bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of TIPS insertion on waitlist mortality and access to liver transplantation in Budd-Chiari syndrome
Authors: Akabane Miho , Imaoka Yuki , Nakayama Toshihiro , Esquivel Carlos O. , Sasaki Kazunari
Published: August 2024

The impact of TIPS on waitlist mortality and liver transplantation (LT) urgency in patients with Budd-Chiari syndrome (BCS) remains unclear. We analyzed patients with BCS listed for LT in the UNOS database (2002–2024) to assess TIPS’s impact on waitlist mortality and LT access through competing-risk analysis. We compared trends across 2 phases: phase 1 (2002–2011) and phase 2 (2012–2024). Of 815 patients with BCS, 263 (32.3%) received TIPS at listing. TIPS group had lower MELD-Na scores (20 vs. 22, p < 0.01), milder ascites (p = 0.01), and fewer Status 1 patients (those at risk of imminent death while awaiting LT) (2.7% vs. 8.3%, p < 0.01) at listing compared to those without TIPS. TIPS patients had lower LT rates (43.3% vs. 56.5%, p < 0.01) and longer waitlist times (350 vs. 113 d, p < 0.01). TIPS use increased in phase 2 (64.3% vs. 35.7%, p < 0.01). Of 426 patients who underwent transplantation, 134 (31.5%) received TIPS, showing lower MELD-Na scores (24 vs. 27, p < 0.01) and better medical conditions (intensive care unit: 14.9% vs. 21.9%, p < 0.01) at LT. Status 1 patients were fewer (3.7% vs. 12.3%, p < 0.01), with longer waiting days (97 vs. 26 d, p < 0.01) in the TIPS group. TIPS use at listing increased from phase 1 (25.6%) to phase 2 (37.7%). From phase 1 to phase 2, ascites severity improved, re-LT cases decreased (phase 1: 9.8% vs. phase 2: 2.2%, p < 0.01), and cold ischemic time slightly decreased (phase 1: 7.0 vs. phase 2: 6.4 h, p = 0.14). Median donor body mass index significantly increased. No significant differences were identified in patient/graft survival at 1-/5-/10-year intervals between phases or TIPS/non-TIPS patients. While 90-day waitlist mortality showed no significant difference (p = 0.11), TIPS trended toward lower mortality (subhazard ratio [sHR]: 0.70 [0.45–1.08]). Multivariable analysis indicated that TIPS was a significant factor in decreasing mortality (sHR: 0.45 [0.27–0.77], p < 0.01). TIPS group also showed significantly lower LT access (sHR: 0.65 [0.53–0.81], p < 0.01). Multivariable analysis showed that TIPS was a significant factor in decreasing access to LT (sHR: 0.60 [0.46–0.77], p < 0.01). Subgroup analysis excluding Status 1 or HCC showed similar trends. TIPS in patients with BCS listed for LT reduces waitlist mortality and LT access, supporting its bridging role.
Informatics-driven solutions for optimal care delivery in liver transplantation
Authors: Spann Ashley , Louissaint Jeremy , Izzy Manhal
Published: August 2024

Clinical informatics, which combines health information technology and clinical expertise, aims to improve health care delivery and outcomes. For candidates and recipients of liver transplants, the complexities of their management are vast. Care often involves significant volumes of data from various sources and multiple health care settings and health care systems. Informatics represents an opportunity to support the care of these patients through this process; however, it has been underutilized to date. Preliminary examples of informatics use exist for this patient population, such as clinical decision support to link patients to hepatology providers, utilization of digital health technologies to track responses to medical therapy, and artificial intelligence to characterize organ donor compatibility. Further deployment of these tools can optimize care delivery for patients with cirrhosis and across the transplant cascade. In this review, we explore the utility of various techniques of clinical informatics mainly within the transplant care cascade, barriers to implementation, and highlight opportunities for future investigation and optimized use. Although barriers to widespread adoption remain such as interoperability, data access and availability, and structured implementation strategies, the integration of informatics and clinical decision support/artificial intelligence-based tools into routine care for liver transplantation represents an opportunity for marked enhancement in how we deliver care to these patients.
Evaluating Autoimmune Markers in Relation to Gastrointestinal Measures in Patients With Symptoms of Gastroparesis
Authors: Chaudhary Dhruv , Jiang Yiran , Khan Fahad , Mathur Prateek , Pinkston Christina , Abell Thomas L.
Published: August 2024

Background:

Patients with symptoms (Sx) of gastroparesis (Gp) may have signs of autoimmune disease.

Goals:

We hypothesized that serum autoantibodies in Gp Sx patients are associated with follow-up at 48 weeks (about 11 mo) and later autoimmune questionnaires (AQ). One hundred eleven patients: 24 male, 87 female, mean age 43 years, with Gp Sx: 27 diabetic (DM), 78 idiopathic (ID), 6 postsurgical (PS) were studied at baseline, 48 weeks (about 11 mo) and long term. Serum western blot (WB) was performed by an enzyme linked immunosorbent assay for qualitative evaluation of serum antibodies to various specific nuclear antigens. A blotting score (GIBS) was used to compare global immunologic reactions. At long-term follow-up (>5 y), 38 AQ-responding patients (34 with baseline WB data) were compared with WB by AQ responses.

Results:

A total of 69/111 (62%) had gastric emptying delay. Correlations exist between WB autoantibodies and clinical follow-up at 48 weeks (about 11 mo). 94/96 (97.9%) were WB positive and 62/96 patients had 48-week data. From 5 years follow-up of 38 patients, AQ Sx responses were recurring abdominal pain (89%), lack of energy (87%), exhaustion (74%), and constipation (68%). From AQ and WB data (34 patients), Anti-SSA was higher in those indicating dry mouth and mouth and nose sores and SM was higher in dysphagia (P=0.01 for both). Conclusions In patients with gastroparesis symptoms baseline western blot has significant associations with a number of clinical findings and autoimmune disorders symptoms. These associations suggest possible undiagnosed autoimmune disorders. Further work with Western blotting and other autoimmune measures in patients with gastroparesis symptoms is needed.
Epigastric discomfort in a young woman: unveiling a case of CREST syndrome
Authors: Gupta Pukar , Adhikari Pradeep , Sitaula Deekshanta , Thapa Sudesh Jang , Thapa Muktinath
Published: August 2024

Introduction and Importance:

CREST syndrome is a clinical condition seen in relation to systemic sclerosis, which meets at least three of its five clinical features: calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. Three of these clinical features (Raynaud’s phenomenon, sclerodactyly, and esophageal dysmotility) are often present in classical subsets of SSc: limited and diffuse, and their presence alone in association does not define CREST syndrome. Laboratory findings (autoimmunity) are crucial for diagnosis. Hence, a comprehensive clinical assessment and autoimmune investigations should be performed to make the final diagnosis of CREST Syndrome, as per the criteria stated. We describe a case involving a 34-year-old female who was diagnosed with CREST Syndrome during a medical evaluation of her epigastric discomfort.

Case Presentation:

We present the case of a 34-year-old female who presented with clinical cutaneous and gastrointestinal manifestations along with autoantibody production when investigated, which was compatible with the diagnosis of a limited form of systemic sclerosis (SSc), CREST syndrome.

Clinical Discussion:

In the absence of a diagnostic test to prove the absence or presence of SSc, the diagnosis is based on a combination of clinical and laboratory findings. Thus, a detailed clinical history and careful physical examination are required. With regard to the diagnosis, an updated classification criteria for SSc, as published by ACR/EULAR in 2013, is used and helped us to reach the final diagnosis.

Conclusion:

CREST syndrome, a rare clinical entity, warrants consideration by primary physicians while evaluating it. Despite its rarity, inclusion in differentials is essential to prevent the worsening of the condition and further complications. Heightened awareness among healthcare providers is pivotal for prompt recognition and appropriate management.
Axillary lesion in a young adult ends up to a peculiar diagnosis: primitive neuro-ectodermal tumor (PNET) of ulnar nerve: a rare case report
Authors: Emamhadi Mohammadreza , Zaresharifi Nooshin , Reihanian Zoheir , Khalili Anita , Ashoobi Mohammad Taghi , Noroozi Guilandehi Sama , Baghi Iraj , Mehrvarz Alireza
Published: August 2024

Introduction and importance:

Primitive neuro-ectodermal tumor (PNET) is a highly aggressive tumor composed of small round blue cells, mostly developing in children and young adults. Being a member of Ewing’s Sarcoma Family of Tumors (ESFT); it has been discussed in two subcategories of central and peripheral PNET. PNETs of peripheral nerves are very uncommon pathologic findings, as to the best of our knowledge only 12 well-documented cases have been yet reported.

Case presentation:

A 30-year-old male presented with progressive paresthesia of his right hand’s little finger and painless swelling of the right axilla. Magnetic resonance (MR) neurography demonstrated a heterogeneous, high-signal, round mass within the right axilla fossa in proximity to the medial aspect of brachial plexus branches. The clinical and radiological study failed to an accurate diagnosis, thus surgical resection of the tumor was done for tissue evaluation. Histopathologic study of the lesion revealed a neoplasm comprising sheets of small, round, blue cells (Hematoxylin and Eosin stain), which immunohistochemically consisted with the diagnosis of PNET.

Clinical discussion:

The differential diagnosis of axillary fossa masses, focusses on peripheral nerve tumors like Schwannoma and PNET. MR neurography aids in evaluation, but tissue diagnosis remains crucial. Treatment involves surgical resection, chemotherapy, and radiotherapy tailored to individual patients.

Conclusion:

Although pPNET is not apparently the first differential diagnosis coming to mind when encountering a rapidly growing mass in the axillary fossa with peripheral nerve origin, its highly malignant behavior, makes it crucial to be considered in the differential diagnoses.
Interprofessional Simulation for Nursing and Paramedicine Students
Authors: Loo Janet , Muise Tammie , MacDonald Jo-Ann
Published: August 2024

Background:

Interprofessional simulations are becoming an important aspect of learning for nursing students. Still, the execution of these types of simulations can prove challenging.

Problem:

Educational institutions often struggle to access faculties from different health care fields for interprofessional simulations. There is limited literature on operationalizing and implementing interprofessional simulations related to scenarios in the community, which makes creating these simulations challenging.

Approach:

Nursing and paramedicine educators from a university and a community college collaborated on a simulation centered on the management of immunization anaphylaxis in the community.

Outcomes:

Feedback from facilitators and students was positive. Both disciplines agreed that collaborative learning significantly enhanced role clarification, team functioning, conflict resolution, collaboration, and communication skills with team members. Challenges included coordinating schedules, space, and training of facilitators.

Conclusions:

Collaborating with other educational institutions to establish an interprofessional simulation can be complex, but the benefits significantly outweighed the challenges.
Cochlear Apex Triangulation Utilizing Ct Measures And Middle Ear Landmarks
Authors: Cottrell Justin , Landsberger David , Breen Matt , Lebowitz Joseph , Hagiwara Mari , Moonis Gul , Shapiro William , Friedmann David R. , Jethanamest Daniel , McMenomey Sean , Roland J. Thomas
Published: August 2024

Objective:

To better characterize the cochlear apex in relation to surgically relevant landmarks to guide surgeons and improve procedural success of apical electrode placement.

Study Design:

Retrospective image analysis.

Setting:

Tertiary referral center.

Patients:

Cochlear implant recipients with available preoperative computed tomography (CT) imaging.

Intervention:

None.

Main Outcome Measure:

Cochlear dimensions and cochlear apex distance measures to surgically relevant middle ear landmarks and critical structures.

Results:

Eighty-two temporal bone CT scans were analyzed utilizing multiplanar reformats. The average lateral width of promontory bone over the cochlear apex was 1.2 mm (standard deviation [SD], 0.3). The anteroposterior distance from the round window (avg, 4.2 mm; SD, 0.5), oval window (avg, 3.3 mm; SD, 0.3), cochleariform process (avg, 2.3; SD, 0.5), and superior-inferior distance from the cochleariform process (avg, −0.9; SD, 0.8) to the cochlear apex were measured. The relationship of the cochlear apex to critical structures was highly variable.

A newly developed stapes vector was created and found to mark the posterior/superior boundary of the apex in 94% of patients. When a vector parallel to the stapes vector was drawn through the round window, it marked the anterior/inferior boundary of the cochlear apex in 89% of patients.

Conclusions:

This study assists in characterizing cochlear apex anatomy and its relation to surrounding structures as a means of improving procedural accuracy and reducing trauma during apical cochleostomy. Understanding both distance relationships and expected boundaries of the apex could help to inform future surgical approaches.
Adolescent Acetaminophen and Ibuprofen Self-Poisoning, 2017–2022
Authors: Weigel Bernard , Adams Axel , Wahrenbrock Taylor , Wahl Michael
Published: August 2024

Background

Acetaminophen and ibuprofen are the most common agents involved in adolescent self-poisoning. With increasing suicidality observed during the COVID-19 pandemic, we sought to compare overdose trends, severity, and outcomes for both agents.

Methods

We performed a retrospective analysis of the National Poison Data System for acetaminophen and ibuprofen single-substance exposures in teenagers 13–19 years of age from 2017–2022. Acetaminophen and ibuprofen overdoses (per 100,000 persons) were plotted by year. Medical outcomes, clinical effects, and therapies were compared to determine if there were differences in overdose severity between the 2 agents.

Results

From 2017 to 2022, US poison centers recorded 50,902 single-substance acetaminophen exposures and 41,674 single-substance ibuprofen exposures in teenagers. Cases peaked in 2021 with 40.0 versus 29.1 cases (per 100,000 persons) for acetaminophen and ibuprofen, respectively. Acetaminophen self-poisoning was significantly more likely to result in death (odds ratio, 13.92; 95% confidence interval, 2.18–581.75; P < 0.001) or inpatient admission (odds ratio, 7.38; 95% confidence interval, 7.10–7.66; P < 0.001) compared with ibuprofen. Abdominal pain and vomiting were the most common clinical effects for both agents, and unsurprisingly, acetaminophen was more likely to cause transaminitis and liver dysfunction, whereas ibuprofen was more likely to cause central nervous system depression and metabolic acidosis. For the acetaminophen group, 19 teenagers underwent organ transplantation.

Conclusions

Given the increased hospitalization and treatment resources needed for acetaminophen overdoses compared with ibuprofen, it is time to implement acetaminophen packaging policy change to protect US adolescents.
The Use of Point-of-Care Ultrasound in Pediatric Emergency Departments and Intensive Care Units
Authors: Şık Nihan , Arslan Gazi , Akca Çağlar Ayla , Ülgen Tekerek Nazan , Fidancı İlknur , Tolu Kendir Özlem , Bal Alkan , Özgür Horoz Özden , Anıl Ayşe Berna , Yıldızdaş Dinçer , Duman Murat , Dursun Oğuz
Published: August 2024

Objectives

The aim was to evaluate the current status of point-of-care ultrasound (POCUS), perceptions, education, training, and barriers to using POCUS in pediatric emergency departments (PEDs) and pediatric intensive care units (PICUs) in Turkey.

Methods

A descriptive, multicenter, cross-sectional study through an online survey was developed using the REDCap online platform. The survey was distributed through the Turkish Society of Pediatric Emergency and Intensive Care e-mail group. Each survey was answered only once by each PED/PICU and by the clinical chief of the department.

Results

A total of 19 PEDs and 26 PICUs responded to the survey. Among them, 84.2% of PEDs and 100% of PICUs reported the clinical use of POCUS. For diagnostic applications, the most common areas for PEDs and PICUs were thoracic (93.7%/100%) and cardiovascular (62.5%/65.4%) assessment, and in the procedural use of POCUS, the most frequent applications were those for vascular access (75.0%/92.3%) and thoracentesis (31.2%/65.4%). The most commonly reported clinical benefits were rapid diagnosis, rapid treatment, and decreased complications during procedural applications for PEDs and PICUs. Evaluating the barriers to POCUS use in PEDs and PICUs, the most common reasons for insufficient use were the lack of ultrasound machines and/or equipment, a shortage of manpower, lack of awareness, and lack of training. For PEDs (68.4%) and for PICUs (84.6%), participants agreed that POCUS training should be mandatory during fellowship programs.

Conclusions

Most participants were aware of the need for POCUS. However, lack of education, equipment, manpower, and infrastructure still emerged as barriers to the use of POCUS. To further promote POCUS use, it would be helpful to improve accessibility by ensuring sufficient numbers of ultrasound devices together with sufficient numbers of appointed physicians and by expanding POCUS education in PEDs and PICUs.
Early Cleft Palate Repair is Associated With Lower Incidence of Velopharyngeal Insufficiency Surgery
Authors: Stanton Eloise W. , Rochlin Danielle , Lorenz Hermann Peter , Sheckter Clifford C.
Published: August 2024

Background:

The timing of primary repair in nonsyndromic cleft palate remains controversial. Recent evidence suggests earlier repair is associated with a lower incidence of velopharyngeal insufficiency (VPI). The authors aim to evaluate these findings in a large cohort study using causal inference.

Methods:

All nonsyndromic cleft palate repairs in California were extracted between 2000 and 2021 from the California Health Care Access and Information (HCAI) database. Cases were linked with VPI surgery following cleft palate repair based on unique identifiers. The main outcome measure was incidence of VPI surgery evaluated with propensity score matching. Early cleft palate repair was defined as <7 months of age versus traditional cleft palate repair at >11 months of age. Standardized mean differences (SMD) were measured before and after matching for potential confounders including sex, race, payer, and distance from patient home to hospital.

Results:

In all, 52,007 cleft palate repairs were included, of which 12,169 (23.3%) were repaired early and 39,838 (76.7%) were repaired traditionally. Early cleft palate repairs underwent VPI surgery in 1.2% (13/1,000) of cases, compared with 6.1% (61/1000) in the traditional repair cohort. Post-matching, the average treatment effect of early repair was a 6.3% reduction in VPI surgery (P<0.001, 95% CI −6.3, −5.4%). All covariate SMDs were <|0.1| after matching.

Conclusion:

Our cohort study demonstrates a significantly reduced incidence of VPI surgery in children with primary cleft palate repair <7 months of age. Craniofacial centers should consider early cleft palate repair in appropriate patients.
MULTIMODAL NUCLEAR FACTOR-ERYTHROID-2–RELATED FACTOR (NRF2) THERAPY IN THE CONTEXT OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) INHIBITION REPROGRAMS THE ACUTE SYSTEMIC AND PULMONARY IMMUNE RESPONSE AFTER COMBINED BURN AND INHALATION INJURY
Authors: Alves Matthew D. , Clark Ryan A. , Hernandez Denise A. , Bucci Madelyn P. , Chen Duo , Efron Philip A. , Wallet Shannon M. , Keselowsky Ben G. , Maile Robert
Published: August 2024

Severe burn injuries induce acute and chronic susceptibility to infections, which is largely attributed to a hyper-proinflammatory response followed by a chronic anti-inflammatory response. Concurrent inhalation injury (B + I) causes airway inflammation. Pulmonary macrophages and neutrophils are “hyperactive” with increased reactive oxygen (ROS) and nitrogen species (RONS) activity, but are unable to clear infection, causing airway damage upon activation. Nuclear factor-erythroid-2–related factor (NRF2) is a critical immunomodulatory component that induces compensatory anti-inflammatory pathways when activated. On the other hand, inhibition of mammalian target of rapamycin (mTOR) reduces proinflammatory responses. The therapeutic use of these targets is limited, as known modulators of these pathways are insoluble in saline and require long-term administration. A biocompatible NRF2 agonist (CDDO) and rapamycin (RAPA) poly(lactic-co-glycolic acid) (PLGA) microparticles (MP) were created, which we hypothesized would reduce the acute hyper-inflammatory response in our murine model of B + I injury. BI-injured mice that received CDDO-MP or both CDDO-MP and RAPA-MP (Combo-MP) an hour after injury displayed significant changes in the activation patterns of pulmonary and systemic immune genes and their associated immune pathways 48 h after injury. For example, mice treated with Combo-MP showed a significant reduction in inflammatory gene expression compared to untreated or CDDO-MP–treated mice. We also hypothesized that Combo-MP therapy would acutely decrease bacterial susceptibility after injury. BI-injured mice that received Combo-MP an hour after injury, inoculated 48 h later with Pseudomonas aeruginosa (PAO1), and sacrificed 48 h after infection displayed significantly decreased bacterial counts in the lungs and liver versus untreated B + I mice. This reduction in infection was accompanied by significantly altered lung and plasma cytokine profiles and immune reprogramming of pulmonary and splenic cells. Our findings strongly suggest that multimodal MP-based therapy holds considerable promise for reprogramming the immune response after burn injuries, particularly by mitigating the hyper-inflammatory phase and preventing subsequent susceptibility to infection.
The Role of Electroconvulsive Therapy in Posttraumatic Stress Disorder
Authors: Callens Laura , Sienaert Pascal
Published: August 2024

Posttraumatic stress disorder (PTSD) is associated with a high burden of disability and mortality. Despite standard treatments with antidepressants and/or psychotherapy, remission is often difficult to achieve. Electroconvulsive therapy (ECT) is an effective treatment for mood disorders but is currently not recognized as a treatment modality for PTSD. The literature about its potential role in the management of PTSD is growing. Thus, we aim to systematically review the available evidence for the role of ECT in PTSD.

Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 guidelines, we performed a systematic literature search from 1958 to December 2023 using PubMed, Embase, Web of Science, Cochrane Central Register of Controlled trials databases, and the Clinicaltrials.gov-registry.

Eighteen studies met our inclusion criteria: 1 meta-analysis, 2 randomized control trials, 2 prospective, 4 retrospective studies, 8 case reports, and 2 reviews.

Accumulating evidence suggests that ECT might have a beneficial effect on the core symptoms of PTSD with comorbid conditions, such as depression or schizophrenia. Although in some studies, the effect on core PTSD symptoms was not related to an antidepressant effect of ECT, these findings need further replication. Nevertheless, in severe and intractable cases, ECT can be considered, especially in the presence of comorbid depression. Further research in patients without comorbidity is warranted.
Cardiac MRI Phasic Assessment of Strain in Right Ventricular Dysfunction
Authors: Janowski Alexandra M , Mueller Finley , Agarwal Shreya , Visovatti Scott , Vanderpool Rebecca R
Published: August 2024

Background

RV strain associates with mortality in pulmonary hypertension (PH) but time-resolved strain is not typically assessed. The aim was to evaluate phasic changes in RV strain using cardiac magnetic resonance (CMR) images. We hypothesized that phasic changes in ejection and filling RV strain significantly associate with outcomes in PH.

Methods

Participants were identified from the Ohio State University CMR PH registry (n=96). RV endocardial areas were segmented from 4-chamber CMR Cine images. Time-resolved strains were calculated for RV global, free wall and septal strain. Ventricular dynamics were assessed during the ejection, early filling and late filling cardiac phases to quantify phasic changes in function. RV contractility, afterload and diastolic stiffness were quantified using the single-beat method. Outcomes were evaluated at one year.

Results

In this retrospective, single-center study, 96 participants with and without pulmonary hypertension were included. Cohort was predominately female (n=53, 55%) with elevated mean pulmonary arterial pressure (38[26-48] mmHg) and reduced RV function (RVEF: 42[31-54] %, TAPSE of 19[15-23] cm). Filling strain patterns described changes in ventricular dynamics but did not associate with RV dilation or other measures characteristic of RV dysfunction. In comparison, decreased free wall strain and increased diastolic stiffness both associated with RV dysfunction but there were no significant differences in strain patterns. Participants with strain pattern 3, decreased free wall strain or increased Eed had increased one-year mortality. When investigated together, participants with decreased free wall strain, RVEF and increased Eed had greatly reduced one-year survival.

Conclusions

Assessment of phasic changes in ventricular function does provide additional pathophysiological information but assessment of strain patterns alone are not sufficient for identifying reduced function. Deep phenotyping using a combination of RV strain and diastolic stiffness is highly selective of participants with increased one-year mortality.
Histone lactylation: a new epigenetic mark in the malaria parasitePlasmodium
Authors: Jabre Ibtissam , Andoh Nana Efua , Naldoni Juliana , Gregory William , Yoon Chae Eun , Cunnington Aubrey J. , Georgiadou Athina , Blagborough Andrew M. , Merrick Catherine J.
Published: August 2024

In the malaria parasitePlasmodium falciparum,epigenetic modifications such as acetylation and methylation play important roles in parasite biology and virulence. Here, we characterised a new epigenetic mark, histone lactylation, recently discovered in humans and also present inPlasmodium. It was found in two human malaria parasites,P. falciparumand the zoonotic macaque parasiteP. knowlesi, and was also foundin vivoin two rodent malaria models. Histones were lactylated rapidly in response to elevated lactate levels, either exogenously added or endogenously generated by the parasite’s own metabolism, and they were rapidly delactylated when lactate levels fell. Thus, this epigenetic mark is well-placed to act as a metabolic sensor, since severe falciparum malaria characteristically leads to hyperlactataemia in infected patients. Mass spectrometry showed that lysines on several parasite histones could be lactylated, and that this was accompanied by lactylation of many non-histone chromatin proteins. Histone lactylation was less abundant and less inducible inP. knowlesithan inP. falciparum, suggesting thatP. falciparummay have evolved particular epigenetic responses to this characteristic feature of its pathology. Finally, in the rodent modelP. yoelii, hyperlactataemia correlated with parasite transcriptomic programmes that suggested metabolic ‘dormancy’.
Transcriptional and epigenetic response of rapeseed (Brassica napusL.) to PEG-triggered osmotic stress
Authors: Prasad Melvin , Shetty Prateek , Pal Avik Kumar , Rigó Gábor , Kant Kamal , Zsigmond Laura , Nagy István , Shivaprasad P. V. , Szabados László
Published: August 2024

Drought hinders growth, development, and productivity of higher plants. While physiological and molecular background of plant responses to drought has extensively studied, the role of epigenetic modifications in response to dehydration remains largely elusive. In this study, we deciphered genome-wide transcriptomic and epigenetic responses of rapeseed (Brassica napusL.) to dehydration. High-throughput transcript profiling (RNA-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq) of PEG-treated rapeseed plants revealed genome-scale changes in transcription and histone methylation patterns, focusing on histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 tri-methylated lysine 27 (H3K27me3). We have identified large gene sets with altered transcript profiles and changed histone methylation marks in response to osmotic stress, revealed a close correlation between gain or loss of histone methylation and activation or repression of gene expression. Significant epigenetic regulation of Delta 1-Pyrroline-5-Carboxylate Synthetase (P5CS) genes, which control the key step in proline synthesis, was discovered as several PEG-inducedBnP5CSAgenes displayed enhanced H3K4me3 and/or H3K36me3 marks. Targeted bisulphite sequencing revealed that oneBnP5CSAgene has stress-dependent gene body DNA methylation also. By integrating physiological, transcriptional and epigenetic data, our study facilitates better understanding drought response control in higher plants.
Detection of novelPlasmodium falciparumhaplotypes under treatment pressure in pediatric severe malaria
Authors: Fogang Balotin , Guillochon Emilie , Kamaliddin Claire , Agbota Gino , Ezinmegnon Sem , Alao Maroufou Jules , Deloron Philippe , Bertin Gwladys , Claessens Antoine
Published: August 2024

Background

In Africa, the clearance time forP. falciparumsevere malaria varies significantly, likely due to the complexity ofP. falciparuminfections and the sequestration phenomenon exhibited by this parasite. This study aims to evaluate different methods to study intra-host dynamics of polygenomic infections during parasite clearance under antimalarial treatment. Additionally, it seeks to determine the association between parasite clearance rate following artesunate or quinine treatment and the genetic complexity ofP. falciparumin Beninese children with severe malaria.

Methods

Sixty-fiveP. falciparumsevere malaria individuals diagnosed by microscopy and treated with artesunate or quinine were sampled every 8 hours for 24 hours. Using whole genome sequencing (WGS) data, we estimated the multiplicity of infection (MOI) with three algorithms (Fws, THE REAL McCOIL, and RoH). We then characterized theP. falciparumgenetic complexity in WGS-identified polyclonal infections using amplicon sequencing (AmpSeq) on DNA extracted from plasma and from the red blood cells pellet.

Results

AmpSeq demonstrated greater sensitivity in detecting multiple genomes within isolates compared to WGS methods. The MOI from AmpSeq was significantly higher in RBC pellets compared to plasma (2.4 vs 1.8 distinct microhaplotypes per isolate). However, at parasitaemia over 1000 parasites/uL, the same MOI was detected in both plasma and pellet samples in 85.4% of the isolates. We observed a high variability in parasite clearance rate among participants, but it was not associated with parasite MOI at diagnostic. Interestingly, in 60.9% of participants, previously undetected microhaplotypes appeared in circulation 16 hours after treatment initiation.

Conclusion

These findings demonstrate that combining different haplotyping techniques effectively determines parasite genetic complexity. Additionally, plasma can be effectively used for parasite genotyping at sufficient parasitaemia levels. The parasite clearance rate of severe malaria is independent of parasite MOI. However, genotyping a single blood sample upon hospital admission does not capture the full spectrum of parasite genotypes present in the infection.
Interrelationship of Substrate Crystallinity, Enzyme Binding Strength, and Cellulase Activity
Authors: Avelar Molina Gustavo , Schaller Kay , Kari Jeppe , Schiano-di-Cola Corinna , Peters Günther H. J. , Borch Kim , Westh Peter
Published: August 2024

Structural polysaccharides are difficult to degrade due to their crystalline structure. Hence, industrial conversion of biomass has focused on both substrate pretreatment and enzyme engineering to improve the biochemical conversion of biomass into fuels and chemicals. However, few studies have explored the interrelationship between substrate crystallinity and cellulase activity. Here, we systematically investigated the kinetics of structurally diverse cellulases on five cellulosic substrates with varying crystallinity. Regardless of enzyme structure and catalytic mechanism, we observed a linear scaling of the kinetic parameters (KMandkcat) in a log-log plot, indicating a linear free energy relationship (LFER) between binding and activation energy. LFERs were observed for all investigated substrates, but their slopes varied distinctly and appeared linked to the substrate crystallinity. Substrates with low crystallinity exhibited LFERs with a slope near 1, while highly crystalline substrates had a slope of approximately 0.25, providing insights into the transition state (TS) for the rate-limiting step. We propose that maximal turnover was limited by slow dissociation, with the TS structurally close to the enzyme-ligand complex on crystalline substrate, while on amorphous substrate, the TS structure was closer to the dissociated system. We suggest that these observations reflect competing interactions of the ligand with respectively the enzyme binding cleft and the substrate matrix. This study emphasizes the interconnected nature of substrate pretreatment and enzyme engineering, urging a holistic approach to propel the biochemical conversion of lignocellulosic biomass, crucial for advancing sustainable production of fuels and chemicals.
Nicotine engages a VTA-NAc feedback loop to inhibit amygdala-projecting dopamine neurons and induce anxiety
Authors: Le Borgne T. , Nguyen C. , Vicq E. , Jehl J. , Solié C. , Guyon N. , Daussy L. , Gulmez A. , Reynolds L.M. , Mondoloni S. , Tolu S. , Pons S. , Maskos U. , Valjent E. , Mourot A. , Faure P. , Marti F.
Published: August 2024

Nicotine activates ventral tegmental area (VTA) dopaminergic (DA) neurons projecting to the nucleus accumbens (NAc) to drive its reinforcing effects. Simultaneously, it inhibits those projecting to the amygdala (Amg) to mediate anxiety through a process that remains unknown. Here we show that NAc- and Amg-projecting DA neurons respond with similar polarities to ethanol and nicotine, suggesting a shared network-based mechanism underlying the inhibitory effect of these otherwise pharmacologically-distinct drugs. Selective activation of NAc-projecting DA neurons, using genetic or optogenetic strategies, produced inhibition of Amg-projecting DA neurons, through a GABAergic feedback loop. Furthermore, optogenetically silencing this feedback loop prevented nicotine from inducing both inhibition of DA neurons and anxiety-like behavior. Therefore, nicotine-induced inhibition of the VTA-Amg DA pathway results from a VTA-NAc inhibitory feedback loop, mediating anxiety.
Epigenetic control of tetrapyrrole biosynthesis bym4C DNA methylation in a cyanobacterium
Authors: Schmidt Nils , Stappert Nils , Nimura-Matsune Kaori , Watanabe Satoru , Sobotka Roman , Hagemann Martin , Hess Wolfgang R.
Published: August 2024

Epigenetic DNA modifications are pivotal in eukaryotic gene expression, but their regulatory significance in bacteria is less understood. InSynechocystis6803, the DNA methyltransferase M.Ssp6803II modifies the first cytosine in the GGCC motif, forming N4-methylcytosine (GGm4CC). Deleting thesll0729gene (Δsll0729) caused a bluish phenotype due to reduced chlorophyll levels, which was reversed by suppressor mutations. Re-sequencing of seven suppressor clones revealed a common GGCC to GGTC mutation in theslr1790promoter’s discriminator sequence, encoding protoporphyrinogen IX oxidase, HemJ, crucial for tetrapyrrole biosynthesis. Transcriptomic and qPCR analyses indicated aberrantslr1790expression in Δsll0729mutants. This aberration led to the accumulation of coproporphyrin III and protoporphyrin IX, indicative of impaired HemJ activity. To confirm the importance of DNA methylation inhemJexpression, native and mutatedhemJpromoter variants were introduced into the wild type, followed bysll0729deletion. Thesll0729deletion segregated in strains with the GGTC motif in thehemJpromoter, resulting in wild-type-like pigmentation, whereas freshly prepared Δsll0729mutants with the nativehemJpromoter exhibited the bluish phenotype. These findings demonstrate thathemJis tightly regulated inSynechocystisand that N4-methylcytosine is essential for properhemJexpression.
Identification of phenotypic and transcriptomic signatures underpinning maize crown root systems
Authors: Callwood Jodi B. , Townsend Ella G. , Malik Shikha , Draves Melissa A. , Khor Jasper , Marshall Jackson P. , Sweers Heather , Cowling Craig L. , Walley Justin W. , Kelley Dior R.
Published: August 2024

Maize is pivotal in supporting global agriculture and addressing food security challenges. Crop root systems are critical for water uptake and nutrient acquisition, which impacts yield. Quantitative trait phenotyping is essential to understand better the genetic factors underpinning maize root growth and development. Root systems are challenging to phenotype given their below-ground, soil-bound nature. In addition, manual trait annotations of root images are tedious and can lead to inaccuracies and inconsistencies between individuals, resulting in data discrepancies. To address these issues, we have developed an automated phenotyping pipeline for field-grown maize crown roots by leveraging open-source software. Phenotypic variation of 20 maize genotypes from the Wisconsin Diversity panel was significant for numerous root traits, suggesting a genetic basis for the observed developmental deviations. In addition, juvenile root traits from controlled environment conditions exhibited inconsistent correlation with field-grown adult root traits, underscoring the developmental plasticity prevalent during maize root morphogenesis. Transcripts involved in hormone signaling and stress responses were among differentially expressed genes in roots from 20 maize genotypes, suggesting many molecular processes may underlie the observed phenotypic variance. This study furthers our understanding of genotype-phenotype relationships, which is relevant for informing agricultural strategies to improve maize root physiology.
CLEAR-IT: Contrastive Learning to Capture the Immune Composition of Tumor Microenvironments
Authors: Spengler Daniel , Korovin Serafim , Prakash Kirti , Bankhead Peter , Debets Reno , Smith Carlas , Balcioglu Hayri E.
Published: August 2024

Accurate phenotyping of cells in the tumor microenvironment is crucial for understanding cancer biology and developing effective therapies. However, current methods require precise cell segmentations and struggle to generalize across different imaging modalities, limiting their utility in digital pathology. Here, we show that Contrastive Learning Enabled Accurate Registration of Immune and Tumor Cells (CLEAR-IT) overcomes these limitations, providing a robust and versatile tool for cell phenotyping. CLEAR-IT accurately phenotypes cells comparable to state-of-the-art methods, generalizes across multiplex imaging modalities, maintains high performance even with limited number of labels, and enables the extraction of prognostic markers. Additionally, CLEAR-IT can be combined with existing methods to boost their performance, whereas its lack of need for precise cell segmentations significantly reduces training efforts. This method enhances the robustness and efficiency of digital pathology workflows, making it a valuable tool for cancer research and diagnostics.
Pollen foraging mediates exposure to dichotomous stressor syndromes in honey bees
Authors: Wizenberg Sydney B. , French Sarah K. , Newburn Laura R. , Pepinelli Mateus , Conflitti Ida M. , Moubony Mashaba , Ritchie Caroline , Jamieson Aidan , Richardson Rodney T. , Travas Anthea , Imrit Mohammed Arshad , Chihata Matthew , Higo Heather , Common Julia , Walsh Elizabeth M. , Bixby Miriam , Guarna M. Marta , Pernal Stephen F. , Hoover Shelley E. , Currie Robert W. , Giovenazzo Pierre , Guzman-Novoa Ernesto , Borges Daniel , Foster Leonard J. , Zayed Amro
Published: August 2024

Recent declines in the health of honey bee colonies used for crop pollination pose a considerable threat to global food security. Foraging by honey bee workers represents the primary route of exposure to a plethora of toxins and pathogens known to affect bee health, but it remains unclear how foraging preferences impact colony-level patterns of stressor exposure. Resolving this knowledge gap is crucial for enhancing the health of honey bees and the agricultural systems that rely on them for pollination. To address this, we carried out a national-scale experiment encompassing 456 Canadian honey bee colonies to first characterize pollen foraging preferences in relation to major crops, then explore how foraging behaviour influences patterns of stressor exposure. We used a metagenetic approach to quantify honey bee dietary breadth and found that bees display distinct foraging preferences that vary substantially relative to crop type and proximity, and the breadth of foraging interactions can be used to predict the abundance and diversity of stressors a colony is exposed to. Foraging on diverse plant communities was associated with increased exposure to pathogens, while the opposite was associated with increased exposure to xenobiotics. Our work provides the first large-scale empirical evidence that pollen foraging behaviour plays an influential role in determining exposure to dichotomous stressor syndromes in honey bees.

Significance Statement

Insect-mediated pollination is an important ecological process that is crucial for food production. Managed honey bee colonies are one of the most important insect pollinators, but their health has been under threat from a variety of stressors. Bee workers are primarily exposed to stressors while foraging and understanding how bee foraging preferences are related to exposure risk could provide pivotal information to improve management efforts. Here, we studied honey bee foraging preferences in relation to prominent Canadian crops and across a gradient of modified environments. We found that honey bees show distinct, measurable foraging preferences and that dietary diversity is a strong predictor of the stressors that colonies are exposed to.
Structure of the T=13 capsid of infectious pancreatic necrosis virus (IPNV) - a salmonid birnavirus
Authors: Munke Anna , Ahmed Abdelrahim Gamil Amr , Mikalsen Aase B. , Wang Han , Evensen Øystein , Okamoto Kenta
Published: August 2024

Birnaviruses infect a broad range of vertebrate hosts, including fishes and birds, and cause substantial economic losses in the fishery and livestock industries. The infectious pancreatic necrosis virus (IPNV), an aquabirnavirus, specifically targets salmonids. While structures on T=1 subviral particles of the birnaviruses, including IPNV, have been studied, structural insights into the infectious T=13 particles have been limited to the infectious bursal disease virus (IBDV), an avibirnavirus. Determining the capsid structure of the T=13 particle of IPNV is crucial for advancing knowledge of its antigenicity, capsid assembly, and possible functional structures. Here, the capsid structure of the IPNV L5 strain has been determined at a resolution of 2.75 Å. The overall structure resembles the T=13 IBDV structure, with notable differences in the surface loops on the P domain of the VP2 capsid protein, essential for antigenicity and virulence. Additionally, previously undescribed structural features have been identified, including the C-terminal regions of the VP2 subunits within the pentagonal assembly unit at each 5-fold axis, which interlock with adjacent VP2 subunits. This interlocking, together with class-averaged projections of triangular and pentagonal units, suggests that the pentagonal unit formation could be important for correct T=13 particle assembly, preventing the formation of T=1 subviral particles. Furthermore, positively charged residues in obstructed capsid pores at each 5-fold axis are speculated to facilitate intraparticle genome synthesis of IPNV.

Importance

Aquabirnaviruses cause deadly infectious diseases in salmonid fish, posing significant challenges for both wild and farmed fish populations. The most prevalent aquabirnavirus worldwide is the infectious pancreatic necrosis virus, whose multifunctional capsid is critical to its infection, replication, and maturation. Previously, research has focused on the structure of the virus’s non-infectious subviral capsid. In this study, however, the first structure of the large, infectious, and functional form of the capsid has been determined. This new capsid structure reveals functional motifs that were previously unclear in the non-infectious capsid. These motifs are believed to be essential for the virus’s replication and particle assembly, making them promising targets for developing strategies to control virus proliferation.
Tree nursery environments and their effect on early trait variation
Authors: Perry Annika , Beaton Joan K. , Stockan Jenni A. , Iason Glenn R. , Cottrell Joan E. , Cavers Stephen
Published: August 2024

Despite the major role of nurseries in raising young plants and trees prior to transplantation, not enough is known about how the nursery climate impacts the growth and development of plants from germination through to maturity. It is important for forestry practitioners to understand the effect that different nursery environments may have on early stage growth as these may exceed differences due to genetic variation and can confound the use of early stage traits for selection. Here, a replicated progeny-provenance experiment of the economically and ecologically important species Scots pine (Pinus sylvestrisL.) was established in three environmentally distinct nurseries in Scotland and traits including survival, growth, form and phenology were measured. Temperature variation and photoperiod were the only uncontrolled environmental variables during this period, and their effect on measured traits was found to be significant among nurseries from the first growing season onwards. Trait interactions were not consistent between nurseries, indicating that the effectiveness of using proxy traits to select for desirable characteristics may depend on the environment in which the trees are grown. This study is the first in a series that will examine trait variation in Scots pine from seedlings to mature trees and highlights the importance of carefully considering and accounting for the nursery environment when growing trees for subsequent transplantation.