced susceptibility toA. alternatainfection. Furthermore, we found that MdWRKY75e directly binds to theMdLAC7promoter to regulate the biosynthesis of laccase and increase the biosynthesis of lignin duringA. alternatainfection. Moreover, the thickening of the cell wall enhanced the mechanical defense capabilities of apple. In addition, we found that jasmonic acid remarkably inducedMdWRKY75eexpression, and its levels in transgenic apple lines were elevated. These results indicate thatMdWRKY75econfers resistance to theA. alternataapple pathotype mainly via the jasmonic acid pathway and that pathogenesis-related genes and antioxidant-related enzyme activity are involved in the disease resistance ofMdWRKY75etransgenic plants. In conclusion, our findings provide insights into the importance ofMdWRKY75efor resistance toA. alternatainfection in apples.
Immune cell infiltration signatures identified molecular subtypes and underlying mechanisms in gastric cancer
Authors: Lin Yilin , Pan Xiaoxian , Zhao Long , Yang Changjiang , Zhang Zhen , Wang Bo , Gao Zhidong , Jiang Kewei , Ye Yingjiang , Wang Shan , Shen Zhanlong
Published: October 2021

Increasing evidence has clarified that the tumor microenvironment (TME) is closely related to the prognosis and therapeutic efficacy of cancer. However, there is no reliable TME evaluation system used to accurately predict the prognosis of and therapeutic efficacy in gastric cancer. We evaluated the immune microenvironment score (IMS) of 1422 gastric cancer samples based on 51 immune cell signatures. We explored the relationship between the IMS and prognosis, immune cell infiltration, cancer subtype, and potential immune escape mechanisms. The results show that activation of the stroma and decreased levels of immune infiltration were associated with a low IMS. A high IMS was characterized by Epstein–Barr virus infection, increased mutation load, microsatellite instability, and immune cell infiltration. A high IMS was also related to high expression of immune checkpoint molecules (PD-1/PD-L1). Finally, patients with a high IMS had a better response to PD-1/PD-L1 inhibitors and may be more suitable for immune checkpoint inhibitors (area under the curve = 0.81). In addition, a low IMS may be converted into the immune-infiltrating subtype after romidepsin treatment. Stratification based on the IMS may enable gastric cancer patients to benefit more from immunotherapy and help identify new cancer treatment strategies.
Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes
Authors: Quadalti Corinne , Calandra-Buonaura Giovanna , Baiardi Simone , Mastrangelo Andrea , Rossi Marcello , Zenesini Corrado , Giannini Giulia , Candelise Niccolò , Sambati Luisa , Polischi Barbara , Plazzi Giuseppe , Capellari Sabina , Cortelli Pietro , Parchi Piero
Published: October 2021

Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs;p = 0.002 vs MSA;p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs;p = 0.751 vs MSA;p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.
First delirium episode in Parkinson’s disease and parkinsonism: incidence, predictors, and outcomes
Authors: Green Samantha , Perrott Sarah L. , McCleary Andrew , Sleeman Isobel , Maple-Grødem Jodi , Counsell Carl E. , Macleod Angus D.
Published: October 2021

To define the incidence, predictors and prognosis of the first hospital delirium episode in Parkinson’s disease (PD) and atypical parkinsonism (AP), we identified the first hospital episode of delirium after diagnosis in the Parkinsonism Incidence in North-East Scotland (PINE) study, a prospective community-based incidence cohort of parkinsonism, using chart-based criteria to define delirium. Of 296 patients (189=PD, 107=AP [dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, vascular parkinsonism]), 152 developed delirium (PD = 98, AP = 54). Incidence of first hospital delirium episode per 100 person years was 8.1 (95% confidence interval [CI] 6.6–9.9) in PD and 18.5 (95% CI 13.9–24.7) in AP. Independent predictors of delirium were atypical parkinsonism (Hazard ratio [HR] vs PD = 2.83 [95% CI 1.60–5.03], age in PD but not in AP (HR for 10-year increase 2.29 [95% CI 1.74–3.02]), baseline MMSE (HR = 0.94 [95% CI 0.89–0.99]), APOE ε4 in PD (HR 2.16 [95% CI 1.15–4.08]), and MAPT H1/H1 in PD (HR 2.08 [95% CI 1.08–4.00]). Hazards of dementia and death after delirium vs before delirium were increased (dementia: HR = 6.93 [95% CI 4.18–11.48] in parkinsonism; death: HR = 3.76 [95% CI 2.65–5.35] in PD, 1.59 [95% CI 1.04–2.42] in AP). Delirium is a common non-motor feature of PD and AP and is associated with increased hazards of dementia and mortality. Whether interventions for early identification and treatment improve outcomes requires investigation.
Full monitoring of ensemble trajectories with 10 dB-sub-Heisenberg imprecision
Authors: Zander Jascha , Schnabel Roman
Published: October 2021

The change of a quantum state can generally only be fully monitored through simultaneous measurements of two non-commuting observables $$\hat{X}$$

X

̂

and $$\hat{Y}$$

Y

̂

spanning a phase space. A measurement device that is coupled to the thermal environment provides at a time a pair of values that have a minimal uncertainty product set by the Heisenberg uncertainty relation, which limits the precision of the monitoring. Here, we report on an optical ensemble measurement setup that is able to monitor the time-dependent change of the quantum state’s displacement in phase space ($$\langle \hat{X}(t)\rangle ;\langle \hat{Y}(t)\rangle$$

⟨

X

̂

(

t

)

⟩
;
⟨

Y

̂

(

t

)

⟩

) with an imprecision 10 dB below the Heisenberg uncertainty limit. Our setup provides pairs of values (X(ti); Y(ti)) from simultaneous measurements at subsequent times ti. The measurement references are not coupled to the thermal environment but are established by an entangled quantum state. Our achievement of a tenfold reduced quantum imprecision in monitoring arbitrary time-dependent displacements supports the potential of the quantum technology required for entanglement-enhanced metrology and sensing as well as measurement-based quantum computing.
The neuroscience of advanced scientific concepts
Authors: Mason Robert A. , Schumacher Reinhard A. , Just Marcel Adam
Published: October 2021

Cognitive neuroscience methods can identify the fMRI-measured neural representation of familiar individual concepts, such as apple, and decompose them into meaningful neural and semantic components. This approach was applied here to determine the neural representations and underlying dimensions of representation of far more abstract physics concepts related to matter and energy, such as fermion and dark matter, in the brains of 10 Carnegie Mellon physics faculty members who thought about the main properties of each of the concepts. One novel dimension coded the measurability vs. immeasurability of a concept. Another novel dimension of representation evoked particularly by post-classical concepts was associated with four types of cognitive processes, each linked to particular brain regions: (1) Reasoning about intangibles, taking into account their separation from direct experience and observability; (2) Assessing consilience with other, firmer knowledge; (3) Causal reasoning about relations that are not apparent or observable; and (4) Knowledge management of a large knowledge organization consisting of a multi-level structure of other concepts. Two other underlying dimensions, previously found in physics students, periodicity, and mathematical formulation, were also present in this faculty sample. The data were analyzed using factor analysis of stably responding voxels, a Gaussian-naïve Bayes machine-learning classification of the activation patterns associated with each concept, and a regression model that predicted activation patterns associated with each concept based on independent ratings of the dimensions of the concepts. The findings indicate that the human brain systematically organizes novel scientific concepts in terms of new dimensions of neural representation.
Optimal control strategies on COVID-19 infection to bolster the efficacy of vaccination in India
Authors: Rajput Ashutosh , Sajid Mohammad , Tanvi  , Shekhar Chandra , Aggarwal Rajiv
Published: October 2021

The Novel Coronavirus which emerged in India on January/30/2020 has become a catastrophe to the country on the basis of health and economy. Due to rapid variations in the transmission of COVID-19, an accurate prediction to determine the long term effects is infeasible. This paper has introduced a nonlinear mathematical model to interpret the transmission dynamics of COVID-19 infection along with providing vaccination in the precedence. To minimize the level of infection and treatment burden, the optimal control strategies are carried out by using the Pontryagin’s Maximum Principle. The data validation has been done by correlating the estimated number of infectives with the real data of India for the month of March/2021. Corresponding to the model, the basic reproduction number $${\mathcal {R}}_0$$

R
0

is introduced to understand the transmission dynamics of COVID-19. To justify the significance of parameters we determined the sensitivity analysis of $${\mathcal {R}}_0$$

R
0

using the parameters value. In the numerical simulations, we concluded that reducing $${\mathcal {R}}_0$$

R
0

below unity is not sufficient enough to eradicate the COVID-19 disease and thus, it is required to increase the vaccination rate and its efficacy by motivating individuals to take precautionary measures.
Usefulness of ultrasonography for dynamic evaluation of medial meniscus hoop function in early knee osteoarthritis
Authors: Shimozaki Kengo , Nakase Junsuke , Asai Kazuki , Yoshimizu Rikuto , Kimura Mitsuhiro , Kanayama Tomoyuki , Kitagawa Takashi , Tsuchiya Hiroyuki
Published: October 2021

This study aimed to evaluate the dynamics of the medial meniscus during knee flexion–extension by ultrasonography and compare them with MRI findings to confirm the usefulness of ultrasonography for evaluating early knee osteoarthritis (KOA). In total, 100 patients were diagnosed with early KOA using clinical and radiographical findings. Dynamic ultrasonographic evaluation and MRI were performed in all patients. Medial meniscal extrusion (MME) and medial meniscal tears were evaluated via ultrasonography and MRI. Abnormal MME was defined as MME > 2 mm on ultrasonography during knee extension. Patients with abnormal MME were divided into two groups: a decrease group (group D) and a non-decrease group (group N). Age, sex, absence or type of meniscus tear, and MME were compared between the two groups. Of the 100 patients, 75 demonstrated MME > 2 mm at knee extension. MME at all assessment positions using ultrasonography and MRI were significantly greater in group N (n = 34) than that in group D (n = 41). Medial meniscus posterior root tears or radial tears were observed in most cases in group N. A lack of decrease in MME from 0° to 90° of flexion on ultrasonography was a characteristic finding in patients with a loss of meniscal hoop function.
Experimental investigation of oil–water flow in the horizontal and vertical sections of a continuous transportation pipe
Authors: Yang Jianlei , Li Peng , Zhang Xuhui , Lu Xiaobing , Li Qing , Mi Lifei
Published: October 2021

A series of experiments were conducted to investigate flow pattern transitions and concentration distribution during simultaneous pipe flow of oil–water two-phase flow through the horizontal and vertical sections. The flowing media applied were white mineral oil and distilled water. Superficial oil and water velocities were between 0 and 0.57 m/s. Flow pattern maps revealed that the horizontal and vertical sections of the pipe lead to different flow pattern characteristics under the same flow conditions. The original contributions of this work are that a transition mechanism for predicting the boundary between oil-in-water (O/W) flow and water-in-oil (W/O) in oil–water two-phase flow was obtained. The effects of input water cut, oil and water superficial velocities on the concentration distribution of the dispersed phase were studied. The empirical formulas for the phase holdup based on the drift-flux model were obtained. The predicted results agreed well with those of the experimental data, especially for the O/W flow pattern.
Positive effects of COVID-19 lockdown on river water quality: evidence from River Damodar, India
Authors: Chakraborty Baisakhi , Bera Biswajit , Adhikary Partha Pratim , Bhattacharjee Sumana , Roy Sambhunath , Saha Soumik , Ghosh Anitabha , Sengupta Debashish , Shit Pravat Kumar
Published: October 2021

The global economic activities were completely stopped during COVID-19 lockdown and continuous lockdown partially brought some positive effects for the health of the total environment. The multiple industries, cities, towns and rural people are completely depending on large tropical river Damodar (India) but in the last few decades the quality of the river water is being significantly deteriorated. The present study attempts to investigate the river water quality (RWQ) particularly for pre- lockdown, lockdown and unlock period. We considered 20 variables per sample of RWQ data and it was analyzed using novel Modified Water Quality Index (MWQI), Trophic State Index (TSI), Heavy Metal Index (HMI) and Potential Ecological Risk Index (RI). Principal component analysis (PCA) and Pearson’s correlation (r) analysis are applied to determine the influencing variables and relationship among the river pollutants. The results show that during lockdown 54.54% samples were brought significantly positive changes applying MWQI. During lockdown, HMI ranged from 33.96 to 117.33 with 27.27% good water quality which shows the low ecological risk of aquatic ecosystem due to low mixing of toxic metals in the river water. Lockdown effects brought river water to oligotrophic/meso-eutrophic condition from eutrophic/hyper-eutrophic stage. Rejuvenation of river health during lockdown offers ample scope to policymakers, administrators and environmentalists for restoration of river health from huge anthropogenic stress.
Leaf 13C and 15N composition shedding light on easing drought stress through partial K substitution by Na in eucalyptus species
Authors: Mateus Nikolas Souza , Florentino Antonio Leite , Oliveira Jessica Bezerra , Santos Elcio Ferreira , Gaziola Salete Aparecida , Rossi Monica Lanzoni , Linhares Francisco Scaglia , Bendassolli José Albertino , Azevedo Ricardo Antunes , Lavres José
Published: October 2021

This work aimed to investigate the partial K-replacement by Na supply to alleviate drought-induced stress in Eucalyptus species. Plant growth, leaf gas exchange parameters, water relations, oxidative stress (H2O2 and MDA content), chlorophyll concentration, carbon (C) and nitrogen (N) isotopic leaf composition (δ13C and δ15N) were analyzed. Drought tolerant E. urophylla and E. camaldulensis showed positive responses to the partial K substitution by Na, with similar dry mass yields, stomatal density and total stomatal pore area relative to the well K-supplied plants under both water conditions, suggesting that 50% of the K requirements is pressing for physiological functions that is poorly substituted by Na. Furthermore, E. urophylla and E. camaldulensis up-regulated leaf gas exchanges, leading to enhanced long-term water use efficiency (WUEL). Moreover, the partial K substitution by Na had no effects on plants H2O2, MDA, δ13C and δ15N, confirming that Na, to a certain extent, can effectively replace K in plants metabolism. Otherwise, the drought-sensitive E. saligna species was negatively affected by partial K replacement by Na, decreasing plants dry mass, even with up-regulated leaf gas exchange parameters. The exclusive Na-supplied plants showed K-deficient symptoms and lower growth, WUEL, and δ13C, besides higher Na accumulation, δ15N, H2O2 and MDA content.
Imputation of missing values for electronic health record laboratory data
Authors: Li Jiang , Yan Xiaowei S. , Chaudhary Durgesh , Avula Venkatesh , Mudiganti Satish , Husby Hannah , Shahjouei Shima , Afshar Ardavan , Stewart Walter F. , Yeasin Mohammed , Zand Ramin , Abedi Vida
Published: October 2021

Laboratory data from Electronic Health Records (EHR) are often used in prediction models where estimation bias and model performance from missingness can be mitigated using imputation methods. We demonstrate the utility of imputation in two real-world EHR-derived cohorts of ischemic stroke from Geisinger and of heart failure from Sutter Health to: (1) characterize the patterns of missingness in laboratory variables; (2) simulate two missing mechanisms, arbitrary and monotone; (3) compare cross-sectional and multi-level multivariate missing imputation algorithms applied to laboratory data; (4) assess whether incorporation of latent information, derived from comorbidity data, can improve the performance of the algorithms. The latter was based on a case study of hemoglobin A1c under a univariate missing imputation framework. Overall, the pattern of missingness in EHR laboratory variables wasnot at randomand was highly associated with patients’ comorbidity data; and the multi-level imputation algorithm showed smaller imputation error than the cross-sectional method.