bluuebunny/crossref_metadata_2025 huggingface dataset:
The feasibility of targeted axillary dissection for breast cancer axillary surgery de-escalation after neoadjuvant therapy: a prospective cohort study
Authors: Fan Qing-Da , Bi Zhao , Gong Li-Guo , Chen Peng , Cong Bin-Bin , Duan Bao-wei , Chen Yu-Guang , Qiu Peng-Fei , Wang Yong-Sheng
Published: August 2024

Purpose:

Targeted axillary dissection (TAD) after neoadjuvant therapy (NAT) includes the removal of both marked and sentinel lymph nodes (SLNs). The aim was to investigate the optimization of TAD localization techniques after NAT in breast cancer patients.

Methods:

From November 2020 to 2022, the authors prospectively enrolled 107 lymph node-positive breast cancer patients at Shandong Cancer Hospital, all of them received complete cycles of NAT. Before treatment, patients were randomly divided into three groups: group A, marked node with clip (n=34); group B, marked node with 125I seed (n=32); and group C, marked node with both a clip and 125I seed (n=41). Dual tracers were used to search for SLNs after NAT. The primary endpoint was the detection rate of marked nodes and false-negative rate (FNR).

Results:

The detection rates using the TAD localization technique were 82.6% (28/34), 100% (32/32), and 100% (41/41) for groups A, B, and C, respectively (P>0.05). The FNR rates were 15.8%, 5.9%, and 5.6% among groups A, B, and C, respectively (P>0.05). The FNR rates in cN1 patients were 5.1%, 2.7%, and 2.6%, among these three groups, respectively (P>0.05). The change in distance between 125I seeds and clips in axillary lymph nodes was <3 mm. The FNR rates of TAD guided by dye tracers, radiolabeled tracers, and dual tracers were 5.4%, 5.2%, and 3.4%, respectively (P>0.05). The negative predictive values were 93.0%, 93.0%, and 95.2%, respectively (P>0.05).

Conclusion:

Considering the inexpensive and high detection rate of 125I seeds, it is recommended to use 125I seeds for localizing metastatic nodes in neoadjuvant setting. The TAD guided by dye tracer is also a feasible option for axillary de-escalation surgery after NAT in countries or regions without access to radiolabeled colloid.
Reappraisal of tacrolimus levels after liver transplant for HCC: A multicenter study toward personalized immunosuppression regimen
Authors: Kojima Lisa , Akabane Miho , Murray Matthew , Fruscione Michael , Soma Daiki , Snyder Abigail , McVey John , Firl Daniel J. , Hernandez-Alejandro Roberto , Kubal Chandrashekhar A. , Markmann James F. , Aucejo Federico N. , Tomiyama Koji , Kimura Shoko , Sasaki Kazunari
Published: August 2024

Post-liver transplant (LT) immunosuppression is necessary to prevent rejection; however, a major consequence of this is tumor recurrence. Although recurrence is a concern after LT for patients with HCC, the oncologically optimal tacrolimus (FK) regimen is still unknown. This retrospective study included 1406 patients with HCC who underwent LT (2002–2019) at 4 US institutions using variable post-LT immunosuppression regimens. Receiver operating characteristic analyses were performed to investigate the influences of post-LT time-weighted average FK (TWA-FK) level on HCC recurrence. A competing risk analysis was employed to evaluate the prognostic influence of TWA-FK while adjusting for patient and tumor characteristics. The AUC for TWA-FK was greatest at 2 weeks (0.68), followed by 1 week (0.64) after LT. Importantly, this was consistently observed across the institutions despite immunosuppression regimen variability. In addition, the TWA-FK at 2 weeks was not associated with rejection within 6 months of LT. A competing risk regression analysis showed that TWA-FK at 2 weeks after LT is significantly associated with recurrence (HR: 1.31, 95% CI: 1.21–1.41, p < 0.001). The TWA-FK effect on recurrence varied depending on the exposure level and the individual’s risk of recurrence, including vascular invasion and tumor morphology. Although previous studies have explored the influence of FK levels at 1–3 months after LT on HCC recurrence, this current study suggests that earlier time points and exposure levels must be evaluated. Each patient’s oncological risk must also be considered in developing an individualized immunosuppression regimen.
Electrical stimulation of the vestibular nerve: evaluating effects and potential starting points for optimization in vestibular implants
Authors: ten Hoor Marieke , van de Berg Raymond , Pérez Fornos Angélica , Stultiens Joost Johannes Antonius
Published: August 2024

Purpose of review

Oscillopsia and unsteadiness are common and highly debilitating symptoms in individuals with bilateral vestibulopathy. A lack of adequate treatment options encouraged the investigation of vestibular implants, which aim to restore vestibular function with motion-modulated electrical stimulation. This review aims to outline the ocular and postural responses that can be evoked with electrical prosthetic stimulation of the semicircular canals and discuss potential approaches to further optimize evoked responses. Particular focus is given to the stimulation paradigm.

Recent findings

Feasibility studies in animals paved the way for vestibular implantation in human patients with bilateral vestibulopathy. Recent human trials demonstrated prosthetic electrical stimulation to partially restore vestibular reflexes, enhance dynamic visual acuity, and generate controlled postural responses. To further optimize prosthetic performance, studies predominantly targeted eye responses elicited by the vestibulo-ocular reflex, aiming to minimize misalignments and asymmetries while maximizing the response. Changes of stimulation parameters are shown to hold promise to increase prosthetic efficacy, together with surgical refinements and neuroplastic effects.

Optimization of the stimulation paradigm, in combination with a more precise electrode placement, holds great potential to enhance the clinical benefit of vestibular implants.
Updates on the use of neuromodulation in geriatric patients
Authors: Kennedy Lauren N. , Griebling Tomas L. , Souders Colby P.
Published: August 2024

Purpose of review

In light of the updated AUA/SUFU guidelines on the diagnosis and treatment of overactive bladder (OAB), increased utilization of advanced therapies is expected in the coming years. The primary aim of this review is to summarize existing outcome and safety data on the use of neuromodulation in geriatric patients, as well as highlight recent advances in neuromodulation that may be particularly advantageous in the geriatric population.

Recent findings

There are mixed data demonstrating efficacy of sacral neuromodulation by decade of life, with older individuals most often demonstrating lower odds of progressing to stage 2 implantation. However, a large majority of patients still undergo stage 2 implantation with no significant increase in complications reported when compared to younger cohorts. Neuromodulation is broadening to have wider indications outside of OAB, which may be particularly beneficial in the elderly population (fecal incontinence, nonobstructive urinary retention, and constipation). Posterior tibial nerve stimulation remains a well tolerated and efficacious treatment for OAB, with new FDA-approved implantable devices joining the commercial market, which may expand access for elderly populations.

The data are encouraging and support the use of neuromodulation in geriatric patients.
Impact of Long-term Storage in 4% Formaldehyde on Immunophenotypic Markers in Glutaraldehyde-treated Bovine Pericardium
Authors: Gewehr Douglas M. , Carvalho Pedro E.P. , Izar Fernanda P. , Haddad Alexandre G. , Falkenbach Tenius Victor D. , Giovanini Allan F. , Kubrusly Luiz F.
Published: August 2024

Bovine pericardium (BP) is widely used as a biomaterial for tissue engineering. Glutaraldehyde and formaldehyde are commonly employed in the reticulation processes to enhance the material’s resistance and preservation. In this study, we assessed the impact of long-term storage in 4% formaldehyde on the quantitative expression of immunophenotypic markers in glutaraldehyde-treated BP. Histologic and immunohistochemical analyses were performed on 2 BP patches, manufactured in 2009 and 2020, respectively. Braile Biomédica provided the BP patches. Sections of BP were stained with H&E, Weigert, and picrosirius red, followed by immunolabeling for vimentin, laminin 5, collagen I, and collagen IV using a standardized protocol. Microscopic images were captured using light and polarized microscopy, and the area of the antibody signal was quantified using Image J Software. Histologic analysis showed no autolysis or significant changes in the patches. Immunohistochemical analysis revealed a diffuse distribution of collagen I and collagen IV throughout the connective tissue of the patches. The 2020 specimen exhibited higher expression levels of collagen I (21.36%) and collagen IV (24.67%) compared with the 2009 specimen (collagen I: 15.87%; collagen IV: 12.02%). Laminin did not show reactivity in either specimen. Notably, vimentin immunopositivity differed significantly between the patches, with a larger area of expression observed in the 2020 patch (54%) compared with the 2009 patch (13%). In summary, there were no substantial differences in immunophenotypic expression between the 2009 and 2020 BP patches, except for the higher vimentin expression in the 2020 BP patch.
Clinicopathological and Molecular Characteristics of Rare EBV-associated Diffuse Large B-cell Lymphoma With IRF4 Rearrangement
Authors: Zhang Yuxiu , Li Anqi , Li Yimin , Ouyang Binshen , Wang Xuan , Zhang Lei , Xu Haimin , Gu Yijin , Lu Xinyuan , Dong Lei , Yi Hongmei , Wang Chaofu
Published: August 2024

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a rare form of aggressive B-cell lymphoma with limited molecular information reported regarding interferon regulatory factor 4 (IRF4) status. Here, we presented 3 EBV-positive DLBCL cases with IRF4 rearrangement (EBV+DLBCL-IRF4-R) verified by fluorescence in situ hybridization (FISH). Three patients, including 1 male and 2 females (median age: 64 y; range: 45 to 68 y), had normal immune function. During a median follow-up of 12 months (range: 0 to 24 mo), 2 patients succumbed to the disease, and 1 patient achieved complete response. Three tumors were present in the mediastinum, stomach, and thalamus, respectively. All three tumors exhibited DLBCL morphology and were identified as the non-germinal center B-cell subtype, with EBV-encoded small RNA positivity ranging from 70% to 80%. RNA sequencing was able to identify RHOH and IGH as fusion partners of IRF4 in two cases. No MYC and BCL2 rearrangements were detected in 3 cases by FISH and RNA sequencing. Next-generation sequencing revealed a low mutation burden, and only IRF4 was recurrently mutated in two EBV+DLBCL-IRF4-R cases. Using the LymphGen 2.0 classifier, 1 case was classified as the MCD (including MYD88
L265P and CD79B mutations) subtype. We report rare EBV+DLBCL-IRF4-R that may enhance our understanding of the diverse spectrum of large B-cell lymphoma.
Association of Local and Distant Organ Metastases With MELF Pattern in Endometrial Cancer
Authors: Gülseren Varol , Şen Ertuğrul , Dolanbay Mehmet , Çağli Fulya , Topaloğlu Nahit , Öztürk Figen , Özçelik Bülent , Serin Serdar , Güngördük Kemal
Published: August 2024

Several types of myometrial invasion in endometrioid-type endometrial adenocarcinoma (EEC) have been identified: adenomyosis-like changes; adenoma malignum; broad front, single-cell/cell clusters; and the microcystic elongated and fragmented (MELF) pattern. This study aims to investigate the effect of the MELF pattern on recurrence type and survival rate among patients with EEC. We retrospectively reviewed the records of patients diagnosed with EEC over a 10-year period from January 2011 to January 2021. Among 108 patients with EEC, 54 had recurrence (study group), and 54 did not (control group). The MELF pattern was more common in the group with recurrence than in the group without recurrence (40.7% vs. 14.8%; P=0.002). The MELF pattern was observed in 60.0% of patients with local recurrence and 29.4% of patients with extrapelvic or distant organ metastases (P=0.027). Evaluation of 5-year disease-free survival (P=0.003) and overall survival (P=0.001) rates showed that MELF positivity was associated with decreased survival. Among patients with grade I-II EEC lacking uterine-localized myometrial invasion, the MELF pattern was less common in the nonrelapsed group than in the local relapse group (10.0% vs. 60.0%; P<0.001). The MELF pattern (odds ratio=19.4, 95% CI=1.2–31.2) was a significant independent negative predictor for local recurrence. The MELF pattern was more common in patients with recurrence, especially local recurrence. This finding suggests that the MELF pattern primarily impacts direct local invasion rather than hematogenous or lymphatic spread.
Radiomics Analysis for the Identification of Invasive Pulmonary Subsolid Nodules From Longitudinal Presurgical CT Scans
Authors: Singh Apurva , Roshkovan Leonid , Horng Hannah , Chen Andrew , Katz Sharyn I. , Thompson Jeffrey C. , Kontos Despina
Published: August 2024

Purpose:

Effective identification of malignant part-solid lung nodules is crucial to eliminate risks due to therapeutic intervention or lack thereof. We aimed to develop delta radiomics and volumetric signatures, characterize changes in nodule properties over three presurgical time points, and assess the accuracy of nodule invasiveness identification when combined with immediate presurgical time point radiomics signature and clinical biomarkers.

Materials and Methods:

Cohort included 156 part-solid lung nodules with immediate presurgical CT scans and a subset of 122 nodules with scans at 3 presurgical time points. Region of interest segmentation was performed using ITK-SNAP, and feature extraction using CaPTk. Image parameter heterogeneity was mitigated at each time point using nested ComBat harmonization. For 122 nodules, delta radiomics features (ΔRAB= (RB-RA)/RA) and delta volumes (ΔVAB= (VB-VA)/VA) were computed between the time points. Principal Component Analysis was performed to construct immediate presurgical radiomics (Rs1) and delta radiomics signatures (ΔRs31+ ΔRs21+ ΔRs32). Identification of nodule pathology was performed using logistic regression on delta radiomics and immediate presurgical time point signatures, delta volumes (ΔV31+ ΔV21+ ΔV32), and clinical variable (smoking status, BMI) models (train test split (2:1)).

Results:

In delta radiomics analysis (n= 122 nodules), the best-performing model combined immediate pre-surgical time point and delta radiomics signatures, delta volumes, and clinical factors (classification accuracy [AUC]): (77.5% [0.73]) (train); (71.6% [0.69]) (test).

Conclusions:

Delta radiomics and volumes can detect changes in nodule properties over time, which are predictive of nodule invasiveness. These tools could improve conventional radiologic assessment, allow for earlier intervention for aggressive nodules, and decrease unnecessary intervention-related morbidity.
Canagliflozin Mitigates Acute Kidney Injury Secondary to Resuscitative Endovascular Balloon Occlusion of the Aorta in a Porcine Model of Hemorrhagic Shock
Authors: Tallowin Simon , Abel Biebele , Mysore Brinda , Mares John , Anderson Joseph A. , Propper Brandon W. , Stewart Ian J. , Burmeister David M.
Published: August 2024

Objective:

We investigated the potential of acute canagliflozin administration to mitigate acute kidney injury (AKI) and attenuate deleterious pro-inflammatory cytokine release in a clinically relevant swine model of severe renal ischemia reperfusion injury (IRI) induced by hemorrhage and aortic occlusion.

Background:

Long-term canagliflozin use attenuates renal function decline and reduces AKI in diabetes mellitus and heart failure patients. Whilst several reports indicate prophylactic SGLT2 inhibition prevents AKI in IRI, the efficacy of acute administration on IRI and inflammation is not known.

Methods:

Female swine (n=16) underwent controlled hemorrhage of 25% blood volume, followed by 90 min of aortic occlusion at the level of the renal ostia (via Resuscitative Endovascular Balloon Occlusion of the Aorta). A single 300 mg dose of oral canagliflozin or vehicle (saline) was delivered 5 mins into aortic occlusion. Hemodynamic monitoring, markers of renal function (serum creatinine, blood urea nitrogen, proteinuria and urinary neutrophil gelatinase-associated lipocalin) and serum cytokine concentrations (including interleukins: IL-1RA, IL-6, IL-8, IL-10, IL-18; and Tumor necrosis factor alpha) were analyzed after IRI, and during a 6h critical care phase.

Results:

Compared to controls, animals receiving canagliflozin had less severe AKI, improved creatinine clearance, reduced proteinuria, and significantly lower tubular damage as evidenced by histopathology and urinary NGAL. Furthermore, the pro-inflammatory cytokine IL-6 was markedly attenuated without reduction in anti-inflammatory cytokines (IL-1RA and IL-10).

Conclusions:

A single dose of canagliflozin administered shortly into ischemic insult mitigates AKI and attenuates harmful pro-inflammatory cytokine release following trauma or surgery. These findings suggest a potential novel therapeutic role for canagliflozin in mitigating the effects of renal IRI worthy of further investigation.
A Computer Vision Algorithm to Predict Superior Mesenteric Artery Margin Status for Patients with Pancreatic Ductal Adenocarcinoma
Authors: Wang Jane , Ashraf Ganjouei Amir , Romero-Hernandez Fernanda , Foroutani Laleh , Bahceci Dorukhan , Deranteriassian Aletta , Casey Megan , Li Po-Yi , Houshmand Sina , Behr Spencer , Jamshidi Neema , Majumdar Sharmila , Donahue Timothy , Kim Grace E. , Wang Zhen Jane , Thornblade Lucas W. , Adam Mohamed , Alseidi Adnan
Published: August 2024

Objective:

To evaluate the feasibility of developing a computer vision algorithm that uses preoperative computed tomography (CT) scans to predict superior mesenteric artery (SMA) margin status in patients undergoing Whipple for pancreatic ductal adenocarcinoma (PDAC), and to compare algorithm performance to that of expert abdominal radiologists and surgical oncologists.

Summary Background Data:

Complete surgical resection is the only chance to achieve a cure for PDAC; however, current modalities to predict vascular invasion have limited accuracy.

Methods:

Adult patients with PDAC who underwent Whipple and had preoperative contrast-enhanced CT scans were included (2010-2022). The SMA was manually annotated on the CT scans, and we trained a U-Net algorithm for SMA segmentation and a ResNet50 algorithm for predicting SMA margin status. Radiologists and surgeons reviewed the scans in a blinded fashion. SMA margin status per pathology reports was the reference.

Results:

Two hundred patients were included. Forty patients (20%) had a positive SMA margin. For the segmentation task, the U-Net model achieved a Dice Similarity Coefficient of 0.90. For the classification task, all readers demonstrated limited sensitivity, although the algorithm had the highest sensitivity at 0.43 (versus 0.23 and 0.36 for the radiologists and surgeons, respectively). Specificity was universally excellent, with the radiologist and algorithm demonstrating the highest specificity at 0.94. Finally, the accuracy of the algorithm was 0.85 versus 0.80 and 0.76 for the radiologists and surgeons, respectively.

Conclusions:

We demonstrated the feasibility of developing a computer vision algorithm to predict SMA margin status using preoperative CT scans, highlighting its potential to augment the prediction of vascular involvement.
Transcranial Direct Current Stimulation in Children With Anisometropic Amblyopia
Authors: El Salmawy Dina Ahmed , Elhadidy Reem , Shuaib Asmaa , Ashraf Mahmoud Eman , Nada Mona M.
Published: August 2024

Background:

Amblyopia is defined clinically as a difference in best-corrected visual acuity of two or more lines of acuity (0.2 logMAR) between the eyes. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that can transiently alter the excitability of targeted brain areas in a polarity-specific manner.

Purpose:

To detect the effect of tDCS on anisometropic amblyopia.

Methods:

This is a randomized controlled trial conducted on 78 patients with anisometropic amblyopia from 4.5 to 12 years of age. All patients presented with monocular amblyopia. They were divided into three groups; each group received five sessions of tDCS (anodal tDCS, cathodal tDCS, and sham tDCS). The active electrode was placed over occipital midline and the reference over central midline. Pattern visual-evoked potentials and contrast sensitivity tests were conducted before, immediately after, and 1 week after tDCS.

Results:

The amplitude of P100 was significantly decreased immediately after and 1 week after cathodal tDCS. The latency of P100 immediately after and 1 week after anodal tDCS was significantly decreased and increased significantly after cathodal tDCS. The amplitude of P100 and maximum and minimum contrast sensitivities were significantly increased immediately after and 1 week after anodal tDCS, and maximum contrast sensitivity was significantly decreased immediately after cathodal tDCS.

Conclusion:

Anodal tDCS is a promising noninvasive modality for improvement of anisometropic amblyopia.
Impact of excessive sucrose intake on mouse behavior across different developmental stages
Authors: Kim Ye-Jin , Jung Jae-Won , Lee Kyung-A , Lee Young-A
Published: August 2024

This study aimed to elucidate the effects of sucrose (SUC) consumption on neurodevelopmental processes through behavioral changes in rodents and determine whether these effects could be because of sweet taste, energy supply, or both. Mice were divided into five groups based on the time of SUC or sucralose (SUR, a noncaloric sweetener) administration: for 6 days from gestation day (GTD) 7, to birth from GTD13 and for 15 days from postnatal day (PND) 21, PND38, and PND56. SUC and SUR administration did not impact body weight. However, food intake in the PND56 group and water intake in the GTD13 and PND56 groups were increased by SUC and SUR administration. Amphetamine (0.5, 1, 2, and 3 mg/kg), a dopamine reuptake inhibitor, administration to assess alterations in the dopaminergic system induced increases in distance traveled after SUC administration in the GTD13 and PND21 groups compared with that in the control (vehicle administration) group. In contrast, the SUR group showed a decrease in the distance traveled in the PND56 group. Although there were no differences in locomotor activity and foraging behavior, SUC preference increased in the SUC group regarding the GTD13 and PND38 groups. The correlations between SUC preference and foraging behavior and between SUC preference and amphetamine response varied in both groups according to the developmental stage. Excessive SUC consumption might affect neural function at different developmental stages, as it could affect brain function through complex mechanisms involving sweet taste and energy supply and influence the dopaminergic system.
Evaluating the implementation of weekly rifapentine-isoniazid (3HP) for tuberculosis prevention among people living with HIV in Uganda: A qualitative evaluation of the 3HP Options Trial.
Authors: Musinguzi Allan , Kasidi Joan R. , Kadota Jillian L. , Welishe Fred , Nakitende Anne , Akello Lydia , Nakimuli Jane , Kunihira Lynn T. , Opira Bishop , Baik Yeonsoo , Patel Devika , Sammann Amanda , Berger Christopher A. , Aschmann Hélène E. , Nahid Payam , Belknap Robert , Kamya Moses R. , Handley Margaret A. , Phillips Patrick PJ , Kiwanuka Noah , Katamba Achilles , Dowdy David W. , Cattamanchi Adithya , Semitala Fred C. , Katahoire Anne R.
Published: August 2024

Three months of isoniazid-rifapentine (3HP) is being scaled up for tuberculosis (TB) preventive treatment (TPT) among people living with HIV (PLHIV) in high-burden settings. More evidence is needed to identify factors influencing successful 3HP delivery. We conducted a qualitative assessment of 3HP delivery nested within the 3HP Options Trial, which compared three optimized strategies for delivering 3HP: facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), and patient choice between facilitated DOT and facilitated SAT at the Mulago HIV/AIDS clinic in Kampala, Uganda. We conducted 72 in-depth interviews among PLHIV purposively selected to investigate factors influencing 3HP acceptance and completion. We conducted ten key informant interviews with healthcare providers (HCPs) involved in 3HP delivery to identify facilitators and barriers at the clinic level. We used post-trial 3HP delivery data to assess sustainability. We conducted an inductive thematic analysis and aligned the emergent themes with the RE-AIM framework dimensions to report implementation outcomes. Understanding the need for TPT, once-weekly dosing, shorter duration, and perceived 3HP safety enhanced acceptance overall. Treatment monitoring by HCPs and reduced risk of HIV status disclosure enabled DOT acceptance. Dosing autonomy enabled SAT acceptance. Switching between DOT and SAT as required enabled acceptance for patient choice. Dosing reminders, reimbursement for clinical visits, and social support enabled 3HP completion; pill burden, side effects, and COVID-19-related treatment restrictions hindered completion. All HCPs were trained and participated in 3HP delivery with high fidelity. Training, care integration, and collaboration among HCPs enabled, whereas initial concerns about 3HP safety among HCPs delayed 3HP adoption and implementation. SAT was maintained post-trial; DOT was discontinued due to inadequate ongoing financial support beyond the study period. Facilitated delivery strategies made 3HP treatment convenient for PLHIV and were feasible and implemented with high fidelity by HCPs. However, the costs of 3HP facilitation may limit wider scale-up.
Preserving friendships in school contacts: an algorithm to construct synthetic temporal networks for epidemic modelling
Authors: Calmon Lucille , Colosi Elisabetta , Bassignana Giulia , Barrat Alain , Colizza Vittoria
Published: August 2024

High-resolution temporal data on contacts between hosts provide crucial information on the mixing patterns underlying infectious disease transmission. Publicly available data sets of contact data are however typically recorded over short time windows with respect to the duration of an epidemic. To inform models of disease transmission, data are thus often repeated several times, yielding synthetic data covering long enough timescales. Looping over short term data to approximate contact patterns on longer timescales can lead to unrealistic transmission chains because of the deterministic repetition of all contacts, without any renewal of the contact partners of each individual between successive periods. Real contacts indeed include a combination of regularly repeated contacts (e.g., due to friendship relations) and of more casual ones. In this paper, we propose an algorithm to longitudinally extend contact data recorded in a school setting, taking into account this dual aspect of contacts and in particular the presence of repeated contacts due to friendships. To illustrate the interest of such an algorithm, we then simulate the spread of SARS-CoV-2 on our synthetic contacts using an agent-based model specific to the school setting. We compare the results with simulations performed on synthetic data extended with simpler algorithms to determine the impact of preserving friendships in the data extension method. Notably, the preservation of friendships does not strongly affect transmission routes between classes in the school but has a clear impact on the infection pathways between individual students. Our results moreover indicate that gathering contact data during two days in a population is sufficient to generate realistic synthetic contact sequences between individuals in that population on longer timescales. The proposed tool will allow modellers to leverage existing contact data, and contributes to the design of optimal future field data collection.
Amber Codon Mutational Scanning and Bioorthogonal PEGylation for Mapping Antibody Binding Sites on Human Arginase-1
Authors: Fernández de Santaella Jaime , Koch Nikolaj G. , Widmer Lorenz , Nash Michael A.
Published: August 2024

Epitope mapping is crucial for understanding immunological responses to protein therapeutics. Here, we combined genetic code expansion and bacterial surface display to incorporate S-allylcysteine (SAC) into human arginase-1 (hArg1) viaMethanococcoides burtoniipyrrolysyl-tRNA synthetase. Using an amber codon deep mutational scanning and sequencing workflow, we mapped SAC incorporation efficiency across the hArg1 sequence, providing insights into structural and sequence dependencies of non-canonical amino acid incorporation. We used mutually bioorthogonal allyl/tetrazine and azide/DBCO chemistries to achieve site-specific PEGylation and fluorescent labeling of hArg1, revealing insights into SAC side chain reactivity and solvent accessibility of residues in hArg1. This system was further applied to determine the binding epitope of a monoclonal antibody on the surface of hArg1, providing high-resolution data on the impact of PEGylation on antibody binding. Our method produces high dimensional data of non-canonical amino acid incorporation efficiency, site-specific functionalization enabled by mutually bioorthogonal chemistries, and epitope mapping of therapeutic proteins.
High throughput mutational scanning of a protein via alchemistry on a high-performance computing resource
Authors: Guclu Tandac F. , Tayhan Busra , Cetin Ebru , Atilgan Ali Rana , Atilgan Canan
Published: August 2024

Antibiotic resistance presents a significant challenge to public health, as bacteria can develop resistance to antibiotics through random mutations during their life cycles, making the drugs ineffective. Understanding how these mutations contribute to drug resistance at the molecular level is crucial for designing new treatment approaches. Recent advancements in molecular biology tools have made it possible to conduct comprehensive analyses of protein mutations. Computational methods for assessing molecular fitness, such as binding energies, are not as precise as experimental techniques like deep mutational scanning. Although full atomistic alchemical free energy calculations offer the necessary precision, they are seldom used to assess high throughput data as they require significantly more computational resources. We generated a computational library using deep mutational scanning for dihydrofolate reductase (DHFR), a protein commonly studied in antibiotic resistance research. Due to resource limitations, we analyzed 33 out of 159 positions, identifying 16 single amino acid replacements. Calculations were conducted for DHFR in its drug-free state and in the presence of two different inhibitors. We demonstrate the feasibility of such calculations, made possible due to the enhancements in computational resources and their optimized use.
Pathogenic fungus expresses effector proteins in combination with a symbiotic virus to behaviourally manipulate housefly hosts
Authors: Edwards Sam , Nielsen Knud Nor , Will Ian , de Bekker Charissa , Kotta-Loizou Ioly , De Fine Licht Henrik Hjarvard
Published: August 2024

Host manipulation by pathogens and parasites is a widespread phenomenon, but the molecular mechanisms are poorly understood. We investigated the summiting disease caused by the fungus Entomophthora muscae in houseflies, where infected flies climb to elevated positions and die, releasing infectious conidia. We performed dual-RNA sequencing of fly heads at different time points and identified candidate genes from both the host and the pathogen that may be involved in this summiting phenotype. Surprisingly, we also detected an extremely high abundance of a novel positive sense single-stranded (+ss) RNA Iflavirus in infected fly heads. We show that the virus load increases over time and shows signs of accumulation in fly heads and thoraces. We also reveal predicted interactions between fungal secreted proteins and insect host proteins related to neurological and immune functions, suggesting a possible role of these proteins in host manipulation. Furthermore, we find that E. muscae encodes a homologue of ecdysteroid UDP-glucosyltransferase (egt), a gene that has been implicated in host manipulation by other pathogens. Our study reveals a complex interplay between a fungus, a virus and a fly, and suggests that convergent evolution of egt for host manipulation mechanisms may occur in different pathogens.
Sex and APOE4-specific links between cardiometabolic risk factors and white matter alterations in individuals with a family history of Alzheimer’s disease
Authors: Tremblay Stefanie A. , Spreng R. Nathan , Wearn Alfie , Alasmar Zaki , Pirhadi Amir , Tardif Christine L. , Chakravarty Mallar M. , Villeneuve Sylvia , Leppert Ilana R. , Carbonell Felix , Iturria Medina Yasser , Steele Christopher J. , Gauthier Claudine J. ,   PREVENT-AD Research Group
Published: August 2024

INTRODUCTION

White matter (WM) alterations are among the earliest changes in Alzheimer’s disease (AD), yet limited work has comprehensively characterized the effects of AD risk factors on WM.

METHODS

In older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors. Multiple MRI-derived metrics were integrated using a multivariate approach based on the Mahalanobis distance (D2). The links between WM D2 and cognition were also explored.

RESULTS

WM D2 in several regions was associated with high systolic blood pressure, BMI, and glycated hemoglobin, and low cholesterol, in both males and females. APOE4+ displayed a distinct risk pattern, with LDL-cholesterol having a detrimental effect only in carriers, and this pattern was linked to immediate memory performance. Myelination was the main mechanism underlying WM alterations.

DISCUSSION

Our findings reveal that combined exposure to multiple cardiometabolic risk factors negatively impacts microstructural health, which may subsequently affect cognition. Notably, APOE4 carriers exhibited a different risk pattern, especially in the role of LDL, suggesting distinct underlying mechanisms in this group.
Evolutionary mismatch between nuclear and mitochondrial genomes does not promote reversion mutations in mtDNA
Authors: Franco Melissa , Popadin Konstantin , Woods Dori , Khrapko Konstantin
Published: August 2024

Serrano et al. (Serrano et al., 2024) use a high-fidelity somatic mtDNA mutation analysis in conplastic mice in which mtDNA was replaced with exogenous mtDNA of different mouse strains. Serrano reported apparent abundant somatic reversion mutations in the exogenous mtDNA that seemed to restore the original mito-nuclear match. If real, such a phenomenon would have important implications for health and genetics. In today’s highly mixed human population, the pairing of potentially mismatched nuclear and mitochondrial genomes is widespread, so the proposed reversion mutagenesis should be commonplace. We demonstrate, however, that thesereversion mutationsare not real but originate from cross-contamination between samples and from NUMTs, the mtDNA pseudogenes located in the nuclear genome.
Phytochemical screening, analgesic, anti-pyretic and antibacterial potentials of Litsea glutinosa (L) leaves extracts in vivo and in vitro technique
Authors: Labu Zubair , Karim Samira , Rahman Md. Tarekur , Hossain Md. Imran , Shakil Md
Published: August 2024

Back ground: Litsea glutinosa leaves (LG) have been used as traditional medicine to treat diseases since ancient times. This study aimed to investigate the cold methanol extract of LG for its analgesic, antipyretic and antibacterial activities, along with preliminary phytochemical screening and acute toxicity test. Methods: In this study, we first investigated the major phytochemicals group present applying modern chromatographic technique HPLC in addition to conventional methods for Phyto screening in cold methanol extracts LG leaves. Both methods simultaneously demonstrated major bioactive compounds found in the extract were phenol, flavonoid. The purposive efficacy and toxicity were then assessed through preclinical testing. Results: In hot plate method, the highest pain inhibitory activity was found at a dose of 500 mg/kg of crude extract (3.37± 0.31sec) which differed significantly (P <0.01 and P <0.001) with that of the standard drug morphine (6.47± 0.23 sec). The extract significantly prolonged reaction latency to thermal-induced pain in hotplate model. Analgesic activity at 500 mg/kg, LG extract produced a 70% suppression of writhing in mice, which was statistically significant (p<0.001) compared to standard morphine's (77.5%) inhibition. In antipyretic activity assay, the crude extract showed notable reduction in body temperature (36.17 ± 0.32°C) at dose of 300 mg/kg-body weight, when the standard (at dose 100 mg/kg-body weight) exerted (36.32 ± 0.67°C) after 3 h of administration. In antibacterial studies, results showed that inhibition of bacterial growth at 400 μg dose of each extract clearly inhibited growth of bacteria from 11 to 22 mm. The extractives carbon tetrachloride fraction, chloroform soluble fraction, ethyl acetate fraction demonstrated notably greater inhibitory zone widths (p < 0.05) against tested strains. Conclusion: Overall, the cold methanol extract of LG leaves demonstrates the therapeutic potential in preclinical settings.
A counterfactual analysis quantifying the COVID-19 vaccination impact in Sweden
Authors: Bergstrom Fanny , Gunther Felix , Britton Tom
Published: August 2024

Vaccination was the single most effective measure in mitigating the impact of the COVID-19 pandemic. Our study aims to quantify the impact of vaccination programmes during this initial year of vaccination by estimating the number of case fatalities avoided, having Sweden as a case study. Using Swedish data on age-specific reported incidence, vaccination uptake, and contact structures, along with age-specific estimates on the vaccine efficacies and under-reporting from the literature, we fit a Bayesian SEIR epidemic model with time-varying community contact rate β(t) for COVID-19 incidence. By adding age-specific infection fatality rates, we obtain an estimate of about 5,540 (95% PI: 5,390-5,690) for the number of case fatalities from the fitted model. This estimate aligns closely with the reported 5,430 case fatalities during the same period. We then use the estimated contact rate β(t) in a counterfactual analysis where the population is unvaccinated, leading to more infections and fatalities. The counterfactual analysis result in a severe epidemic outbreak during the early autumn of 2021, resulting in about 52,600 (49,900-55,500) number of case fatalities. Consequently, the number of lives saved by the vaccination program is estimated to be about 47,100 (44,500-49,800), out of which 6,460 are directly saved and 40,600 are indirectly saved, mainly by drastically reducing the severe outbreak in the early autumn of 2021, which would have occurred without vaccination and unchanged community contact rate. Our mathematical model is used to analyze the impact of COVID-19 vaccination on lives saved in Sweden during 2021, but the same methodology can be applied to other countries. The counterfactual analysis offers insights into an alternative trajectory of the pandemic without vaccination. By incorporating estimated vaccination-related parameters, age-specific infection fatality ratio and under-reporting, our model estimates the number of case fatalities avoided. The results not only show the direct impact of vaccination on reducing deaths for infected individuals but also shed light on the indirect effects of reduced transmission dynamics.
Optimized tacrolimus dosing strategy in kidney transplant recipients receiving nirmatrelvir-ritonavir for COVID-19
Authors: Yan Han , Hu Shanbiao , Zhang Hedong , Zhou Yangang , Fu Rao , Xu Ping , Cai Hualin , Li Xi , Lan Gongbin
Published: August 2024

Kidney transplantation recipients (KTRs) represent a vulnerable population for COVID-19 infection and severe disease. Nirmatrelvir-ritonavir has demonstrated efficacy in treating COVID-19 among KTRs, and interacts with tacrolimus leading to a precipitous increase in tacrolimus blood levels when co-administered, potentially resulting in toxicity. This study conducted a real-world analysis of KTRs treated with nirmatrelvir-ritonavir for COVID-19 to investigate the relationship between tacrolimus levels and dosing during and within 10 days post-discontinuation of nirmatrelvir-ritonavir. In the experimental group, tacrolimus was initiated at 20-25% of the baseline dose 48 hours after discontinuation of nirmatrelvir-ritonavir, with daily increments of 20-25% until the baseline dose was restored. The patients who did not adhere to the experimental protocol were included in the control group. Findings indicated that withholding tacrolimus 12 hours prior to commencing nirmatrelvir-ritonavir maintained tacrolimus blood levels above 83% of the baseline throughout the nirmatrelvir-ritonavir treatment period. Compared to the control group, the experimental group achieved target trough concentrations of tacrolimus more rapidly and maintained a higher proportion within the therapeutic range (p=0.029), and exhibited significantly lower rates of adverse events (p<0.001). This investigation provides a safe and effective pharmacological strategy for KTRs infected with COVID-19, enabling the safe co-administration of nirmatrelvir-ritonavir and tacrolimus.
Social risk coding by amygdala activity and connectivity with dorsal anterior cingulate cortex
Authors: Kim Jae-Chang , Zangemeister Leopold , Tobler Philippe N. , Schultz Wolfram , Grabenhorst Fabian
Published: August 2024

Risk is a fundamental factor affecting individual and social economic decisions, but its neural correlates are largely unexplored in the social domain. The amygdala, together with the dorsal anterior cingulate cortex (dACC), is thought to play a central role in risk taking. Here, we investigated in human volunteers (n=20; 11 females) how risk (defined as variance of reward probability distributions) in a social situation affects decisions and concomitant neural activity as measured with fMRI. We found social variance-risk signals in the amygdala. Activity in lateral parts of the amygdala increased parametrically with social reward variance of the presented options. Behaviorally, 75% of participants were averse to social risk as estimated in a Becker-DeGroot-Marschak auction-like procedure. The stronger this aversion, the more negative was the coupling between risk-related amygdala regions and dACC. This negative relation was significant for social risk attitude but not for the attitude towards variance-risk in juice outcomes. Our results indicate that the amygdala and its coupling with dACC process objective and subjectively evaluated social risk. Moreover, while social risk can be captured with a framework originally established by finance theory for individual risk, the amygdala appears to processes social risk largely separately from individual risk.
Protocol for muscle fiber type and cross-sectional area analysis in cryosections of whole lower mouse hindlimbs
Authors: Battey Edmund , Biswas Dipsikha , Dos Santos Matthieu , Maire Pascal , Sakamoto Kei
Published: August 2024

We outline a robust, simple, and cost-effective method to simultaneously visualize all mouse lower hindlimb skeletal muscles. We describe procedures for orientating the whole lower hindlimb in gum tragacanth prior to freezing, simplifying the proceeding experimental steps, and enhancing the clarity and comprehensiveness of characterizations. We then detail steps for quantifying muscle fiber size and fiber type characteristics in a single cryosection using immunofluorescence and histochemistry. This protocol can be applicable for commonly used histological and (immuno) histochemical evaluations such muscle degeneration/regeneration, fibrosis, immune cell infiltration, enzymatic activity and glycogen content.
Functional capacities drive recruitment of bacteria into plant root microbiota
Authors: Selten Gijs , Lamouche Florian , Gomez-Repolles Adrian , Blahovska Zuzana , Kelly Simon , de Jonge Ronnie , Radutoiu Simona
Published: August 2024

Host-associated microbiota follow predictable assembly patterns but exhibit significant variation at the bacterial isolate level, depending on the host and environmental context. This variability poses challenges for studying, predicting, and engineering microbiomes. Here we examined how Arabidopsis, Barley, and Lotus plants recruit specific bacteria from highly complex synthetic communities (SynComs) composed of hundreds of bacterial isolates originating from these plants when grown in natural soil. We discovered that, despite their taxonomic diversity, bacteria enriched by these three plant species encode largely overlapping functions. A set of 266 functions common among all host-associated communities was identified at the foundation of the microbiota's functional potential. Analysis of the differences observed between root-associated communities revealed that functions recruited by Arabidopsis and Barley were primarily driven by the SynCom composition, while Lotus selected fewer isolates but with more diverse functionalities, akin to a "Swiss army knife" strategy. We analysed the variation at the functional level and found this can be explained by the combined functions of bacteria at the family level. Additionally, across major taxa, the isolates covering a broader range of their family's functional diversity achieved higher relative abundance in the root communities. Our work sheds light on key functions and principles guiding the recruitment of bacterial isolates into root microbiota, offering valuable insights for microbiome engineering and inoculant discovery at a previously inaccessible taxonomic level.
Enhancing Challenging Target Screening via Multimodal Protein-Ligand Contrastive Learning
Authors: Wang Zhen , Wang Zhanfeng , Yang Maohua , Pang Long , Nie Fangyuan , Liu Siyuan , Gao Zhifeng , Zhao Guojiang , Ji Xiaohong , Huang Dandan , Zhu Zhengdan , Li Dongdong , Yuan Yannan , Zheng Hang , Zhang Linfeng , Ke Guolin , Wang Dongdong , Yu Feng
Published: August 2024

Recent advancements in genomics and proteomics have identified numerous clinically significant protein targets, with notably 85% categorized as undruggable. These targets present widespread challenges due to their complex structures and dynamics, rendering conventional drug design strategies not always effective. In this study, we introduce Uni-Clip, a contrastive learning framework that incorporates multi-modal features of proteins (structure and residue) and ligands (conformation and graph). Optimized with a specifically designed CF-InfoNCE loss, Uni-Clip enhances the modeling of protein-ligand interactions for both undruggable and druggable proteins. Uni-Clip demonstrates superior performance in benchmark evaluations on widely acknowledged datasets, LIT-PCBA and DUD-E, achieving a 147% and 218% improvements in enrichment factors at 1% compared to baselines. Furthermore, Uni-Clip proves to be a practical tool for various drug discovery applications. In virtual screening for the challenging protein target GPX4 with flat surface, it identified non-covalent inhibitors with an IC50of 4.17 μM, in contrast to the predominantly covalent inhibitors currently known. Through target fishing for benzbromarone, Uni-Clip identified the intrinsically disordered protein c-Myc as a potential target, highlighting benzbromarone’s potential for repurposing in cancer therapy. Explainable analyses effectively identified binding sites consistent with molecular dynamics and experimental results, even for challenging undruggable targets.