bluuebunny/crossref_metadata_2025 huggingface dataset:
Chinese Medicine in the United States: Historical Development and Growth
Authors: Bu Liping
Published: March 2023

Chinese medicine is growing rapidly in the United States both as a field of research and in the daily treatment of illnesses. The popularity of Chinese medicine, particularly acupuncture, as a healing mechanism demonstrates American people’s positive experience with Chinese medicine and their embracing it as an alternative to the mainstream Western biomedicine. Chinese medicine is an important part of the Alternative and Complementary Medicine or Integrated Medicine in the United States health system. It is increasingly used and covered by health insurance. Although Chinese medicine has been in the United States since colonial times, it was discriminated against by local authorities. However, things began to change in the 1970s when individual states gradually passed laws to legalize the practice of acupuncture as a healing mechanism. American public interest in Chinese medicine, particularly acupuncture, was aroused by the media’s report of the “magic” power of acupuncture during President Nixon’s visit to China. Non-Asians studied acupuncture in the following decades, which contributed to the establishment of acupuncture as a profession in the American health system. The history of Chinese medicine in the United States illustrates that Chinese and Asian immigrants promoted Chinese medicine in the communities, while Chinese American medical scientists who were trained in biomedicine played an important role in shaping the biomedical method of acupuncture research. This article investigates the changes of Chinese medicine in the United States, with a focus on acupuncture. Situating the discussion in a larger context of social and cultural changes, this study examines the contributions of Chinese immigrants and the popularity of acupuncture in the United States. It analyzes the development of acupuncture practice and research, the professional training in Chinese medicine, and American people’s interest in using Chinese medicine as a reliable healing mechanism to many health problems, including chronic pain, cancer, and drug addictions.
Publishing and Medicine: A Potentially Integrated Field?
Authors: Fan MANG
Published: March 2023

This article focuses on the intersection of English-language scholarship between the history of publishing and the history of medicine in Imperial China. As an important part of cultural and social history, both topics have attracted attention from a number of historians. This article contains three sections. The first section introduces the evolution of Chinese book and publishing history in recent years and examines what book historians have done in relation to traditional Chinese medicine. The second section explores how medical historians have considered the role of printing in the history of Chinese medicine and the ways in which medical publications were used as primary sources or subjects of research. The third section explores scholarship on medical epistemic genres, a subfield of medical history, in Chinese medicine, specifically focusing on medical case histories and recipes from the comparative and cross-cultural perspectives. Finally, the conclusion explores potential future directions from the integration of Chinese publishing history and medical history.
Perinatal outcomes of intrauterine fetal arrhythmias: A 10-year retrospective cohort study
Authors: Hu Qing , Liao Hua , Xu Tingting , Liu Hongyan , Wang Xiaodong , Yu Haiyan
Published: March 2023

Sustained fetal arrhythmia can produce life-threatening fetal distress, fetal hemodynamic compromise, hydrops fetalis, or even fetal death. Survivors may subsequently possess severe neurologic deficits. We conducted a retrospective observational study of pregnant women hospitalized with fetal arrhythmias from January 2011 to May 2020 at West China Second University Hospital, and fetal arrhythmias were diagnosed by specialists in cardiac ultrasonography. Of 90 cases of fetal arrhythmias, 14 (15.6%) were complicated by fetal congenital heart disease (CHD), 21 (23.33%) by fetal-hydrops, 15 (16.67%) cases by intrauterine therapy, and 6 (6.67%) by maternal auto-immune disease. In the fetal-hydrops group, the intrauterine therapy rate was significantly higher (47.62% vs 7.24%, P < .001) and the survival rate significantly lower (47.62% vs 92.75%, P < .001) than in the nonfetal hydrops group. A fetus whose arrhythmia was complicated by fetal-hydrops and CHD was delivered earlier and exhibited a lower cardiovascular profile score at diagnosis and birth, lower birth weight, and a higher rate of pregnancy termination than cases without hydrops and CHD (P < .05). Among the cases with maternal auto-immune disease, 71.43% (5/7) manifested fetal atrioventricular block. Multiple linear regression analysis revealed that 3 variables – fetal-hydrops (P < .001), body mass index (P = .014), and gestational age at diagnosis of fetal arrhythmia (P = .047) – were correlated with the gestational delivery age of arrhythmic fetuses. Parents should be counseled by the multidisciplinary team regarding the individualized management and prognosis of the arrhythmic fetus, and individualized fetal intrauterine therapy should be performed if necessary.
Challenges in the diagnosis and treatment of the malignant adnexal neoplasms of the head and neck
Authors: Wierzbicka Małgorzata , Kraiński Patryk , Bartochowska Anna
Published: March 2023

Purpose of review

The current review is to present the current knowledge regarding epidemiology, diagnostics, and management of malignant adnexal neoplasms (MANs).

Recent findings

Immunotherapy and gene-related therapies are still being developed as the methods of salvage treatment in advanced and disseminated cases: CACNA1S, ATP2A1, RYR1, and MYLK3, as well as p53 or the JAK/STAT pathways, may be therapeutic targets; the efficiency of talimogene laherparepvec and nivolumab is assessed.

MANs are rare tumors, but due to the aging of population their incidence is increasing. Their clinical presentation is unspecific, which makes the diagnosis challenging. Histopathological assessment is difficult even for experienced pathologists. Mohs micrographic surgery or wide local excision are recommended to treat primary lesions. Adjuvant radiotherapy may be beneficial in case of insufficient or positive surgical margins, in nodal metastases, in selected types of MANs like sebaceous, trichilemmal, and pilomatrix carcinomas, and as the induction treatment in large tumors located in medically fragile or cosmetically important regions. The role of chemotherapy is not well defined; however, it is recommended in distant metastases. Immunotherapy can improve the prognosis in advanced stage of the disease.
Cardiovascular and Thyroid Late Effects in Pediatric Patients With Hodgkin Lymphoma Treated With ABVD Protocol
Authors: Ali Nesreen , Selim Mustafa , Salah Zeinab , El Nabarawy Nahla M. , Hussein Hany , Sidhom Iman
Published: March 2023

Background:

Hodgkin lymphoma (HL) survivors are at risk of developing a range of therapy-related complications. The goal of this study is to investigate therapy-related late-effects in HL survivors.

Materials and Methods:

We performed a cross-sectional study on 208 HL survivors who were treated at the National Cancer Institute or at the Children Cancer Hospital Egypt with doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy.

Results:

Age at diagnosis ranged from 2.5 to 17.5 with a median of 8.7 years. The cumulative incidence of cardiac toxicity at 5 and 9 years were 18.7%±2.7% and 43.3%±4.4%, respectively. Preexisting cardiac abnormalities, cumulative anthracycline dose, and end of treatment cardiac status are strong predictors of late cardiotoxicity. Hypertension was observed in ~31% of patients. Young age and obesity at the time of treatment are important risk factors for hypertension. Thyroid abnormalities developed with a 5-year cumulative incidence of 2%±1%, whereas at 9 years the cumulative incidence was 27.9%±4.5%. Thyroid dysfunction was observed in 21.2% and thyroid tumors in 1.6% of cases. Subclinical hypothyroidism was the most common thyroid abnormality.

Conclusions:

Cardiotoxicity, hypertension, and thyroid dysfunction are frequent late effects after doxorubicin, bleomycin, vinblastine, and dacarbazine regimen, especially if combined with radiation therapy.
Improvements and Residual Limitations Experienced by Patients with Guillain-Barré Syndrome Undergoing Inpatient Rehabilitation
Authors: Andrews Addison Williams , Bohannon Richard Wallace
Published: March 2023

The purposes of this study were to: 1) describe the level of functional independence of patients with Guillain-Barré Syndrome (GBS) before and after inpatient rehabilitation (IPR), 2) determine whether the level of functional independence increased in each functional domain during IPR, and 3) determine whether independence at the end of IPR differed significantly between domains. Data from patients with GBS discharged from IPR settings in 2019 were obtained from the Uniform Data System for Medical Rehabilitation® database. The primary variables analyzed were paired, dichotomous variables of the number of patients who achieved full independence in the admission and discharge scores for the activities that comprise the domains, subscales, and total of the Functional Independence Measure. All patients admitted to IPR required assistance with at least one if not several domains of function, motor as well as cognitive. By the end of the IPR stay, for each domain of function, significantly more patients were independent (p < 0.0001). Independence at the end of IPR differed significantly between domains (p < 0.0001); more patients achieved independence in the communication (87.5%) and social cognition (74.8%) domains while fewer patients achieved independence in the self-care (35.9%), transfers (34.2%), and locomotion domains (24.7%).
Successful Implementation of Workflow-Embedded Clinical Pathways During the COVID 19 Pandemic
Authors: Wendel Sarah K. , Bookman Kelly , Holmes Molly , Wiler Jennifer L.
Published: March 2023

Background and Objectives:

Clinical pathways have been found effective for improving adherence to evidence-based guidelines, thus providing better patient outcomes. As coronavirus disease-2019 (COVID-19) clinical guidance changed rapidly and evolved, a large hospital system in Colorado established clinical pathways within the electronic health record to guide clinical practice and provide the most up-to-date information to frontline providers.

Methods:

On March 12, 2020, a system-wide multidisciplinary committee of specialists in emergency medicine, hospital medicine, surgery, intensive care, infectious disease, pharmacy, care management, virtual health, informatics, and primary care was recruited to develop clinical guidelines for COVID-19 patient care based on the limited available evidence and consensus. These guidelines were organized into novel noninterruptive digitally embedded pathways in the electronic health record (Epic Systems, Verona, Wisconsin) and made available to nurses and providers at all sites of care. Pathway utilization data were analyzed from March 14 to December 31, 2020. Retrospective pathway utilization was stratified by each care setting and compared with Colorado hospitalization rates. This project was designated as a quality improvement initiative.

Results:

Nine unique pathways were developed, including emergency medicine, ambulatory, inpatient, and surgical care guidelines. Pathway data were analyzed from March 14 to December 31, 2020, and showed that COVID-19 clinical pathways were used 21 099 times. Eighty-one percent of pathway utilization occurred in the emergency department setting, and 92.4% applied embedded testing recommendations. A total of 3474 distinct providers employed these pathways for patient care.

Conclusions:

Noninterruptive digitally embedded clinical care pathways were broadly utilized during the early part of the COVID-19 pandemic in Colorado and influenced care across many care settings. This clinical guidance was most highly utilized in the emergency department setting. This shows an opportunity to leverage noninterruptive technology at the point of care to guide clinical decision-making and practice.
Ultra-High-Resolution Photon-Counting CT Imaging of the Chest
Authors: Remy-Jardin Martine , Hutt Antoine , Flohr Thomas , Faivre Jean-Baptiste , Felloni Paul , Khung Suonita , Remy Jacques
Published: March 2023

After a decade of preclinical testing, photon-counting computed tomography (PCCT) has now entered daily routine, enabling radiologists to start investigating thoracic disorders in unprecedented conditions. The improved spatial resolution of the ultra-high-resolution (UHR) scanning mode is a major step for the analysis of bronchopulmonary disorders, making abnormalities at the level of small anatomical structures such as secondary pulmonary lobules accessible to radiologists. Distal divisions of pulmonary and systemic vessels also benefit from UHR protocols as alterations of lung microcirculation were previously excluded from confident analysis with energy-integrating detector CT. Although noncontrast chest CT examinations were the initial target of UHR protocols, the clinical value of this mode is also applicable to chest CT angiographic examinations with improved morphological evaluation and higher-quality lung perfusion imaging. The clinical benefits of UHR have been evaluated in initial studies, allowing radiologists to foresee the field of future applications, all combining high diagnostic value and radiation dose reduction. The purpose of this article is to highlight the technological information relevant to daily practice and to review the current clinical applications in the field of chest imaging.
Dosing of convalescent plasma and hyperimmune anti-SARS-CoV-2 immunoglobulins: a phase I/II dose finding study
Authors: Huygens Sammy , Preijers Tim , Swaneveld Francis H. , Budde Ilona Kleine , GeurtsvanKessel Corine H. , Koch Birgit C.P. , Rijnders Bart J.A.
Published: March 2023

Background

During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing neutralizing antibody (Nab) titers following the administration of ConvP or hyperimmune globulins(COVIg).

Methods

Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19.

Results

44 patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile-range: 17–25 days). Simulations demonstrated that even monthly infusions of 600ml of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody levels for >90% of the time. However, as a result of hybrid immunity and/or repeated vaccination plasma donors with extremely high Nab-titers are now readily available, and a >90% target attainment should be possible.

Conclusion

The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg.
Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma
Authors: Joulia Régis , Puttur Franz , Stölting Helen , Traves William J. , Entwistle Lewis J. , Voitovich Anastasia , Martín Minerva Garcia , Al-Sahaf May , Bonner Katie , Scotney Elizabeth , Molyneaux Philip L. , Hewitt Richard J. , Walker Simone A. , Yates Laura , Saglani Sejal , Lloyd Clare M.
Published: March 2023

Allergic asthma generally starts during early life and is linked to substantial tissue remodelling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLS), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MCs) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-Cadherin. Furthermore, spatial transcriptomics of paediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodelling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.
Spatiotemporal mapping of the contractile and adhesive forces sculpting earlyC. elegansembryos
Authors: Yamamoto Kazunori , Ichbiah Sacha , Perez Matthieu , Borrego-Pinto Joana , Delbary Fabrice , Goehring Nate , Turlier Hervé , Charras Guillaume
Published: March 2023

Embryo shape is determined by individual cell mechanics, intercellular interaction strength, and geometrical constraints. Models based on surface tensions at cell interfaces can predict 3D static cellular arrangements within aggregates. However, predicting the dynamics of such arrangements is challenging due to difficulties in measuring temporal changes in tensions. Here, we characterise the spatiotemporal changes in cellular tensions shaping the early nematode embryo using AFM, live microscopy, and tension inference. Using excoriated embryos, we validate a hybrid inference pipeline that calibrates relative inferred tensions temporally using cortical myosin enrichment and absolute tensions using AFM measurements. Applied to embryos within their native shell, we infer a spatiotemporal map of absolute tensions, revealing that ABa, ABp, and EMS compaction is driven by increased tension at free surfaces, while P2’s initial exclusion is due to high tension at intercellular contacts. We uncover a direct and non-affine contribution of cadherins to cell-cell contact tension, comparable to cadherins’ indirect contribution via actomyosin regulation.

Highlights

P lineage cells have lower cortical tensions than AB lineage cells

Enrichment of Myosin-II at the cell cortex is a good predictor of cell-medium tension but is not sufficient to determine tension at cell-cell contacts.

Myosin-informed tension inference allows determination of the spatiotemporal evolution of all surface tensions within the embryo.

ABa, ABp, and EMS compact due to high tensions at their cell-medium interfaces compared to their cell-cell interfaces, while P2is initially excluded due to high cell-cell contact tensions.

Cadherins contribute directly in a non-linear way by reducing cell-cell contact tension by nearly 50%.

Open Access

For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
STORM imaging buffer with refractive index matched to standard immersion oil
Authors: Lee Youngseop , Lee Yeunho , Lee Minchol , Koo Donghoon , Kim Dongwoo , Lee Kangwon , Kim Jeongmin
Published: March 2023

Stochastic optical reconstruction microscopy (STORM) provides exceptional super-resolution imaging by sparsely blinking individual dye molecules in thiol-containing media. STORM is now well-established for imaging thin biological specimens, and recent technological advancements have expanded its use to thick tissues. While the use of mounting media with an oil refractive index has been shown to reduce light scattering within tissues and thus greatly improve imaging depth and resolution in optical microscopy, the refractive index of STORM imaging buffers is typically water-like and oil-index (OI) buffers have never been considered for this purpose. In this study, we report a 3-pyridinemethanol-based STORM buffer that matches the refractive index of standard immersion oil. Our OI buffer exhibits similar superior performance in terms of photoswitching of Alexa Flour 647 dye and STORM image quality in fixed cells as conventional STORM buffers, despite having a completely different refractive index. Interestingly, it shows remarkable stability for at least 25 days, and potentially longer, which will enable STORM imaging of a large number of cells on a single prepared slide, as well as larger field-of-view imaging through multiple field stitching. By achieving perfect index matching with oil immersion objectives, OI buffers can produce accurate nanoscale morphology of thin biological specimens, without the need for complex microscope calibrations across sample depth. More importantly, our STORM buffer is expected to play a crucial role in lightsheet STORM applications for thick tissues by reducing light scattering, thereby leading to improved imaging depth and localization performance.
Operant training for highly palatable food alters translating mRNA in nucleus accumbens D2 neurons and reveals a modulatory role ofNeurochondrin
Authors: Montalban Enrica , Giralt Albert , Taing Lieng , Nakamura Yuki , Pelosi Assunta , Brown Mallory , de Pins Benoit , Valjent Emmanuel , Martin Miquel , Nairn Angus C. , Greengard Paul , Flajolet Marc , Hervé Denis , Gambardella Nicolas , Roussarie Jean-Pierre , Girault Jean-Antoine
Published: March 2023

BACKGROUND

Highly palatable food triggers behavioral alterations reminiscent of those induced by addictive drugs. These effects involve the reward system and dopamine neurons, which modulate neurons in the nucleus accumbens (NAc). The molecular mechanisms underlying the effects of highly palatable food on feeding behavior are poorly understood.

METHODS

We studied the effects of 2-week operant conditioning of mice with standard or isocaloric highly palatable food. We investigated the behavioral effects and dendritic spine modifications in the NAc. We compared the translating mRNA in NAc neurons identified by the type of dopamine receptors they express, depending on the type of food and training. We tested the consequences of invalidation of an abundant downregulated gene, Ncdn (Neurochondrin).

RESULTS

Operant conditioning for highly palatable food increases motivation for food even in well-fed mice. In control mice, free access to regular or highly palatable food results in increased weight as compared to regular food only. Highly palatable food increases spine density in the NAc. In animals trained for highly palatable food, translating mRNAs are modified in NAc dopamine D2-receptor-expressing neurons, mostly corresponding to striatal projection neurons, but not in those expressing D1-receptors. Knock-out of Ncdn, an abundant down-regulated gene, opposes the conditioning-induced changes in satiety-sensitive feeding behavior and apparent motivation for highly palatable food, suggesting down-regulation may be a compensatory mechanism.

CONCLUSIONS

Our results emphasize the importance of mRNA alterations D2 striatal projection neurons in the NAc in the behavioral consequences of highly palatable food conditioning and suggest a modulatory contribution of Ncdn downregulation.
Evolution of pollination-induced plasticity of flower longevity
Authors: Xu Kuangyi
Published: March 2023

In many plants, pollen deposition or removal can lead to early flower senescence, while flowers will live longer when pollination is excluded, and the strength of this pollination-induced plasticity of flower longevity varies across populations. This study builds models to investigate the evolution of the plasticity of flower longevity through group and individual selection under stochastic pollination environments. Generally, stronger plasticity evolves when female and male fitness accrual rates are higher and more volatile, and the evolution of plasticity is also strongly affected by daily maintenance cost of flowers relative to construction costs. Group selection only selects for plasticity in the female function (i.e., ovule fertilization) but not in the male function (i.e., pollen removal), and plasticity is optimal in maximizing fitness only when saved resources through plasticity greatly enhance individual fitness. Plasticity is more likely to evolve under individual selection, but under the same pollination environment, any combination of the plasticity in female and male functions that adds up to a certain overall strength of plasticity can be evolutionarily stable. Given the fact that plasticity in the male function is rare in hermaphroditic populations, the plasticity of flower longevity may evolve mainly through group selection instead of individual selection.
The Role of Reproductive Periodicity in Dispersal Among Hydrothermal Vents and its Implications for Regional Connectivity and Conservation
Authors: Brunner Otis , Methou Pierre , Mitarai Satoshi
Published: March 2023

Connectivity among isolated habitat patches via planktonic larval dispersal is crucial for maintaining the regional diversity of hydrothermal vents. Despite, increasing sophistication of techniques for simulating dispersal, limited information on biological and behavioural traits of vent-associated species has unknown affects on the applicability of these methods for conservation. Here we focus on the role of periodic reproduction on dispersal among hydrothermal vents, as periodic spawning has increasingly been observed in a variety of taxa. For generalizeability, we simulate the dispersal of larvae under treatments of periodic and aperiodic release timing at various depths, with a consistant but variable planktonic larval duration. Our results show a highly variable effect of periodicity on the characteristics and distribution of dispersal, which are heavily modified by the dispersal depth and source location. The capacity for reproductive periodicity to impact the among-site dispersal warrents further investigation into its prevelance and timing among vent-associated fauna.
Direct prediction of Homologous Recombination Deficiency from routine histology in ten different tumor types with attention-based Multiple Instance Learning: a development and validation study
Authors: Lavinia Loeffler Chiara Maria , El Nahhas Omar S.M. , Muti Hannah Sophie , Seibel Tobias , Cifci Didem , Treeck Marko van , Gustav Marco , Carrero Zunamys I. , Gaisa Nadine T. , Lehmann Kjong-Van , Leary Alexandra , Selenica Pier , Reis-Filho Jorge S. , Bruechle Nadina Ortiz , Kather Jakob Nikolas
Published: March 2023

Background

Homologous Recombination Deficiency (HRD) is a pan-cancer predictive biomarker that identifies patients who benefit from therapy with PARP inhibitors (PARPi). However, testing for HRD is highly complex. Here, we investigated whether Deep Learning can predict HRD status solely based on routine Hematoxylin & Eosin (H&E) histology images in ten cancer types.

Methods

We developed a fully automated deep learning pipeline with attention-weighted multiple instance learning (attMIL) to predict HRD status from histology images. A combined genomic scar HRD score, which integrated loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) was calculated from whole genome sequencing data for n=4,565 patients from two independent cohorts. The primary statistical endpoint was the Area Under the Receiver Operating Characteristic curve (AUROC) for the prediction of genomic scar HRD with a clinically used cutoff value.

Results

We found that HRD status is predictable in tumors of the endometrium, pancreas and lung, reaching cross-validated AUROCs of 0.79, 0.58 and 0.66. Predictions generalized well to an external cohort with AUROCs of 0.93, 0.81 and 0.73 respectively. Additionally, an HRD classifier trained on breast cancer yielded an AUROC of 0.78 in internal validation and was able to predict HRD in endometrial, prostate and pancreatic cancer with AUROCs of 0.87, 0.84 and 0.67 indicating a shared HRD-like phenotype is across tumor entities.

Conclusion

In this study, we show that HRD is directly predictable from H&E slides using attMIL within and across ten different tumor types.
Integrin-αVβ3 is a fundamental factor in medulloblastoma tumorigenicity and radioresistance: A new game for an old player
Authors: Echavidre William , Durivault Jérôme , Gotorbe Célia , Blanchard Thays , Pagnuzzi-Boncompagni Marina , Vial Valérie , Raes Florian , Broisat Alexis , Villeneuve Rémy , Amblard Régis , Garnier Nicolas , Ortholan Cécile , Faraggi Marc , Serrano Benjamin , Picco Vincent , Montemagno Christopher
Published: March 2023

Medulloblastoma (MB) is the most frequent solid tumor in children, localized in the brain’s posterior fossa. Its standard of care comprises maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. Relevant targets for naive and recurrent MB are urgently needed. Primary and recurrent MBs are characterized by aggressive invasion into surrounding brain tissue, active angiogenesis, and radioresistance. Integrin-αvβ3 was a major driver of these features in glioblastoma. Nevertheless, such observations have not yet been reported in MB. Integrin-αvβ3 was found to be expressed in a subset of MB patients. We investigated the role of integrin-αvβ3 using MB-derived cell lines with β3-subunit depletion or overexpression both in vitro and in vivo. Radioresistant MB cell lines were generated and showed increased integrin-αvβ3 expression, which correlated with increased susceptibility to pharmacological integrin-αvβ3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/magnetic resonance imaging (MRI) studies on orthotopic models using a radiolabeled integrin-αvβ3 ligand (99mTc-RAFT-RGD). This approach offers the prospect of a novel predictive imaging modality in MB. Altogether, our data pave the way for SPECT/MRI-based selection of a subpopulation of MB patients eligible for integrin-αvβ3-directed therapies.

SIGNIFICANCE

This study demonstrates integrin-αvβ3’s fundamental role in MB tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.
The fork restart factor PHF6 interacts with RRM2 and binds to H3K56ac marked nascent DNA
Authors: Depestel Lisa , Bekaert Sarah-Lee , Sanders Ellen , Damme Carolien Van , Eggermont Aline , Loontiens Siebe , Tilleman Laurentijn , Nieuwerburgh Filip Van , Delhaye Louis , Vlierberghe Pieter Van , Eyckerman Sven , Speleman Frank , Durinck Kaat
Published: March 2023

The PHF6 protein is a presumed chromatin reader implicated in disease through germline loss-of-function mutations causing cognitive disability syndromes and somatic mutations are predominantly observed in acute T-cell leukemia. Previous reports support a role for PHF6 in DNA damage repair, replication fork restart as well as hematopoietic precursor cell self-renewal capacity and lineage commitment. To explore better how PHF6 mediates these functions, we mapped the PHF6 interactome and identified RRM2 as a consistent binding partner across different normal and malignant cell types. Next, PHF6 knockdown imposed increased replicative stress/DNA damage and suggested possible binding of PHF6 to H3K56ac, a marker for nascent DNA at sites of DNA damage repair. Genome-wide mapping of PHF6 chromatin binding indeed revealed overlap with sites of active DNA damage, binding sites of replication fork proteins and functional crosstalk with the neuroblastoma transcription core regulatory circuitry. Altogether, we show a canonical PHF6-RRM2 interaction enabling active transport of RRM2 to genomic sites of PHF6 mediated fork restart and PHF6 localization to H3K56ac at highly transcribed genes facilitating fork restart following replication-transcription conflicts.
BE3 is the major branching enzyme isoform required for amylopectin synthesis in Chlamydomonas reinhardtii
Authors: Courseaux Adeline , George Océane , Deschamps Philippe , Bompard Coralie , Duchêne Thierry , Dauvillée David
Published: March 2023

Starch-branching enzymes (BEs) are essential for starch synthesis in both plants and algae where they influence the architecture and physical properties of starch granules. Within Embryophytes, BEs are classified as type 1 and type 2 depending on their substrate preference. In this article, we report the characterization of the three BE isoforms encoded in the genome of the starch producing green algaeChlamydomonas reinhardtii: two type 2 BEs (BE2 and BE3) and a single type 1 BE (BE1). Using single mutant strains, we analyzed the consequences of the lack of each isoform on both transitory and storage starches. The transferred glucan substrate and the chain length specificities of each isoform were also determined. We show that only BE2 and BE3 isoforms are involved in starch synthesis and that, although both isoforms possess similar enzymatic properties, BE3 is critical for both transitory and storage starch metabolism. Finally, we propose putative explanations for the strong phenotype differences evidenced between theC. reinhardtii be2andbe3mutants, including functional redundancy, enzymatic regulation or alterations in the composition of multimeric enzyme complexes.
Evaluating targeted COVID-19 vaccination strategies with agent-based modeling
Authors: Hladish Thomas J. , Pillai Alexander N. , Pearson Carl A. B. , Toh Kok Ben , Tamayo Andrea , Stoltzfus Arlin , Longini Ira M.
Published: March 2023

We evaluate approaches to vaccine distribution using an agent-based model of human activity and COVID-19 transmission calibrated to detailed trends in cases, hospitalizations, deaths, seroprevalence, and vaccine breakthrough infections in Florida, USA. We compare the incremental effectiveness for four different distribution strategies at four different levels of vaccine availability, reflecting different income settings’ historical COVID-19 vaccine distribution. Our analysis indicates that the best strategy to reduce severe outcomes is to actively target high disease-risk individuals. This was true in every scenario, although the advantage was greatest for the middle-income-country availability assumptions, and relatively modest compared to a simple mass vaccination approach for rapid, high levels of vaccine availability. Ring vaccination, while generally the most effective strategy for reducing infections, ultimately proved least effective at preventing deaths. We also consider using age group as a practical, surrogate measure for actual disease-risk targeting; this approach still outperforms both simple mass distribution and ring vaccination.

We also find that the magnitude of strategy effectiveness depends on when assessment occurs (e.g., after delta vs. after omicron variants). However, these differences in absolute benefit for the strategies do not change the ranking of their performance at preventing severe outcomes across vaccine availability assumptions.
Global landscape ofStreptococcus pneumoniaeserotypes colonising healthy individuals worldwide before vaccine introduction; a systematic review and meta-analysis
Authors: Clifford Samuel , Knoll Maria D , O’Brien Katherine L , Pollington Timothy M , Moodley Riya , Prieto-Merino David ,   RESPICAR Consortium, Edmunds W John , Flasche Stefan , de Waroux Olivier le Polain
Published: March 2023

Background

Monitoring pneumococcal carriage prevalence and serotype distribution is critical to understanding pneumococcal transmission dynamics and vaccine impact, particularly where routine disease surveillance is limited. This study aimed to describe and interpret heterogeneity in serotype-specific carriage globally before widespread use of pneumococcal conjugate vaccines (PCVs).

Methods

A systematic literature review was undertaken to summarise all pneumococcal carriage studies across continents and age groups before PCV introduction. Serotype distributions were assessed via Bayesian nested meta-regression and hierarchical clustering.

Findings

In total 237 studies from 74 countries were included, comprising 492 age-specific datasets that contained 47,769 serotyped isolates.The modelled carriage prevalence differed substantially across regions, ranging in <5y from 35% (95%CrI 34%-35%) in Europe to 69% (95%CrI 69-70%) in Africa. Serotypes 19F, 6B, 6A, 23F, and 14 were the five most prevalent in children <5 years. The modelled proportion of Synflorix-10 (PCV10) serotypes carried by <5y ranged from 45% (95% CrI: 44% to 46%) in Asia to 59% (58% to 60%) in Europe, and that of Prevenar-13 (PCV13) from 60% (59% to 61%) in Asia to 76% (75% to 77%) in Europe. The diversity of carried serotypes increased with age, and so did the prevalence of vaccine-type serotypes. However, variation in serotype distribution did not cluster by age, ethnicity, region, or overall carriage prevalence.

Interpretation

Globally, pre-PCV pneumococcal carriage was dominated by a few serotypes. Serotype distribution variability was not easily attributable to a single discriminatory factor.

Funding

The review was funded by a grant to OlPdW from the World Health Organisation (grant number: SPHQ14-APW-2639) and by a Fellowship to SF jointly funded by the Wellcome Trust and the Royal Society (grant number: 208812/Z/17/Z).
Cause of Death by Race and Ethnicity in Minnesota Before and During the COVID-19 Pandemic, 2019-2020
Authors: Blake Madelyn J. , Marka Nicholas A. , Steer Clifford J. , Ravdin Jonathan I.
Published: March 2023

Objectives

To measure changes in cause of death dynamics in 2019 and 2020 and the relationship between concurrent occurrence of the COVID-19 pandemic and mortality outcome by race and ethnicity.

Patients and Methods

We used resident mortality data from the Minnesota Department of Health (MDH) to conduct retrospective statistical analysis of deaths in Minnesota in 2019 relative to 2020 to assess changes in mortality in a pre-pandemic and pandemic period.

Results

COVID-19 strongly contributed to ethnicity-related mortality disparities in Minnesota. Not only was there a greater proportion of COVID-19 decedents within the Black and Hispanic populations, but their average decedent age was markedly lower relative to the White population. The Black population experienced a disproportionate increase in decedents with a 34% increase during 2020 compared to 2019.

Conclusions

This retrospective analysis of death dynamics and mortality outcomes in Minnesota from 2019 to 2020 demonstrated an increase in adverse mortality outcomes relative to the pre-pandemic period that disproportionately impacted Black and Hispanic minority populations. Access to non-pharmaceutical interventions combating COVID-19 infection in Black and Hispanic communities should be expanded in Minnesota.
Clinical performance of a chemiluminescence SARS-CoV-2 antibody assay in a cohort of healthcare workers, blood donors and COVID-19 patients
Authors: Rangel Giselle , Lopez Daysa , Chavarría Athneris , Mudarra Laiss , Britton Gabrielle , Villarreal Alcibiades
Published: March 2023

Introduction

Serological detection of antibodies against SARS-CoV-2 has become an essential tool to test vaccine efficacy and epidemiological surveillance of COVID-19. There have been limited published studies documenting the performance of SARS-CoV-2 antibody assays within hispanic populations.

Materials and methods

We evaluated the diagnostic performance of a chemiluminescence enzyme immunoassay (CLIA) on a set of 1,035 samples including pre-pandemic samples, healthcare workers (HCW), blood donors (BD) and COVID-19 positive confirmed by RT-PCR collected from April to December 2020.

Results

Through a ROC curve the CLIA test had a high diagnostic performance, with an AUC of 0.9854 (CI95%95.68-100), P <0.0001. The analysis yielded a cut-off point 0.1950, sensitivity of 98.4% (CI95%95 91.54-99.9), and specificity of 93.8% (CI95%79.8 - 98.9). The diagnostic performance was also evaluated comparing the results with those obtained using other diagnostic techniques. Substantial agreement with the lateral flow chromatography and RT-PCR tests was found, and a high level of agreement with ELISA, with %PPA of 91.3 (CI95%84.0-95.5), % NPA of 97.7 (CI95%96.3-98.6), % OPA of 97.7 (CI95%96.3-98.6) and Cohen’s kappa value of 90.4 (CI95%85.8-94.9). A logistic regression was used to determine which of the independent variables predicted reactivity to CLIA test. A higher age was associated with an odds ratio (OR) of 1.043 (CI95%1.022-1.065), while the presence of at least one chronic disease was associated with an OR of 5.649 (CI95%3.089-10.329) greater likelihood of reactivity.

Conclusions

CLIA test exhibited excellent performance making it a suitable test for seroprevalence surveillance at the community level.
Families Experience of a Relatives Brain Stem Death Diagnosis: A Systematic Review
Authors: Cade-Smith Ella , Mackay Liam , Wijayatilake Dhuleep Sanjay , Kingsley Marc , Shaikh Madiha
Published: March 2023

AIM

Being diagnosed as Brain Stem Dead is a very challenging experience for families. Most research regarding brain stem death focuses on Organ Donation and there is currently little research into families’ experience of brain stem death. The aim is to review the family’s experience of brain stem death.

DESIGN

Systematic review

METHOD

A narrative synthesis was conducted for 9 studies including qualitative and quantitative study designs. Four electronic databases: AHMED (Allied and Complimentary Medicine), Emcare (1995-present), Medline (Ovid) and APA Psych Info (Ovid) were searched. No limit was placed on date of publishing due to this being a relatively under researched topic. The original search was conducted on 4thNovember 2021 and rerun on 6thDecember 2022 to ensure the inclusion of any new published studies.

RESULTS

Six main themes were identified, including: The Unexpected Prognosis; Coming to terms with brain stem death- grieving process; Request for organ donation; Observing brain stem death testing; The impact of staff on families’ experience; and the lasting impact.

CONCLUSION

Families of patients with brain stem death are often left with a lack of understanding surrounding the diagnosis, the process, and the short and long term distress it can cause. There is need for research into family’s experiences and brain stem death testing specifically so that more reliable data can be produced. There is a need to establish national, or international practice surrounding family care in intensive care in cases of brain stem death. This review highlights the importance of establishing specific brain stem death protocols, enabling more effective and consistent support for families.
Sex-stratified GWAS of Body Fat Percentage after Adjusting for Testosterone and SHBG in the UK Biobank
Authors: Roshandel Delnaz , Paterson Andrew D. , Dash Satya
Published: March 2023

Introduction

Adiposity, particularly centripetal adiposity/reduced gluteofemoral adiposity, increases dyslipidemia, type 2 diabetes (T2D) and coronary artery disease (CAD). Genome-wide association studies (GWAS) to date have identified 12 loci associated with body fat percentage (BFP). Biological sex influences both overall adiposity and fat distribution. Further, testosterone and sex hormone binding globulin (SHBG) influence adiposity and metabolic function, with differential effects of testosterone in men and women.

Methods

We performed sex-stratified GWAS of BFP in white British individuals from the UK biobank adjusting for SHBG and testosterone. We further investigated association of the identified loci with high density cholesterol (HDL), triglyceride (TG), T2D, CAD, and MRI-derived abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT) and gluteofemoral adipose tissue (GFAT) using publicly available data from large GWAS. We also performed 2-sample Mendelian Randomization (MR) using identified BFP variants as instruments to investigate causal effect of BFP on HDL, TG, T2D and CAD in males and females separately.

Results

We identified 193 and 174 autosomal loci explaining 3.35% and 2.60% of the variation in BFP in males and females, respectively. In addition, we identified 2 Chr X loci in men. Only 38 of these loci associated with BFP in both males and females. Seven loci in men including the 2 loci on Chr X and ten loci in females have not been associated with any adiposity or cardiometabolic traits previously. The majority of BFP loci did not associate with cardiometabolic traits. Of the BFP loci associated with cardiometabolic traits several had paradoxically beneficial cardiometabolic effects with favourable fat distribution. Consistent with that sex-stratified MR analyses using identified BFP variants as instruments did not find convincing supportive evidence that increased BFP has deleterious cardiometabolic effects in either sex with highly significant heterogeneity.

Conclusions

Adjusting for testosterone and SHBG with sex-stratified analyses substantially increased the number of BFP associated loci. Despite this adjustment, there was limited genetic overlap in BFP in males and females. Further identified loci in general did not have adverse cardiometabolic effects which may reflect the protective effect of favourable fat distribution and the modulation of cardiometabolic risk by testosterone and SHBG.
Fit by design: Developing substrate-specific seed mixtures for functional dike grasslands
Authors: Bauer Markus , Huber Jakob K. , Kollmann Johannes
Published: March 2023

Sowing is a well-established restoration technique to overcome dispersal limitation. Site-specific seed mixtures are most effective to achieve functional communities. This is especially important if the restored vegetation has to protect critical infrastructure like roadsides and dikes. Here, an improved seed–substrate combination will secure slope stability, reduce mowing efforts, and generate species-rich grasslands.

A factorial field experiment addressed this topic on a dike at River Danube in SE Germany in 2018–2021. Within 288 plots, we tested three sand admixtures, two substrate depths, two seed densities and two seed mixture types (mesic hay meadow, semi-dry calcareous grassland) in north and south exposition, and measured the recovery completeness by calculating the successional distance to reference sites, the persistence of sown species, and the Favourable Conservation Status (FCS) of target species.

Overall, the sown vegetation developed in the desired direction, but a recovery debt remained after four years, and some plots still showed similarities to negative references from ruderal sites. In north exposition, hay meadow-seed mixtures developed closer to the respective reference communities than dry-grassland mixtures.

In south exposition, the sown communities developed poorly which might be due to a severe drought during establishment. This initial negative effect remained over the entire observation period.

Sand admixture had a slightly positive effect on target variables, while substrate depth, seed density and mixture type had no effects on species persistence or FCS.

Synthesis and applications: Site-adapted seed mixtures make restoration more effective. However, applying several seed–substrate combinations might foster beta diversity. Furthermore, additional management efforts are recommended, as they might be necessary to reduce the recovery debt, as well as re-sowing after unfavourable conditions.