bluuebunny/crossref_metadata_2025 huggingface dataset:
Vaccination During Pregnancy in the Vaccine Safety Datalink, 2002–2022
Authors: Naleway Allison L. , Crane Bradley , Irving Stephanie A. , Daley Matthew F. , Dixon Brian , Donahue James , Fuller Candace C. , Fuller Sharon , Getahun Darios , Glenn Sungching , Hambidge Simon J. , Jackson Lisa A. , Kharbanda Elyse O. , Klein Nicola P. , Schmidt Teresa , Sznajder Katharine , Weinfield Nancy S. , Williams Joshua T.B. , Zerbo Ousseny
Published: February 2025

We described vaccinations during pregnancies starting in 2002 through 2022 in 8 Vaccine Safety Datalink healthcare organizations in the United States. During this period, the number of vaccinations per pregnancy increased, influenza and Tdap were the most frequently administered vaccines, and administration of contraindicated vaccines was infrequent. The Vaccine Safety Datalink can provide information about the real-world implementation of vaccination recommendations during pregnancy.
Protecting Against Respiratory Syncytial Virus: An Online Questionnaire Study Exploring UK Parents’ Acceptability of Vaccination in Pregnancy or Monoclonal Antibody Administration for Infants
Authors: Paulson Simone , Munro Alasdair P. S. , Cathie Katrina , Bedford Helen , Jones Christine E.
Published: February 2025

Background:

Maternal vaccination and infant monoclonal antibodies are promising avenues to protect young infants from respiratory syncytial virus (RSV) infection. Successful inclusion into the UK immunization schedule depends on parental acceptability, among other factors.

Methods:

An online cross-sectional survey from August to September 2023 exploring the likelihood of accepting, and preference for, either method of RSV prophylaxis, and reasons given for these. A questionnaire was distributed via social media networks to UK participants with a child under the age of 2 years and/or pregnant.

Results:

A total of 1620 participants completed the survey. Participants’ median age was 33 years [interquartile range (IQR), 31–36], 92% were of White ethnicity. Acceptability was high, but higher for a maternal vaccine than an infant monoclonal antibody (P < 0.0001). Concerns about safety, need for more information and number of vaccines given to infants already were common reasons for hesitancy. Lacking knowledge about RSV was associated with a lower likelihood of accepting either option [maternal vaccine: odds ratio (OR): 0.32, 95% confidence interval (CI): 0.16–0.68, P = 0.002; infant monoclonal antibody: OR: 0.35, 95% CI: 0.19–0.68, P = 0.002], as was identifying as Black, Black British, African or Caribbean ethnic group, or having declined the routinely recommended antenatal vaccines.

Conclusions:

While most parents would accept a maternal vaccine or infant monoclonal antibody to protect their infant against RSV, understanding preferences, influencing factors and concerns is essential to optimize immunization programs. This study highlights the information parents require to make an informed choice about RSV protection.
Immunogenicity of COVID-19 Vaccines During Pregnancy: A Systematic Review and Comparison of Pregnant Versus Nonpregnant Persons
Authors: Ballivian Jamile , Parker Edward P.K. , Berrueta Mabel , Ciapponi Agustín , Argento Fernando , Bardach Ariel , Brizuela Martin , Castellana Noelia , Comande Daniel , Kampmann Beate , Mazzoni Agustina , Sambade Juan M. , Stegelmann Katharina , Xiong Xu , Munoz Flor M. , Stergachis Andy , Buekens Pierre
Published: February 2025

Background:

The COVID-19 pandemic induced the rapid deployment of novel vaccines with pregnant persons identified as an at-risk population due to their increased risk of severe outcomes. Limited data on the immunogenicity of COVID-19 vaccines in pregnant persons were available at the time of implementation. To address this data gap, we developed a living systematic review summarizing emerging evidence on vaccine immunogenicity in pregnancy.

Methods:

Following Cochrane, World Health Organization, and Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, we included studies on COVID-19 vaccines during pregnancy. We carried out comprehensive biweekly literature searches from March 2022 to October 2023, covering multiple databases. Study selection, data extraction and risk of bias assessment were conducted by pairs of authors independently. Immunogenicity outcomes, primarily post-vaccination neutralizing or binding antibody concentrations, were analyzed descriptively. Post-vaccination antibody ratios in pregnant versus nonpregnant individuals were calculated for the subset of studies that included nonpregnant comparators.

Results:

By October 2023, our review encompassed 62 studies predominantly analyzing maternal sera (87%), with limited investigation regarding cord, neonatal and infant sera. Most studies investigated mRNA vaccines (97%) and focused on primary vaccination (82%), with some investigating booster doses (15%). Immunogenicity end points included spike-specific IgG (84%) and neutralizing antibodies (24%), with limited data on T-cell responses (3%). Antibodies were detectable after primary vaccination in most pregnant individuals, with similar or modestly attenuated concentrations compared to nonpregnant individuals (ratios > 0.7 for 5/6 estimates of spike-specific IgG), albeit with modest differences in antibody quality and kinetics. Long-term antibody-waning trajectories were similar between pregnant and nonpregnant individuals for up to 8 months after vaccination.

Conclusions:

mRNA COVID-19 vaccines induce a robust antibody response during pregnancy comparable (or modestly attenuated) relative to nonpregnant individuals. Immunogenicity data on non-mRNA vaccines are notably underrepresented in the existing literature.
Sociodemographic Factors Associated With Established and Novel Antenatal Vaccination Uptake in a Cohort of Pregnant Women in Uganda
Authors: Sturrock Sarah , Davies Hannah , Rukundo Gordon , Komugisha Cleophas , Kipyeko Sam , Nakabembe Eve , Mboizi Robert , Sekikubo Musa , Le Doare Kirsty
Published: February 2025

Introduction:

Vaccination is a key strategy to safeguard the health of pregnant women and newborns. Although vaccine acceptance is often higher in low- and middle-income countries, the COVID-19 pandemic has highlighted increasing vaccine hesitancy. Vaccine hesitancy, specifically in pregnant women, must be understood to increase uptake. We used data from a Ugandan pregnancy registry study to examine sociodemographic factors linked to uptake of vaccines (tetanus toxoid and later COVID-19) in pregnancy.

Methods:

Pregnant women were recruited in Kampala, Uganda, as part of the PREPARE (Prevention of invasive Group B Streptococcus disease in young infants: a pathway for the evaluation & licensure of an investigational maternal GBS vaccine) study from September 1, 2020 until February 24, 2022. Demographic, socioeconomic and obstetric data were collected alongside COVID-19 and tetanus vaccination.

Results:

One thousand five hundred sixty-eight participants were included: 151 (10%) were unvaccinated, 11 (1%) received COVID-19 vaccine only, 1230 (78%) received a tetanus vaccine only and 176 (11%) received both. Lower vaccination rates were seen in participants attending fewer than 4 antenatal care episodes (P < 0.001), and those with higher parity (P = 0.036). Higher vaccination rates were seen with a managerial or professional occupation or higher maternal education level, but paternal occupation was not significantly associated with maternal vaccination. Parish vaccination rates varied from 0% to 100%, with 49 (29%) of parishes showing a vaccination rate <90%.

Conclusions:

This study highlights antenatal care as a key route for health promotion, and the stark difference in uptake between new and established antenatal vaccines. Further qualitative studies should investigate effective interventions to establish the safety and benefit of newer maternal vaccines across all demographic groups.
Immunizing Pregnant Women and Infants (IMPRINT) Network: Building and Sustaining an Interdisciplinary Network Tackling the Complex Challenges of Vaccination in Pregnancy and Early Life
Authors: Kampmann Beate , Jones Christine E. , Faber Hannah
Published: February 2025

Immunising Pregnant Women and Infants is a UK-funded, international research network that supports interdisciplinary research addressing key challenges in the best use of vaccines in pregnancy and in newborns. The goal of this short review paper is to introduce readers to the network’s aims and objectives and highlight its initiatives and outputs for research and innovation within the UK and in low- and middle-income countries. The long-term goal of this network is to contribute to improved maternal and newborn health globally through the safe and effective use of vaccines.
Vaccine Utilization and Timing of Administration in Pregnant Women: A South African Perspective
Authors: Bourne Julia , Sawry Shobna , Le Roux Jean , Fairlie Lee , Barnabas Shaun , Cutland Clare L.
Published: February 2025

Background:

Maternal immunization is a valuable public health measure protecting the mother, fetus and newborn infant against targeted infectious diseases, playing an integral role in pregnancy outcomes. Limited literature exists from the African continent pertaining to the timing and utilization of maternal influenza and tetanus toxoid immunization. Maintaining high vaccine coverage is imperative for successful disease control, highlighting the importance of continued maternal immunization. We aimed to describe the utilization and timing of influenza and tetanus vaccinations during pregnancy, within South African publicly financed antenatal care facilities.

Methods:

A secondary analysis was conducted of clinical antenatal, vaccination and delivery data collected during a retrospective review of randomly selected maternity charts of women who delivered between July 2018 and June 2019 in Johannesburg and Cape Town, South Africa.

Results:

Influenza vaccination uptake within the sampled population was 16.6% (806/4851), with significantly higher odds of influenza vaccination in women 21-30 years of age and women with ≥6 antenatal care visits. Of 7031 (99.0% of the population) women who received at least 1 dose of tetanus toxoid–containing vaccine (TTCV), 39.2% (2759) received 1 dose; 51.0% (3590) received 2 and 9.7% (682) received 3 doses in their index pregnancy.

Conculsions:

Antenatal facilities are ideally suited to administer vaccines to pregnant women; however, targeted educational campaigns and immunization promotion by antenatal staff will improve maternal influenza immunization coverage. There is high utilization of TTCV in South Africa, with over 99% of women receiving at least 1 dose of TTCV, which is encouraging, especially considering that South Africa is implementing a single dose of a combination tetanus-diphtheria-acellular pertussis vaccine to replace tetanus toxoid (TT) in pregnancy.
Maternal and Placental Antibody Responses in SARS-CoV-2 Vaccination and Natural Infection During Pregnancy
Authors: Sturrock Sarah , Cavell Breeze , Alexander Frances , Apostolakis Kostis , Barro Camille , Daniel Olwenn , Dixon Louisa , Halkerston Rachel , Hall Tom , Hesp J. Richard , Hill Andrew M. , Leung Stephanie , Lim Suzy , McStraw Nikki , Otter Ashley , Ramkhelawon Laxmee , Watts Robert , Etti Melanie , T. Heath Paul , Lee-Wo Chelone , Greening Vanessa , Khalil Asma , Turner Kim , Taylor Stephen , Le Doare Kirsty , Ladhani Shamez
Published: February 2025

Background:

As COVID-19 becomes endemic, understanding antibody response and transfer during pregnancy is crucial to inform policy and vaccination schedules. While good immunogenicity has been shown from SARS-CoV-2 vaccines, few data are available demonstrating functional responses in pregnant populations and infants.

Methods:

A prospective, multi-site observational study was completed across 14 centers in England from April 23, 2020, to December 21, 2022. Demographic, COVID infection and vaccination data were collected. Maternal and cord blood samples were taken at delivery, with maternal and neonatal blood samples taken at 6 weeks for participants who had been infected or vaccinated. Antibody concentrations were measured using antibody-dependent complement deposition, antibody-dependent neutrophil phagocytosis, ACE2 inhibition and Roche and EuroImmun antibody binding assays at the UK Health Security Agency.

Results:

Maternal vaccination and infection both produced an antibody response in 100% of mothers and 93.8% and 92.9% of neonates, respectively, which persisted at 6 weeks in 95%. The strongest response was seen in mothers who were both vaccinated and infected. Anti-spike antibody response decreased almost 25-fold from first to third trimester vaccination (P=0.013). Placental transfer of antibodies post-infection showed varied results depending on the assay used, with higher transfer ratios observed in assays measuring Fc-mediated antibody effector functions and IgG-specific responses.

Conclusions:

Maternal vaccination is associated with good immunogenicity and successful antibody transfer to the neonate, particularly with vaccination in early pregnancy. Further study is needed to determine the mechanism by which the timing of vaccination affects antibody transfer. When measuring placental transfer of antibodies, consideration of the assay to use is essential.
Risk of Vulvar HSIL and Penile Neoplasias in Anogenital Lichen Planus: A Case-Control Study
Authors: Hieta Niina K. , Tapana Lotta , Söderlund Jenni M. , Huvila Jutta K. , Talve Lauri A.I. , Haataja Marjut A.M.
Published: February 2025

Objective

Lichen planus (LP) is a chronic inflammatory skin disease that may affect the skin, scalp, nails, and mucosa. The aim of this study was to investigate the risk of genital premalignant and malignant conditions in patients with anogenital LP (agLP).

Methods

We identified 60 male and 56 female patients with agLP by searching the biobank archives for a genital or perianal skin biopsy showing LP between 2004 and 2020. We also included 10 randomly selected age- and sex-matched controls for each patient. The risks of genital cancers and their precursors were evaluated.

Results

The incidence of agLP was 1.54 per 100,000 men and 1.36 per 100,000 women. There was no statistical difference between male and female incidence (p = .5721). The odds ratio (OR) for high-grade squamous intraepithelial lesion (HSIL) of the vulva was 31.2 (95% CI = 2.46–1645.00; p = .01). The OR for penile neoplasias could not be calculated because control patients had no neoplasias, but the difference was suggestive of statistical significance (95% CI = 1.90–infinite; p = .008). The mean age at the time of diagnosis of agLP was 59.9 years (median 62 years) in female patients and 40.8 years (median 33 years) in male patients. The difference in the mean ages of female and male patients was statistically significant (95% CI = 11.92–26.13; p < .001).

Conclusions

Patients with agLP may have an increased risk for vulvar HSIL and penile neoplasia.
Hearing Preservation and Functional Outcomes After Resection of Epidermoid Lesions of the Cerebellopontine Angle With High Hearing Risk
Authors: Papazian Michael , Cottrell Justin , Yang Jackie , Kay-Rivest Emily , Friedmann David R. , Jethanamest Daniel , Kondziolka Douglas , Pacione Donato , Sen Chandranath , Golfinos John G. , Thomas Roland J. , McMenomey Sean O.
Published: February 2025

Objectives

To assess a decade of experience of treating patients with high hearing risk cerebellopontine angle (CPA) epidermoid lesions and examine factors influencing postoperative outcomes, particularly hearing preservation.

Study Design

Retrospective chart review.

Setting

Single tertiary-referral center.

Patients

Adults with CPA epidermoid lesions who presented with hearing loss or evidence of lesion involving vestibulocochlear nerve.

Interventions

The studied intervention was microsurgical resection.

Main Outcome Measures

Main outcome measures included extent of resection, hearing preservation rate for patients with postoperative audiograms, and disease progression.

Results

Twenty-three adults with an average tumor volume of 15.63 ± 16.2 cm3 were included. Five lesions (22%) involved the full internal auditory canal (IAC), 11 (48%) had partial involvement, and 5 (22%) were IAC sparing. Most patients with IAC involvement (88%) had circumferential invasion of the canal. Patients underwent either a retrosigmoid (18, 79%) or combined retrolabyrinthine transpetrosal approach (5, 22%), and gross total resection was achieved in most cases (13, 57%). Of 12 patients with postoperative audiograms, 10 (83%) had preoperative hearing preserved. There was no statistically significant change in hearing scores with treatment based on preoperative extent of IAC involvement. Ten patients (43%) had residual lesions postoperatively, and 6 exhibited progression. One patient ultimately required reoperation 6 years after initial surgery.

Conclusions

Preoperative hearing was preserved in the majority of the patients who underwent resection of CPA epidermoids via a retrosigmoid or transpetrosal approach. CPA epidermoids often invaded the IAC; however, degree of invasion was not associated with hearing outcomes.
Symptoms Associated With Gadolinium Exposure
Authors: Shahid Imran , Lancelot Eric
Published: February 2025

Objective

Some patients who received multiple administrations of gadolinium-based contrast agents (GBCAs) have been reported to develop “symptoms associated with gadolinium exposure” (SAGE). The aim of this study was to analyze pharmacovigilance data and to explore the various SAGE patterns of linear and macrocyclic GBCAs among patients exhibiting 3 or more SAGE symptoms.

Materials and Methods

SAGE were identified from a review of the scientific literature, and the corresponding preferred terms (PTs) were searched in each system organ class recorded in the FDA Adverse Event Reporting System (FAERS). To ensure the comparability of data, 3 macrocyclic and 3 linear extracellular GBCAs currently approved for intravenous administration in the United States were considered. Only patients with 3 or more SAGE symptoms were included. SAGE weights, representing the percentage of SAGE symptoms among all adverse events collected over a 6-year period from 2014 to 2019, were calculated for each GBCA. The frequency of these symptoms to occur in sets of “3 PT combinations” was also analyzed. The 3 PT combinations were calculated by first selecting the PT with the highest occurrence for a GBCA and then combining it with all the PTs accounting for 5% or more of the total adverse events reported for the respective GBCA. This led to identify the most prevalent 3 PT combinations per GBCA. Moreover, in order to determine whether or not SAGE symptoms were specific to GBCAs, data for 4 water-soluble iodinated contrast media were also extracted from the FAERS database over the same period, using the SAGE list of symptoms as reference.

Results

The analysis of FAERS data revealed a significantly higher SAGE weight for the linear GBCAs (20%–24%) than for the macrocyclic GBCAs (5%–9%). For the linear agents, the most prevalent 3 PT combinations of SAGE symptoms were reported in 152–164 occurrences, whereas for the macrocyclic agents, this range was significantly lower (1–13 occurrences). Moreover, all these agents could be categorized in 3 groups with different patterns of 3 PT combinations (ie, [gadodiamide and gadopentetate dimeglumine], [gadobenate dimeglumine and gadoteridol], and [gadoterate dimeglumine and gadobutrol]). The most prevalent PTs were found to be “pain,” “arthralgia,” and “headache” in each group, respectively.

Conclusions

The global SAGE weights were significantly lower for the macrocyclic GBCAs as compared with the linear GBCAs. Moreover, the frequency of occurrence of 3 PT combinations was notably lower with the macrocyclic agents and comparable to the iodinated contrast media, indicating that SAGE may be negligible for this class of GBCAs. Different patterns of 3 PT combinations were also observed among the GBCAs involved in this study. A causal relationship could not be established between SAGE and the corresponding GBCAs, therefore, further research on this topic and routine pharmacovigilance are warranted.
Maxillary Jaw-in-a-Day: The Role of Point-of-Care Manufacturing and Implant Stability Quotient in Centrofacial Chondrosarcoma
Authors: Ruiz-de-Leon Gonzalo , Navarro-Cuellar Carlos , Tousidonis Manuel
Published: February 2025

Chondrosarcoma is a rare malignant tumor of epithelial origin, with fewer than 0.1% of cases affecting the nasal septum. Maxillofacial oncological surgery presents significant challenges, particularly in maxillary reconstruction, often requiring complex rehabilitation. This case report describes the use of point-of-care manufacturing, customized cutting guides, and 3D printing technology for fibular-free flap reconstruction and guided dental implant placement in a 42-year-old male with centrofacial nasal chondrosarcoma. After a bilateral maxillectomy, continuity across the maxillomalar buttress was restored using a fibular-free flap and a patient-specific reconstruction plate. Immediate implant placement and prosthetic loading were performed, supported by the Implant Stability Quotient (ISQ), which provided objective data on implant stability, allowing immediate loading due to high primary stability. The integration of point-of-care manufacturing and ISQ enhances precision in guided surgery, facilitating quicker functional and esthetic rehabilitation, and offering faster recovery and improved quality of life for oncological patients requiring complex maxillofacial reconstruction.
Comparison of the virulence of community- and hospital- isolated Acinetobacter baumannii in HeLa cell line and insect model, Galleria mellonella
Authors: Muzahid Nazmul Hasan , Ramesh Aarthi , Siew Tan Hock , Hasan Md Zobaer , Narayanan Kumaran , Rahman Sadequr
Published: February 2025

Acinetobacter baumannii is an important nosocomial pathogen causing high infections and morbidity among affected individuals, and most studies focus on nosocomial strains. However, A. baumannii can also be isolated from healthy community individuals. This study compared the pathogenicity of hospital and community A. baumannii isolates using Galleria mellonella and human cell cultures. The insect model, G. mellonella, and in vitro HeLa cell line were used with ten A. baumannii isolates (six community and four hospital isolates from Segamat, Malaysia). G. mellonella killing assays and HeLa cell adherence, invasion and cytotoxicity assays were performed to investigate the virulence and invasion potential of the isolates. Out of the ten isolates investigated, three community and two hospital isolates were found to be highly virulent in the G. mellonella infection model, killing 100% of larvae within 96 h. These strains were also found to be invasive and have significant cytotoxicity in HeLa cells. Our study revealed that community- and hospital-isolated A. baumannii could be equally virulent judged by both model systems. Undoubtedly, besides hospital settings, the presence of highly virulent A. baumannii in community reservoirs poses a significant public health risk and requires additional investigation.
Quantification of Pseudomonas aeruginosa biofilms using electrochemical methods
Authors: Riordan Lily , Lasserre Perrine , Corrigan Damion , Duncan Katherine
Published: February 2025

Currently, 2.29% of deaths worldwide are caused by antimicrobial resistance (AMR), compared to 1.16% from malaria and 1.55% from human immunodeficiency virus and acquired immunodeficiency syndrome. Furthermore, deaths resulting from AMR are projected to increase to more than 10 million per annum by 2050. Biofilms are common in hospital settings, such as medical implants, and pose a particular problem as they have shown resistance to antibiotics up to 1000-fold higher than planktonic cells because of dormant states and reduced growth rates. This is compounded by the fact that many antibiotics target mechanisms of active metabolism and are therefore less effective. The work presented here aimed to develop a method for biofilm quantification, which could be translated into the clinical setting, as well as used in the screening of antibiofilm agents. This was carried out alongside crystal violet staining, as a published point of reference. This work builds upon work previously presented by Dunphy et al., in which the authors attempted to quantify the biofilm formation of Pseudomonas aeruginosa strain using hyperspectral imaging. Here, using electrochemical impedance spectroscopy and square wave voltammetry, the biofilm formation of two P. aeruginosa strains was detected within an hour after seeding P. aeruginosa on the sensor. A 40% decrease in impedance modulus was shown when P. aeruginosa biofilm had formed, compared to the media-only control. As such, this work offers a starting point for the development of real-time biofilm sensing technologies, which can be translated into implantable materials.
Viral vectors: design and delivery for small RNA
Authors: Koh Wei Chin , Yusoff Khatijah , Song Adelene Ai Lian , Saad Norazalina , Chia Suet Lin
Published: February 2025

RNA interference regulates gene expression by selectively silencing target genes through the introduction of small RNA molecules, such as microRNA, small interfering RNA and short hairpin RNA. These molecules offer significant therapeutic potential for diverse human ailments like cancer, viral infections and neurodegenerative disorders. Whilst non-viral vectors like nanoparticles have been extensively explored for delivering these RNAs, viral vectors, with superior specificity and delivery efficiency, remain less studied. This review examines current viral vectors for small RNA delivery, focusing on design strategies and characteristics. It compares the advantages and drawbacks of each vector, aiding readers in selecting the optimal one for small RNA delivery.
Long-range electrostatic forces govern how proteins fold on the ribosome
Authors: Streit Julian O. , Chan Sammy H.S. , Burridge Charles , Wallace Joel , Waudby Christopher A. , Cabrita Lisa D. , Christodoulou John
Published: February 2025

Protein biosynthesis and folding are tightly intertwined processes regulated by the ribosome and auxiliary factors. Nascent proteins can begin to fold on their parent ribosome but formation of the native state is often inhibited well beyond the emergence of the necessary residues from the exit tunnel. The dominant forces driving this apparent destabilisation have remained unclear. We investigate this here, combining NMR experiments and atomistic simulations of a folded nascent chain on and off the ribosome. While its native structure and internal dynamics remain unaltered, co-translational folding is disfavoured due to intermolecular electrostatic repulsion between the negatively charged ribosome surface and nascent protein. Partially folded intermediates are less destabilised, resulting in their high populations. Specifically, we show that the polypeptide’s net charge is the dominant factor determining nascent folding thermodynamics, with smaller contributions from charge distribution. Consequently, positively charged proteins can fold on the ribosome without populating stable intermediates. These findings reconcile conflicting observations of previous studies and establish the general physical principles underpinningde novoprotein folding.
Probing the Role of Membrane in Neutralizing Activity of Antibodies Against Influenza Virus
Authors: Ozgulbas Defne G. , Tan Timothy J. C. , Wen Po-Chao , Teo Qi Wen , Lv Huibin , Ghaemi Zhaleh , Frank Martin , Wu Nicholas C. , Tajkhorshid Emad
Published: February 2025

Influenza poses a major health issue globally. Neutralizing antibodies targeting the highly conserved stem region of hemagglutinin (HA) of the influenza virus provide considerable protection against the infection. Using an array of advanced simulation technologies, we developed a high-resolution structural model of full-length, Fab-bound HA in a native viral membrane to characterize direct membrane interactions that govern the efficacy of the antibody. We reveal functionally important residues beyond the antibody’s complementary-determining regions that contribute to its membrane binding. Mutagenesis experiments and infectivity assays confirm that deactivating the membrane-binding residues of the antibody decreases its neutralization activity. Therefore, we propose that the association with the viral membrane plays a key role in the neutralization activity of these antibodies. Given the rapid evolution of the influenza virus, the developed model provides a structural framework for the rational design and development of more effective therapeutic antibodies.
Comparative population pangenomes reveal unexpected complexity and fitness effects of structural variants
Authors: Edwards Scott V. , Fang Bohao , Khost Danielle , Kolyfetis George E , Cheek Rebecca G , Deraad Devon , Chen Nancy , Fitzpatrick John W , McCormack John E , Funk W. Chris , Ghalambor Cameron K , Garrison Erik , Guarracino Andrea , Li Heng , Sackton Timothy B
Published: February 2025

Structural variants (SVs) are widespread in vertebrate genomes, yet their evolutionary dynamics remain poorly understood. Using 45 long-read de novo genome assemblies and pangenome tools, we analyze SVs within three closely related species of North American jays (Aphelocoma, scrub-jays) displaying a 60-fold range in effective population size. We find rapid evolution of genome architecture, including ~100 Mb variation in genome size driven by dynamic satellite landscapes with unexpectedly long (> 10 kb) repeat units and widespread variation in gene content, influencing gene expression. SVs exhibit slightly deleterious dynamics modulated by variant length and population size, with strong evidence of adaptive fixation only in large populations. Our results demonstrate how population size shapes the distribution of SVs and the importance of pangenomes to characterizing genomic diversity.
A century of theories of balancing selection
Authors: Ruzicka Filip , Zwoinska Martyna K. , Goedert Debora , Kokko Hanna , Richter Xiang-Yi Li , Moodie Iain R. , Nilén Sofie , Olito Colin , Svensson Erik I. , Czuppon Peter , Connallon Tim
Published: February 2025

Traits that affect organismal fitness are often very genetically variable. This genetic variation is vital for populations to adapt to their environments, but it is also surprising given that nature (after all) “selects” the best genotypes at the expense of those that fall short. Explaining the extensive genetic variation of fitness-related traits is thus a longstanding puzzle in evolutionary biology, with cascading implications for ecology, conservation, and human health. Balancing selection—an umbrella term for scenarios of natural selection that maintain genetic variation— is a century-old explanation to resolve this paradox that has gained recent momentum from genome-scale methods for detecting it. Yet evaluating whether balancing selection can, in fact, resolve the paradox is challenging, given the logistical constraints of distinguishing balancing selection from alternative hypotheses and the daunting collection of theoretical models that formally underpin this debate. Here, we track the development of balancing selection theory over the last century and provide an accessible review of this rich collection of models. We first outline the range of biological scenarios that can generate balancing selection. We then examine how fundamental features of genetic systems—including non-random mating between individuals, differences in ploidy, genetic drift, and different genetic architectures of traits— have been progressively incorporated into the theory. We end by linking these theoretical predictions to ongoing empirical efforts to understand the evolutionary processes that explain genetic variation.
Real-world brain imaging in a population-based cohort enables accurate markers for dementia
Authors: Sund Reijo , Seppänen Juho , Moradi Elaheh , Väänänen Sami , Miettinen Jani , Hakumäki Juhana , Rikkonen Toni , Kröger Heikki , Koivumaa-Honkanen Heli , Solomon Alina , Tohka Jussi ,   Alzheimer’s Disease Neuroimaging Initiative
Published: February 2025

INTRODUCTION

While a vast amount of MRI data are collected for healthcare delivery, generating real-world evidence (RWE) in Alzheimer’s and related diseases (ADRD) research is substantially limited by lack of methods and results showing how routine MRIs can be used for ADRD imaging studies.

METHODS

We compared three established ADRD biomarkers (total gray matter, hippocampal and ventricular volumes) in four groups (normal, subjective complaints, mild cognitive impairment, and dementia) between the general population of women born in 1932-1941 in the Kuopio region of eastern Finland (population-based OSTPRE cohort, N=14220) and a well-characterized research cohort (ADNI).

RESULTS

A total of 2434 brain MRIs for 1885 women were collected between 2003-2022 by the public healthcare provider covering all residents in the region. The established biomarkers were overall aligned between these cohorts.

DISCUSSION

Typical biomarkers extracted from real-world brain MRI scans collected over 20 years are suitable for generating RWE in ADRD research.

Highlights

Real-world brain MRI is applicable for generating evidence in ADRD research

First study comparing a real-world MRI cohort with an established research cohort reference

A methodological framework for RWE ADRD studies using routinely collected MRIs
Neoadjuvant chemotherapy response and genetic susceptibility in recently parous women with breast cancer
Authors: Dennis Saya , Tsukioki Takahiro , Kocherginsky Masha , Qi Andrea Keya , DeHorn Sarah , Gurley Michael , Wrubel Erica , Luo Yuan , Khan Seema Ahsan
Published: February 2025

Introduction

Women with recent parity are at increased short-term breast cancer (BC) risk and face a worse prognosis. The effect of parity on response to neoadjuvant chemotherapy (NAC) is unstudied, and the influence of inherited susceptibility on parity-related short-term risk remains unclear.

Methods

We conducted a retrospective case-cohort study among women aged ≤50 with non-metastatic BC diagnosed between 2010 and 2020 who underwent genetic testing and were treated at Northwestern Medicine. Associations between NAC response and recency of parity were evaluated using multivariate logistic regression, stratified by tumor biologic subtypes. Relationships between germline mutations, recency of parity, and BC were explored via multi-state modeling and linear regression.

Results

Among 1,080 eligible women, 231 received NAC. Treatment response was poorer in parous women with triple negative tumors compared to nullipara, regardless of the recency of parity (P<0.03). Among 122 women (11.3%) with detectable pathogenic mutations, adjusted analyses with both modeling approaches revealed no indications thatBRCA1/2carriers had an increased hazard of BC diagnosis in the decade following recent parity, compared to nulliparous mutation carriers. ForBRCA2andPALB2carriers, breast cancer diagnosis occurred less frequently in the post-partum intervals.

Conclusion

We observed a poor response to NAC in parous TNBC patients compared to nullipara; effects of immunotherapy-based regimens deserve evaluation in the context of parity. Post-partum BC occurrence is not increased inBRCA1/2carriers; effects of rarer susceptibility genes may differ. These important effects of parity on BC in young women and those at genetic risk warrant larger prospective studies.
MMR vaccination coverage in the U.S. before and after the COVID-19 pandemic: A modelling study
Authors: Dong Ensheng , Nearchou Andreas , Okura Yamato , Saiyed Samee , Gardner Lauren M.
Published: February 2025

Background

Childhood vaccination rates have been declining in the United States since the COVID-19 pandemic began. While COVID-19 exacerbated the decline in routine vaccination through disruption of healthcare services and the diversion of resources, factors including vaccine hesitancy, socioeconomic disparities and vaccine policy also contribute to changes in vaccination behavior. Understanding the factors that influence vaccination choice is necessary to develop effective public health policy.

Methods

We collect county-level MMR vaccination rates for kindergarten children from 2017 – 2024 for 2,266 U.S. counties, evaluate coverage patterns and trends before and after the COVID-19 pandemic, and implement multivariable weighted logistic regression models to identify factors associated with low and declining MMR vaccination rates in U.S. counties.

Findings

We reveal a nationwide decline in MMR rates following the COVID-19 pandemic, with declines observed in 1,688 of the counties evaluated. We find state-level non-medical exemption (NME) policies to be strongly associated with low and declining MMR rates. We identify a positive association in vaccination rates across vaccine types. We find higher MMR rates are positively associated with Republican-aligned counties and declines in MMR rates to be positively associated with COVID-19 death rates.

Interpretation

The significant association between NMEs and low and declining MMR rates suggest these state level policies are harmful and reduce vaccination coverage. The positive associations among vaccine types suggest spillover effects in vaccine seeking behavior. The association between MMR rates and Republican-aligned counties contrast COVID-19 vaccination patterns, highlighting the complex nature of political polarization on vaccine-related behavior, while the association between MMR declines and COVID-19 death rate reveals an additional burden posed by the pandemic.

Funding

This work was supported by a grant from Bloomberg Philanthropies awarded to the Johns Hopkins Bloomberg Center for Government Excellence, City Analytics Initiative.
Estimating health facility-level catchment populations using routine surveillance data and a Bayesian gravity model
Authors: Millar Justin , Arambepola Rohan , Cameron Ewan , Hamainza Busiku , Silumbe Kafula , Miller John , Bennett Adam , Slater Hannah
Published: February 2025

Accurate estimates of health facility catchment populations are crucial for understanding spatial heterogeneity in disease incidence, targeting healthcare interventions, and allocating resources effectively. Despite improvements in health facility reporting, reliable catchment population data remain sparse. This study introduces a Bayesian gravity model-based approach for estimating catchment populations at health facilities, with a focus on Zambia’s routine malaria surveillance data from 2018-2023. Our method integrates health-seeking behavior, facility attractiveness, and travel time, allowing for the development of probabilistic catchment areas that reflect the treat-seeking and facility selection process. We developed an open-source R package to implement this method, and we apply this model to Zambian health facilities and compare the results to reported headcount data, highlighting improvements in stratification of malaria incidence rates. Additionally, we validate the model’s sensitivity using real-world treatment-seeking data from household surveys in Southern Province, Zambia, demonstrating its utility in enhancing sub-district-level health facility data for strategic planning. Validation of model facility selection rates compared to the treatment-seeking data showed a model sensitivity of 0.72 overall, with sensitivity reaching 0.89 for households within 2 kilometers of their preferred facility. This validation supports the model’s ability to closely estimate treatment-seeking behavior patterns, offering a scalable, accurate tool for enhancing local-level decision-making for health interventions, contributing to improved targeting and understanding of healthcare access patterns.
Evaluation of an Integrated Digital and Mobile Intervention for COPD Exacerbation
Authors: O’Connor Laurel , Wang Biqi , Ye Zehao , Behar Stephanie , Tarrant Seanan , Stamegna Pamela , Pretz Caitlin , Soni Apurv
Published: February 2025

Background

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and healthcare utilization, with frequent exacerbations contributing to emergency department visits and hospitalizations. This study evaluates a multimodal, community-based digital health intervention’s association with changes in acute care utilization among patients with COPD to develop preliminary estimates of intervention effects.

Methods

In this decentralized, nonrandomized pilot clinical trial, participants with moderate to severe COPD were offered biometric monitoring, symptom tracking, on-demand MIH services, and a digital pulmonary rehabilitation program. Outcomes were compared between intervention participants and a weighted synthetic control group using full optimal matching. Weighted odds ratios derived from regression models were used to estimate intervention effect size. The primary outcome was hospitalization during the study period. Secondary outcomes included 30 and 90-day readmission rates, emergency department visits, and hospital length of stay.

Results

In total, 88 participants from the intervention arm (mean age 67, 50% female) were compared to a weighted synthetic control of 14,492 participants (weighted mean age 66, 48.7% female). We observed that participants in the intervention arm had a trend toward decreased hospitalization with an OR of 0.69 (CI 0.44-1.03, p=0.066). The intervention was also associated with 61% decreased odds of 30-day readmission after an index admission compared to controls (OR: 0.39, 95% CI: 0.16–0.95, p = 0.04). Trends toward reductions in ED visits and hospital length of stay were also observed.

Conclusions

A combined digital and mobile health approach to COPD management was associated with reductions in acute care utilization. These findings support further investigation into hybrid care models to enhance COPD self-management and improve patient outcomes. Future research should evaluate scalability, cost-effectiveness, and long-term clinical impact.
Identifying single origin rare variants in population genomic data
Authors: Reynolds Josh J. , Koufopanou Vassiliki , Burt Austin
Published: February 2025

Genomic analyses have shown that some mutations in large population genomic datasets may be the result of repeated, independent events at the same locus. However, the possibility of this recurrent mutation is often ignored, even when it has the potential to introduce errors, such as when assuming co-ancestry through variant sharing for demographic analysis. Even rare variants such as doubletons, which should be particularly informative about recent demography, may have multiple origins despite arising relatively recently in the population. Here, we develop methods first to estimate the frequency of recurrent doubletons in a population genomic dataset from the occurrence of tri-allelic sites with two different singleton mutations, and then to identify a subset of high confidence single origin doubletons based on the presence of a linked rare variant on the surrounding shared haplotype. Applying these methods to data for the malaria mosquitoAnopheles gambiae, we estimate that up to ∼16% of reported doubletons have independent origins. We then identify a set of doubletons likely (∼99%) to have a single origin, which consists of ∼68% of all the expected single origin doubletons (and ∼57% of all observed doubletons). The effectiveness of our approach is queried, and these doubletons are then used to test population genetic hypotheses about recombination, selection, and isolation by distance. The methods developed here should be useful for demographic inference when populations are large enough such that recurrent mutation cannot be ignored.
Genetic regulation of nascent RNA maturation revealed by direct RNA nanopore sequencing
Authors: Choquet Karine , Chaumont Louis-Philippe , Bache Simon , Baxter-Koenigs Autum R. , Churchman L. Stirling
Published: February 2025

Quantitative trait loci analyses have revealed an important role for genetic variants in regulating alternative splicing (AS) and alternative cleavage and polyadenylation (APA) in humans. Yet, these studies are generally performed with mature mRNA, so they report on the outcome rather than the processes of RNA maturation and thus may overlook how variants directly modulate pre-mRNA processing. The order in which the many introns of a human gene are removed can substantially influence AS, while nascent RNA polyadenylation can affect RNA stability and decay. However, how splicing order and poly(A) tail length are regulated by genetic variation has never been explored. Here, we used direct RNA nanopore sequencing to investigate allele-specific pre-mRNA maturation in 12 human lymphoblastoid cell lines. We find frequent splicing order differences between alleles and uncover significant single-nucleotide polymorphism (SNP)-splicing order associations in 17 genes. This includes SNPs located in or near splice sites as well as more distal intronic and exonic SNPs. Moreover, several genes showed allele-specific poly(A) tail lengths, many of which also have a skewed allelic abundance ratio.HLAclass I transcripts, which encode proteins that play an essential role in antigen presentation, show the most allele-specific splicing orders, which frequently co-occur with allele-specific AS, APA, or poly(A) tail length differences. Together, our results expose new layers of genetic regulation of pre-mRNA maturation and highlight the power of long-read RNA sequencing for allele-specific analyses.
Commissioning of a compact multibend achromat lattice NanoTerasu: A new 3 GeV synchrotron radiation facility
Authors: Obara Shuhei , Ueshima Kota , Asaka Takao , Hosaka Yuji , Kan Koichi , Nishimori Nobuyuki , Aoki Toshitaka , Asano Hiroyuki , Haga Koichi , Iba Yuto , Ihara Akira , Ito Katsumasa , Iwashita Taiki , Kadowaki Masaya , Kanahama Rento , Kobayashi Hajime , Kobayashi Hideki , Nishihara Hideo , Nishikawa Masaaki , Oikawa Haruhiko , Saida Ryota , Sakuraba Keisuke , Sugimoto Kento , Suzuki Masahiro , Takahashi Kouki , Takahashi Shunya , Tanaka Tatsuki , Tsuchiyama Tsubasa , Yoshioka Risa , Aoki Tsuyoshi , Dewa Hideki , Fujita Takahiro , Kawase Morihiro , Kiyomichi Akio , Hamano Takashi , Masaki Mitsuhiro , Masuda Takemasa , Matsubara Shinichi , Okada Kensuke , Saji Choji , Taniuchi Tsutomu , Taniuchi Yukiko , Ueda Yosuke , Yamaguchi Hiroshi , Yanagida Kenichi , Fukami Kenji , Hosoda Naoyasu , Ishii Miho , Itoga Toshiro , Iwai Eito , Magome Tamotsu , Oishi Masaya , Ohshima Takashi , Kondo Chikara , Sakurai Tatsuyuki , Shoji Masazumi , Sugimoto Takashi , Takano Shiro , Tamura Kazuhiro , Watanabe Takahiro , Tomai Takato , Azumi Noriyoshi , Inagaki Takahiro , Maesaka Hirokazu , Takahashi Sunao , Tanaka Takashi , Inoue Shinobu , Kumazawa Hirosuke , Moriya Kazuki , Sakai Kohei , Seno Toshio , Sumitomo Hiroshi , Takesako Ryoichi , Tanaka Shinichiro , Yamamoto Ryo , Yokomachi Kazutoshi , Yoshioka Masamichi , Hara Toru , Matsui Sakuo , Hiraiwa Toshihiko , Tanaka Hitoshi , Ego Hiroyasu
Published: February 2025

NanoTerasu, a new 3 GeV synchrotron light source in Japan, began user operation in April 2024. It provides high-brilliance soft to tender x-rays and covers a wide spectral range from ultraviolet to tender x-rays. Its compact storage ring with a circumference of 349 m is based on a four-bend achromat lattice to provide two straight sections in each cell for insertion devices with a natural horizontal emittance of 1.14 nm rad, which is small enough for soft x-rays users. The NanoTerasu accelerator incorporates several innovative technologies, including a full-energy injector C-band linear accelerator with a length of 110 m, an in-vacuum off-axis injection system, a four-bend achromat with B-Q combined bending magnets, and a TM020-mode accelerating cavity with built-in higher-order-mode dampers in the storage ring. This paper presents the accelerator machine commissioning over a half-year period and our model-consistent ring optics correction. The first user operation with a stored beam current of 160 mA is also reported. We summarize the storage ring parameters obtained from the commissioning. This is helpful for estimating the effective optical properties of synchrotron radiation at NanoTerasu.

Published by the American Physical Society
2025