bluuebunny/crossref_metadata_2025 huggingface dataset:
Obinutuzumab treatment for membranous nephropathy: effectiveness and safety concerns during the COVID-19 pandemic
Authors: Xu Mingyue , Chen Ruiying , Wang Yifeng , Huang Xiaoyun , Zhang Hanzhen , Zhao Wenqian , Zhang Min , Xu Yunyu , Liu Shaojun , Hao Chuan-Ming , Xie Qionghong
Published: October 2024

Background

Obinutuzumab is a humanized and glycoengineered anti-CD20 monoclonal antibody that has been shown to induce more profound B-cell depletion than rituximab. The effectiveness and safety of obinutuzumab in the treatment of membranous nephropathy remain unclear.

Methods

This was a retrospective study conducted in Huashan Hospital, Fudan University between 1 December 2021 and 30 November 2023. Patients with membranous nephropathy were included to assess the effectiveness and safety of obinutuzumab and prevalence of severe pneumonia during the outbreak of COVID-19 in China.

Results

Eighteen patients were included in the study assessing the effectiveness of obinutuzumab. After a 12-month follow-up, 14 patients (78%) achieved remission, with six (33%) achieving complete remission and eight (44%) achieving partial remission. Among the 18 obinutuzumab-treated patients contracting COVID-19 for the first time, six (33%) developed severe pneumonia, and one died. By contrast, two of the 37 patients receiving glucocorticoids combined with cyclophosphamide, and none of the 44 patients on calcineurin inhibitors or the 46 patients on rituximab developed severe pneumonia. However, compared to patients receiving rituximab or glucocorticoids plus cyclophosphamide, the obinutuzumab-treated patients had a longer duration of membranous nephropathy and immunosuppressive therapy. Therefore, cardinal matching was employed to balance these baseline characteristics. Owing to small sample size for each regimen, patients receiving all the three non-obinutuzumab immunosuppressive regimens were grouped as a control cohort. After matching for age, gender, remission status, duration of membranous nephropathy, duration of immunosuppressive therapy, and ongoing immunosuppression, the obinutuzumab-treated patients still had a significantly higher incidence of severe pneumonia compared to those on other regimens (P = .019).

Conclusion

Obinutuzumab was an effective treatment option for patients with membranous nephropathy. On the other hand, it was associated with a higher incidence of severe pneumonia following COVID-19 infection compared to other immunosuppressive regimens.
Tolvaptan and the role of kidney aquaporin-2 abundance in managing volume overload in patients with CKD
Authors: Yan Yu , Li Xiao-min , Yang Yan , Wang Feng-mei , Liu Hong , Tang Ri-ning , Zhang Xiao-liang , Liu Bi-cheng , Wang Bin
Published: October 2024

Objective

This retrospective study evaluated tolvaptan's efficacy, safety, and predictive indicators in managing volume overload in chronic kidney disease (CKD) patients.

Methods

CKD patients with volume overload, treated with loop diuretics alone or with tolvaptan at Zhongda Hospital, Southeast University, from 1 March 2022 to 31 December 2023, were included. Patients were divided into loop diuretic (Group C) and loop diuretic combined with tolvaptan (Group T) cohorts. Primary outcomes included volume control, changes in weight, urine output, and laboratory parameters within 1 week post-medication. Adverse events such as hypernatremia and hyperkalemia, etc., were recorded. We further conducted immunohistochemical staining of renal biopsy tissues to investigate the roles of aquaporin-2 (AQP2) in the collecting duct and plasma albumin in predicting the efficacy of tolvaptan.

Results

Of 174 CKD patients with volume overload, 108 (67.07%) were male. Group C and Group T each comprised 87 patients. At baseline, no significant differences in urine output and weight were noted. By day 3, Group T exhibited a greater increase in urine output (P < .001) and weight reduction (P < .001). At day 7, Group T maintained more significant diuretic effects (P < .001). More Group C patients required ultrafiltration therapy (P = .040). Adverse event rates did not significantly differ. Notably, AQP2 expression in the collecting duct may predict tolvaptan responsiveness, while plasma albumin did not affect efficacy.

Conclusion

Tolvaptan showed efficacy and safety in managing volume overload in CKD patients. The expression of AQP2 in the collecting duct could predict tolvaptan's efficacy.

This study protocol was approved by the Ethics Committee of Zhongda Hospital Affiliated to Southeast University (Approval No. 2023ZDSYLL180-P01, Clinical Trial Registration No. ChiCTR2300075274, Trial Registration Link: https://www.chictr.org.cn/guide.html).
Evaluation of the Symptoms and Clinical Characteristics of Crohn’s Disease and Ulcerative Colitis That Affect Healthcare Providers’ Treatment Choices
Authors: Hunter Gibble Theresa , Sweeney Carolyn , Wolin Daniel , McSorley David , Wang Jinyi , Moses Richard , Dubinsky Marla
Published: October 2024

Background

Treatment of inflammatory bowel disease—Crohn’s disease (CD) and ulcerative colitis (UC)—is dependent on healthcare providers’ (HCPs’) clinical assessment of patient symptoms. We therefore evaluated which CD and UC symptoms impact HCPs’ treatment choices and assessed the impact of those symptoms on treatment decision-making. We also examined the role of complete control (mucosal/histologic healing, clinical remission, no bowel urgency) in treatment decision-making, considerations for dose escalation or switching treatments, and HCPs’ willingness to use the Urgency Numeric Rating Scale (NRS) to assess bowel urgency severity.

Methods

We conducted an observational, cross-sectional, self-administered survey among HCPs (N = 459, across types/specialties) who work in direct patient care and treat patients with CD and UC in the United States. Data were collected from eligible participants between November 21, 2022, and December 6, 2022, and responses were summarized through descriptive statistics.

Results

For CD and UC, the symptoms of greatest importance when deciding on the course of treatment included cramping or abdominal pain, rectal bleeding, diarrhea, anemia, weight loss, and bowel urgency. Furthermore, most HCPs ranked rectal bleeding, clinical remission, abdominal pain, and complete control as “very” to “extremely” important in decisions about the course of treatment, dose escalation, or switching treatments. In total, 22.9% of HCPs indicated that they use the Urgency NRS, while 89.3% were at least somewhat willing to use it in the future.

Conclusions

Our study provides real-world insights into the symptoms and clinical characteristics that most impact HCPs’ treatment choices for CD and UC in clinical practice.
Costly calling: Marmots who alarm call at higher rates are less likely to survive the summer and live shorter lives
Authors: Blumstein Daniel T , Adler Katie A , Uy Jazmine
Published: October 2024

Emitting alarm calls may be costly, but few studies have asked whether calling increases a caller’s risk of predation and survival. Since observing animals calling and being killed is relatively rare, we capitalized on over 24,000 h of observations of marmot colonies and asked whether variation in the rate that yellow-bellied marmots (Marmota flaviventer) alarm called was associated with the probability of summer mortality, a proxy for predation. Using a generalized mixed model that controlled for factors that influenced the likelihood of survival, we found that marmots who called at higher rates were substantially more likely to die over the summer. Because virtually all summer mortality is due to predation, these results suggest that calling is indeed costly for marmots. Additionally, the results from a Cox survival analysis showed that marmots that called more lived significantly shorter lives. Prior studies have shown that marmots reduce the risk by emitting calls only when close to their burrows, but this newly quantified survival cost suggests a constraint on eliminating risks. Quantifying the cost of alarm calling using a similar approach in other systems will help us better understand its true costs, which is an essential value for theoretical models of calling and social behavior.
Association between communication patterns, benefit finding, and relationship satisfaction in stroke couples: an actor-partner interdependence mediation model
Authors: Liu Zhiwei , Zhang Zhenxiang , Wang Wenru , Ping Zhiguang , Chen Suyan , Yuan Yan , Zhang Weihong , Li Xin , Mei Yongxia
Published: October 2024

Aims

To explore the mediating role of relationship satisfaction between communication patterns and benefit findings in stroke couples using the actor–partner interdependence mediation model.

Methods and results

A cross-sectional study was conducted from October 2022 to April 2023 in China. Based on the actor–partner interdependence mediation model, we used structural equation modelling to explore the mediating role of relationship satisfaction of stroke patients and their spouses in communication patterns and benefit findings. A total of 381 stroke couples (patients, 61.4% male, mean age 54.06; caregivers, mean age 53.58) were included in the data analysis. Actor effects showed that stroke couples’ relationship satisfaction mediated each of their own three communication patterns (constructive communication, demand/withdraw communication, and mutual avoidance) and benefit findings. In addition, patients’ relationship satisfaction mediated patient demand–spouse withdraw and spouses’ benefit findings. Partner effect showed that patients’ relationship satisfaction mediated the association between their own three communication patterns and spouses’ benefit findings. Patients’ relationship satisfaction mediated the association between patient demand–spouse withdraw and patients’ benefit findings. Moreover, spouses’ relationship satisfaction mediated the association between the two communication avoidance patterns exhibited by patients (spouse demand–patient withdraw and mutual avoidance) and the spouses’ benefit findings.

Conclusion

The results have demonstrated a reciprocal influence on benefit findings between stroke patients and their spouses. The communication patterns within these couples have impacted not only their own benefit findings but also those of their spouses, with relationship satisfaction playing a mediating role.
Evolution and functional implications of stinger shape in ants
Authors: Casadei-Ferreira Alexandre , Procópio Camacho Gabriela , van de Kamp Thomas , Lattke John E , Machado Feitosa Rodrigo , Economo Evan P
Published: October 2024

Trait diversification is often driven by underlying performance tradeoffs in the context of different selective pressures. Evolutionary changes in task specialization may influence how species respond to tradeoffs and alter diversification. We conducted this study to investigate the functional morphology, evolutionary history, and tempo and mode of evolution of the Hymenoptera stinger using Ectatomminae ants as a model clade. We hypothesized that a performance tradeoff surface underlies the diversity of stinger morphology and that shifts between predatory and omnivorous diets mediate the diversification dynamics of the trait. Shape variation was characterized by X-ray microtomography, and the correlation between shape and average values of von Mises stress, as a measure of yield failure criteria under loading conditions typical of puncture scenarios, was determined using finite element analysis. We observed that stinger elongation underlies most of the shape variation but found no evidence of biomechanical tradeoffs in the performance characteristics measured. In addition, omnivores have increased phenotypic shifts and accelerated evolution in performance metrics, suggesting the evolution of dietary flexibility releases selection pressure on a specific function, resulting in a greater phenotypic evolutionary rate. These results increase our understanding of the biomechanical basis of stinger shape, indicate that shape diversity is not the outcome of simple biomechanical optimization, and reveal connections between diet and trait diversification.
Inferring bacterial interspecific interactions from microcolony growth expansion
Authors: Miguel Trabajo Tania , Guex Isaline , Dubey Manupriyam , Sarton-Lohéac Elvire , Todorov Helena , Richard Xavier , Mazza Christian , van der Meer Jan Roelof
Published: October 2024

Bacterial species interactions significantly shape growth and behavior in communities, determining the emergence of community functions. Typically, these interactions are studied through bulk population measurements, overlooking the role of cell-to-cell variability and spatial context. This study uses real-time surface growth measurements of thousands of sparsely positioned microcolonies to investigate interactions and kinetic variations in monocultures and cocultures of Pseudomonas putida and P. veronii under substrate competition (succinate) or substrate independence (d-mannitol and putrescine). In monoculture, microcolonies exhibited expected substrate-dependent expansion rates, but individual colony sizes were affected by founder cell density, spatial positioning, growth rates, and lag times. In coculture, substrate competition favored P. putida, but unexpectedly, reduced the maximum growth rates of both species. In contrast, 10% of P. veronii microcolonies under competition grew larger than expected, likely due to founder cell phenotypic variation and stochastic spatial positioning. These effects were alleviated under substrate independence. A linear relationship between founder cell ratios and final colony area ratios in local neighborhoods (6.5–65 µm radius) was observed in coculture, with its slope reflecting interaction type and strength. Measured slopes in the P. putida to P. veronii biomass ratio under competition were one-third reduced compared to kinetic predictions using a cell-agent growth model, which exometabolite analysis and simulations suggested may be due to metabolite cross-feeding or inhibitory compound production. This indicates additional factors beyond inherent monoculture growth kinetics driving spatial interactions. Overall, the study demonstrates how microcolony growth experiments offer valuable insights into bacterial interactions, from local to community-level dynamics.
The Unseen Shift: How Partnership Long-term Care Insurance Influences Caregiving Among Older Adults
Authors: Zai Xianhua
Published: October 2024

Objectives

Although the partnership long-term care insurance (PLTC) program was designed to mitigate the low uptake of long-term care insurance (LTCI) and reduce Medicaid’s financial burden, research has predominantly focused on its direct impacts, leaving the effects on informal caregiving unexplored. This study aimed to investigate how the program alters the dynamics of family-provided care, leveraging nationally representative data to unveil the broader consequences of informal caregiving arrangements among older individuals.

Methods

Data for this study were sourced from the U.S. Health and Retirement Study (1992–2018) and linked with the timing of the PLTC program implementation across states. The analysis compared individuals exposed to the program with those who were not, employing 2-way-fixed-effects and dynamic models to assess its impact on LTCI coverage and reliance on informal caregiving.

Results

The program positively affected LTCI coverage, increasing insurance uptake among older individuals in the long run. Conversely, a significant negative effect was observed on the receipt of assistance from any helper, indicating a reduced reliance on informal care. This reduction extended specifically to family helpers and children’s assistance with activities of daily living. The analysis suggests that the program effectively reduced the necessity for informal caregiving across several domains.

Discussion

These findings highlight the program’s potential to reshape caregiving dynamics, suggesting the need for policies that balance promoting private insurance uptake with the implications for family caregiving roles. Policymakers should consider both the economic benefits and the social shifts induced by such programs in the long-term care landscape.
Survey on competition law developments in the sports sector—January 2022 to June 2024
Authors: Ianc Sînziana , Hömann Aurélien
Published: October 2024

The survey offers a comprehensive overview of the EU competition law and policy developments between January 2022 and June 2024, covering competition authorities and courts at both EU and national level.

Once considered exempt of the application of competition law due to its ‘specificity’, the sports industry and in particular the rules and sanctions imposed by sports governing bodies now face enhanced scrutiny under Articles 101 and 102 TFEU and the scope of the initial exemption is getting gradually more limited. The Court of Justice’s established Meca-Medina doctrine is being re-shaped, with questions of interpretation and the scope of application challenging competition authorities and courts. Competition law enforcement is strongly driven by private complaints and litigation and the case law of the Court of Justice of the EU. Requests for interim measures are growing in importance. Moreover, national competition authorities also keep themselves busy with sports matters, ranging from investment and reclassification rules to no-poach agreements, with the German authority at the forefront.
Super-resolution microscopy unveils the nanoscale organization and self-limiting clustering of CD47 in human erythrocytes
Authors: Yang Jianyu , Xing Fulin , Hu Fen , Hou Mengdi , Dong Hao , Cheng Jiayu , Li Wan , Yan Rui , Xu Jingjun , Xu Ke , Pan Leiting
Published: October 2024

The transmembrane protein CD47, an innate immune checkpoint protein, plays a pivotal role in preventing healthy erythrocytes from immune clearance. Our study utilized stochastic optical-reconstruction microscopy (STORM) and single-molecule analysis to investigate the distribution of CD47 on the human erythrocyte membrane. Contrary to previous findings in mouse erythrocytes, we discovered that CD47 exists in randomly distributed monomers rather than in clusters across the human erythrocyte membrane. Using 2nd antibody-induced crosslinking, we found that CD47 aggregates into stable clusters within minutes. By comparing these STORM results with those of the fully mobile protein CD59 and the cytoskeleton-bound membrane protein glycophorin C under similar conditions, as well as devising two-color STORM co-labeling and co-clustering experiments, we further quantitatively revealed an intermediate, self-limiting clustering behavior of CD47, elucidating its fractional (∼14%) attachment to the cytoskeleton. Moreover, we report reductions in both the amount of CD47 and its clustering capability in aged erythrocytes, providing new insight into erythrocyte senescence. Together, the combination of STORM and 2nd antibody-based crosslinking unveils the unique self-limiting clustering behavior of CD47 due to its fractional cytoskeleton attachment.
Outcomes Associated with Healthcare-Associated Respiratory Syncytial Virus in Children’s Hospitals
Authors: Saiman Lisa , Coffin Susan E , Kociolek Larry K , Zerr Danielle M , Milstone Aaron M , Aldrich Margaret L , Vargas Celibell Y , Zalot Morgan A , Reyna Megan E , Adler Amanda , Koontz Danielle , Egbert Emily R , Alrikaby Jassour , Alba Luis , Gollerkeri Sonia , Ruggieri Madelyn , Finelli Lyn , Choi Yoonyoung
Published: October 2024

To determine if healthcare-associated (HA)-respiratory syncytial virus (RSV) is associated with worse outcomes, this multicenter cohort study studied 26 children with HA-RSV and 78 matched non-HA-RSV patients of whom 58% and 55%, respectively, had ≥2 comorbidities. Overall, 39% of HA-RSV versus 18% of non-HA-RSV patients required respiratory support escalation (adjusted odds ratio (aOR) 5.1, CI95 1.4, 19.1).
Duration, Cost, and Escalation of Care Events for Physical Therapy Management of Low Back Pain in Service Members With Limb Loss
Authors: Gunterstockman Brittney M , Hendershot Brad D , Kakyomya Joseph , Patterson Charity G , Dearth Christopher L , Farrokhi Shawn
Published: October 2024

Introduction

Physical therapy (PT) is recommended as a primary treatment for low back pain (LBP), a common and impactful musculoskeletal condition after limb loss. The purpose of this brief report is to report the duration and cost of PT care, and subsequent escalation of care events, for LBP in service members with and without limb loss.

Materials and Methods

This was a retrospective cohort, descriptive study. Service members with and without limb loss (matched) who received PT for LBP at a military treatment facility from 2015 to 2017 were included. Duration of PT care, number of PT visits, and escalation of care events 1 year after PT were extracted from medical records. Escalation of care events was identified as epidural steroid injections, referrals to specialists (e.g., orthopedists, spine surgeons, and pain management), and LBP-related hospitalizations.

LBP-related PT encounters were queried; duration of care, number of visits, and cost of care were quantified. Escalation of care events, including opioid prescription, epidural steroid injections, specialty referrals, and hospitalizations, were identified up to 1 year after PT care.

Results

The average course of PT care for LBP was 12.9 more visits, 48.7 days longer, and $764.50 more expensive in service members with limb loss (n = 16) vs. those without limb loss (n = 48). Higher rates of opioid prescriptions and specialty referrals were observed in service members with limb loss.

Conclusions

This study suggests that service members with limb loss and LBP received higher quantities and longer durations of PT than those without limb loss, yielding a nearly 4 times higher cost of PT.
Mapping the Fetal Alcohol Spectrum Disorder Continuum of Care Across the Military Health System
Authors: Rivera Ilse , Lee Elizabeth H , Solomon Zoe , Koehlmoos Tracey P
Published: October 2024

Introduction

Although a leading cause of developmental disability in the United States, many individuals with fetal alcohol spectrum disorders (FASDs) do not receive a timely diagnosis, are misdiagnosed, or are never diagnosed. Prevention, diagnosis, and clinical management of FASD have not been previously studied in the U.S. Military Health System (MHS), where nearly 1 million of the nation’s children receive health care. To address this gap, we undertook an environmental scan of the clinical guidelines, services, programs, educational resources, and policies within the MHS pertaining to alcohol use (AU), AU disorder (AUD), prenatal alcohol exposure, and FASD.

Materials and Methods

From March to June 2023, we undertook an environmental scan of MHS clinical guidelines, services, programs, educational resources, and policies that address AU, AUD, prenatal alcohol exposure, and FASD.

Results

We identified multiple resources that attended to AU and AUD before and during pregnancy in the MHS. However, despite numerous resources for other neurodevelopmental disorders, we did not find any MHS-specific resources that address diagnosis and management of FASD.

Conclusions

Findings suggest opportunities to raise awareness, educate providers, and improve guidelines, policies, and practices in the MHS.
The ACCEL2 project: Simulating Lyman-α forest in large-volume hydrodynamical simulations
Authors: Chabanier Solène , Ravoux Corentin , Latrille Lucas , Sexton Jean , Armengaud Éric , Bautista Julian , Dumerchat Tyann , Lukić Zarija
Published: October 2024

Cosmological information is usually extracted from the Lyman-α (Lyα) forest correlations using only either large-scale information interpreted through linear theory or using small-scale information interpreted by means of expensive hydrodynamical simulations. A complete cosmological interpretation of the 3D correlations at all measurable scales is challenged by the need of more realistic models including the complex growth of non-linear small scales that can only be studied within large hydrodynamical simulations. Past work were often limited by the trade off between the simulated cosmological volume and the resolution of the low-density intergalactic medium from which the Lyαsignal originates. We conduct a suite of hydrodynamical simulations of the intergalactic medium, including one of the largest Lyαsimulations ever performed in terms of volume (640  h−1 Mpc), alongside simulations in smaller volumes with resolutions up to 25  h−1 kpc, which will be further improved to show resolution convergence in future studies. We compare the 3D Lyα power spectra (P3D, α) predicted by those simulations to different non-linear models. The inferred Lyαbias and redshift space distortion (RSD) parameters, bα and βα are in remarkable agreement with those measured in SDSS and DESI data. We find that, contrary to intuition, the convergence of large-scale modes of the P3D, α, which determines βα, is primarily influenced by the resolution of the simulation box through mode coupling, rather than the box size itself. Finally, we study the BAO signal encoded in P3D, α. For the first time with a hydrodynamical simulation, we clearly detect the BAO signal, however we only marginally detect its damping, associated with the non-linear growth of the structures.
Optical and X-ray studies of the Be/X-ray binary IGR J06074+2205
Authors: Chhotaray Birendra , Naik Sachindra , Jaisawal Gaurava K , Ahuja Goldy
Published: October 2024

We present the results obtained from X-ray and optical analysis of the Be/X-ray binary IGR J06074+2205, focusing on before, during, and after the X-ray outbursts in 2023 October and December. The properties of the neutron star in the binary are investigated using NICER and NuSTAR observations during the X-ray outbursts. The pulse profiles across a broad energy range, are found to be strongly dependent on luminosity and energy, revealing the complex nature of the emitting region. An absorbed power law can describe each NICER spectrum in the 1–7 keV band. The 3–79 keV NuSTAR spectrum can be well described by a negative and positive power law with an exponential cut-off model. Utilizing the MAXI/GSC long-term light curve, we estimate the probable orbital period to be 80 or 80/n (n = 2, 3, 4) d. We investigate the evolution of the circumstellar disc around the Be star by using optical spectroscopic observations of the system between 2022 and 2024. We observe variable H $\alpha$ and Fe ii emission lines with an increase in equivalent width, indicating the presence of a dynamic circumstellar disc. A distinct variation in the V/R value for H $\alpha$ and Fe ii lines is also observed. The appearance of additional emission lines, such as He i (5875.72 Å), He i (6678 Å), and He i (7065 Å), during the post-outburst observation in 2024 February suggests the growing of a larger or denser circumstellar disc. The disc continues to grow without any noticeable mass-loss, even during the 2023 X-ray outbursts, which may lead to a future giant X-ray outburst.
Piloting a Collaborative Psychosocial Intervention for Hospitalized Infants and Their Caregivers
Authors: Kim Dana , Perrotti Morgan , Keller Briana , Boles Jessika
Published: October 2024

The diagnosis of cancer or cardiac abnormalities in infants is often associated with prolonged hospitalization, which can negatively impact caregiver-child bonding due to separation, medical stressors, and changes in the caregiving role. The purpose of this study was to pilot an interdisciplinary psychosocial intervention including songwriting, an expressive journal and activity book, and a bonding assessment. Interventions were facilitated by a board-certified music therapist and Certified Child Life Specialist. A total of 15 families completed the pretest, four intervention sessions, and post intervention test. Quantitative data suggest increased caregiver–child bonding and increased caregiver confidence. Caregivers reported high levels of satisfaction with the intervention in qualitative responses. In summary, results from this pilot study lay the groundwork for a future larger-scale evaluation.
Design and conduct of theranostic trials in neuro-oncology: Challenges and opportunities
Authors: Wen Patrick Y , Preusser Matthias , Albert Nathalie L
Published: October 2024

Theranostics is a new treatment modality integrating molecular imaging with targeted radionuclide therapy. Theranostic agents have received regulatory approval for some systemic cancers and have therapeutic potential in neuro-oncology. As clinical trials are developed to evaluate the efficacy of theranostic agents in brain tumors, specific considerations will have to be considered, taking into account lessons learned from previous studies examining other treatment modalities in neuro-oncology. These include the need for molecular imaging or surgical window-of-opportunity studies to confirm adequate passage across the blood-brain barrier, optimize eligibility criteria, and selection of the most appropriate response criteria and endpoints to address issues such as pseudoprogression. This review will discuss some of the issues that should be considered when designing clinical trials for theranostic agents.
Betel Quid Use and Tuberculosis Transmission: A Neglected Focus Area for Tuberculosis Control in Low- and Middle-Income Countries
Authors: Manghani Priyanka , Prasad Narayana , Khatri Nishtha , Paulino-Ramirez Robert , Gokhale Shishir , Islam K M Monirul , Majumdar Piyusha , Hoang Tran , Denny Hanifa
Published: October 2024

Habitual betel quid consumption and spitting contribute to tuberculosis (TB) transmission due to direct exposure to pathogens, immunosuppression, and social contact. Despite betel quid being classified as a group 1 human carcinogen and a high prevalence of betel quid consumption in patients with TB, there exists a knowledge gap in the relationship between quid use and TB, which presents as a neglected opportunity to address the global burden of TB in low- and middle-income countries. Understanding such a knowledge gap is crucial when taking measures at various levels, including research prioritization, behavior change communication, and legislation to address the availability and access of quid products, coupled with community-based interventional strategies. This article thus presents empirical evidence on quid use and its effects on TB spread and identifies feasible, applicable changes required at various levels to curtail the spread of TB among betel quid users.
The Psychosis MRI Shared Data Resource (Psy-ShareD)
Authors: Allen Paul , Zurita Mariana , Easmin Rubaida , Bucci Sara , Kempton Matthew J , Rogers Jack , Mehta Urvakhsh M , McGuire Philip K , Lawrie Stephen M , Whalley Heather , Gadelha Ary , Murray Graham K , Garrison Jane R , Frangou Sophia , Upthegrove Rachel , Evans Simon L , Kumari Veena ,   the Psy-ShareD Partnership
Published: October 2024

A key line of research in the field of schizophrenia and other psychotic disorders has been to investigate neuroanatomical markers, relative to healthy control groups. In recent decades, a large number of structural Magnetic Resonance Imaging (MRI) studies have been funded and undertaken, but their small sample sizes and heterogenous methods have led to inconsistencies across findings. To tackle this, efforts have been made to combine datasets across studies and sites. While notable recent multi-centre initiatives and both meta- and mega-analytical studies have progressed the field, efforts have generally been restricted to MRI scans in one or two illness stages which are not always representative of the diversity of patients who experience psychosis. Furthermore, access to these datasets is usually restricted to consortia members, often from high income countries. The Psychosis MRI Shared Data Resource (Psy-ShareD) is a new open access structural MRI data sharing partnership that will host pre-existing structural T1-weighted MRI data collected across multiple sites worldwide, including the Global South. MRI T1 data included in Psy-ShareD will be available in image and feature level formats, having been harmonised using state-of-the-art approaches. All T1 data will be linked to demographic and illness-related (diagnosis, symptoms, medication status) measures and in a number of datasets IQ and cognitive data, and medication history will also be available. Psy-ShareD will be free to access for all researchers. Comprehensive data catalogues, support and training resources will be available to facilitate use by early career researchers and build capacity in the field. We are actively seeking new collaborators to contribute further T1 data. Collaborators will benefit in terms of authorships, as all publications arising from Psy-ShareD will include data contributors as authors.
Classifying Alzheimer’s Disease and Dementia Patients Using Non-invasive EEG Biomarkers
Authors: Hasan Wali , Khan Sheraz , Sohrabpour Abbas
Published: October 2024

Researchers are currently exploring methods to detect early-stage Alzheimer’s Disease (AD) and other forms of dementia such as frontotemporal dementia (FTD), especially through non-invasive biomarkers, i.e., measurements that reflect biological processes. This paper utilizes a dataset of electroencephalogram (EEG) recordings, a noninvasive biomarker, to distinguish individuals with Alzheimer’s or frontotemporal dementia from healthy control subjects. This paper explores the usage of machine learning methods to more accurately predict the cognitive status of patients from these non-invasive EEG Biomarkers. We found that AD patients could be easily separated from healthy controls based on their EEG features using simple linear classifiers with an accuracy of 77% and the AD, FTD, and healthy controls with an accuracy of around 57% (randomly selecting the right class is about one third or 33% in the 3-way classification).
A Deep Learning Pipeline for Analysis of the 3D Morphology of the Cerebral Small Perforating Arteries from Time-of-Flight 7 Tesla MRI
Authors: Li Rui , Chatterjee Soumick , Jiaerken Yeerfan , Radhakrishna Chethan , Benjamin Philip , Nannoni Stefania , Tozer Daniel J. , Markus Hugh S. , Rodgers Christopher T.
Published: October 2024

The lenticulostriate arteries (LSA) supply important subcortical structures in the brain and are affected in cerebral small vessel disease (CSVD), leading to changes in their morphology. 7 Tesla Time-of-Flight magnetic resonance angiography (7T-TOF-MRA) now allows their visualisation in humans, but current analysis of LSA morphology largely relies on manual tracing on 2D coronal maximum-intensity-projection (MIP) images, which discards significant information from the third spatial dimension. We aimed to develop a semi-automatic pipeline for quantifying the 3D morphology of LSAs from 7T-TOF-MRA in patients with CSVD.

We used contrast-enhanced 7T-TOF-MRA data from 15 subjects enrolled in a local CSVD study. Our pipeline consists of two main stages: vessel segmentation and LSA quantification. For segmentation, we fine-tuned a state-of-the-art deep learning model, “DS6”, for vessel segmentation and compared its performance against a classical Frangi filter-based pipeline, Multi-Scale Frangi Diffusive Filter (MSFDF). Both methods were evaluated against manually labelled ground-truth masks in LSA regions. In the LSA quantification stage, the user defines a region-of-interest around LSAs and checks the segmentation. Based on this, the LSA centrelines are extracted, and branch counts, length, tortuosity, and curvature are computed. Additionally, we conducted the traditional LSA analysis using 2D coronal MIPs, and we evaluated the correlation between the results from the 2D and 3D analyses.

For vessel segmentation, the fine-tuned DS6 model achieved a mean Dice similarity coefficient (DSC) of 0.814±0.029 during testing, outperforming MSFDF on DSC, sensitivity, and balanced average Hausdorff distance in terms of both mean value and stability. Visual inspection confirmed that DS6 was more sensitive in detecting LSA branches with weak signals. On average, the 15 subjects had 5.9±1.6 LSA stems and 28.7±9.9 branches. The mean length of an LSA branch was 42.5±5.7mm, and mean tortuosity was 1.9±0.2. Finally, the branch counts from 2D and 3D analyses correlated well (ρ=0.741,p=2.816e-06), whereas the stem count, branch length and tortuosity measurements were significantly different, showing the insufficiency of MIP analysis (stem:ρ=0.230,p=2.207e-01; length:r=0.565,p=1.153e-03; tortuosity:r=0.400,p=2.847e-02).

We have developed an open-source semi-automatic pipeline using deep learning for evaluating the 3D morphology of LSAs in CSVD patients from 7T-TOF-MRA. We show that analysing LSA morphology in 3D reveals previously inaccessible aspects of morphology. Our pipeline offers a valuable tool for clinical research studies to characterise the 3D morphology of LSAs in CSVD.
A multi-omics census reveals obesity-associated microRNAmiR-let-7as novel instigator of adipose mitochondrial dysfunction and of intergenerational metabolic decline
Authors: Huang Chien , Park Joo Hyun , Altintas Ali , Stanic Natasa , Batarlar Hande Topel , Malmros Rocio Valdebenito , Havelund Jesper , Færgeman Nils Joakim , Marcher Larsen Bjørk Ditlev , Szczepanowska Karolina , Lackmann Jan-Wilm , Trifunovic Aleksandra , Hejbøl Eva Kildall , Detlefsen Sönke , Jepsen Ida Engberg , Kolstrup Stefanie Hansborg , Laguna-Barraza Ricardo , Gonzalez Javier-Martin , Khodosevich Konstantin , Barrès Romain , Kornfeld Jan-Wilhelm
Published: October 2024

We here describe that obesity and weight loss in male mice causes reversible abnormalities in glucose and lipid metabolism, serum metabolomes and reduced expression of genes controlling mitochondrial energy dissipation in white adipose tissue. When mating obese male mice with lean females, we observed concordant reductions in adipose mitochondrial gene expression and translation in offspring (F1) that resemble those observed in the paternal (F0) generation. When mapping miRNA differential expression across somatic organs and the germline (i.e., liver, adipose tissue, sperm) and generations, we found that obesity and weight loss reversible affected miRNA levels, and thatmiR-let7isoforms were induced in adipose tissues of obese F0and F1adipose tissue and sperm of obese F0mice. OverexpressingmiR-let-7in adipocytes silenced DICER1, a cellular rheostat required for adipose tissue adaptation in obesity as evidenced by deficiencies in mitochondrial function following DICER1 loss in adipocytes. Delivery ofmiR-let-7into lean oocytes elicited glucose intolerance and impediments in adipose mitochondrial gene expression in mice sired from miRNA-injected embryos, thus phenocopying important aspects of obesity heredity. When performing single-cell RNA-Seq of miRNA-injected embryos,miR-let7impaired mitochondrial gene expression, suggesting altered energy metabolism following alterations in zygotic miRNAs. When studying miRNA alterations in human semen, lifestyle-induced weight loss downregulatedMIR-LET-7in human subjects, suggesting similar roles for humanMIR-LET-7in gametic epigenomes and embryogenesis.
Modeling the dynamics of EMT reveals genes associated with pan-cancer intermediate states and plasticity
Authors: McDermott MeiLu , Mehta Riddhee , Roussos Torres Evanthia T. , MacLean Adam L.
Published: October 2024

Epithelial-mesenchymal transition (EMT) is a developmental cell state transition co-opted by cancer to drive metastasis and resistance. Stable EMT intermediate states play a particularly important role in cell state plasticity and confer metastatic potential. To explore the dynamics of EMT and identify marker genes of highly metastatic intermediate cells, we analyzed EMT across multiple tumor types and stimuli via mathematical modeling with single-cell RNA-sequencing (scRNA-seq) data. We identified pan-cancer genes consistently expressed or upregulated in EMT intermediate states, most of which were not previously annotated as markers of EMT. Using Bayesian parameter inference, we fit a simple mathematical model to scRNA-seq data, revealing tumor-specific transition rates. This mathematical model offers a framework to quantify EMT progression. A consensus analysis of differential intermediate expression, regulation, and model-derived dynamics identified marker genes associated with persistence of the intermediate EMT state.SFNandNRG1emerged as genes with the strongest evidence for their role influencing intermediate EMT dynamics. Through analysis of an independent cell line, we verified the role ofSFNas a marker intermediate EMT transition. Modeling and inference of genes associated with EMT dynamics offer means to find biomarkers and to identify therapeutic approaches to harness or reverse tumor-promoting cell state transitions driven by EMT.
Conflict neurons in cingulate cortex of macaques
Authors: Corrigan Benjamin W. , Errington Steven P. , Sajad Amirsaman , Schall Jeffrey D.
Published: October 2024

Conflict—the magnitude of co-activation of mutually incompatible response processes—was proposed to explain how cognitive control is invoked (Botvinick et al. 2001) and continues to engage debate (Becker et al. 2024). Original observations consistent with this construct emphasized the primary contribution of cingulate cortex (CC) based on human functional imaging (Botvinick et al., 1999; Carter et al., 2000) and electroencephalogram (Yeung, Botvinick, & Cohen, 2004). In countermanding tasks conflict arises through co-activation of competing GO and STOP processes (Boucher et al. 2007; Schall & Boucher 2007; Sajad et al. 2022). Single neuron activity representing conflict has been described in the supplementary motor cortex of human epilepsy patients (Fu et al., 2019; Sheth et al., 2012) and of macaque monkeys (Sajad, Errington, & Schall, 2022; Stuphorn, Taylor, & Schall, 2000) and in human cingulate cortex (Fu et al., 2019; Sheth et al., 2012) but not in monkey cingulate cortex (Ebitz & Platt, 2015; Ito, Stuphorn, Brown, & Schall, 2003; Nakamura, Roesch, & Olson, 2005). This lack of homology generated debate about the utility of macaques for investigation of cognitive control (Cole et al. 2009; Schall & Emeric 2010). With higher-resolution, less-biased samples, we re-examined the presence of a conflict signal in cingulate cortex of monkeys. Neurons modulating specifically when response conflict was maximal were found in cingulate cortex— more commonly in the dorsal than the ventral bank. However, such neurons were much more common in supplementary motor cortex. These data confirm the presence of a conflict signal in medial frontal cortex and demonstrate that it can be found in a small fraction of neurons in cingulate cortex. Further research is needed to determine if the weak response conflict signal in cingulate cortex is sufficient or negligible.
RUVBL1 and RUVBL2 are druggable MYCN regulators in neuroblastoma
Authors: Siaw Joachim Tetteh , Claeys Arne , Lai Wei-Yun , Borenäs Marcus , Hilgert Elien , Bekaert Sarah-Lee , Sanders Ellen , Kaya Irem , Dorpe Jo Van , Speleman Frank , Durinck Kaat , Hallberg Bengt , Palmer Ruth H. , Van den Eynden Jimmy
Published: October 2024

High-risk neuroblastoma is characterized byMYCNamplification and highMYCNorMYCgene expression. These patients have a poor prognosis and there is an urgent need for more effective drugs. While strategies to develop inhibitors that directly target the MYC proteins have remained largely unsuccessful, recent preclinical studies have identified ATR, a key protein of the DNA damage response, as a promising alternative therapeutic target. Here we identified a strong RUVBL1 and RUVBL2 signature in transcriptomics data derived from differentMYCN-driven mice tumors treated with ATR inhibitors. The RUVBL proteins form a complex with ATPase activity that has broad cellular functions and we demonstrate that pharmacological inhibition of this protein complex results in a strong reduction of MYC signaling, cell cycle arrest, DNA damage and apoptosis. We confirmed the association withMYCNand identified theRUVBLgenes as independent prognosticators in human primary neuroblastoma data.
Enhanced Pooling for Weakly Supervised Gigapixel WSI Training Improves Classification and Lesion Localization
Authors: Chen Chi-Chung , Yeh Yi-Chen , Lin Matthew MY , Yeh Chao-Yuan
Published: October 2024

A robust artificial intelligence-assisted workflow for tumor assessment in pathology requires not only accurate classification but also precise lesion localization. While current weakly supervised learning methods significantly reduce the need for extensive annotations and leverage large quantities of annotation-free whole-slide images (WSIs) to enhance classification robustness, they often fall short in segmentation accuracy. We attribute this limitation to the optimization goals in classification, which tend to focus solely on the most representative features—an approach that is particularly inefficient for WSIs with gigapixel resolution. To address this challenge, we introduce a novel approach based on streaming convolution, an end-to-end method for WSI training. Our contributions include the Rectified LogSumExp pooling method and adaptive pseudo annotation generation for self-training, both designed to encourage models to learn from sub-representative features. Using only slide-level annotations from the CAMELYON16 dataset, our method achieves a significant improvement in metastasis localization, with a recall from 49.85% to 71.33% at a precision of 90%. This conclusion also holds true for a 3,024-LN dataset used in the assessment of lung cancer lymph node metastasis with a recall improved from 28.31% to 50.82%.
Growth of Stress-Responsive Bacteria in 3D Colonies under Confining Pressure
Authors: Rahbar Samaneh , Mohammad-Rafiee Farshid , Santen Ludger , Shaebani Reza
Published: October 2024

We numerically study three-dimensional colonies of nonmotile stress-responsive bacteria growing under confining isotropic pressure in a nutrient-rich environment. We develop a novel simulation method to demonstrate how imposing an external pressure leads to a denser aggregate and strengthens the mechanical interactions between bacteria. Unlike rigid confinements that prevent bacterial growth, confining pressure acts as a soft constraint and allows colony expansion with a nearly linear long-term population growth and colony size. Enhancing the mechanosensitivity reduces instantaneous bacterial growth rates and the overall colony size, though its impact is modest compared to pressure for our studied set of biologically relevant parameter values. The doubling time grows exponentially at low mechanosensitivity or pressure in our bacterial growth model. We provide an analytical estimate of the doubling time and develop a population dynamics model consistent with our simulations. Our findings align with previous experimental results forE. colicolonies under pressure. Understanding the growth dynamics of stress-responsive bacteria under mechanical stresses provides insight into their adaptive response to varying environmental conditions.