bluuebunny/crossref_metadata_2025 huggingface dataset:
Troglitazone Reduction of Intracellular Mycobacterium tuberculosis Survival Via Macrophage Autophagy Through LKB1-AMPKα Signaling
Authors: Bi Jing , Guo Qinglong , Gong Yaqi , Chen Xi , Wu Haojia , Song Li , Xu Yating , Ou Min , Wang Zhaoqin , Chen Jiean , Jiang Chenran , Liu Aimei , Li Guobao , Zhang Guoliang
Published: October 2024

Tuberculosis caused by Mycobacterium tuberculosis (Mtb), results in significant disease and death worldwide. Host-directed therapy, including conventional drugs, is a promising antituberculosis strategy that shows synergistic antibacterial effects when combined with antituberculosis drugs. Here, the mycobactericidal effect of 3 antidiabetic drugs was examined. Of these, only troglitazone (Trog) enhanced the antimycobacterial effect in vitro and in vivo. This was due to Trog-mediated autophagy activation. Moreover, a knock-down experiment revealed that Trog activated autophagy and exhibited antimycobacterial activity through the serine/threonine-protein kinase STK11 (LKB1)-5'-AMP-activated protein kinase (AMPK) signaling pathway. Molecular docking and coimmunoprecipitation experiments demonstrated that Trog promoted LKB1 phosphorylation and activation by targeting STE20-related kinase adapter protein alpha (STRADA). Finally, we found that Trog inhibited the intracellular survival of clinical isoniazid-resistant Mtb, and the combination of Trog and isoniazid showed additive antibacterial effects against Mtb H37Rv. Taken together, antidiabetic Trog may be repurposed as a candidate for host-directed therapy and combined with first-line antituberculosis drugs.
Soil nutrient amendment increases the potential for inter-kingdom resource competition among foliar endophytes
Authors: Hansen Zoe A , Fulcher Michael R , Wornson Nicholas , Spawn-Lee Seth A , Johnson Mitch , Song Zewei , Michalska-Smith Matthew , May Georgiana , Seabloom Eric W , Borer Elizabeth T , Kinkel Linda L
Published: October 2024

Foliar endophytes play crucial roles in large-scale ecosystem functions such as plant productivity, decomposition, and nutrient cycling. While the possible effects of environmental nutrient supply on the growth and carbon use of endophytic microbes have critical implications for these processes, these impacts are not fully understood. Here, we examined the effects of long-term elevated nitrogen, phosphorus, potassium, and micronutrient (NPKμ) supply on culturable bacterial and fungal foliar endophytes inhabiting the prairie grass Andropogon gerardii. We hypothesized that elevated soil nutrients alter the taxonomic composition and carbon use phenotypes of foliar endophytes and significantly shift the potential for resource competition among microbes within leaves. We observed changes in taxonomic composition and carbon use patterns of fungal, but not bacterial, endophytes of A. gerardii growing in NPKμ-amended versus ambient conditions. Fungal endophytes from NPKμ-amended plants had distinct carbon use profiles and demonstrated greater specialization across carbon sources compared to control plots. Resource niche overlap between bacterial and fungal endophytes also increased with plot nutrient supply, suggesting enhanced potential for inter-kingdom competition. Collectively, this work suggests that soil nutrient enrichment alters how fungal endophyte communities exist in the foliar environment, with potentially significant implications for broad-scale ecosystem function.
Antibiotic use and adherence to the WHO AWaRe guidelines across 16 hospitals in Zambia: a point prevalence survey
Authors: Chizimu Joseph Yamweka , Mudenda Steward , Yamba Kaunda , Lukwesa Chileshe , Chanda Raphael , Nakazwe Ruth , Shawa Misheck , Chambaro Herman , Kamboyi Harvey K , Kalungia Aubrey Chichonyi , Chanda Duncan , Fwoloshi Sombo , Jere Elimas , Mufune Tiza , Munkombwe Derick , Lisulo Peter , Mateele Tebuho , Thapa Jeewan , Kapolowe Kenneth , Sinyange Nyambe , Sialubanje Cephas , Kapata Nathan , Mpundu Mirfin , Masaninga Freddie , Azam Khalid , Nakajima Chie , Siyanga Makomani , Bakyaita Nathan Nsubuga , Wesangula Evelyn , Matu Martin , Suzuki Yasuhiko , Chilengi Roma
Published: October 2024

Background

The inappropriate use of antibiotics in hospitals contributes to the development and spread of antimicrobial resistance (AMR). This study evaluated the prevalence of antibiotic use and adherence to the World Health Organization (WHO) Access, Watch and Reserve (AWaRe) classification of antibiotics across 16 hospitals in Zambia.

Methods

A descriptive, cross-sectional study employing the WHO Point Prevalence Survey (PPS) methodology and WHO AWaRe classification of antibiotics was conducted among inpatients across 16 hospitals in December 2023, Zambia. Data analysis was performed using STATA version 17.0.

Results

Of the 1296 inpatients surveyed in the 16 hospitals, 56% were female, and 54% were aged between 16 and 50 years. The overall prevalence of antibiotic use was 70%. Additionally, 52% of the inpatients received Watch group antibiotics, with ceftriaxone being the most prescribed antibiotic. Slightly below half (48%) of the inpatients received Access group antibiotics. Compliance with the local treatment guidelines was 53%.

Conclusions

This study found a high prevalence of prescribing and use of antibiotics in hospitalized patients across the surveyed hospitals in Zambia. The high use of Watch group antibiotics was above the recommended threshold indicating non-adherence to the WHO AWaRe guidelines for antibiotic use. Hence, there is a need to establish and strengthen antimicrobial stewardship programmes that promote the rational use of antibiotics in hospitals in Zambia.
Postmortem diphenhydramine blood concentrations in children
Authors: Wallage H. Rachelle , Elliot Marie
Published: October 2024

Diphenhydramine has been available for decades in non-prescription formulations for the treatment of allergic reactions, insomnia, and symptomology associated with colds. In addition, dimenhydrinate, a precursor to diphenhydramine, is available in preparations for the treatment of nausea and vomiting. Diphenhydramine and other first-generation antihistamines are being replaced by second- and third-generation antihistamines, which are associated with fewer side effects, notably the lack of drowsiness; however, there are still a variety of therapeutic uses that have persisted in both adults and children. In this study, postmortem blood concentrations of diphenhydramine were determined, by liquid chromatography–tandem mass spectrometry, in seven children with concentrations ranging from 0.051 to 2.6 mg/l. The cause of death in two cases was attributed, at least in part, to diphenhydramine toxicity, while diphenhydramine detection in five cases was considered incidental to the cause of death.
Engaging Burn Survivors, Their Families, and the Burn Community in Patient-Centered Outcomes Research: A Burn Survivor- and Burn Community Stakeholder-Generated and Prioritized Research Agenda
Authors: Thompson Callie M , Acton Amy , Alexander William , Beyene Robel , Brownson Elisha G , Carrougher Gretchen J , Christensen Brennan , Hoarle Kimberly , Irven Jessica , Johnson Laura S , Kirkham Monica P , Lewis Giavonni M , Lucio J Xavier , Matagi Samoana , Morris Laura , Prazak Ann Marie B , Price-Smith Erin , Stuchly Bridget , Webb Crystal , Quinn Kristen ,   Burn Survivor-Centered Outcomes Research (BSCOR) Collaborative, Bergfeld Megan , Haley Mark , Johnson Erin , Matagi Fatu , Steffensen Dan
Published: October 2024

Burn survivors are involved in burn research, but typically in the role of research subject. We believe that the outcomes and impact of burn research can be improved by engaging survivors as collaborators in the planning, implementation, and dissemination of burn research. The goal of this work was to produce the first burn research agenda generated and prioritized by burn survivors and other stakeholders from the burn community. A series of structured focus groups covering 5 topics (Patient and Family Education, Aftercare, Navigating the Healthcare System, Recovery: Physical and Psychosocial, and Barriers to Research) were held with burn survivors and their family members. Specific research questions/topics were identified from the transcripts and prioritized via an anonymous survey of burn survivors, their caregivers, and other stakeholders from the burn community. From these sessions, 37 specific research questions/topics were identified and ranked. In addition, 19 research barriers were identified and ranked. This work presents an innovative approach to burn research through co-production with survivors and other stakeholders. Burn survivors and their caregivers are experts in their lived experiences. By involving them in burn research as collaborators and contributors from the very first steps of research and throughout the continuum of the research planning, conducting projects, and distributing findings, we believe that the research will be both more successful and more impactful. We have taken the first steps in burn research co-production with this novel stakeholder-generated research agenda for the burn community.
CD56 does not contribute to the antitumor, tissue homing, and glycolytic capacity of human NK cells
Authors: Portillo Ana L , Rojas Eduardo A , Mehboob Misaal , Moinuddin Adnan , Balint Elizabeth , Feng Emily , Silvestri Christopher , Vahedi Fatemeh , Ritchie Tyrah M , Mansour Alexa J , Bramson Jonathan L , Ashkar Ali A
Published: October 2024

Natural killer (NK) cells are critical innate immune cells involved in the clearance of virally infected and malignant cells. Human NK cells are distinguished by their surface expression of CD56 and a lack of CD3. While CD56 expression and cell surface density has long been used as the prototypic marker to characterize primary human NK cell functional subsets, the exact functional role of CD56 in primary human NK cells is still not fully understood. Here, we eliminated the expression of CD56 in human ex vivo expanded NK cells (CD56bright) using CRISPR/Cas9 in order to assess the function of CD56 in this highly activated and cytotoxic NK cell population. We show that the expression of CD56 has no effect on NK cell proliferative capacity or expression of various activation and inhibitory markers. Further, CD56 does not contribute to NK cell–mediated cytotoxicity, inflammatory cytokine production, or the ability of NK cells to control tumor engraftment in vivo. We also found that while deletion of CD56 did not impact NK cell glycolytic metabolism, it did increase NK cell reliance on oxidative phosphorylation. Last, CD56 does not alter expanded NK cell in vivo tissue trafficking. Our results indicate that while CD56 expression could be used to indicate a hyperfunctional state of NK cells, it does not directly influence the antitumor functions of expanded NK cells.
Barriers to healthy behaviors: perspectives from teens with comorbid Type 1 diabetes and overweight/obesity, caregivers, and pediatric endocrinologists
Authors: Warnick Jennifer L , Darling Katherine E , Swartz Topor Lisa , Jelalian Elissa
Published: October 2024

Objectives

This study aimed to understand barriers to engagement in healthy lifestyle behaviors among adolescents with comorbid Type 1 diabetes (T1D) and overweight/obesity (n = 12), their caregivers (n = 12), and pediatric endocrinologists (n = 9).

Methods

Participants (n = 33) completed individual, semi-structured interviews. Interviews were transcribed verbatim, and applied thematic analysis was used to analyze the interview data.

Results

Results from adolescents, caregivers, and pediatric endocrinologists revealed three thematic barriers to healthy lifestyle behaviors for adolescents with T1D and overweight/obesity: (1) discomfort with aspects of T1D that draw attention to the self; (2) T1D as a barrier to engagement in healthy lifestyle behaviors; and (3) physiological dysregulation due to T1D impacting health behaviors.

Conclusions

Results identify perceived limitations to engaging in recommended healthy lifestyle behaviors and diabetes management concurrently. Results may assist research and clinical care in identifying supports and guidance needed to support adolescents in meeting behavioral recommendations for their health.
Primary Adjunctive Corticosteroids in the Acute Management of High-Risk Kawasaki Disease in a North American Cohort
Authors: Wang Alan P , Khan Huthaifah , Dong Siyuan , Kim Kwang-Youn A , Jone Pei-Ni , Lee Simon , Shulman Stanford , Innocentini Nancy , Zielinski Tresa , Rowley Anne H
Published: October 2024

Background

Primary adjunctive therapy with corticosteroids has been shown to reduce coronary artery (CA) abnormalities in high-risk Kawasaki disease (KD) patients in Japan (the randomized control trial to assess immunoglobulin plus steroid efficacy [RAISE] study). We evaluated their effect on outcomes in North American patients with high-risk KD.

Methods

We performed a single-center retrospective review of high-risk KD patients between 2010 and 2023. From 2017 to 2023, adjunctive corticosteroids in a modified RAISE regimen (mRAISE) were given to high-risk patients as primary adjunctive therapy with intravenous gammaglobulin (IVIG) and aspirin. We compared CA outcomes in these patients and those presenting from 2010 to 2016, when mRAISE therapy was not administered.

Results

A total of 221 high-risk KD patients were treated at our institution between 2010 and 2023. Among these, 83 received the mRAISE regimen and 138 did not (no corticosteroid, n = 82, corticosteroid in a non-mRAISE regimen, n = 56). There were no significant differences in CA outcomes in the mRAISE and non-mRAISE groups. Patients receiving the mRAISE regimen were significantly less likely to receive more than one dose of IVIG when compared to those who did not receive this regimen (11% vs 33%, p < .001).

Conclusions

Use of adjunctive primary therapy with corticosteroids in a mRAISE regimen in high-risk KD patients resulted in significantly decreased IVIG retreatment.
Global burden, trends and inequalities for typhoid and paratyphoid fever among children younger than 15 years over the past 30 years
Authors: Wang Haitao , Zhang Ping , Zhao Qi , Ma Wei
Published: October 2024

Background

Typhoid and paratyphoid fever, collectively known as enteric fever, are systemic infections caused by Salmonella enterica and are highly prevalent in children. We aimed to describe the global burden, trends and inequalities of enteric fever among children under 15 years from 1990 to 2019 based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019).

Methods

In this secondary analysis of GBD 2019, we extracted data for incident cases, deaths and disability-adjusted life-years (DALYs) as measures of enteric fever burden. We estimated the average annual percentage changes (AAPCs) in enteric fever incidence, mortality and DALYs rate to quantify trends over time. Cross-country inequalities in enteric fever incidence were measured using the slope index of inequality and concentration index.

Results

In 2019, the global cases of typhoid and paratyphoid were 4 833 282 and 1 793 172, respectively, both lower than those in 1990. On secondary analysis, paratyphoid incidence decreased at a faster rate than typhoid from 1990 to 2009, whereas the incidence of paratyphoid (AAPC = −3.78, 95% CI: −4.07, −3.49) declined slower than that of typhoid (AAPC = −4.32, 95% CI: −4.50, −4.13) from 2010 to 2019 (P < 0.05) at the global level. The incidence burden of enteric fever increased in Australasia (AAPC = 1.28, 95% CI: 0.77, 1.78) and Western Europe (AAPC = 0.77, 95% CI: 0.44, 1.11). Death and DALYs burden in low socio-demographic index (SDI) region showed a stable trend. A significant reduction in SDI-related inequality occurred, with the concentration index falling from −0.31 in 1990 to −0.22 in 2019.

Conclusions

The global disease burden of enteric fever and the magnitude of inequalities across countries have declined since 1990, but low SDI countries remain a region of concern. Travellers from Oceania and Western Europe to endemic regions should be particularly aware of the risk of enteric fever.
Travel to malaria-endemic areas: using digital geo-location to assess potential exposure risks and health behaviours
Authors: Farnham Andrea , Hatz Christoph , Fehr Jan , Baroutsou Vasiliki , Puhan Milo A , Veit Olivia , Bühler Silja
Published: October 2024

Background

Travellers frequently visit popular destinations like Brazil, India, Peru, Thailand and Tanzania, each presenting varying malaria risks. The extent to which travellers enter high-risk malaria-endemic areas in destinations with heterogeneous malaria risk remains unclear. We used geo-location via a smartphone application to (i) describe where travellers go within countries with heterogeneous malaria risk (Brazil, India, Peru, Thailand) and (ii) compare mosquito bite prevention behaviours between these destinations and Tanzania, considered entirely high risk for malaria.

Methods

This analysis is a sub-study of the Tracking of Urgent Risks in Swiss Travellers (TOURIST2) cohort, which prospectively recruited 1000 travellers (≥18 years, travelling ≤4 weeks) from Swiss travel clinics (Zurich and Basel) between September 2017 and April 2019. We included 734 travellers to Brazil, India, Peru, Thailand and Tanzania who provided geo-location data. Daily health and geo-location data were collected using a smartphone application. Malaria risk was categorized using 2022 malaria maps from the Swiss Expert Committee for Travel Medicine.

Results

Of the 734 travellers, 525 travelled to Brazil, India, Peru and Thailand and 225 to Tanzania. In Brazil, India, Peru and Thailand, only 2% (n = 13) visited high-risk malaria areas. In Peru, 4% (n = 4) visited a high-risk area; in Brazil, 3% (n = 6); in Thailand, 2% when crossing the border into Myanmar (n = 3); and in India, 0%. Travellers to high-risk areas were more often male (62%), slightly older (median age 42.0) and planned longer trips (median 23.0 days) than other travellers. No participants were diagnosed with malaria. Travellers to Brazil, India, Peru and Thailand used mosquito bite prevention measures less frequently than travellers to Tanzania. Those in Tanzania had higher, but still suboptimal, use of insect spray (65% of travel days).

Conclusions

Travellers to Brazil, India, Peru and Thailand rarely visited high-risk malaria areas, and their adherence to mosquito bite prevention measures was generally low. In Tanzania, adherence was higher but still suboptimal.
Introduction
Authors: Bridge Michael , Gullifer Louise , Lomnicka Eva
Published: October 2024

This chapter provides a general account of the structure of proprietary security, whether it is security granted by a debtor or quasi-security, amounting to a reservation of property rights by a party providing financial accommodation. Security granted by a debtor includes mortgages and charges, of which in practice charges are the more important, as well as possessory security in the form of pledge and liens arising by operation of law. The reservation of property rights includes devices such as retention of title clauses and structures such as hire purchase and finance leases. The chapter lays emphasis on the contribution of equity to the law of security and deals with the background to the law, involving issues of insolvency, form and substance, and recharacterization risk.
Types of Interest
Authors: Bridge Michael , Gullifer Louise , Lomnicka Eva
Published: October 2024

This chapter considers the conceptual and practical differences between security interests and absolute interests which perform the same economic function as security interests. Practical examples of different situations in which absolute interests perform this function are analysed, including both by retention and transfer of title. The chapter examines the approach of the courts to characterization of interests labelled in a contractual structure as absolute (or, more rarely, security) interests in cases where that label is challenged. The general approach of the courts is discussed and compared to the approach to characterization in the context of fixed and floating charges. The approach in relation to particular financing structures is also examined.
Interests Created By Debtors Who Are Not Companies
Authors: Bridge Michael , Gullifer Louise , Lomnicka Eva
Published: October 2024

This chapter deals with the grant of charges by non-corporate entities and the requirement of their registration for them to be opposable to third parties. The applicable legislation is the archaic and often criticized Bills of Sale Acts 1878–91 and the application of this legislation to different types of instrument, along with the numerous exemptions (both types of goods and types of transactions), is discussed in detail. The very detailed formal requirements for both absolute and security bills are discussed, account being taken that the legislation does not apply to oral agreements where these are permissible. Also considered are agricultural charges and charges granted by cooperative and similar societies.
Other Priority Issues
Authors: Bridge Michael , Gullifer Louise , Lomnicka Eva
Published: October 2024

This short chapter deals with sundry priority issues that are not discussed in other chapters. The priority issues that are herein discussed consist of the various forms of set-off, with particular reference to floating charges; the bank’s right to combine accounts; direct payment clauses that arise in shipping and in landlord and tenant cases; Quistclose trusts; and negative pledge and flawed asset clauses. Finally,there is a discussion of circular priority.
Enforcement of Financial Devices Involving the Transfer or Retention of Title
Authors: Bridge Michael , Gullifer Louise , Lomnicka Eva
Published: October 2024

This chapter considers the enforcement of those ‘quasi-security’ interests considered in chapter 7 in that the general characteristics that ‘true’ security interests display when they are enforced (in particular the obligation of the secured creditor to account for any surplus (or ‘windfall’) and the obligation of the debtor to make good any deficit (or ‘shortfall’)) do not arise. The financing devices are treated as straightforward commercial contracts and are generally enforced according to their terms, without the application of any of those ‘security’ principles, although in so far as these devices perform a security function, their express terms often reflect these ‘security’ characteristics, with the contract often providing for a financial adjustment so as to preclude the ‘secured creditor’ receiving a ‘windfall’ or suffering a ‘shortfall’. Reference is made to the consumer credit regulatory regime in so far as these devices fall within its scope.
Enforcement of Security in Insolvency
Authors: Bridge Michael , Gullifer Louise , Lomnicka Eva
Published: October 2024

This chapter deals in detail with the effect of various insolvency procedures on security and, to a lesser extent, quasi-security. It deals with dispositions of an insolvent party’s assets in the run-up to formal insolvency proceedings; the extent to which creditors with a floating charge are postponed behind preferential and other unsecured creditors; the extent to which the expenses of the liquidation and of the administration are paid for preferential creditors and floating charge creditors; the effect of a moratorium on the exercise of security rights; the effect of receivership on secured creditors; company voluntary arrangements and schemes of arrangement, together with their effect on secured creditors.
Comparative Analysis of Treatment Patterns in DoD Beneficiaries With Malignant Central Nervous System Tumors: A Focus on Care Setting
Authors: Hill Aaron J , Eaglehouse Yvonne L , Darmon Sarah , Tracy Heather J , Theeler Brett J , Zhu Kangmin , Shriver Craig D , Xue Hong
Published: October 2024

Introduction

Malignant brain and other central nervous system tumors (MBT) are deadly and disproportionately affect younger men and women in the age range of most active-duty service members. Timely and appropriate treatment is important to both survival and quality of life of patients. Information on treatment factors across direct care (DC) and private sector care (PSC) networks may be important for provider training and staffing for the DoD. The aim of this study was to analyze treatment patterns for patients with MBT within the DoD’s universal access Military Health System (MHS), comparing DC and PSC networks.

Materials and Methods

The Military Cancer Epidemiology database was used to identify patients 18 years and older who were diagnosed with an MBT between 1999 and 2014 who received primary treatment. Differences in first treatment type and time from diagnosis to initial treatment between DC and PSC were assessed using chi-square and Wilcoxon–Mann–Whitney tests, respectively. Frequency of treatment initiation beyond the 28-day TRICARE Prime access standard for Specialty Care was also compared between care settings using chi-square and Fisher’s exact tests. Then logistic regression models generated odds of treatment initiation beyond 28 days and 95% confidence intervals (CIs) associated with care setting. Kaplan–Meier survival curves and log-rank tests compared survival between DC and PSC.

Results

The study included 857 patients, with n = 540 treated in DC and n = 317 treated in PSC. The proportion of patients receiving each initial treatment type did not differ by care setting (P = .622). Median time from diagnosis to initial treatment (interquartile range) varied significantly between DC at 6 (0 to 25) days and PSC at 12 (0 to 37) days for all treatment types combined (P < .001). For all years combined, treatment was initiated beyond 28 days for 21% of patients using DC compared to 31% of patients using PSC (P = .001). The odds of treatment initiation beyond 28 days for a patient treated in PSC were 1.61 (95% CI, 1.11 to 2.33, P = .012) compared to patients treated in DC when controlling for demographic, military, tumor, and patient variables. Survival did not differ by care setting (P = 1.000).

Conclusions

Based on the available data between 1999 and 2014, care setting was associated with differences in time to initial treatment and odds of treatment initiation beyond 28 days among DoD beneficiaries with MBT receiving care in the MHS. Information on these differences may help inform MHS leadership decisions on the most appropriate location for military provider training and staffing.
Ultraviolet extinction correlation with 3D dust maps using white dwarfs
Authors: Sahu Snehalata , Tremblay Pier-Emmanuel , Lallement Rosine , Redfield Seth , Gänsicke Boris T
Published: October 2024

Accurate astrometric and photometric measurements from Gaia have led to the construction of 3D dust extinction maps which can now be used for estimating the integrated extinctions of Galactic sources located within 5 kpc. These maps based on optical observations may not be reliable for use in the ultraviolet (UV) which is more sensitive to reddening. Past studies have focussed on studying UV extinction using main-sequence stars but lack comparison with 3D dust maps. White dwarfs with well-modelled hydrogen-dominated (DA) atmospheres provide an advantage over main-sequence stars affected by magnetic activity. In this work, we study the variation of UV extinction with 3D dust maps utilizing Hubble Space Telescope (HST) and Galaxy Evolution Explorer (GALEX) observations of DA white dwarfs located within 300 pc. We used HST COS spectroscopic data of 76 sightlines to calculate the optical extinction from Si ii column densities and validate our results with the kinematic model predictions of the local interstellar medium. Also, we combined GALEX and Gaia photometric observations of 1158 DA white dwarfs to study UV reddening by comparing observed and modelled colour–colour relations. We calculated GALEX non-linearity corrections and derived reddening coefficients [$R(NUV-G)=6.52\pm 1.53$ and $R(FUV-G)=6.04\pm 2.41$] considering their variations with optical extinction ($\rm{A_{V}}\lt 0.1$ mag), and found them to be in good agreement with known extinction laws. HST analysis suggests a positive bias of 0.01–0.02 mag in the optical extinction from 3D maps depending on the Galactic latitude. These results independently confirm the validity of 3D dust maps to de-redden the optical and UV observations of white dwarfs.
Chimeric antigen receptor T-cell therapy in patients with malignant glioma—From neuroimmunology to clinical trial design considerations
Authors: Gallus Marco , Young Jacob S , Cook Quackenbush Sarah , Khasraw Mustafa , de Groot John , Okada Hideho
Published: October 2024

Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.
A common future amidst unknowns: an NSR forum on polar science
Authors: Zhu He
Published: October 2024

The final frontiers on our planet challenge humans’ survival as much as our ambition. The Arctic and Antarctic areas together exert enormous influence on the climate of the whole planet, as they contain 87% of its fresh water, 90% of its ice and snow, 90% of its permafrost and 69% of its glaciers. However, our lack of understanding of changes in the polar regions, such as melting ice sheets, results in major uncertainties in our estimates and predictions with regard to rising sea levels and other effects of climate change. For example, as the Arctic region is warming up two to four times faster than the global average, Eurasia now experiences colder winters. As its mechanism is yet to be elucidated, forecasts of extreme weather events in China, which aim to avert severe damages, remain inadequate. In order to raise awareness of polar science, National Science Review invited Dr. Dake Chen of the Second Institute of Oceanography, Ministry of Natural Resources (MNR) to organize a forum discussion with five Chinese experts to explore these crucial topics.

Jianfang Chen (陈建芳)

Professor, Second Institute of Oceanography, MNR

Ruibo Lei (雷瑞波)

Professor, Polar Research Institute of China, MNR

Jiping Liu (刘骥平)

Professor, School of Atmospheric Science, Sun Yat-sen University

Qinghua Yang (杨清华)

Professor, Sun Yat-sen University and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)

Meng Zhou (周朦)

Professor, School of Oceanography, Shanghai Jiao Tong University

Dake Chen (陈大可) (Chair)

Professor, The Second Institute of Oceanography, MNR and Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)
Estimating Young Adult Uptake of Smoking by Area Across the United Kingdom
Authors: Jackson Sarah E , Tattan-Birch Harry , Hopkinson Nicholas S , Brown Jamie , Shahab Lion , Bunce Laura , Laverty Anthony A , Arnott Deborah
Published: October 2024

Introduction

There is majority support in parliament and across the United Kingdom to implement a “smoke-free generation” policy which would mean people born on or after January 1, 2009, could never legally be sold tobacco. To explore the potential impact this policy could have, we estimated the number of young adults (18–25 years) currently taking up smoking each year by area across the United Kingdom.

Methods

Using data from the Office for National Statistics (ONS), Annual Population Survey (APS), and Smoking Toolkit Study (STS), we estimated the total number of 18- to 25-year-olds taking up smoking each year, based on national estimates of population size (ONS) and the proportion who reported ever having regularly smoked (STS). We used local data on adult smoking rates (APS) to apportion the national estimated number of young adults taking up smoking to specific areas.

Results

Around 127 500 18- to 25-year-olds in the United Kingdom start smoking regularly each year (~350 each day); 105 700 each year in England, 11 500 in Scotland, 6500 in Wales, and 3800 in Northern Ireland. Uptake estimates varied across localities: for example, North East Lincolnshire had the highest proportion of young adults taking up smoking each year (3.9%) and Wokingham had the lowest (0.9%).

Conclusions

Despite reductions in smoking prevalence over recent decades, hundreds of young adults in the United Kingdom start smoking every day.

Implications

Data on rates of uptake among individual local authorities can be used to focus attention locally prior to the introduction of new age of sale laws.
Legal Regulation, Technological Management and the Future of Human Agency
Authors: Lucy William
Published: October 2024

This article examines the role of human agency within two competing regulatory paradigms: law and technological management. It sketches both paradigms and suggests that the direction of regulatory travel in familiar jurisdictions is from the former towards the latter. It then examines the possible effect of this transition upon human agency. It defends a general account of agency, distinguishing that notion from autonomy, and shows that that account informs the legal regulatory paradigm. It then considers whether agency, so conceived, can persist and flourish within a technological management regulatory context. It does so by reference to a thought-experiment. That experiment, and two of three responses to it, assumes that agency can be quantified, and the article shows how this can be done. It concludes that a transition from legal regulation to technological management will reduce the amount of human agency in the world and imperil other important values.
Functional assessment in patients with castration-resistant prostate cancer treated with darolutamide: results from the DaroAcT study
Authors: Beer Tomasz M , George Daniel J , Shore Neal D , Winters-Stone Kerri , Wefel Jeffrey S , Verholen Frank , Srinivasan Shankar , Ortiz Jorge , Morgans Alicia K
Published: October 2024

Background

Androgen receptor inhibitors (ARIs) are approved for the treatment of advanced prostate cancer; however, some patients may experience symptoms and side effects that hinder their physical functioning. The Timed Up and Go (TUG) and Short Physical Performance Battery (SPPB) tests are used to assess physical functioning in older adults and are recommended assessments for patients with prostate cancer, despite lacking validation in this setting.

Methods

DaroAct (NCT04157088) was an open-label, multicenter, phase 2b study designed to evaluate the effects of the ARI darolutamide (lead-in phase) and darolutamide vs enzalutamide (randomized phase) on physical functioning in men with castration-resistant prostate cancer (CRPC). Only the lead-in phase, in which participants received darolutamide 600 mg twice daily, was completed. The TUG and SPPB tests were used to assess physical functioning.

Results

The lead-in phase enrolled 30 participants. During 24 weeks of treatment, 8 (32.0%) of 25 evaluable participants exhibited clinically meaningful worsening in TUG from baseline (primary endpoint). At the week 24 visit, 5 (21.7%) of 23 participants had worsening in TUG time, and 8 (33.3%) of 24 participants had worsening in SPPB score. Because only 48% of participants had the same outcome on the TUG and SPPB tests, the study was terminated without initiating the randomized comparison.

Conclusion

Most participants showed no clinically meaningful worsening in physical functioning after 24 weeks of darolutamide treatment, but poor agreement between tests was observed. Tools to accurately and consistently measure the impact of ARIs on physical functioning in patients with CRPC are needed.
Substrate binding and catalytic mechanism of UDP-α-D-galactofuranose: β-galactofuranoside β-(1→5)-galactofuranosyltransferase GfsA
Authors: Oka Takuji , Okuno Ayana , Hira Daisuke , Teramoto Takamasa , Chihara Yuria , Hirata Rio , Kadooka Chihiro , Kakuta Yoshimitsu
Published: October 2024

UDP-α-D-galactofuranose (UDP-Galf): β-galactofuranoside β-(1→5)-galactofuranosyltransferase, known as GfsA, is essential in synthesizing β-(1→5)-galactofuranosyl oligosaccharides that are incorporated into the cell wall of pathogenic fungi. This study analyzed the structure and function of GfsA from Aspergillus fumigatus. To provide crucial insights into the catalytic mechanism and substrate recognition, the complex structure was elucidated with manganese (Mn2+), a donor substrate product (UDP), and an acceptor sugar molecule (β-galactofuranose). In addition to the typical GT-A fold domain, GfsA has a unique domain formed by the N and C termini. The former interacts with the GT-A of another GfsA, forming a dimer. The active center that contains Mn2+, UDP, and galactofuranose forms a groove structure that is highly conserved in the GfsA of Pezizomycotina fungi. Enzymatic assays using site-directed mutants were conducted to determine the roles of specific active-site residues in the enzymatic activity of GfsA. The predicted enzyme–substrate complex model containing UDP-Galf characterized a specific β-galactofuranosyltransfer mechanism to the 5ʹ-OH of β-galactofuranose. Overall, the structure of GfsA in pathogenic fungi provides insights into the complex glycan biosynthetic processes of fungal pathogenesis and may inform the development of novel antifungal therapies.
Less work for theories of natural kinds
Authors: Slater Matthew H
Published: October 2024

What sort of philosophical work are natural kinds suited for? Scientific realists often contend that they provide the ‘aboutness’ of successful of scientific classification and explain their epistemic utility (among other side hustles). Recent history has revealed this to be a tricky job—particularly given the present naturalistic climate of philosophy of science. As a result, we've seen an explosion of different sorts of theories. This phenomenon that has suggested to some that philosophical theorizing about natural kinds has reached a sort of ‘scholastic twilight’ and that the concept (or family of concepts) has outlived its utility: perhaps there's no work natural kinds are suited for. While I think this pessimistic take is unwarranted, I will argue that it is worth rethinking the roles to which a reasonably naturalistic account of natural kinds can be fruitfully put. Natural kinds deserve a shorter work week.
Magnetic particle imaging enables nonradioactive quantitative sentinel lymph node identification: feasibility proof in murine models
Authors: Sehl Olivia C , Guo Kelvin , Mohtasebzadeh Abdul Rahman , Kim Petrina , Fellows Benjamin , Weyhmiller Marcela , Goodwill Patrick W , Wintermark Max , Lai Stephen Y , Foster Paula J , Greve Joan M
Published: October 2024

Background

Sentinel lymph node biopsy (SLNB) is an important cancer diagnostic staging procedure. Conventional SLNB procedures with 99mTc radiotracers and scintigraphy are constrained by tracer half-life and, in some cases, insufficient image resolution. Here, we explore an alternative magnetic (nonradioactive) image-guided SLNB procedure.

Purpose

To demonstrate that magnetic particle imaging (MPI) lymphography can sensitively, specifically, and quantitatively identify and map sentinel lymph modes (SLNs) in murine models in multiple regional lymphatic basins.

Materials and Methods

Iron oxide nanoparticles were administered intradermally to healthy C57BL/6 mice (male, 12-week-old, n = 5). The nanoparticles (0.675 mg Fe/kg) were injected into the tongue, forepaw, base of tail, or hind footpad, then detected by 3-dimensional MPI at multiple timepoints between 1 hour and 4 to 6 days. In this mouse model, the SLN is represented by the first lymph node draining from the injection site. SLNs were extracted to verify the MPI signal ex vivo and processed using Perl’s Prussian iron staining. Paired t-test was conducted to compare MPI signal from SLNs in vivo vs. ex vivo and considered significant if P < .05.

Results

MPI lymphography identified SLNs in multiple lymphatic pathways, including the cervical SLN draining the tongue, axillary SLN draining the forepaw, inguinal SLN draining the tail, and popliteal SLN draining the footpad. MPI signal in lymph nodes was present after 1 hour and stable for the duration of the study (4-6 days). Perl’s Prussian iron staining was identified in the subcapsular space of excised SLNs.

Conclusion

Our data support the use of MPI lymphography to specifically detect SLN(s) using a magnetic tracer for a minimum of 4 to 6 days, thereby providing information required to plan the SLN approach in cancer surgery. As clinical-scale MPI is developed, translation will benefit from a history of using iron-oxide nanoparticles in human imaging and recent regulatory-approvals for use in SLNB.
Spectral dynamics prior to motor events differ between NREM sleep parasomnias and healthy sleepers
Authors: Castelnovo Anna , Mainieri Greta , Loddo Giuseppe , Balafas Spyros , Brombin Chiara , Balella Giulia , Montini Angelica , Di Serio Clelia , Manconi Mauro , Provini Federica
Published: October 2024

Study Objectives

The umbrella term “Disorders of Arousal” (DoA), encompassing sleepwalking, confusional arousals, and sleep terrors, refers to parasomnias manifesting during nonrapid eye movement (NREM) sleep, commonly thought to arise from an aberrant arousal process. While previous studies have detailed electroencephalographic (EEG) changes linked to DoA episodes, it remains uncertain how these alterations differ from a physiological arousal process. This study directly compared brain activity between DoA episodes and arousals associated with physiological movements (motor arousal) in individuals with DoA and healthy sleepers.

Methods

Fifty-three adult participants with DoA (25 males, 32.2 ± 15.5 years) and 33 control participants (14 males, 31.4 ± 11.4 years) underwent one or more home EEG recordings. A semiparametric regression model was employed to elucidate the complex relationship between EEG activity across channels, within and across different groups, including motor arousals in DoA (n = 169), parasomnia episodes in DoA (n = 361), and motor arousals in healthy sleepers (n = 137).

Results

Parasomnia episodes and motor arousals in both groups were preceded by a diffuse increase in slow-wave activity (SWA) and beta power, and a widespread decrease in sigma power. However, motor arousals in DoA displayed lower beta and central sigma than in healthy sleepers. Within participants with DoA, episodes were preceded by lower beta, frontal sigma, and higher SWA than motor arousals.

Conclusions

Our findings suggest that the arousal process is altered in participants with DoA, and that specific EEG patterns are required for DoA episodes to emerge. These insights will help guide future research into the underlying circuits and objective markers of DoA.
Petrel extinction in Macaronesia (North-East Atlantic Ocean): the case of the genus Pterodroma (Aves: Procellariiformes: Procellariidae)
Authors: Rando Juan C , Pieper Harald , Pereira Fernando , Torres-Roig Enric , Alcover Josep Antoni
Published: October 2024

The Late Quaternary fossil record indicates that formerly in the North Atlantic volcanic Macaronesian archipelagos (Azores, Madeira, Selvagens, Canary Islands, and Cape Verde) there was a higher avian diversity, including numerous now extinct species. Currently, only three gadfly petrels (genus Pterodroma) remain in two archipelagos: the Fea’s petrel, Pt. feae, in Cape Verde (islands of Santiago, Fogo, Santo Antão, and São Nicolau); the Zino’s petrel of Madeira, Pt. madeira, on the island of Madeira; and the Desertas petrel, Pt. deserta, on the islet of Bugio (Desertas Islands, Madeira Archipelago). Herein we describe the former distribution of the genus in Macaronesia based on the palaeontological record. However, the original specific diversity cannot be accurately established through the biometry of their fossil bones but the fossil record of Pterodroma in Macaronesia indicates: (i) its former presence in all Macaronesian archipelagos; (ii) the extinction of at least 16 island populations (73% of its original distribution on these islands); and (iii) the extinction of, at least, one species from Azores, here named Pterodroma zinorum sp. nov.. Radiocarbon dates indicate than this species was still alive at sometime among 1104 and 1672 CE, documenting its extinction in the last millennium.