bluuebunny/crossref_metadata_2025 huggingface dataset:
The genetic basis of replicated bullseye pattern reduction across the Trionum Complex
Authors: Yeo May T. S. , Fairnie Alice L. M. , Travaglia Valentina , Walker Joseph F. , Riglet Lucie , Zeyrek Selin , Moyroud Edwige
Published: October 2024

Angiosperm flowers exhibit a wide diversity of colorful motifs on their petals. Such patterns fulfill both biotic and abiotic functions, mediating plant-pollinator communication and providing protection against damaging UV rays or desiccation. These motifs are often evolutionary labile, varying in size, shape and hue between closely related species and constitute excellent systems to illuminate the evolutionary processes that generate morphological diversity or instead lead to the repetitive emergence of similar forms.Hibiscus trionumflowers have a prominent bullseye pattern combining a purple center contrasting against a white margin.H. trionumbelongs to a small clade ofHibiscusknown as the Trionum Complex that displays a range of petal patterns within and between species. Here, we integrate phylogenomic approaches, molecular techniques and genetic manipulation to solve species relationships across the Trionum Complex, identify key genes involved in the production of bullseye pigmentation, and reveal molecular events underpinning pattern variation during the evolution of the group. We find that repetitive bullseye reduction events primarily occur through independent modifications of a single genetic locus encoding BERRY1, an R2R3 MYB that regulates anthocyanin pigment production in petals. Moreover, we demonstrate that buff-tailed bumblebees(Bombus terrestris)discriminate against flowers with smaller bullseye sizes suggesting that a reduction in bullseye proportions potentially impacts plant fitness and contributes to trait distribution across the group. Collectively, our results demonstrate how repeated mutations in a single locus led to morphological variation in petal patterning, a trait that contributes to angiosperm reproductive isolation and speciation.
Differences in metagenome coverage may confound abundance-based and diversity conclusions
Authors: Riquelme Borja Aldeguer , Rodriguez-R Luis M , Konstantinidis Konstantinos T
Published: October 2024

Although the importance of rarefying 16S rRNA gene data to the same coverage for reliable comparisons of diversity between samples has been well appreciated, the impact of (shotgun) metagenome coverage (i.e., what fraction of diversity was sequenced) on biological conclusions is commonly overlooked. We demonstrate that uneven coverage can lead to misleading conclusions about which features (e.g., genes, genomes) may differentiate two metagenomes or their diversity comparisons. We outline an approach to minimize this impact.
RAD51 Paralogs and RAD51 Paralog Complexes BCDX2 and CX3 Interact with BRCA2
Authors: Thrasher Jacob G , Fagunloye Adeola Augustus G , Justiniano Fabricio S , Bernstein Kara A , Jensen Ryan B
Published: October 2024

Homologous recombination (HR) is an important mechanism for repairing DNA double-strand breaks (DSBs) and preserving genome integrity. Pathogenic mutations in the HR proteins BRCA2 and the RAD51 paralogs predispose individuals to breast, ovarian, pancreatic, and prostate cancer. The RAD51 paralogs: RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 form two complexes RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2) and RAD51C-XRCC3 (CX3). Similar to BRCA2, loss of RAD51 paralog functions in mammalian cells lead to chromosomal abnormalities, growth defects, disrupted RAD51 foci formation, and PARP inhibitor sensitivity. Despite significant effort over the past three decades, the specific molecular functions of the human RAD51 paralogs have remained elusive due to technical challenges such as low protein expression in human cell lines and instability of the purified proteins. Recent studies have determined the molecular structures of the BCDX2 and CX3 complexes dramatically enhancing our understanding of these challenging proteins. Using multiple approaches, we demonstrate that the RAD51 paralogs interact with BRCA2 at two distinct interaction hubs located in the BRC repeats and the DNA binding domain. We confirm, using a yeast 3-hybrid approach, that human RAD51 paralogs interact directly with BRC repeats one and two (BRC1-2) of BRCA2. Because of the dynamic nature of the RAD51B C-terminal domain (CTD), identified in the recently solved cryo-EM structures, we focused on elucidating the interaction with RAD51B. We determined that BRCA2 interacts with the CTD of RAD51B and not the N-terminal domain (NTD) that is involved in stacking interactions with RAD51C and RAD51D. Furthermore, the interaction with RAD51B is dependent upon an FxxA motif located on a surface exposed region of the CTD. Our study has identified novel interactions between the RAD51 paralogs and BRCA2 and further demonstrated that a previously unrecognized FxxA motif located within a mobile element of RAD51B is critical for the interaction.
Vibrioare a potential source of novel colistin-resistance genes in European coastal environments
Authors: Saad Jamal , Boulo Viviane , Goudenège David , Broquard Coralie , Andree Karl B. , Auguste Manon , Petton Bruno , Labreuche Yannick , Tris Pablo , Furones Dolors , Gil Augusti , Vezzulli Luigi , Corno Gianluca , Di Cesare Andrea , Koechlin Hugo , Labadie-Lafforgue Emilie , Courtay Gaelle , Romatif Océane , Pouzadoux Juliette , Escoubas Jean-Michel , Munaron Dominique , Charrière Guillaume M. , Toulza Eve , Travers Marie-Agnès , Montagnani Caroline , Wegner Mathias K. , Destoumieux-Garzón Delphine
Published: October 2024

Colistin is a widespread last resort antibiotic for treatment of multidrug-resistant bacteria. The recent worldwide emergence of colistin resistance (Col-R) conferred bymcr-1 in human pathogens has raised concern, but the putative sources and reservoirs of novelmcrgenes in the marine environment remain underexplored. We observed a high prevalence of Col-R, particularly inVibrioisolated from European coastal waters by using a unique stock of specific-pathogen-free (SPF) oysters as a bioaccumulator. The high sequence diversity found in themcr/eptA gene family was geographically structured, particularly for three noveleptAgene variants, which were restricted to the Mediterranean (France, Spain) and occurred as adgkA-eptA operon controlled by the RstA/RstB two component system. By analyzing 29427Vibrionaceaegenome assemblies, we showed that this mechanism of intrinsic resistance is prevalent and specific to the Harveyi clade, which includes strains ofVibrio parahaemolyticusandVibrio alginolyticuscausing infections in humans. The operon conferred colistin-resistance when transferred to sensitive non-Vibriostrains. Whilemcr-andarn-based Col-R mechanisms were also identified, the widespread presence ofeptA gene variants inVibriosuggests they play a key role in intrinsic resistance to colistin. Beyond these ancienteptA gene copies having evolved with theVibriolineage, we also identified mobileeptA paralogues that have been recently transferred between and withinVibrioclades. This highlightsVibrioas a potential source of Col-R mechanisms, emphasizing the need for enhanced surveillance to prevent colistin-resistant infections in coastal areas.
An approach for coherent periodogram averaging of tilt-series data for improved CTF estimation
Authors: Khavnekar Sagar , Wan William
Published: October 2024

Cryo-electron microscopy (cryo-EM) has become an indispensable technique for determining three-dimensional structures of biological macromolecules. A critical aspect of achieving high-resolution cryo-EM reconstructions is accurately determining and correcting for the microscope’s contrast transfer function (CTF). The CTF introduces defocus-dependent distortions during imaging; if not properly accounted for, the CTF can distort features in and limit the resolution of 3D reconstructions. For tilt-series data used in cryo-electron tomography (cryo-ET), CTF estimation becomes even more challenging due to the tilt of the specimen, which introduces a defocus gradient across the field of view, as well as the low dose and signal in individual tilt images. Here, we describe a simple algorithm to improve the accuracy of CTF estimation of tilted images by leveraging the tilt-series alignment parameters determined for tomographic reconstruction to explicitly account for the tilted specimen geometry. In brief, each tilt image is divided into patches, each of which are then stretched according to their defocus shift. These are then summed to provide a coherent power spectra at the tilt axis, which can then be used in standard CTF estimation algorithms. This uses all the data in each image to enhance the visibility of Thon rings, thereby improving high-resolution CTF estimation and subsequent enhancements in the resolution of subtomogram averages.
The fire blight pathogenErwinia amylovoraenters apple leaves through naturally-occurring wounds from the abscission of trichomes
Authors: Millett Felicia , Standish James , Scanley Jules , Miller Katelyn , Inguagiato John , Zuverza-Mena Nubia , Abril Maritza , Robinson Victoria , Li Yan , Sundin George W. , Zeng Quan
Published: October 2024

The plant epidermis is a single layer of cells covering all plant organs. How pathogens overcome this barrier and enter plants is an important aspect of plant-pathogen interactions. For bacterial plant pathogens, known entry points include natural openings such as stomata, hydathodes, and mechanical injuries caused by insect feeding, wind damage or hailstorms.

Here, we report that the fire blight pathogenErwinia amylovoraenters apple leaves through naturally-occurring wounds caused by the abscission of trichomes during the course of leaf development.

Through macroscopic and microscopic observations, we depicted a clear invasion path forE. amylovoracells, from epiphytic growth on glandular trichomes (GT) and non-glandular trichomes (NT), to entry through wounds caused by abscised trichomes, into the epithem, and subsequent spread through xylem. We further observed that GT and NT undergo an abscission process, and that the amount of naturally-occurring wounds during abscission is associated with the increase inE. amylovorapopulation. Key genes important for the colonization of GT and NT were identified. Contribution of the type III secretion system and amylovoran biosynthesis during GT colonization was validated.

Our findings propose a novel host entry mechanism of plant pathogenic bacteria through naturally-occurring wounds during abscission of plant surface structures.
Systematic, high-throughput characterization of bacteriophage gene essentiality on diverse hosts
Authors: Chen Jackie , Nilsen Erick D. , Chitboonthavisuk Chutikarn , Mo Charlie Y. , Raman Srivatsan
Published: October 2024

Understanding core and conditional gene essentiality is crucial for decoding genotype-phenotype relationships in organisms. We present PhageMaP, a high-throughput method to create genome-scale phage knockout libraries for systematically assessing gene essentiality in bacteriophages. Using PhageMaP, we generate gene essentiality maps across hundreds of genes in the model phage T7 and the non-model phage Bas63, on diverse hosts. These maps provide fundamental insights into genome organization, gene function, and host-specific conditional essentiality. By applying PhageMaP to a collection of anti-phage defense systems, we uncover phage genes that either inhibit or activate eight defenses and offer novel mechanistic hypotheses. Furthermore, we engineer synthetic phages with enhanced infectivity by modular transfer of a PhageMaP-discovered defense inhibitor from Bas63 to T7. PhageMaP is generalizable, as it leverages homologous recombination, a universal cellular process, for locus-specific barcoding. This versatile tool advances bacteriophage functional genomics and accelerates rational phage design for therapy.
Extensive longevity and DNA virus-driven adaptation in nearcticMyotisbats
Authors: Vazquez Juan M , Lauterbur M. Elise , Mottaghinia Saba , Bucci Melanie , Fraser Devaughn , Gray-Sandoval Genavieve , Gaucherand Léa , Haidar Zeinab R , Han Melissa , Kohler William , Lama Tanya M. , Le Corf Amandine , Loyer Clara , Maesen Sarah , McMillan Dakota , Li Stacy , Lo Johnathan , Rey Carine , Capel Samantha LR , Singer Michael , Slocum Kathleen , Thomas William , Debelak Tyburec Janet , Villa Sarah , Miller Richard , Buchalski Michael , Vazquez-Medina Jose Pablo , Pfeffer Sébastien , Etienne Lucie , Enard David , Sudmant Peter H
Published: October 2024

The genusMyotisis one of the largest clades of bats, and exhibits some of the most extreme variation in lifespans among mammals alongside unique adaptations to viral tolerance and immune defense. To study the evolution of longevity-associated traits and infectious disease, we generated near-complete genome assemblies and cell lines for 8 closely related species ofMyotis. Using genome-wide screens of positive selection, analyses of structural variation, and functional experiments in primary cell lines, we identify new patterns of adaptation contributing to longevity, cancer resistance, and viral interactions in bats. We find thatMyotisbats have some of the most significant variation in cancer risk across mammals and demonstrate a unique DNA damage response in primary cells of the long-livedM. lucifugus. We also find evidence of abundant adaptation in response to DNA viruses - but not RNA viruses - inMyotisand other bats in sharp contrast with other mammals, potentially contributing to the role of bats as reservoirs of zoonoses. Together, our results demonstrate how genomics and primary cells derived from diverse taxa uncover the molecular bases of extreme adaptations in non-model organisms.
Relative effectiveness of high-dose vs standard-dose influenza vaccines in preventing hospitalizations: a national retrospective cohort study in France, 2022/23 season
Authors: Bricout Hélène , Levant Marie-Cécile , Crépey Pascal , Gavazzi Gaëtan , Gaillat Jacques , Dufournet Marie , Assi Nada , Grenier Benjamin , Raguideau Fanny , Péretz Fabienne , Salamand Camille , Mosnier Anne , Watier Laurence , Launay Odile , Loiaconol Matthew M.
Published: October 2024

Background

A French retrospective observational cohort study conducted during the 2021/22 influenza season found that the high-dose influenza vaccine (HD) was more effective than standard-dose vaccines (SDs) in preventing influenza-related hospitalizations in the elderly. The study continued during the 2022/23 season to obtain more accurate results and validate the findings during a different influenza season.

Material and methods

Data from community-dwelling 65+ adults vaccinated with HD or SD during the 2022/23 vaccination campaign were extracted from the National Health database. Hospitalizations were recorded from 14 days after vaccination until 30 June 2023. HD and SD recipients were matched using a propensity score with an exact constraint on age, sex, vaccination week, and geographical region. Associations between vaccines and hospitalizations (influenza or non-influenza related) were assessed by estimating incidence rate ratios and converting them to HD vs SD vaccine relative effectiveness (rVE).

Results

675,412 HD recipients were matched to 2,701,648 SD recipients. The HD vs SD rVE for influenza-related hospitalizations was 27.39% [95%CI: 19.79;34.27]. It ranged from 22.65% [9.84;33.64] to 33.55% [21.19;43.98] across age groups, indicating that HD resulted in consistently better protection than SDs against influenza-related hospitalizations in all age groups, with the highest effect observed in 85+.

Conclusion

Our study is the first to publish rVE data comparing HD and SD in France, for the 2022/23 influenza season. Its findings reaffirm the benefit of HD vs SD in reducing influenza-related hospitalizations in a real-world setting. HD could help reduce the burden of severe respiratory infections in the elderly.

Registration number: Not applicable.

Highlights

Take-home message

In France, during the 2022/23 influenza season, the high-dose vaccine has reduced influenza-related hospitalizations by 27.4% compared to standard-dose vaccines among community-dwelling 65+ adults, with a clinical benefit observed across all age groups.
Some markers of placental inflammation in pregnant women with gestational diabetes
Authors: De Luccia Thiago Paes de Barros
Published: October 2024

Background

analysis of fetal/placental components of women with gestational diabetes presented a slightly inflammatory profile, compared with non-diabetic pregnant women in previous studies by our group. Leptin, resistin and IL-6 are involved in the inflammatory process while adiponectin can act in anti-inflammatory processes.

Purpose

Since both obesity and gestational diabetes are associated with inflammatory conditions, through these mediators we seek to evaluate systemic patterns in pregnant women and fetal patterns of this possible inflammation.

Materials and Methods

Three adipokines (leptin, resistin and adiponectin) and one cytokine (IL-6) were studied in three different compartments (maternal serum, fetal serum and amniotic membrane culture supernatant). Four pregnant groups were analyzed (eutrophic, overweight, obese and gestational diabetics (GDM)). Maternal and fetal serum and amnion membrane biopsies were collected from 20 GDM and 28 normoglycemic subjects (Controls) who underwent elective cesarean sections.

Results

We found a higher production of IL-6 in the culture supernatant of the amniotic membrane of obese pregnant women and more significantly in pregnant women with gestational diabetes. We did not observe correlation between the levels of mediators detected in the three compartments (mother serum, fetal serum and culture supernatant of amniotic membrane).

Conclusion

Mainly in the amniotic membrane of pregnant women with GDM, a slight increase in inflammatory markers was observed.
Wearable Sensing in Eating Episode Monitoring: An Updated Systematic Review Protocol
Authors: Zhou Jiaying , Cai Mingzhu , Shi Mayue
Published: October 2024

Introduction

Objective and accurate dietary monitoring is critical for comprehensive dietary assessment and improving nutritional health outcomes. The rapid development of wearable sensing technology presents a promising solution for effective dietary monitoring that reduces recall bias and increases user convenience, contributing to clinical chronic disease management and nutritional research. This systematic review aims to explore the effectiveness and practicality of wearable sensors in monitoring dietary behaviours, while also examining the latest advancements in the field since 2020.

Methods and Analysis

Adhering to PRISMA-P guidelines, we will conduct a comprehensive search across MEDLINE, EMBASE, PubMed, IEEExplore, and Web of Science for research published between January 2020 and January 2024 Studies that involved human participants using wearable sensors for monitoring dietary intake will be included. However, studies solely discussing the development of algorithms or applications for these sensors will be excluded. Our review outcomes focused on evaluating the design of the sensors, their performance metrics, and user experience.

Ethics and Dissemination

Findings of this systematic review will be disseminated through peer-reviewed journals, conferences, and seminar presentations. The data used does not include individual patient data, so no ethical approval is required.

Systematic Review Registration Number

PROSPERO Registration ID: CRD42024531570

Strengths and Limitations of This Study

1. This study will update the latest advancements in wearable sensing devices for monitoring food intake published from 2020 to date.

2. This study follows a PICOS framework to formulate research questions and inclusion/exclusion criteria.

3. This study uses a well-structured search strategy, using MeSH and equivalent terms to search across five medical and engineering databases to provide a precise, comprehensive, and multidisciplinary perspective on the topic.

4. The nature of the available data precludes the possibility of conducting a meta-analysis, limiting the ability to quantitatively synthesize study findings. However, the narrative data synthesis adheres to the Synthesis Without Meta-analysis (SWiM) guidelines, ensuring a structured approach to qualitatively integrating study outcomes.

5. The inclusion criteria were restricted to peer-reviewed journals published in English. This excludes potentially relevant conference papers and studies published in other languages, which may limit the comprehensiveness of the analysis.
Determinants of Antibody Levels and Protection against Omicron BQ.1/XBB Breakthrough Infection
Authors: Pérez Carla Martín , Ramírez-Morros Anna , Jimenez Alfons , Vidal Marta , Pradenas Edwards , Barrios Diana , Canyelles Mar , Rubio Rocío , Cuamba Inocencia , Izquierdo Luis , Santamaria Pere , Trinité Benjamin , Vidal-Alaball Josep , Molinos-Albert Luis M. , Blanco Julià , Aguilar Ruth , Ruiz-Comellas Anna , Moncunill Gemma , Dobaño Carlota
Published: October 2024

The ongoing evolution of SARS-CoV-2, particularly through the emergence of new variants, continues to challenge our understanding of immune protection. While antibody levels correlate with protection against earlier variants like Alpha and Delta, their relationship with Omicron sub-variants remains unclear. To investigate the role of antibody levels and neutralizing activity in preventing breakthrough infections, we analyzed longitudinal SARS-CoV-2 humoral responses and neutralizing activity against the ancestral virus and major emerging variants in a well-characterized cohort of healthcare workers in Spain (N = 405). We found that antibody levels and neutralization titers are key indicators of protection against SARS-CoV-2, including the BQ.1 and XBB Omicron variants. Higher IgG and IgA levels were associated with protection over three 6-month follow-up periods sequentially dominated by BA.1, BA.2, BA.5, BQ.1, and XBB Omicron sub-variants, although the strength of the association between antibody levels and protection declined over time. Our findings demonstrate that binding antibody levels and neutralizing responses are a valid correlate of protection against more evasive BQ.1 and XBB Omicron variants, although the strength of this association declined over time. Additionally, our results underscore the importance of continuous monitoring and updating vaccination strategies to maintain effective protection against emerging SARS-CoV-2 variants.
Feasibility trial of a new digital training package to enhance primary care practitioners’ communication of clinical empathy and realistic optimism
Authors: Bishop Felicity L , Howick Jeremy , Vennik Jane , Bostock Jennifer , Little Paul , Mallen Christian , Morrison Leanne , Steele Mary , Stuart Beth , Hughes Stephanie , Smith Kirsten , Ratnapalan Mohana , Lyness Emily , Dambha-Miller Hajira , Tiwari Riya , Lockyer-Stevens Clare , Everitt Hazel
Published: October 2024

Background

Patients can benefit when primary care practitioners communicate clinical empathy and optimism during consultations, but previous training interventions for practitioners are overly time-consuming and evidence on patient outcomes is limited. This study assessed the feasibility of a cluster-randomized controlled trial in UK general practice to evaluate effects of a new brief digital learning package in empathy and optimism (EMPathicO) for primary care practitioners.

Methods

The study ran January to October 2020, with COVID-19 related modifications (mostly, practitioner and patient data had to be collected separately) from March 2020. 9 practices and 12 primary care practitioners recruited from UK (Southern England, Midlands). 12 practitioners completed EMPathicO training and 11 completed qualitative telephone interviews. Patients recruited through social media completed web-based questionnaires at baseline (<2 weeks post- consultation) and 2-week follow-up (n=437). Purposively sampled patients completed qualitative telephone interviews (n=30). Data analysed descriptively and thematically.

Results

Practitioners were keen to reflect on and enhance communication skills and were willing to undertake digital training, even during COVID-19 pandemic. However, some practices and practitioners would have declined if video-recording consultations was a mandatory aid to reflection during training. Practitioners found EMPathicO brief, relevant and engaging and could implement techniques taught in the training. Patients found the online questionnaires acceptable, though retention was suboptimal at 57%; minor easily remedied feasibility and process issues were identified (including incentivizing participation); and patients were enthusiastic about research to improve communication.

Conclusions

An agile research strategy enabled useful feasibility data to be collected despite the challenges of the COVID pandemic. It is feasible to proceed to a full trial of the effects of EMPathicO on patient outcomes in primary care, if video-recording consultations is optional not mandatory.

Feasibility work to develop and test sophisticated questionnaire structures is valuable when planning primary care patient surveys.
Untargeted viral metagenomics of indoor air as a novel surveillance tool for respiratory, enteric and skin viruses
Authors: Karatas Mustafa , Geenen Caspar , Keyaerts Els , Budts Lore , Raymenants Joren , Eggers Charlotte , Craessaerts Bastiaan , André Emmanuel , Matthijnssens Jelle
Published: October 2024

Conventional hospital-based infectious disease surveillance struggles to detect mild or asymptomatic infections and incurs high costs for large-scale testing during outbreaks. In contrast, environmental surveillance can effectively monitor viral circulation and capture asymptomatic or mildly symptomatic infections that may otherwise go unnoticed. This longitudinal study explores the use of indoor air, in combination with targeted qPCR panels and untargeted viral metagenomics, as a novel virus surveillance tool. Indoor air samples were collected weekly from a daycare center in Leuven, Belgium, over a 12-month period using active indoor air sampling, followed by screening using respiratory and enteric qPCR panels, as well as untargeted viral metagenomics.

Human-associated viruses were detected in 95.2% (40/42) of samples, with MW polyomavirus being the most prevalent at 80.9%. Several other respiratory viruses (e.g., rhinoviruses, RSV-B) and enteric viruses (e.g.. rotavirus, astrovirus, adenovirus) were identified, correlating with their known epidemiological circulation patterns. Metagenomics resulted in multiple complete viral genome reconstructions, allowing discrimination of viral subtypes and the identification of coinfections with closely related virus variants. Finally, a plethora of animal, insect, fungal and plant-infecting viruses could be detected, representing the indoor and outdoor environment. Indoor air surveillance can be a robust complementary tool for virus surveillance.
KNOWLEDGE AND PERCEPTION ABOUT HUMAN PAPILLOMAVIRUS IN TRADITIONAL QUILOMBOLA COMMUNITIES IN NORTHEAST BRAZIL
Authors: de Campos Mariel Rodrigues , Carvalho Larissa Helena Sousa Baldez , Campos Ana Julya Rodrigues , Côra Gabriel Rodrigues , Machado Rayane Alves , Elehamer Nafisa M.K , Villa Luisa Lina , de Ribamar Ross José , Vidal Flávia Castello Branco
Published: October 2024

The study analyzed knowledge about Human Papillomavirus among adults in traditional quilombola communities in northeast Brazil while discussing their sociodemographic characteristics and evaluating sociodemographic variables among different quilombola communities. It was a descriptive, cross-sectional, and quantitative mixed-method study, with face-to-face interviews and a questionnaire application. There is a significant gap in the precise understanding of HPV. Most information was acquired through traditional media, such as TV, newspapers, and radio. Women and younger individuals demonstrated more comprehensive knowledge of the subject. The results highlight the need for specific instructions to improve knowledge about HPV in these communities, with strategies adapted to their sociodemographic characteristics. Enhanced understanding of HPV and the importance of vaccination can significantly contribute to the health and well-being of these populations, decreasing health disparities. With better knowledge about HPV and its consequences, the vaccination rate will increase, which in the long term will mean a reduction in the incidence of cancer cases associated with this virus, especially cervical cancer.
Dissecting the genetic and proteomic risk factors for delirium
Authors: Raptis Vasilis , Bhak Youngjune , Cannings Timothy I , MacLullich Alasdair M. J. , Tenesa Albert
Published: October 2024

Delirium is an acute change in cognition, common in hospitalised older adults, and associated with high healthcare and human cost. In this work we shed light into the currently poorly understood genetic and proteomic background of delirium. We conducted the largest to date multi-ancestry analysis of genetic variants associated with delirium (1,059,130 individuals, 11,931 cases), yielding theApolipoprotein E(APOE) gene as a strong risk factor with possible population and age-varying effects. A multi-trait analysis of delirium with Alzheimer disease identified 5 delirium genetic risk loci. Investigation of plasma proteins associated with up to 16-years incident delirium (32,652 individuals, 541 cases) revealed known and novel protein biomarkers, implicating brain vulnerability, inflammation and immune response processes. Integrating proteins andAPOEgenetic risk with demographics significantly improved incident delirium prediction compared to demographics alone. Our results pave the way to better understanding delirium’s aetiology and guiding further research on clinically relevant biomarkers.
Predictors of Burnout Among Academic Family Medicine Faculty: Looking Back to Plan forward
Authors: Antao Viola , Krueger Paul , Meaney Christopher , Kwong Jeffrey C. , White David
Published: October 2024

Objective

To identify the prevalence and predictors of burnout among academic family medicine faculty.

Design

A comprehensive survey of academic family medicine faculty on burnout, perceptions of work life, and practice in 2011.

Setting

A large, distributed Department of Family and Community Medicine at the University of Toronto.

Participants

All 1029 faculty members were invited to participate.

Main outcome measures

Maslach Burnout Inventory three subscales (emotional exhaustion, depersonalization, personal accomplishment).

Results

The survey response rate was 66.8% (687/1029). The prevalence of high emotional exhaustion scores was 27.0% and high depersonalization was 9.2%, whereas the prevalence of high personal accomplishment scores was 99.4%. Bivariate analyses identified 27 variables associated with emotional exhaustion and 18 variables associated with depersonalization, including: ratings of the practice setting; leadership and mentorship experiences; job satisfaction; health status; and demographic variables. Multivariate analyses found four predictors of emotional exhaustion: lower ratings of job satisfaction, poorer ratings of workplace quality, working ≥50 hrs/week, and poorer ratings of health status. Predictors of depersonalization included lower ratings of job satisfaction, ≤5 years in practice, lower ratings of health status, and poor ratings of mentorship received.

Conclusions

This study describes the prevalence and predictors of burnout among physicians prior to the COVID-19 pandemic. Predictors that are potentially modifiable at local practice and systems levels include job satisfaction, workplace quality, hours worked, and mentorship received. New family physicians (≤5 years in practice) were at increased risk of depersonalization; strategies specific to this group may limit burnout and address the healthcare workforce crisis. Periodic studies are recommended to identify the impact of strategies implemented, emergent predictors, trends, and mitigating factors associated with burnout. The current crisis in family medicine indicates an urgent need to look back and plan forward.
Epidemiology of Cannabis Use Among Middle-Aged and Older Adults in the United States
Authors: Livne Ofir , Stohl Malka , Gilman Jodi , Goldberg Terry E. , Wall MM , Hasin Deborah S.
Published: October 2024

Importance

Studies report disproportionate increases in cannabis use among middle-aged (50-64) and older (65+) U.S. adults, groups particularly vulnerable to its adverse effects. However, national data on attitudes towards cannabis use and legalization, as well as prevalences of key cannabis-related behaviors are lacking for these groups.

Objective

To present national prevalences of past-year any cannabis use, medical use, consumption methods, and other important use-related behaviors, and attitudes toward use, as well as associations of such behaviors and attitudes to cannabis use among U.S. adults ages 50 and older.

Design

Cross-sectional data from the Health and Retirement Study (HRS) were used to calculate weighted prevalences for all cannabis measures by primary age groups (50-64, ≥65) as well as two specified older age groups (65-74, ≥75) and sex. Associations between sociodemographics and cannabis use were evaluated using multivariable logistic regression.

Main Outcomes and Measures

Self-reported past-year cannabis use (outcome), consumption methods, medical use and health conditions for which cannabis was used, prescriptions by healthcare providers, current and past perception of acceptability, perceptions of risk, and attitudes toward legalization (exposures). Covariates included sex, race/ethnicity, household income, and employment status.

Setting and Participants

HRS participants who completed the 2018 cannabis use experimental module (n=1,324).

Results

Past year cannabis use was reported by 18.5% (SE=2.17) and 5.9% (SE=1.19) of middle-age and older adults, respectively in the U.S. In both groups, a majority of individuals consumed cannabis exclusively by smoking. Approximately 25% of middle-aged adults and 20% of older adults used cannabis for medical purposes, with ∼20% in both groups receiving a prescription or recommendation for medical use from a healthcare provider. Over 75% of individuals in both age groups viewed medical use of cannabis as acceptable, and older adults were more likely to view cannabis as a gateway drug and to support restrictions of cannabis laws.

Conclusions and Relevance

Cannabis use among both middle-aged and older U.S. adults is higher than previously reported in state- and national-level studies, with many engaging in cannabis behaviors associated with increased harm. Greater public health and clinical efforts are needed for tailored prevention and intervention strategies.
Understanding end-user preferences for hand hygiene enabling technologies: a mixed-methods study in peri-urban Lusaka
Authors: Kazimbaya Katayi , Davies Katherine , Mwenge Mwamba M. , Tadiri Elisabeth , Chipungu Jenala , Dreibelbis Robert
Published: October 2024

Introduction

Handwashing facilities (HWFs) are associated with higher rates of handwashing with soap, and the presence of a HWF is the global proxy indicator of household handwashing behaviour. There is limited information on attributes of HWFs important to end-users with few comparative assessments of HWFs from a user-perspective. We aimed to identify attributes of HWFs important to end-users and determine how pre-manufactured HWFs ranked against these attributes.

Method

We identified eight pre-existing HWFs: two locally manufactured (Kalingalinga bucket and Tippy tap) and six industrially produced designs (Jengu, SatoTap, SaniTap, HappyTap, SpaTap, and Kohler Cleanse). Two rounds of focus group discussions were conducted with a diverse group of targeted end-users in two peri-urban communities in Lusaka, Zambia. In the first, participants discussed aspects of each HWF they liked and disliked, and thematic analysis was used to define nine attributes for comparision across each HWF. In the second round, participants individually ranked each HWF against the identified attributes, their overall preference, and overall preference once estimated retail prices were revealed. Participants also ranked attributes by importance. Ranking data were modelled using rank-ordered logistic regression.

Results

Discussions revealed nine attributes important to end users: appearance, water management, hygienic use, convenience, water disposal, vulnerability to theft or breakage, ease of use, price and maintenance. Hygienic use and water management were considered most important attributes. Excluding price, facilities resembling a sink, such as the Happy Tap (34%) and Jengu (28%), had the highest probability of being ranked first. With consideration for price, participants preferred lower-cost HWFs such as the Kalingalinga bucket (44%), Tippy Tap (13%) and SATO Tap (10%).

Conclusion

This study identified nine attributes important to end-users that can inform future design efforts. Future work will explore user preferencesin situby rotating households through specific HWF for an extended period. Potential manufacturers should continue to iterate on HWF designs emphasizing on reducing costs.
Infections are not alike: the effects of covariation between individual susceptibility and transmissibility on epidemic dynamics
Authors: Harris Jeremy D. , Gallmeier Esther , Dushoff Jonathan , Beckett Stephen J. , Weitz Joshua S.
Published: October 2024

Individual-level variation in susceptibility to infection and transmissibility of infection can affect population-level dynamics in epidemic outbreaks. Prior work has incorporated independent variation in susceptibility or transmissibility of individuals into epidemic compartmental models. Here, we develop and assess a mathematical framework that includes covariation in susceptibility and transmissibility. We show that uncorrelated variation in susceptibility and transmissibility leads to an effective transmissibility distribution that has a constant coefficient of variation such that the epidemic dynamics match those with variation in susceptibility alone, providing a baseline for comparison across different correlation structures. Increasing the correlation between susceptibility and transmissibility increases both the speed and strength of the outbreak – and is indicative of outbreaks which might be strongly structured by contact rate variation. In contrast, negative correlations between susceptibility and transmissibility lead to overall weaker outbreaks – with the caveat that the strength of effective transmission increases over time. In either case, correlations can shift the transmissibility distribution, thereby modifying the speed of the epidemic as the susceptible population is depleted. Overall, this work demonstrates how (often unaccounted) covariation in susceptibility and transmission can shape the course of outbreaks and final outbreak sizes.

Highlights

Developed models incorporating susceptibility and transmissibility covariation.

Identified eigendistributions of the force of infection.

Uncorrelated transmissibility reduces to variation in susceptibility alone.

Positive correlations lead to increases in the basic reproduction number.

Positive correlations give faster, stronger, more likely outbreaks.

Effective transmission rates increase over time with negative correlations.
Enhanced anti-tumor activity by Zinc Finger Repressor-driven epigenetic silencing of immune checkpoints and TGFBR2 in CAR-T cells and TILs
Authors: David Marion , Schiele Phillip , Monteferrario Davide , Saviane Gaëlle , Martelli Angélique E. , Dupont Coralie F. , Jeanneau Caroline , Marchetti Irène , Tadi Satish K. , Vahldick Julia , Truong Lynn N. , Zhou Yuanyue , Sauer Igor M. , Schöning Wenzel , Na Il-Kang , Reik Andreas , Frentsch Marco , de la Rosa Maurus , Fenard David
Published: October 2024

CAR-T therapies have shown remarkable success in treating hematological malignancies. However, effectiveness against solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), such as TGF-β signaling and upregulated immune checkpoints (ICs). Furthermore, identifying universal, tumor-specific targets for CAR-T cells in solid tumors is challenging, but using reinvigorated, immunosuppressive-resistant tumor-infiltrating lymphocytes (TILs) could be a promising alternative approach. Unlike nucleases, which may induce genotoxic DNA double-strand breaks, multiplexed Zinc Finger Repressors (ZFR) offer a safer alternative for knocking out TME-related immunosuppressive factors. We epigenetically repressed PD-1 expression both in CAR-T cells and TILs from colorectal liver metastases. PD-1 repression did not affect T cell viability, proliferation, or functionality. In a murine B cell lymphoma model, PD-1-repressed CD19-CAR-T cells exhibited enhanced anti-tumor activity and improved survival. Notably, PD-1 repression alone did not increase cytotoxicity against a PD-L1-positive colorectal cell line in vitro. To further increase anti-tumor potency in this context, ZFR-expressing lentiviral vectors targeting PD-1 and other ICs (LAG-3, TIM-3, TIGIT) or TGFBR2 were developed, improving significantly the cytotoxic activity in TILs. This strategy highlights the potential to enhance tumor-reactive T cells and improve anti-cancer immunotherapies by epigenetically repressing immunosuppressive factors in the TME using multiplexed ZFRs.
Ruxolitinib clears CRYAB p.Arg120Gly aggregates through the ubiquitin-proteasome system
Authors: Alizoti Erda , Ewald Leonie , Parretta Simona , Meyer-Jens Moritz , Orthey Ellen , Conze Christian , Carrier Lucie , Robbins Jeffrey , Singh Sonia R
Published: October 2024

Rationale

Protein accumulation is a hallmark of many neurodegenerative and muscular diseases. Desmin-related (cardio-) myopathy (DRM), a well-studied model for cardiac muscle protein accumulation, is an autosomal dominant-inherited disease presenting with progressive muscle weakness, reduced quality of life, and shortened life span. To date, DRM patients are treated symptomatically and there is no causal treatment available. Independent of the genetic cause, most DRM patients display intracellular accumulation of desmin and its chaperone αB-crystallin (CRYAB). We previously conducted an unbiased high-throughput screen to identify novel effectors that reduce cardiomyocyte aggregate levels and found that downregulation of Janus kinase 1 (JAK1) resulted in lower aggregate load in neonatal mouse cardiomyocytes.

Objective

In this study, we tested if the approved JAK inhibitor ruxolitinib ameliorates the disease phenotype in rodent and human CRYAB p.Arg120Gly DRM models.

Methods and Results

We found that the mRNA levels ofJak1andStat3were higher than any other JAK-signal transducer and activator of transcription (STAT) family members in neonatal rat ventricular myocytes (NRVMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The approved JAK1/2 inhibitor ruxolitinib and the JAK1 inhibitors solcitinib, upadacitinib, and filgotinib prevented accumulation of and cleared pre-existing CRYAB p.Arg120Gly protein aggregates in NRVMs and hiPSC-CMs. Importantly, the knockdown ofJak1andStat3, but notJak2resulted in fewer aggregates. Moreover, ruxolitinib,Jak1orStat3siRNA treatment enhanced the ubiquitin-proteasome system (UPS)-mediated degradation. Blocking UPS function blunted the effect of ruxolitinib orJak1siRNA on CRYAB p.Arg120Gly accumulation. RNAseq of NRVMs treated withJak1siRNA extracts revealed higher gene expression of important muscle E3 ubiquitinating enzymes. Knockdown of the E3 ligaseAsb2(Ankyrin Repeat And SOCS Box Protein 2) abolished the effect of ruxolitinib on CRYAB p.Arg120Gly aggregates. In DRM mice, phospho-STAT3 levels were markedly higher than in non-transgenic (NTG) mice with age. Ruxolitinib treatment orJak1knockout prevented cardiac dysfunction and reduced CRYAB p.Arg120Gly aggregate load in DRM mice.

Conclusion

In this study, we uncovered the previously unknown effect of the approved drug ruxolitinib to enhance UPS-mediated degradation and prevent protein aggregates in cardiomyocytes.
Mapping the Temporal Landscape of Breast Cancer Using Epigenetic Entropy
Authors: Monyak Daniel L. , Holloway Shannon T. , Gumbert Graham J. , Grimm Lars J. , Hwang E. Shelley , Marks Jeffrey R. , Shibata Darryl , Ryser Marc D.
Published: October 2024

Although generally unknown, the age of a newly diagnosed tumor encodes valuable etiologic and prognostic information. Here, we estimate the age of breast cancers, defined as the time from the start of growth to detection, using a measure of epigenetic entropy derived from genome-wide methylation arrays. Based on an ensemble of neutrally fluctuating CpG (fCpG) sites, this stochastic epigenetic clock differs from conventional clocks that measure age-related increases in methylation. We show that younger tumors exhibit hallmarks of aggressiveness, such as increased proliferation and genomic instability, whereas older tumors are characterized by elevated immune infiltration, indicative of enhanced immune surveillance. These findings suggest that the clock captures a tumor’s effective growth rate resulting from the evolutionary-ecological competition between intrinsic growth potential and external systemic pressures. Because of the clock’s ability to delineate old and stable from young and aggressive tumors, it has potential applications in risk stratification of early-stage breast cancers and guiding early detection efforts.
Fibromyalgia patients have altered lipid concentrations associated with disease symptom severity and anti-satellite glial cell IgG antibodies
Authors: Jakobsson Jenny E. , Menezes Joana , Krock Emerson , Hunt Matthew A. , Carlsson Henrik , Vaivade Aina , Emami Khoonsari Payam , Agalave Nilesh M. , Sandström Angelica , Kadetoff Diana , Tour Jeanette , Erngren Ida , Al-Grety Asma , Freyhult Eva , Sandor Katalin , Kosek Eva , Svensson Camilla I. , Kultima Kim
Published: October 2024

Autoimmunity and immunoglobulin G (IgG) autoantibodies may contribute to pain in a subset of fibromyalgia (FM) patients. Previously, we saw that IgG from FM patients induces pain-like behavior in mice and binds to satellite glial cells (anti-SGC IgG). The anti-SGC IgG levels were also associated with more severe symptomatology. Lipid metabolism in FM subjects is altered with lysophosphatidylcholines (LPCs) acting as pain mediators. The relationship between autoantibodies, lipid metabolism, and FM symptomatology remains unclear. We analyzed serum lipidomics with liquid chromatography mass spectrometry, anti-SGC IgG levels, and clinical measures in 35 female FM subjects and 33 age- and body mass index-balanced healthy controls (HC). Fibromyalgia subjects with higher anti-SGC IgG levels experienced more intense pain than those with lower levels. Sixty-three lipids were significantly altered between FM subjects and HC or between FM subjects with severe (FM severe) and mild symptoms (FM mild). Compared to HC, FM subjects had lower concentrations of lipid species belonging to the classes LPC (n = 10), lysophosphatidylethanolamine (n = 7), phosphatidylcholine (n = 4), and triglyceride (n = 5), but higher concentrations of diglyceride (n = 3). Additionally, FM severe had higher LPC 19:0, 22:0, and 24:1 and lower sphingomyelin (n = 9) concentrations compared to FM mild. A positive association was seen for LPC 22:0 and 24:1 with pain intensity and anti-SGC IgG levels in FM subjects. Taken together, our results suggest an association between altered lipid metabolism and autoimmune mechanisms in FM.

Perspective

Our results suggest an association between the postulated autoimmunity in FM and lipids that can act as pain mediators.