bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunotherapy for Solitary Fibrous Tumor (Hemangiopericytoma)
Authors: Singer Lauren , Singer Jorie , Horbinski Craig , Penas-Prado Marta , Lukas Rimas V.
Published: May 2024

Introduction:

Solitary fibrous tumors (SFTs) of the central nervous system represent a unique entity with limited data on best treatment practices.

Case Report:

Here, we present a case of multiply recurrent central nervous system SFT treated with radiation and immunotherapy. Immunotherapy was chosen based on mutations of genes encoding DNA repair enzymes detected through next-generation sequencing of the tumor, DNA polymerase epsilon catalytic subunit (POLE) and mutL homolog 1. The use of radiation and immunotherapy led to slight shrinkage and no recurrence of the tumor for over 2 years.

Conclusion:

The presence of somatic DNA repair enzyme gene mutations in SFT may suggest a benefit from a combination of radiotherapy and immunotherapy. This may serve as a biomarker for guiding management in patients with this rare tumor.
Protocol for the Prone and Oscillation Pediatric Clinical Trial (PROSpect)
Authors: Kneyber Martin C.J. , Cheifetz Ira M. , Asaro Lisa A. , Graves Todd L. , Viele Kert , Natarajan Aruna , Wypij David , Curley Martha A.Q. ,   for the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Published: May 2024

OBJECTIVES:

Respiratory management for pediatric acute respiratory distress syndrome (PARDS) remains largely supportive without data to support one approach over another, including supine versus prone positioning (PP) and conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV).

DESIGN:

We present the research methodology of a global, multicenter, two-by-two factorial, response-adaptive, randomized controlled trial of supine versus PP and CMV versus HFOV in high moderate-severe PARDS, the Prone and Oscillation Pediatric Clinical Trial (PROSpect, www.ClinicalTrials.gov, NCT03896763).

SETTING:

Approximately 60 PICUs with on-site extracorporeal membrane oxygenation support in North and South America, Europe, Asia, and Oceania with experience using PP and HFOV in the care of patients with PARDS.

PATIENTS:

Eligible pediatric patients (2 wk old or older and younger than 21 yr) are randomized within 48 h of meeting eligibility criteria occurring within 96 h of endotracheal intubation.

INTERVENTIONS:

One of four arms, including supine/CMV, prone/CMV, supine/HFOV, or prone/HFOV. We hypothesize that children with high moderate-severe PARDS treated with PP or HFOV will demonstrate greater than or equal to 2 additional ventilator-free days (VFD).

MEASUREMENTS AND MAIN RESULTS:

The primary outcome is VFD through day 28; nonsurvivors receive zero VFD. Secondary and exploratory outcomes include nonpulmonary organ failure-free days, interaction effects of PP with HFOV on VFD, 90-day in-hospital mortality, and among survivors, duration of mechanical ventilation, PICU and hospital length of stay, and post-PICU functional status and health-related quality of life. Up to 600 patients will be randomized, stratified by age group and direct/indirect lung injury. Adaptive randomization will first occur 28 days after 300 patients are randomized and every 100 patients thereafter. At these randomization updates, new allocation probabilities will be computed based on intention-to-treat trial results, increasing allocation to well-performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol for primary, secondary, and exploratory analyses.

CONCLUSIONS:

PROSpectwill provide clinicians with data to inform the practice of PP and HFOV in PARDS.
Reconstructed Mid-Face Lifting After Tissue Expansion by Suspending the Expander Capsule
Authors: Yang Jifan , Gan Cheng , Han Bing , Song Jipeng , Zhang Tiran , Yan Yucheng , Fan Jincai
Published: May 2024

Background:

An obvious saggy tendency was observed in the expanded flaps from mid-facial reconstruction and resulted in an unsatisfactory postoperative cosmetic outcome. At the time of this writing, the authors introduced a novel technique of mid-face lifting to correct the phenomenon by suspending the expander capsule.

Methods:

From September 2018 to August 2023, 11 patients who had undergone our mid-face lifting technique were enrolled in our study. The expanded flap was divided into 2 layers during the surgical procedure. The upper layer, which consists of the skin and the subcutaneous layer, was lifted, and the lower layer, consisting of the expander capsule and SMAS system, was left at the base. Then a capsular flap was lifted from the base and folded upward to lift the reconstructed mid-face. The capsular flap was fixed in the temporal or mastoid region when the saggy tendency was corrected, and the mid-facial contour became symmetric. Finally, the upper layer was trimmed and fixed at the base. Facial movements were restricted after the surgery.

Results:

The saggy tendency of all the expanded flaps was corrected, and the mid-facial symmetry was rebuilt immediately after the surgery. The effect were long-lasting at 3 months to 2 years of follow-ups. No serious postoperative complications occurred. The patients or their legal guardians were satisfied with the esthetic improvement.

Conclusion:

Reconstructed mid-face lifting with capsular flap was an effective and reliable way to correct the saggy tendency of a mid-facial expanded flap and rebuilt the mid-facial symmetry.
Current Management of T1 Colon Cancer in Denmark
Authors: Ebbehøj Anders L. , Jørgensen Lars N. , Smith Henry G. , Krarup Peter-Martin
Published: May 2024

Objective:

To describe the management of T1 colon cancer in a retrospective study of a national cancer registry.

Background:

There is increasing interest in the potential of local excision (LE) as an organ-preserving treatment for early colon cancer. However, accurate identification of patients who may have lymph node metastases (LNM) and require further surgery is a major challenge.

Methods:

Patients diagnosed with T1 colon cancer in Denmark from 2016 to 2020 were included and divided according to treatment: polypectomy (referred to as LE), upfront colectomy and completion colectomy. Primary outcome was the proportion of patients diagnosed by LE. Secondary outcomes included the rate of LNM, the association of histopathological risk factors with LNM, and overall survival.

Results:

1,749 patients were included, and 1,022 patients (58.4%) underwent initial LE. The rate of R1 margins after initial LE was 31.0%. Colectomy was performed in 1,160 patients (upfront in 727, completion in 433), of whom 58.3% had pT1 cancer. The rate of LNM was 11.5%. Rates of LNM were similar in patients undergoing upfront or completion colectomy (10.2% vs 12.4%, P=0.392), and in patients with any single histopathological risk factor compared to those with none (8.9% vs 10.6%, P=0.565). Although overall survival was significantly shorter in patients undergoing LE alone, no association between survival and treatment strategy was found on multivariable analysis.

Conclusions:

LE is the most common mode of diagnosis in patients with T1 colon cancer and does not negatively impact survival and postoperative outcomes. Current strategies to stratify patients to completion surgery appear insufficient, and more robust predictors are needed.
Transcatheter Aortic Valve Replacement Use in Young Patients Before and After Low-Risk Indication Approval
Authors: Waldron Christina , Pirelli Luigi , George Isaac , Takayama Hiroo , Geirsson Arnar , Assi Roland , Mori Makoto
Published: May 2024

Transcatheter aortic valve replacement (TAVR) use in young patients has recently increased following FDA approval for use in low-risk patients. How TAVR use among young patients may have accelerated in the interval between the FDA approval and the guideline publication remain unknown. We sought to characterize the national trends in aortic valve replacement (AVR) among young patients before and after the low-risk indication approval. Using the National Inpatient Sample data, we conducted a cross-sectional study of patients younger than 65 years of age who underwent TAVR, SAVR, or Ross operations between January 1, 2016, and February 29, 2020. We compared in-hospital mortality before and after the low-risk indication approval to infer whether the expansion occurred among lower-risk strata within the TAVR group in relation to SAVR. We identified 106,340 AVRs, including 13,095 TAVR (12.3%), 63,620 bioprosthetic SAVR (59.8%), 28,370 mechanical SAVR (26.7%), and 1,255 Ross (1.2%). The mean age was 54 (10.9), including 32,775 (30.8%) women. Before and after the low-risk approval, the TAVR share increased at 0.25 (0.03%) and 0.60 (0.09%) per month, respectively (interaction term p-value <0.001). Expansion of TAVR use among young patients around the time of FDA approval in low surgical risk patients serves as a case study to highlight the potential importance of specifying the indicated age group in future FDA approvals of transcatheter valve intervention devices.
Inherent Metabolic Adaptations in Adult Spiny Mouse (Acomys) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction
Authors: Kuppa Annapurna , Alzamrooni Afnan , Lopez Rachel , Suhan Tahra , Chaudhary Rajesh , Collins Nicole , Van den Bergh Fran , Abouleisa Riham , Wang Harrison , Mohamed Tamer , Satin Jonathan , Lyssiotis Costas , Beard Daniel A. , Abdel-Latif Ahmed
Published: May 2024

The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse (Acomys) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes inAcomyscompared to the non-regenerativeMus musculus.

We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes’ transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury.

Transcriptomic analysis revealed thatAcomyscardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways inAcomysat baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis inAcomyscompared toMus, underscoring the unique metabolic phenotype ofAcomyshearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation inAcomys.

In conclusion, our study identifies unique metabolic characteristics ofAcomyscardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishesAcomysas a valuable model for studying cardiac ischemic resilience in adult mammals.

Graphical abstract
Rationally Minimizing Natural Product Libraries Using Mass Spectrometry
Authors: Ness Monica , Peramuna Thilini , Wendt Karen L. , Collins Jennifer E. , King Jarrod B. , Paes Raphaella , Santos Natalia Mojica , Okeke Crystal , Miller Cameron R. , Chakrabarti Debopam , Cichewicz Robert H. , McCall Laura-Isobel
Published: May 2024

Natural product libraries are crucial to drug development, but large libraries drastically increase the time and cost during initial high throughput screens. Here, we developed a method that leverages liquid chromatography-tandem mass spectrometry spectral similarity to dramatically reduce library size, with minimal bioactive loss. This method offers a broadly applicable strategy for accelerated drug discovery with cost reductions, which enable implementation in resource-limited settings.
Genotype-to-phenotype mapping of somatic clonal mosaicism via single-cell co-capture of DNA mutations and mRNA transcripts
Authors: Yuan Dennis J , Zinno John , Botella Theo , Dhingra Dalia , Wang Shu , Hawkins Allegra , Swett Ariel , Sotelo Jesus , Raviram Ramya , Hughes Clayton , Potenski Catherine , Yokoyama Akira , Kakiuchi Nobuyuki , Ogawa Seishi , Landau Dan A
Published: May 2024

Somatic mosaicism is a hallmark of malignancy that is also pervasively observed in human physiological aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissue microdissection captures mutation frequencies, but cannot distinguish which mutations co-occur in the same clones to reconstruct clonal architectures, nor phenotypically profile clonal populations to delineate how driver mutations impact cellular behavior. To address these challenges, we developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, single-cell joint capture of recurrently mutated genomic regions and mRNA phenotypic markers in cells or nuclei isolated from solid tissues. We applied scG2P to aged esophagus samples from five individuals with high alcohol and tobacco exposure and observed a clonal landscape dominated by a large number of clones with a single driver event, but only rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants and double-driver mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.
Timing antigenic escape in multiple myeloma treated with T-cell redirecting immunotherapies
Authors: Papadimitriou Marios , Ahn Sungwoo , Diamond Benjamin , Lee Holly , McIntyre John , Truger Marietta , Durante Michael , Ziccheddu Bachisio , Landgren Ola , Rasche Leo , Bahlis Nizar J. , Neri Paola , Maura Francesco
Published: May 2024

Recent data highlight genomic events driving antigen escape as a recurring cause of chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (TCE) resistance in multiple myeloma (MM). Yet, it remains unclear if these events, leading to clonal dominance at progression, result from acquisition under treatment selection or selection of pre-existing undetectable clones. This differentiation gains importance as these immunotherapies progress to earlier lines of treatment, prompting the need for innovative diagnostic testing to detect these events early on. By reconstructing phylogenetic trees and exploring chemotherapy mutational signatures as temporal barcodes in 11 relapsed refractory MM patients with available whole genome sequencing data before and after CART/TCE treatment, we demonstrated that somatic antigen escape mechanisms for BCMA- and GPRC5D-targeting therapies are acquired post-diagnosis, likely during CART/TCE treatment. Longitudinal tracking of these mutations using digital PCR in 4 patients consistently showed that genomic events promoting antigen escape were not detectable during the initial months of therapy but began to emerge nearly 1 year post therapy initiation. This finding reduces the necessity for a diagnostic panel to identify these events before CART/TCE. Instead, it underscores the importance of surveillance and identifying patients at higher risk of acquiring these events.

KEY POINTS

Genomic events driving antigen escape are recurrent mechanisms of resistance to CART and T-cell engagers in multiple myeloma.

Using chemotherapy mutational signatures, we demonstrated that these events are most likely acquired during treatment.
Starve a cold or feed a fever? Identifying cellular metabolic changes following infection and exposure to SARS-CoV-2
Authors: Loveday Emma Kate , Welhaven Hope , Erdogan Ayten Ebru , Hain Kyle , Chang Connie B. , June Ronald K. , Taylor Matthew P.
Published: May 2024

Viral infections induce major shifts in cellular metabolism elicited by active viral replication and antiviral responses. For the virus, harnessing cellular metabolism and evading changes that limit replication are essential for productive viral replication. In contrast, the cellular response to infection disrupts metabolic pathways to prevent viral replication and promote an antiviral state in the host cell and neighboring bystander cells. This competition between the virus and cell results in measurable shifts in cellular metabolism that differ depending on the virus, cell type, and extracellular environment. The resulting metabolic shifts can be observed and analyzed using global metabolic profiling techniques to identify pathways that are critical for either viral replication or cellular defense. SARS-CoV-2 is a respiratory virus that can exhibit broad tissue tropism and diverse, yet inconsistent, symptomatology. While the factors that determine the presentation and severity of SARS-CoV-2 infection remain unclear, metabolic syndromes are associated with more severe manifestations of SARS-CoV-2 disease. Despite these observations a critical knowledge gap remains between cellular metabolic responses and SARS-CoV-2 infection. Using a well-established untargeted metabolomics analysis workflow, we compared SARS-CoV-2 infection of human lung carcinoma cells. We identified significant changes in metabolic pathways that correlate with either productive or non-productive viral infection. This information is critical for characterizing the factors that contribute to SARS-CoV-2 replication that could be targeted for therapeutic interventions to limit viral disease.
Polygenic architecture of brain structure and function, behaviors, and psychopathologies in children
Authors: Joo Yoonjung Yoonie , Lee Eunji , Kim Bo-Gyeom , Kim Gakyung , Seo Jungwoo , Cha Jiook
Published: May 2024

The human brain undergoes structural and functional changes during childhood, a critical period in cognitive and behavioral development. Understanding the genetic architecture of the brain development in children can offer valuable insights into the development of the brain, cognition, and behaviors. Here, we integrated brain imaging-genetic-phenotype data from over 8,600 preadolescent children of diverse ethnic backgrounds using multivariate statistical techniques. We found a low-to-moderate level of SNP-based heritability in most IDPs, which is lower compared to the adult brain. Using sparse generalized canonical correlation analysis (SGCCA), we identified several covariation patterns among genome-wide polygenic scores (GPSs) of 29 traits, 7 different modalities of brain imaging-derived phenotypes (IDPs), and 266 cognitive and psychological phenotype data. In structural MRI, significant positive associations were observed between total grey matter volume, left ventral diencephalon volume, surface area of right accumbens and the GPSs of cognition-related traits. Conversely, negative associations were found with the GPSs of ADHD, depression and neuroticism. Additionally, we identified a significant positive association between educational attainment GPS and regional brain activation during the N-back task. The BMI GPS showed a positive association with fractional anisotropy (FA) of connectivity between the cerebellum cortex and amygdala in diffusion MRI, while the GPSs for educational attainment and cannabis use were negatively associated with the same IDPs. Our GPS-based prediction models revealed substantial genetic contributions to cognitive variability, while the genetic basis for many mental and behavioral phenotypes remained elusive. This study delivers a comprehensive map of the relationships between genetic profiles, neuroanatomical diversity, and the spectrum of cognitive and behavioral traits in preadolescence.
Assessing Large Language Models for Oncology Data Inference from Radiology Reports
Authors: Chen Li-Ching , Zack Travis , Demirci Arda , Sushil Madhumita , Miao Brenda , Kasap Corynn , Butte Atul , Collisson Eric A. , Hong Julian
Published: May 2024

Purpose

We examined the effectiveness of proprietary and open Large Language Models (LLMs) in detecting disease presence, location, and treatment response in pancreatic cancer from radiology reports.

Methods

We analyzed 203 deidentified radiology reports, manually annotated for disease status, location, and indeterminate nodules needing follow-up. Utilizing GPT-4, GPT-3.5-turbo, and open models like Gemma-7B and Llama3-8B, we employed strategies such as ablation and prompt engineering to boost accuracy. Discrepancies between human and model interpretations were reviewed by a secondary oncologist.

Results

Among 164 pancreatic adenocarcinoma patients, GPT-4 showed the highest accuracy in inferring disease status, achieving a 75.5% correctness (F1-micro). Open models Mistral-7B and Llama3-8B performed comparably, with accuracies of 68.6% and 61.4%, respectively. Mistral-7B excelled in deriving correct inferences from “Objective Findings” directly. Most tested models demonstrated proficiency in identifying disease containing anatomical locations from a list of choices, with GPT-4 and Llama3-8B showing near parity in precision and recall for disease site identification. However, open models struggled with differentiating benign from malignant post-surgical changes, impacting their precision in identifying findings indeterminate for cancer. A secondary review occasionally favored GPT-3.5’s interpretations, indicating the variability in human judgment.

Conclusion

LLMs, especially GPT-4, are proficient in deriving oncological insights from radiology reports. Their performance is enhanced by effective summarization strategies, demonstrating their potential in clinical support and healthcare analytics. This study also underscores the possibility of zero-shot open model utility in environments where proprietary models are restricted. Finally, by providing a set of annotated radiology reports, this paper presents a valuable dataset for further LLM research in oncology.
Summer of Translational Aging Research for Undergraduates (STAR U): Short-term outcomes of a training program to advance diversity in aging research
Authors: Chan Kiana K. , Manly Jennifer J. , Cosentino Stephanie A. , Brickman Adam M.
Published: May 2024

Purpose

The Summer of Translational Aging Research for Undergraduates (STAR U) program, funded by the National Institute on Aging and the Alzheimer’s Association, aims to advance diversity in aging research through undergraduate education. Here, we evaluate the effectiveness of the program in cultivating a diverse cohort of scientists from underrepresented backgrounds.

Method

Forty-eight (96%) of 50 STAR U alumni completed a program evaluation survey between April and August 2023. The survey collected data on demographic characteristics of the alumni, educational/career goals, program experiences, and post-program outcomes, including information about continued education and scientific engagement.

Results

Ninety-one percent of respondents indicated that STAR U was “extremely significant” or “very significant” in influencing them to pursue a career in science, and 93% found STAR U to be effective in influencing decisions to pursue a career in aging research specifically. Forty one percent of all respondents were already accepted or enrolled in science-related advanced degree programs, with half enrolled in doctoral degree programs. Of the students who were not enrolled in graduate school, 89% of respondents indicated they had plans to enroll in advanced degrees in the future. Respondents actively disseminated their research, with 10% of STAR U scholars reporting leading or co-authoring papers intended for publication in a peer-reviewed journal (10%). In fact, review of PubMed shows that to date, 22 students (44%) have a combined total of 44 publications in peer reviewed journals. Qualitative feedback underscored the program’s impact on career exploration, as well as the impact of mentorship and the supportive environment provided by STAR U.

Conclusions

The STAR U program shows promise as an impactful model for advancing diversity in the scientific workforce focused on aging research by strengthening scholars’ goals for pursuing graduate education, careers in science, and research in aging in particular. Its individualized approach supports students in addressing challenges and fosters a supportive environment. STAR U serves as a catalyst for underrepresented students in STEM, showcasing the significance of tailored initiatives in promoting diversity and inclusion in aging research.
Assessing the role of local health departments in implementing PrEP in the US, 2020 update
Authors: Zigman Julia R. , Hoover Karen W. , Patel Rupa R. , Hall Kellie , Gvetadze Roman J. , Huang Ya-lin A.
Published: May 2024

Objectives

To identify current and potential roles for, and systematic barriers encountered by, local health departments (LHDs) engaging in PrEP implementation.

Methods

Web-based assessment created with Qualtrics® from Oct.-Dec. 2020 distributed via e-mail to 1,096 LHDs that indicated they provided HIV or STD screening and/or treatment in NACCHO’s 2019 National Profile of Local Health Departments.

Results

Of 354 respondents, 46% of LHDs were engaged in PrEP implementation compared with 29% in 2015. Activities included: referring to PrEP providers (68%); conducting consumer education (65%); promoting PrEP (59%); educating providers; (48%); and prescribing PrEP (42%). The top challenges to initiating or expanding PrEP implementation were lack of funding and staff, and 41% described staff reductions during COVID-19.

Conclusions

LHD engagement in PrEP implementation has increased significantly since 2015 but many LHDs still encounter barriers to initiating or expanding PrEP activities.

Policy Implications

Robust funding of public health infrastructure can ensure that LHDs and their partners are equipped to provide PrEP access for all who may benefit from it during future public health emergencies.
Minding the margins: Evaluating the impact of COVID-19 among Latinx and Black communities with optimal qualitative serological assessment tools
Authors: Binder Raquel A. , Matta Angela M. , Forconi Catherine S. , Oduor Cliff I. , Bedekar Prajakta , Patrone Paul N. , Kearsley Anthony J. , Odwar Boaz , Batista Jennifer , Forrester Sarah N. , Leftwich Heidi K. , Cavacini Lisa A. , Moormann Ann M.
Published: May 2024

COVID-19 disproportionately affected minorities, while research barriers to engage underserved communities persist. Serological studies reveal infection and vaccination histories within these communities, however lack of consensus on downstream evaluation methods impede meta-analyses and dampen the broader public health impact. To reveal the impact of COVID-19 and vaccine uptake among diverse communities and to develop rigorous serological downstream evaluation methods, we engaged racial and ethnic minorities in Massachusetts in a cross-sectional study (April - July 2022), screened blood and saliva for SARS-CoV-2 and human endemic coronavirus (hCoV) antibodies by bead-based multiplex assay and point-of-care (POC) test and developed across-plate normalization and classification boundary methods for optimal qualitative serological assessments. Among 290 participants, 91.4 % reported receiving at least one dose of a COVID-19 vaccine, while 41.7 % reported past SARS-CoV-2 infections, which was confirmed by POC- and multiplex-based saliva and blood IgG seroprevalences. We found significant differences in antigen-specific IgA and IgG antibody outcomes and indication of cross-reactivity with hCoV OC43. Finally, 26.5 % of participants reported lingering COVID-19 symptoms, mostly middle-aged Latinas. Hence, prolonged COVID-19 symptoms were common among our underserved population and require public health attention, despite high COVID-19 vaccine uptake. Saliva served as a less-invasive sample-type for IgG-based serosurveys and hCoV cross-reactivity needed to be evaluated for reliable SARS-CoV-2 serosurvey results. Using the developed rigorous downstream qualitative serological assessment methods will help standardize serosurvey outcomes and meta-analyses for future serosurveys beyond SARS-CoV-2.
Molecular phenotypes segregate missense mutations in SLC13A5 Epilepsy
Authors: Jaramillo-Martinez Valeria , Sennoune Souad R. , Tikhonova Elena B. , Karamyshev Andrey L. , Ganapathy Vadivel , Urbatsch Ina L.
Published: May 2024

The sodium-coupled citrate transporter (NaCT, SLC13A5) mediates citrate uptake across the plasma membrane via an inward Na+gradient. Mutations in SLC13A5 cause early infantile epileptic encephalopathy type-25 (EIEE25, SLC13A5 Epilepsy) due to impaired citrate uptake in neurons. Despite clinical identification of disease-causing mutations, underlying mechanisms and cures remain elusive. We mechanistically classify the molecular phenotypes of six mutations. C50R, T142M, and T227M exhibit impaired citrate transport despite normal expression at the cell surface. G219R, S427L, and L488P are hampered by low protein expression, ER retention, and reduced transport. Mutants’ mRNA levels resemble wildtype, suggesting post-translational defects. Class II mutations display immature core-glycosylation and shortened half-lives, indicating protein folding defects. These experiments provide a comprehensive understanding of the mutation’s defects in SLC13A5 Epilepsy at the biochemical and molecular level and shed light into the trafficking pathway(s) of NaCT. The two classes of mutations will require fundamentally different treatment approaches to either restore transport function, or enable correction of protein folding defects.

Loss-of-function mutations in the SLC13A5 causes SLC13A5-Epilepsy, a devastating disease characterized by neonatal epilepsy. Currently no cure is available. We clarify the molecular-level defects to guide future developments for phenotype-specific treatment of disease-causing mutations.
Molecular Characterization and Antibiotic Resistance Profile ofEscherichia coliIsolated From Liver Abscess
Authors: Nasar Mohammad , Grazza Sarrar
Published: May 2024

Background

Bacterial liver abscess is the most common hepatic infection, which can lead to death.Escherichia coliis among the many species of bacteria that cause it. This study was conducted to isolateE. colifrom liver abscess and then to characterise the bacteria’s molecular makeup and antibiotic resistance profile.

Methods

A total of 208 stool samples were collected from patients showing symptoms of liver abscess.E. coliwas isolated from these samples followed by identification by biochemical tests. Pure and biochemically positive colonies were confirmed by polymerase chain reaction. The disk diffusion method was used to ascertain the pattern of antibiotic resistance exhibited byE. coliisolates.

Results

The PCR amplification efficiency was nearly 100% since all of the samples appeared at 284 molecular base pairs (bp), which is considered to be the optimal parameter assay. The antimicrobial susceptibility pattern showed that isolates were resistant to many drugs but 100% and 92% of the isolates were susceptible to imipenem and azithromycin, respectively. All isolates were resistant to ampicillin, vancomycin, and cefotaxime. This was followed by ceftazidime (72%), tetracycline (84%), trimethoprim (80%), streptomycin (96%), linezolid (92%), Teicoplanin (80%), nalidixic acid (84%), ciprofloxacin (92%), and chloramphenicol (72%).

Conclusion

Multiple drug resistantE. coliis one of the causes of liver abscesses in humans.
Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread
Authors: Pahmeier Felix , Monticelli Stephanie R. , Feng Xinyi , Hjorth Christy K. , Wang Albert , Kuehne Ana I. , Bakken Russell R. , Batchelor Thomas G. , Lee Saeyoung E. , Middlecamp Marissa , Stuart Lauren , Abelson Dafna M. , McLellan Jason S. , Biering Scott B. , Herbert Andrew S. , Chandran Kartik , Harris Eva
Published: May 2024

Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells secrete the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design as GP38-specific antibodies can protect against severe disease in animal models, albeit through a currently unknown mechanism of action. Here, we show that GP38 induces endothelial barrier dysfunctionin vitro, and that CCHFV infection, and GP38 alone, can trigger vascular leak in a mouse model. Protective antibodies that recognize specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibit endothelial hyperpermeabilityin vitroand vascular leakin vivoduring CCHFV infection. This work uncovers a function of the secreted viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates the mode of action of non-neutralizing GP38-specific antibodies.
Adhesion ofE. colibacteria is force-modulated due to fimbriae-mediated surface repulsion and multivalent binding irrespective of surface specificity
Authors: Lundgren Anders , van Oostrum Peter , Iturri Jagoba , Malkoch Michael , Toca-Herrara José Luis , Reimhult Erik
Published: May 2024

Escherichia colibacteria that express type 1 fimbriae migrate along surfaces when pushed by a slow flow but stick more firmly when the flow increases. This and other examples of force-modulated biological binding are often described as due to lectin–glycan catch-bonds. Here we quantitatively track the 3D movements of fimbriatedE. coliflowing over surfaces nanopatterned with mannose or hydrophobic binding sites. We reveal that flow-modulated surface adhesion and motion are consequences of bacteria adhering via polydisperse, elastic fimbriae, irrespective of binding affinity and specificity. The fimbria-mediated surface repulsion and the flow forces on tethered bacteria establish an equilibrium bacteria-surface separation. The separation controls the number of potential tethers between the bacterium and the surface. Combined with the individual fimbria affinity, this determines the surface avidity and surface motion. This provides a broadly applicable mechanism by which bacteria acquire adaptive surface avidity, responding super-selectively to different flow environments, concentration, and affinity of available binding sites, essential to explaining how fimbriae govern tropism and surface colonization.
Tackling the primary healthcare workforce crisis: time to talk about health systems and governance. A comparative assessment of the European region
Authors: Kuhlmann E , Falkenbach M , Brinzac MG , Correia T , Panagioti M , Rechel B , Sagan A , Santric-Milicevic M , Ungureanu M-I , Wallenburg I , Burau V
Published: May 2024

Background

Primary healthcare has emerged as a powerful global concept, but little attention has been directed towards the pivotal role of the healthcare workforce and the diverse institutional setting in which they work. This study aims to bridge the gap between the primary healthcare policy and the ongoing healthcare workforce crisis debate by introducing a health system and governance approach to identify transformative capacities in health system contexts.

Methods

A qualitative comparative methodology was employed, and a rapid assessment of the primary healthcare workforce was conducted across nine countries: Denmark, Germany, Kazakhstan, Netherlands, Portugal, Romania, Serbia, Switzerland, and the United Kingdom/ England.

Results

Our findings reveal both convergence and pronounced diversity across the healthcare systems, with none fully aligning with the ideal attributes of primary healthcare suggested by WHO. However, across all categories, Denmark, the Netherlands, and to a lesser extent Kazakhstan, depict closer alignment to this model than the other countries. Workforce composition and skill-mix vary strongly, while disparities persist in education and data availability, particularly within Social Health Insurance systems. Policy responses and interventions span governance, organisational, and professional realms, although with weaknesses in the implementation of policies and a systematic lack of data and evaluation. The WHO primary healthcare model only marginally informs policy decisions, with the exception being in Kazakhstan.

Conclusion

We conclude that aligning primary healthcare and workforce considerations within the broader health system context may help move the debate forward and build governance capacities to improve resilience in both areas.
Spatiotemporal distribution of neural crest cells in the common wall lizardPodarcis muralis
Authors: Pranter Robin , Feiner Nathalie
Published: May 2024

Background

Neural crest cells (NCCs) are migratory embryonic stem cells that give rise to a diverse set of cell types. Here we describe the dynamic distribution of NCCs in developing embryos of the common wall lizardPodarcis muralisinferred from ten markers. Our aim is to provide insights into the NCC development of lacertid lizards and to infer evolutionary modifications by comparisons to other tetrapods.

Results

NCC migration is ongoing at oviposition, following three streams in the head and multiple in the trunk. From 21ss, we observe expression patterns indicating the beginning of differentiation towards mesenchymal and neuronal fates. By 35ss, migration is restricted to caudal levels, and fully differentiated chromaffin cells are observed.

Conclusions

We find that some markers show patterns that differ from other tetrapods. For example, the antibody HNK-1 labels three NCC streams from the hindbrain while some comparable reptile studies describe four. However, the information emerging from all markers combined shows that the overall spatiotemporal distribution of NCCs in the common wall lizard is largely conserved with that of other tetrapods. Our study highlights the dynamic nature of seemingly canonical marker genes and provides the first description of spatiotemporal NCC dynamics in a lacertid lizard.
Sex-specific risk loci and modifiedMEF2Cexpression in ALS
Authors: Byrne Ross P , van Rheenen Wouter , Gomes Tomás DS , Kelly Ciarán M , Kaçar Emrah ,   Project MinE ALS GWAS Consortium,   International ALS/FTD Genomics Consortium, Al Khleifat Ahmad , Iacoangeli Alfredo , Al-Chalabi Ammar , Veldink Jan H , McLaughlin Russell L
Published: May 2024

Significantly more men develop amyotrophic lateral sclerosis (ALS) than women, and heritability is not uniform between male and female transmissions, together suggesting a role for sex in the genetic aetiology of the disease. We therefore performed sex-stratified genome-wide and transcriptome-wide analyses of ALS risk, identifying six novel sex-specific risk loci includingMEF2C, which shows increased expression in female ALS motor neurones. X-chromosome analysis revealed an additional risk locus atIL1RAPL2.
Application of RNA-sequencing based predictive model for endometrial WOI in patients with recurrent implantation failure: a prospective cohort study
Authors: He Aihua , Yang Tianli , Lu Sijia , Zou Yangyun , Wan Cheng , Zhao Jing , Liu Nenghui , Liu Donge , Li Yumei , Wang Yonggang , Xu Bin , Hao Jie , Xie Shi , Fu Jing , Li Hui , Wu Hong , Zhang Qiong , Li Yanping
Published: May 2024

Background

Accurate prediction for endometrial window of implantation (WOI) would maximize the effectiveness of assisted reproductive technology. Previously, we have established a predictive model for endometrial WOI (rsERT) by three-time points sampling from the same patient at 48-hour intervals during one menstrual cycle. However, it is imperative to build a modified rsERT by single time point sampling in order to prevent multiple sampling and collateral harm.

Methods

A two-phase study was conducted. In the first phase, patients with successful clinical pregnancy after personalized embryo transfer (pET) guided by three-time points rsERT were recruited. Endometrial tissues obtained from single time point were used for the modified rsERT establishment. In the second phase, recurrent implantation failure (RIF) patients were recruited and assigned to experimental group underwent pET guided by modified rsERT’ or control group underwent conventional ET. Pregnant outcomes were recorded and analyzed.

Results

The modified rsERT was established using 91 eligible participants and could provide hour-based predictive result of endometrial WOI with an average accuracy of 94.51% with sensitivity and specificity being 92.73% and 96.27% using 10-fold CV. 176 RIF patients were recruited in the second phase (experimental group: n=88; control group: n=88). 40 of 88 (45.45%) patients showed WOI displacement, and 5.00% (2/40) of them were with advanced WOI, and the remaining 95.00% (38/40) with delayed WOI. The β-hCG positive rate, intrauterine pregnancy rate (IPR) and implantation rate (IR) of the experimental group were significantly improved (β-hCG positive rate: 67.05% vs. 39.77%, P=0.000; IPR: 61.36% vs. 31.82%, P=0.000; IR: 42.86% vs. 24.66%, P=0.001). While, pregnancy outcomes were not significantly different using different endometrial preparation protocols (β-hCG positive rate: 42.86% vs. 35.90%, P=0.508; IPR: 38.78% vs. 23.08%, P=0.116; IR: 30.12% vs. 17.46%, P=0.085).

Conclusions

The modified rsERT allowed WOI prediction using a single time point endometrial biopsy and pregnancy outcomes were significantly improved. This could provide an enhanced endometrial receptivity test as an alternative, requiring only a single time point sampling for RIF patients.

Funding

Research grants from Hunan Provincial Natural Science Foundation General Program (2023JJ30823) and Postdoctoral Fellowship Program of CPSF (GZC20233157).
Marsupial single-cell transcriptomics provides an atlas of developmental heterochrony
Authors: Menchero Sergio , Barrington Christopher , Alanis-Lobato Gregorio , Varsally Wazeer , Niakan Kathy K. , Turner James M. A.
Published: May 2024

Single-cell transcriptomics has revealed conserved and divergent programmes of organogenesis in mammals, but existing studies have focused on eutherians. Marsupials exhibit short gestation and complete development externally, necessitating accelerated differentiation of anterior features required for locomotion and feeding. As such, they represent a unique outgroup with which to understand temporal shifts in development, known as heterochrony. Here, we generate the first single-cell transcriptomic atlas of gastrulation and early organogenesis in a marsupial, the opossumMonodelphis domestica. We find that anterior prioritisation is achieved by earlier initiation and shorter duration of transcriptional programmes relative to eutherians. The result is uncoupling of transcriptional and morphological progression, revealing unforeseen diversity in the order of developmental sequences in mammals. We uncover novel tissues for which heterochrony has not previously been documented. Our findings indicate that accelerated activation of transcriptional programmes facilitates the rapid growth needed for survival of the marsupial neonate.
Reduction of spectroscopic overlap across the
Z=8
shell in neutron-rich nuclei
Authors: Redpath T. , Guèye P. , Baumann T. , Brown B. A. , Cunningham A. , DeYoung P. A. , Frank N. , Hoffman C. R. , Kuchera A. N. , Godoy B. Monteagudo , Persch C. , Revel A. , Rogers W. F. , Thoennessen M. , Tostevin J. A. , Votaw D.
Published: May 2024

The recent discovery and spectroscopic measurements of O27 and O28 suggests the disappearance of the N=20 shell structure in these neutron-rich oxygen isotopes.

We measured one- and two-proton removal cross sections from F27 and Ne29, respectively, extracting spectroscopic factors and comparing them to shell model overlap functions coupled with eikonal reaction model calculations.

The invariant mass technique was used to reconstruct the two-body (O24+n) and three-body (O24+2n) decay energies from knockout reactions of F27 (106.2 MeV/u) and Ne29 (112.8 MeV/u) beams impinging on a

Be

9

target.

The one-proton removal from F27 strongly populated the ground state of O26 and the extracted cross section of 3.4−1.5+0.3 mb agrees with eikonal model calculations that are normalized by the shell model spectroscopic factors and account for the systematic reduction factor observed for single nucleon removal reactions within the models used. For the two-proton removal reaction from Ne29 an upper limit of 0.08 mb was extracted for populating states in O27 decaying though the ground state of O26.

The measured upper limit for the population of the ground state of O26 in the two-proton removal reaction from Ne29 indicates a significant difference in the underlying nuclear structure of F27 and Ne29.

Published by the American Physical Society2024
Near-quantum-limited haloscope search for dark-photon dark matter enhanced by a high-
Q
superconducting cavity
Authors: Kang Runqi , Jiao Man , Tong Yu , Liu Yang , Zhong Youpeng , Cai Yi-Fu , Zhou Jingwei , Rong Xing , Du Jiangfeng
Published: May 2024

We report new experimental results on the search for dark photons based on a near-quantum-limited haloscope equipped with a superconducting cavity. The loaded quality factor of the superconducting cavity is 6×105, so that the expected signal from dark-photon dark matter can be enhanced by more than one order compared to a copper cavity. A Josephson parametric amplifier with a near-quantum-limited noise temperature has been utilized to minimize the noise during the search. Furthermore, a digital acquisition card based on field programmable gate arrays has been utilized to maximize data collection efficiency with a duty cycle being 100%. This work has established the most stringent constraints on dark photons at around 26.965  μeV. In the future, our apparatus can be extended to search for other dark matter candidates, such as axions and axionlike particles, and scrutinize new physics beyond the Standard Model.

Published by the American Physical Society
2024
Microwave Photon Detection at Parametric Criticality
Authors: Petrovnin Kirill , Wang Jiaming , Perelshtein Michael , Hakonen Pertti , Paraoanu Gheorghe Sorin
Published: May 2024

The detection of microwave fields at single-photon power levels is a much-sought-after technology, with practical applications in nanoelectronics and quantum information science. Here we demonstrate a simple yet powerful criticality-enhanced method of microwave photon detection by operating a magnetic-field-tunable Kerr Josephson parametric amplifier at the border of a first-order phase transition and close to the critical point. We obtain an efficiency of 73% and a dark-count rate of 167 kHz, corresponding to a responsivity of 1.3×1017W−1 and noise-equivalent power of 3.28 zW/Hz. We verify the single-photon operation by extracting the Poissonian statistics of a coherent probe signal.

Published by the American Physical Society
2024