bluuebunny/crossref_metadata_2025 huggingface dataset:
639 - Efficacy and safety of once-daily roflumilast cream 0.05% in pediatric patients 2 to 5 years of age with mild to moderate atopic dermatitis (INTEGUMENT-PED): a phase 3 randomized controlled trial
Authors: Eichenfield Lawrence , Browning John , Funk Tracy , Gonzalez Mercedes E , Hebert Adelaide A , Lee Mark , Prajapati Vimal H , Serrao Rocco , Swanson Lisa , Higham Robert , Berk David
Published: August 2024

Background

Roflumilast is a highly potent phosphodiesterase 4 inhibitor under investigation as a non-steroidal, once-daily cream for atopic dermatitis (AD).

Methods

INTEGUMENT-PED (NCT04845620) was a Phase 3 parallel-group, double-blind, vehicle-controlled trial. Children aged 2 to 5 years with mild to moderate AD were treated with roflumilast cream 0.05% (n=437) or vehicle (n=215) once-daily for 4 weeks. The primary efficacy endpoint was validated Investigator Global Assessment-Atopic Dermatitis (vIGA-AD) Success (defined as a score of 0 [clear] or 1 [almost clear] with 2-grade improvement from baseline) at Week 4. Secondary endpoints included 75% improvement in Eczema Area and Severity Index (EASI-75). Worst-Itch-Numeric Rating Score (WI-NRS) Success (≥4-point improvement in patients with baseline ≥4), safety, and tolerability were also assessed.

Results

At Week 4, significantly more roflumilast-treated than vehicle-treated patients achieved vIGA-AD Success (25.4% vs 10.7%; P<0.0001), EASI-75 (39.4% vs 20.6%; P<0.0001), and WI-NRS Success (35.3% vs 18.0%; nominal P=0.0002). Improvement in pruritus was observed by 24 hours after first application (nominal P=0.0014 versus vehicle). Incidence of treatment-emergent adverse events (AEs) was low in both arms, with 98.9% assessed as mild to moderate. AEs occurring in >2% of patients and greater in the roflumilast-treated group were upper respiratory tract infection, diarrhea, and vomiting. For local tolerability, >92% of roflumilast-treated patients reported no or mild sensation across arms at any timepoint.

Conclusion

In this phase 3 trial, once-daily roflumilast cream 0.05% improved AD in pediatric patients (2 to 5 years of age), while demonstrating favorable safety and tolerability.
651 - Improvement of the head and neck regions with continuous tralokinumab treatment for up to 4 years in adults with moderate-to-severe atopic dermatitis
Authors: Chovatiya Raj , Wollenberg Andreas , Ribero Simone , Saeki Hidehisa , Øland Christian B , Steffensen Louise A , Tindberg Ann-Marie , Thyssen Jacob P , Blauvelt Andrew
Published: August 2024

Introduction/Background

Atopic dermatitis (AD) is a chronic, inflammatory disease that can affect multiple regions of the body, but can be particularly burdensome on exposed areas of skin, such as the head and neck (H&N).Tralokinumab, a high-affinity monoclonal antibody that specifically neutralizes interleukin-13, is approved in multiple countries for adults with moderate-to-severe AD. Phase 3 trials showed tralokinumab provided significant improvements in AD severity and was well-tolerated up to 52 weeks of treatment. The ongoing open-label, 5-year extension trial, ECZTEND (NCT03587805), assesses the safety and efficacy of tralokinumab after the completion of parent trials (PT).

Objective

To assess tralokinumab efficacy in the H&N region.

Methods

This post hoc analysis included adult patients with moderate-to-severe AD initially randomized to tralokinumab 300mg Q2W in the phase 3 PTs ECZTRA 1 (NCT03131648) or ECZTRA 2 (NCT03160885). Patients on active tralokinumab treatment were followed for up to 52 weeks in PTs and for up to 152 weeks in ECZTEND as of data cutoff April 30, 2022. Patients re-randomized to placebo at Week (Wk) 16 were not included beyond that timepoint. For this analysis, overall EASI and H&N regional EASI (H&N EASI) were evaluated. H&N EASI (0-7.2) was calculated based on the severity of erythema, induration/papulation, excoriation, lichenification and area of involvement. All data were analyzed and presented as observed.

Results

At baseline, 87.8% (1047/1192) of patients had H&N involvement (H&N EASI>1), and 49.9% (591/1192) of patients exhibited severe AD (IGA 4). Baseline median H&N EASI for the pooled PTs was 3.0 (IQR 1.8; 4.5). In the pooled PTs, 48.2% (542/1125) and 71.2% (558/784) of patients achieved H&N EASI≤1, at Wk16 and Wk52, respectively. After 3 years additional treatment (Wk152 in ECZTEND), the proportion of patients with H&N EASI≤1 was 87.2% (232/266) and the median H&N EASI was 0.2 (IQR 0.0; 0.5). In the subgroup of patients (n=301) with severe AD (IGA 4) and high H&N involvement (H&N EASI≥4), median H&N EASI improved from 5.4 at baseline to 2.4 and 0.8 at Wk16 and Wk52, respectively, and 0.4 at Wk152. Improvements in H&N region were comparable to overall EASI improvement.

Conclusions

Tralokinumab provided sustained improvements in the H&N regions in patients with moderate-to-severe AD for up to 4 years. Sustained improvements were also seen in patients with severe disease and substantial H&N involvement at baseline.
731 - Quality of life in atopic dermatitis: the patient perspective
Authors: Jiminez Victoria , Crawford Michaela , Mayo Tiffany
Published: August 2024

Introduction

Atopic Dermatitis (AD) is a cutaneous disease affecting all ages and demographics. Even in an era of biological treatments, many patients continue to struggle with disease factors that influence their overall quality of life.

Objectives

This study aims to highlight perceived influential factors related to QOL in atopic dermatitis from patient-reported experiences.

Methods

This study is an IRB-approved cross-sectional survey of patients with a diagnosis of atopic dermatitis at a single academic institution. The survey was conducted via phone calls. Patients were asked to self-report information related to their diagnosis, comorbidities, residential community, and factors that contribute to quality of life. Statistical analysis was performed with SPSS.

Results

Sixty-four patients agreed to participate in the survey, with a response rate of 78%. Responders were mostly female (55%) with a mean age of 41 and were racially diverse (White/Caucasian) 48%, Black or African American 36%, and Asian or Asian American 16%). Self-reported disease severity was labeled as mild (17%), moderate (33%), or severe (50%). Many patients had psychiatric comorbidities (anxiety 39%, depression 22%). Subjective feelings of being less attractive or less confident due to AD were significant on logistic regression in those with severe disease (p=0.048, OR 2.78, CI (1.0-7.6) and female gender (p=0.007). The severe group also reported experiencing prior judgment or discrimination (63%) and felt their work or school performance had been affected by their AD (47%), more commonly in males (p=0.026). Differences in race were not significant. Most patients reported itch as being the most bothersome symptom (66%). When asked to choose the top factors contributing to their quality of life related to their AD, symptom burden was the most common (88%) followed by time spent obtaining medical care (45%), and treatment regimen difficulty (39%). More than one in every ten patients (16%) reported that their life goals or dreams had been affected by their disease.

Conclusion

The psychosocial implications of atopic dermatitis remain a significant barrier to patient-perceived quality of life. While symptomatic management remains a large proponent of barriers to QOL improvement, perceived stigmatization anecdotally affects those with AD to a significant degree. Further studies and interventions are needed to discern specific areas of improvement for QOL in atopic dermatitis.
Cortical CD200–CD200R and CD47–SIRPα expression is associated with multiple sclerosis pathology
Authors: van den Bosch Aletta M R , Wever Dennis , Schonewille Pleun , Schuller Sabine L , Smolders Joost , Hamann Jörg , Huitinga Inge
Published: August 2024

Control of microglia activity through CD200–CD200R and CD47–SIRPα interactions has been implicated in brain homeostasis. Here, we assessed CD200, CD47, CD200R and SIRPα expression with qPCR and immunohistochemistry in multiple sclerosis (MS) normal-appearing cortical grey matter (NAGM), normal-appearing white matter (NAWM), cortical grey matter (GM) lesions and perilesional GM, and compared this to control GM and white matter (WM), to investigate possible altered control of microglia in MS. In MS NAGM, CD200 expression is lower compared with control GM, specifically in cortical layers 1 and 2, and CD200 expression in NAGM negatively correlates with the cortical lesion rate. Interestingly, NAGM and NAWM CD200 expression is positively correlated, and NAGM CD200 expression negatively correlates with the proportion of active and mixed WM lesions. In GM lesions, CD200 and CD47 expressions are lower compared with NAGM and perilesional GM. CD200R expression is lower in MS NAGM, whereas SIRPα was increased in and around GM lesions. Taken together, our data indicate that CD200 and CD47 play a role in GM MS lesion formation and progression, respectively, and that targeting CD200 pathways may offer therapeutic avenues to mitigate MS pathology in both WM and GM.
Gastric preconditioning via percutaneous angioembolization before esophagectomy in patients at high risk for esophageal leak
Authors: Bevers Kaitlin C , Sewell Marisa , Bott Matthew J , Sihag Smita , Park Bernard J , Ridouani Fourat , Muñoz Fernando Gómez , Santos Ernesto , Molena Daniela
Published: August 2024

Anastomotic leaks and stenoses remain critical complications in esophagectomy and are related to conduit perfusion. Surgical gastric preconditioning has been described but requires additional surgery and creates scar tissue, potentially hindering future operation. We sought to evaluate the feasibility and safety of percutaneous gastric preconditioning by angioembolization to improve perfusion of gastric conduits before esophagectomy in a high-risk patient cohort. Patients pending an esophagectomy for cancer and deemed to be high risk for anastomotic complications underwent preconditioning by image-guided angioembolization. Preconditioning was performed on an outpatient basis by means of superselective embolization of the left gastric and short gastric arteries. Intraoperative conduit perfusion evaluation with indocyanine green and postoperative surgical outcomes was reviewed. Seventeen patients underwent gastric preconditioning, with no complications observed. Thirteen of the 17 patients ultimately underwent esophagectomy; the remaining four patients were not candidates for an operation. Patients proceeded to surgery a median of 23 days (interquartile range, 21–27 days) after preconditioning. The intraoperative indocyanine green perfusion of all conduits was appropriate, with no tip demarcation and with a median time to dye uptake of 20s (interquartile range, 15–20s). There were no anastomotic stenoses or leaks noted within the series. Gastric conduit preconditioning by percutaneous angioembolization of the left gastric and short gastric arteries can be performed safely and without operative delay in high-risk patients. Further evaluation of preconditioning for conduit optimization is warranted to limit the critical complications of anastomotic leak and stenosis in esophagectomy.
Alterations in left atrial and left ventricular coupling in mixed aortic valve disease
Authors: Sooriyakanthan Maala , Graham Fraser J , Ho Natalie , Leong-Poi Howard , Tsang Wendy
Published: August 2024

Aims

To characterize left atrial (LA) and left ventricular (LV) function and atrioventricular (AV) coupling in patients with moderate mixed aortic valve disease (MMAVD) against those with isolated moderate or severe aortic valve disease and controls.

Methods and results

Retrospective LA and LV peak longitudinal strain (LS) analysis were performed on 260 patients [46 MMAVD, 81 moderate aortic stenosis (AS), 50 severe AS, 48 moderate aortic regurgitation (AR), and 35 severe AR] and 66 controls. Peak LV and LA LS and AV coupling, assessed by combined peak LA and LV strain, was compared between the groups. Analysis of variance and two-sided t-tests were used, and a P-value of <0.01 was considered significant. LV strain was significantly lower in those with MMAVD compared with controls and those with moderate or severe isolated AR but comparable to those with moderate or severe AS (−17.1 ± 1.1% MMAVD vs. −17.7 ± 1.5% moderate AS, P = 0.02, vs. −17.0 ± 1.5% severe AS, P = 0.74). AV coupling was significantly lower in those with MMAVD compared with controls and those with moderate AS or AR but comparable to those with severe AS or AR (47.1 ± 6.8% MMAVD vs. 45.1 ± 5.6% severe AS, P = 0.13, vs. 50.4 ± 9% severe AR, P = 0.07).

Conclusion

Impairments in AV coupling are comparable for patients with MMAVD and those with severe isolated AS or AR. Impairments in LV GLS in MMAVD mirror those found in severe AS. These findings suggest that haemodynamic consequences and adverse remodelling are similar for patients with MMAVD and isolated severe disease.
Ocular blood flow dynamics following sinus rhythm restoration through catheter ablation: laser speckle flowgraphy in patients with persistent atrial fibrillation
Authors: Yamamoto Nobuhiko , Nakano Makoto , Nochioka Kotaro , Yasuda Masayuki , Kunikata Hiroshi , Nakazawa Toru , Yasuda Satoshi
Published: August 2024

Aims

Laser speckle flowgraphy (LSFG) is a well-established tool renowned for its non-invasive and reproducible assessment of ocular blood flow. While rhythm control therapies, such as catheter ablation (CA), have shown promise in enhancing cognitive function in atrial fibrillation (AF) patients, the acute impact of CA on microcirculatory changes, particularly in ocular blood flow, remains a topic of limited understanding. The present study aims to delve into the potential of LSFG in detecting microcirculatory alterations following the restoration of sinus rhythm (SR) through CA in patients with AF.

Methods and results

We studied 8 paroxysmal AF (Paf) and 20 persistent AF (PeAF) patients (mean age 67 ± 6 years, 26% female) undergoing CA. Ocular blood flow was assessed using LSFG by measuring the mean blur rate (MBR) pre- and post-CA. Post-CA, all PeAF patients achieved SR restoration, resulting in a significant increase in tissue MBR (10.0 ± 2.2 to 10.8 ± 2.9, P = 0.021). In contrast, Paf patients showed no significant difference between pre- and post-MBR (12.0 ± 2.7 vs. 11.8 ± 2.6, P = 0.76).

Conclusion

LSFG analysis effectively identified microcirculatory changes in patients undergoing CA for PeAF, suggesting that therapeutic interventions targeting the heart may have broader implications for ocular and cerebral health, establishing a novel ‘cardio-oculo-cerebral relationship’.
Thoracic sarcopenia measured by Hounsfield unit average calculation predicts morbidity and mortality in coronary artery bypass grafting
Authors: Krombholz-Reindl Philipp , Winkler Andreas , Vötsch Andreas , Hitzl Wolfgang , Schernthaner Christiana , Hecht Stefan , Seitelberger Rainald , Gottardi Roman
Published: August 2024

OBJECTIVES

The aim of the study was to investigate the potential prognostic role of preoperative measurement of erector spinae myosteatosis with Hounsfield unit average calculation as a marker for sarcopenia and frailty in patients undergoing coronary bypass surgery.

METHODS

Preoperative computer tomography-derived measurements of 479 consecutive patients undergoing coronary bypass surgery between January 2017 and December 2019 were retrospectively performed. The erector spinae muscle at the level of the 12th vertebra was manually outlined bilaterally on the axial computer tomography slices and Hounsfield unit average calculation was performed. The lower quartile of muscle density values was defined as myosteatotic and thus sarcopenic. Sarcopenic (n = 121) versus non-sarcopenic patients (n = 358) were compared regarding postoperative morbidity and short- and long-term mortality. Results were adjusted for age, body mass index, atrial fibrillation and hypertension using inverse probability weighting.

RESULTS

Sarcopenia was associated with higher 30-day mortality (4.1% vs 0.8%; P = 0.012), mid-term mortality after 1 year (9.3% vs 3.1%; P = 0.047) and 2 years (10.8% vs 4.2%; P = 0.047). Long-term mortality (5 years) was 20.8% for sarcopenic and 13.0% for non-sarcopenic patients but was not found to be significantly different (P = 0.089). Sarcopenia was associated with higher rates of reintubation (7.5% vs 1.1%; P < 0.001), sternal wound infections (7.5% vs 2.8%; P = 0.039) and acute kidney injury requiring haemodialysis (2.5% vs 0.4%; P = 0.021).

CONCLUSIONS

In patients undergoing coronary bypass surgery, sarcopenia was associated with increased short-term mortality, mid-term mortality and morbidity. The measurement of erector spinae myosteatosis could be an easy and useful parameter in preoperative risk assessment.
Revisiting Dominance in Population Genetics
Authors: Di Chenlu , Lohmueller Kirk E
Published: August 2024

Dominance refers to the effect of a heterozygous genotype relative to that of the two homozygous genotypes. The degree of dominance of mutations for fitness can have a profound impact on how deleterious and beneficial mutations change in frequency over time as well as on the patterns of linked neutral genetic variation surrounding such selected alleles. Since dominance is such a fundamental concept, it has received immense attention throughout the history of population genetics. Early work from Fisher, Wright, and Haldane focused on understanding the conceptual basis for why dominance exists. More recent work has attempted to test these theories and conceptual models by estimating dominance effects of mutations. However, estimating dominance coefficients has been notoriously challenging and has only been done in a few species in a limited number of studies. In this review, we first describe some of the early theoretical and conceptual models for understanding the mechanisms for the existence of dominance. Second, we discuss several approaches used to estimate dominance coefficients and summarize estimates of dominance coefficients. We note trends that have been observed across species, types of mutations, and functional categories of genes. By comparing estimates of dominance coefficients for different types of genes, we test several hypotheses for the existence of dominance. Lastly, we discuss how dominance influences the dynamics of beneficial and deleterious mutations in populations and how the degree of dominance of deleterious mutations influences the impact of inbreeding on fitness.
Advance Directives Revisited (2002 vs 2023): Are We Closer to Uniformity?
Authors: Luck George R , Bautista Adriana , Peters Darian , Attonito Jennifer , Fridman Sabina , Sohmer Joshua , Jacomino Mario
Published: August 2024

Background and Objectives

Advance directives (ADs) are based on state-specific statutes that vary in structure, terminology, and options. This variability leads to inconsistent end-of-life (EOL) care for patients who have executed an AD in 1 state but fall ill in another state. This study revisits a 2002 article that identified considerable differences in ADs to determine whether ADs have become more uniform.

Research Design and Methods

ADs from all 50 states and the District of Columbia were examined to determine the frequency of document types and seven key issues. The results were compared to the 2002 study using nonparametric approaches. Mean numbers of key issues were compared using t-tests and 1-way analysis of variance.

Results

Consistent with 2002, 3 states in 2023 provide statutes for a healthcare power of attorney (HCPOA). However, states offering a combined HCPOA, and living will (LW), deemed an advance directive for healthcare (ADHC), increased from 13 to 30. Between both studies, Long-Term Care increased significantly in LW and ADHC, whereas Artificial Sustenance significantly increased in LW. Despite the rising prevalence of Alzheimer’s in the United States, only 10% of states included this issue in 2023.

Discussion and Implications

Despite evolving healthcare trends, minimal revisions have been made to ADs since 2002. This lack of uniformity can cause confusion regarding the proper understanding of EOL wishes. The authors recommend that the Uniform Act for Advance Directives be revisited to promote greater uniformity in ADs and ensure that individuals’ preferences are understood and respected across different states.
Current status of global conservation and characterisation of wild and cultivated Brassicaceae genetic resources
Authors: Castillo-Lorenzo Elena , Breman Elinor , Gómez Barreiro Pablo , Viruel Juan
Published: August 2024

Background

The economic importance of the globally distributed Brassicaceae family resides in the large diversity of crops within the family and the substantial variety of agronomic and functional traits they possess. We reviewed the current classifications of crop wild relatives (CWRs) in the Brassicaceae family with the aim of identifying new potential cross-compatible species from a total of 1,242 species using phylogenetic approaches.

Results

In general, cross-compatibility data between wild species and crops, as well as phenotype and genotype characterisation data, were available for major crops but very limited for minor crops, restricting the identification of new potential CWRs. Around 70% of wild Brassicaceae did not have genetic sequence data available in public repositories, and only 40% had chromosome counts published. Using phylogenetic distances, we propose 103 new potential CWRs for this family, which we recommend as priorities for cross-compatibility tests with crops and for phenotypic characterisation, including 71 newly identified CWRs for 10 minor crops. From the total species used in this study, more than half had no records of being in ex situ conservation, and 80% were not assessed for their conservation status or were data deficient (IUCN Red List Assessments).

Conclusions

Great efforts are needed on ex situ conservation to have accessible material for characterising and evaluating the species for future breeding programmes. We identified the Mediterranean region as one key conservation area for wild Brassicaceae species, with great numbers of endemic and threatened species. Conservation assessments are urgently needed to evaluate most of these wild Brassicaceae.
Impact of reference design on estimating SARS-CoV-2 lineage abundances from wastewater sequencing data
Authors: Aßmann Eva , Agrawal Shelesh , Orschler Laura , Böttcher Sindy , Lackner Susanne , Hölzer Martin
Published: August 2024

Background

Sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA from wastewater samples has emerged as a valuable tool for detecting the presence and relative abundances of SARS-CoV-2 variants in a community. By analyzing the viral genetic material present in wastewater, researchers and public health authorities can gain early insights into the spread of virus lineages and emerging mutations. Constructing reference datasets from known SARS-CoV-2 lineages and their mutation profiles has become state-of-the-art for assigning viral lineages and their relative abundances from wastewater sequencing data. However, selecting reference sequences or mutations directly affects the predictive power.

Results

Here, we show the impact of a mutation- and sequence-based reference reconstruction for SARS-CoV-2 abundance estimation. We benchmark 3 datasets: (i) synthetic “spike-in”’ mixtures; (ii) German wastewater samples from early 2021, mainly comprising Alpha; and (iii) samples obtained from wastewater at an international airport in Germany from the end of 2021, including first signals of Omicron. The 2 approaches differ in sublineage detection, with the marker mutation-based method, in particular, being challenged by the increasing number of mutations and lineages. However, the estimations of both approaches depend on selecting representative references and optimized parameter settings. By performing parameter escalation experiments, we demonstrate the effects of reference size and alternative allele frequency cutoffs for abundance estimation. We show how different parameter settings can lead to different results for our test datasets and illustrate the effects of virus lineage composition of wastewater samples and references.

Conclusions

Our study highlights current computational challenges, focusing on the general reference design, which directly impacts abundance allocations. We illustrate advantages and disadvantages that may be relevant for further developments in the wastewater community and in the context of defining robust quality metrics.
Putting meat on the bone: how to fast-track innovative medicines to those who need them and generate data to justify continued use
Authors: Ollendorf Daniel , Henshall Christopher , Phillips Marie , Synnott Patricia , Sansom Lloyd , Tunis Sean
Published: August 2024

Regulatory agencies worldwide have taken significant steps to expedite approval and market authorization of medicines based on their potential to address areas of significant unmet medical need and severe disease burden. However, initial approval of such medicines is often accompanied by limited evidence of benefit, posing a conundrum for payers and health systems who may desire greater certainty of their value. This paper describes a system of “accelerated access” to manage these tensions and coordinate activities across stakeholders, based on discussions held at a multi-stakeholder convening in June 2023. We focus on 6 core, near-term actions that can be taken to improve the current system: clarifying criteria for expedited regulatory approval, enhancing stakeholder coordination, creating expedited pathways in payer and health technology assessment settings, developing joint regulatory/payer/health technology assessment guidance on study design and data needs, linking pricing policy to data uncertainty, and improving patient and public understanding of the processes involved as well as the risks and benefits of the relevant medicines. Many of these actions will require additional resources and personnel, and some will necessitate unprecedented levels of coordination. Nevertheless, each action is designed to work with minimal adjustments to the current system rather than demanding an entirely new approach.
Microbial communities living inside plant leaves or on the leaf surface are differently shaped by environmental cues
Authors: Mahmoudi Maryam , Almario Juliana , Lutap Katrina , Nieselt Kay , Kemen Eric
Published: August 2024

Leaf-associated microbial communities can promote plant health and resistance to biotic and abiotic stresses. However, the importance of environmental cues in the assembly of the leaf endo- and epi-microbiota remains elusive. Here, we aimed to investigate the impact of seasonal environmental variations, on the establishment of the leaf microbiome, focusing on long-term changes (five years) in bacterial, fungal, and nonfungal eukaryotic communities colonizing the surface and endosphere of six wild Arabidopsis thaliana populations. While leaf-microbial communities were found to be highly stochastic, the leaf niche had a predominant importance with endophytic microbial communities consistently exhibiting a lower diversity and variability. Among environmental factors, radiation- and humidity-related factors are the most important drivers of diversity patterns in the leaf, with stronger effects on epiphytic communities. Using linear models, we identified 30 important genera whose relative abundance in leaf compartments could be modeled from environmental variables, suggesting specific niche preferences for these taxa. With the hypothesis that environmental factors could impact interactions within microbial communities, we analyzed the seasonal patterns of microbial interaction networks across leaf compartments. We showed that epiphytic networks are more complex than endophytic and that the complexity and connectivity of these networks are partially correlated with the mentioned environmental cues. Our results indicate that humidity and solar radiation function as major environmental cues shaping the phyllosphere microbiome at both micro (leaf compartment) and macro (site) scales. These findings could have practical implications for predicting and developing field-adapted microbes in the face of global change.
The improbability of detecting trade-offs and some practical solutions
Authors: Johnson Marc T J , Nassrullah Zain
Published: August 2024

Trade-offs are a fundamental concept in evolutionary biology because they are thought to explain much of nature’s biological diversity, from variation in life-histories to differences in metabolism. Despite the predicted importance of trade-offs, they are notoriously difficult to detect. Here we contribute to the existing rich theoretical literature on trade-offs by examining how the shape of the distribution of resources or metabolites acquired in an allocation pathway influences the strength of trade-offs between traits. We further explore how variation in resource distribution interacts with two aspects of pathway complexity (i.e., the number of branches and hierarchical structure) affects tradeoffs. We simulate variation in the shape of the distribution of a resource by sampling 106 individuals from a beta distribution with varying parameters to alter the resource shape. In a simple “Y-model” allocation of resources to two traits, any variation in a resource leads to slopes less than −1, with left skewed and symmetrical distributions leading to negative relationships between traits, and highly right skewed distributions associated with positive relationships between traits. Adding more branches further weakens negative and positive relationships between traits, and the hierarchical structure of pathways typically weakens relationships between traits, although in some contexts hierarchical complexity can strengthen positive relationships between traits. Our results further illuminate how variation in the acquisition and allocation of resources, and particularly the shape of a resource distribution and how it interacts with pathway complexity, makes its challenging to detect trade-offs. We offer several practical suggestions on how to detect trade-offs given these challenges.
Ileocolic intussusception secondary to Peutz-Jeghers polyp: the need for oncological resection surgery
Authors: Ylli Kristali , Eljack Wala , Hayes Brian , Murphy Thomas
Published: August 2024

In this case report, we detail the management of a woman in her late 30s with ileocolic intussusception, emphasizing the high malignancy risk inherent in adult intussusception cases. Given the patient’s acute symptoms and significant family history of ovarian and breast cancers, radical oncological resection was pursued. The surgical intervention comprised a right hemicolectomy and right ovarian cystectomy, with histopathological findings revealing a Peutz-Jeghers polyp and benign thyroid tissue, but no malignancy. This case underscores the imperative for a surgical approach that anticipates the potential for malignancy in adult intussusception, advocating for radical resection as a fundamental strategy, even in the absence of confirmed malignant histopathology, to ensure comprehensive management and alignment with oncological best practices.
Autologous vascular proximal fibular graft in the treatment of giant cell tumor of the distal radius—a case report
Authors: Todorova Teodora , Gramatnikovski Nikola , Angelovska Tamara , Kostadinova-Kunovska Slavica , Manevska Nevena , Foteva Marta , Samardziski Milan
Published: August 2024

Giant cell tumor of bone (GCTB) represents an intermediate, locally aggressive tumor, with a peak of incidence in the third decade of life with female predominance (2:1). The distal radius is the third most common localization and especially challenging in the treatment is saving the wrist joint function. In this report, we present a case of a 32-year-old patient diagnosed with a giant cell tumor of the distal radius, primarily treated with curettage of the bone. Due to aggressive tumor recurrence, considering local control of the tumor, we decided to perform a resection of the distal radius and reconstruction with an autologous proximal vascular fibular graft. We performed a SPECT/CT scan to confirm the functionality of the graft. We find this procedure a safe technique for local control of tumor recurrence and an ideal substitute for a limb salvage procedure.
Delayed presentation of splenic laceration in a postpartum patient: a case of wandering spleen
Authors: Zayed Alaa , Samara Enas , Shubietah Abdalhakim , Awwad Ahmad , Zakaria Zaid , Daraghma Rawan , Hajhamad Mohammed
Published: August 2024

Wandering spleen (WS) is a rare condition where the spleen is abnormally mobile due to lax or poorly developed ligaments, leading to complications like torsion and laceration after trauma. We describe a case of a 31-year-old postpartum female who presented with severe abdominal pain following blunt trauma. Diagnostics showed an enlarged, ectopic spleen, and significant hematoma. Surgical exploration revealed a 10-cm splenic laceration, necessitating a splenectomy due to extensive blood loss and organ damage. This case highlights the challenges of diagnosing WS, particularly in postpartum patients with increased ligamentous laxity, emphasizing the need for vigilant monitoring and potentially preventive surgical measures to manage this complex condition effectively.
Type 2 diabetes: a sacrifice program handling energy surplus
Authors: Ye Jianping , Yin Jun
Published: August 2024

Type 2 diabetes mellitus (T2DM) is closely associated with obesity, while interactions between the two diseases remain to be fully elucidated. To this point, we offer this perspective to introduce a set of new insights into the interpretation of T2DM spanning the etiology, pathogenesis, and treatment approaches. These include a definition of T2DM as an energy surplus-induced diabetes characterized by the gradual decline of β cell insulin secretion function, which ultimately aims to prevent the onset of severe obesity through mechanisms of weight loss. The body employs three adaptive strategies in response to energy surplus: the first one is adipose tissue expansion to store the energy for weight gain under normal weight conditions; the second one is insulin resistance to slow down adipose tissue expansion and weight gain under overweight conditions; and the third one is the onset of T2DM following β cell failure to reverse the weight gain in obese conditions. The primary signaling molecules driving the compensatory responses are adenosine derivatives, such as adenosine triphosphate (ATP), acetyl coenzyme A (acetyl-CoA), and reduced nicotinamide adenine dinucleotide (NADH). These molecules exert their effects through allosteric, post-translational, and transcriptional regulation of metabolic pathways. The insights suggest that insulin resistance and T2DM are protective mechanisms in the defense against excessive adiposity to avert severe obesity. The perspective provides a unified framework explaining the interactions between the two diseases and opens new avenues in the study of T2DM.
Truth and Finite Conjunction
Authors: Luo Guanglong , Horsten Leon , Roberts Sam
Published: August 2024

This note is a critical response to Kentaro Fujimoto’s new conservativeness argument about truth, which centres on the notion of finite conjunction. We argue that Fujimoto’s arguments turn on a specific way of formalizing the notions of finite collection and finite conjunction in first-order logic. In particular, by instead formalizing these concepts in a natural way in set theory or in second-order logic, Fujimoto’s new conservativeness argument can be resisted.
Septic cardioembolic stroke secondary to infective endocarditis in a young patient with rheumatic heart disease: a case report
Authors: Buque Helena Agostingo , Namburete Evangelina , Vaz Deise Catamo , Sebasteão Frederico João , Baduro Yanina , Rosales Elder Lorenzo , Arroz Nachan , Bacallao Lazara , Pizzol Damiano , Smith Lee
Published: August 2024

The risk of stroke due to infective endocarditis is particularly high during the first week. Moreover, in low-resource settings where imaging access is limited, and diagnostic pathways are inaccurate the risk further increases. In addition to antibiotic therapy, treatment may include intravenous thrombolysis, with high risk of hemorrhagic complications in patients with infective endocarditis or mechanical thrombectomy. We report here a case of a 24-year-old male with rheumatic heart disease presenting a septic cardioembolic stroke secondary to infective endocarditis that was successfully treated in a low-resource setting.
Reversible cerebral vasoconstriction syndrome due to teprotumumab: two case reports
Authors: Elfil Mohamed , Lookian Pashayar P , Kumari Kanchan , Aladawi Mohammad , Jedras Mark , Phillips Steven M , Sattur Mithun G
Published: August 2024

Background: Reversible Cerebral Vasoconstriction Syndrome (RCVS) involves cerebral vasculature constriction and dilation. While the exact pathophysiology of RCVS is still not fully understood, there are multiple etiological factors suggested to be implicated in triggering RCVS. We report two RCVS cases potentially linked to teprotumumab. Case 1: A 59-year-old female with Graves’ eye disease (GED) developed leg weakness and headache after initiating teprotumumab, and neuroimaging studies revealed multifocal cerebral vasospasm (CVS). Verapamil mitigated vasospasm and the patient overall improved. Case 2: A 71-year-old female with GED developed thunderclap headache two months after starting teprotumumab, with subarachnoid hemorrhage (SAH) and CVS revealed on neuroimaging studies. The patient improved on verapamil and was discharged without deficits. Conclusions: The temporal correlation between teprotumumab initiation and RCVS’s symptom onset raises concern for the potential involvement of teprotumumab in triggering RCVS via disrupting cerebrovascular modulation. Further research is needed to investigate this proposed association.
Low-affinity LFA1-dependent outside-in signaling mediates avidity modulation via the Rabin8–Rab8 axis
Authors: Kondo Naoyuki , Ueda Yoshihiro , Kinashi Tatsuo
Published: August 2024

Lymphocyte interactions mediated by leukocyte integrin lymphocyte function–associated antigen 1 (LFA1) and intercellular adhesion molecules (ICAMs) are important for lymphocyte trafficking and antigen recognition. Integrins are regulated by the modulation of ligand-binding affinity and avidity (valency). Although the mechanism underlying high-affinity LFA1 binding has been investigated extensively, the molecular mechanisms by which low-affinity multivalent binding initiates adhesion remain unclear. We previously showed that ICAM1 and monoclonal antibodies that recognize specific LFA1 conformations induce the accumulation of LFA1 at the contact surface. In this study, we found that the small GTPase Rab8 is critical for intracellular transport and accumulation of LFA1 at cell contact areas mediated by low-affinity LFA1-dependent outside-in signaling. Super-resolution microscopy revealed that Rab8 co-localized with LFA1 in small vesicles near the contact membrane. Inactivation of Rab8 decreased ICAM1-dependent adhesion and substantially reduced LFA1 density on the contact membrane. The GTP-bound active form of Rab8 increased cell adhesiveness and promoted LFA1 accumulation at the contact area through co-trafficking with LFA1. Rab8 activation was induced by low-affinity conformation-dependent outside-in signaling via the guanine exchange factor Rabin8, which induced Rab8 activation at the cell contact area independent of Rap1. Single-molecule imaging of ICAM1 on a supported planner lipid bilayer demonstrated that Rab8 increased the frequency of LFA1–ICAM1 interactions without affecting their binding lifetime, indicating that Rab8 is mainly involved in the modulation of LFA1 avidity rather than LFA1 affinity. The present findings underscore the importance of low-affinity conformation-dependent outside-in signaling via the Rabin8–Rab8 axis leading to the initiation of LFA1 transport to the contact area.
Adenosine-to-inosine RNA editing in cancer: molecular mechanisms and downstream targets
Authors: Cheng Hao , Yu Jun , Wong Chi Chun
Published: August 2024

Adenosine-to-inosine (A-to-I), one of the most prevalent RNA modifications, has recently garnered significant attention. The A-to-I modification actively contributes to biological and pathological processes by affecting the structure and function of various RNA molecules, including double-stranded RNA, transfer RNA, microRNA, and viral RNA. Increasing evidence suggests that A-to-I plays a crucial role in the development of human disease, particularly in cancer, and aberrant A-to-I levels are closely associated with tumorigenesis and progression through regulation of the expression of multiple oncogenes and tumor suppressor genes. Currently, the underlying molecular mechanisms of A-to-I modification in cancer are not comprehensively understood. Here, we review the latest advances regarding the A-to-I editing pathways implicated in cancer, describing their biological functions and their connections to the disease.
Study on the mechanism of hepatotoxicity of Aucklandiae radix through liver metabolomics and network pharmacology
Authors: Song Shen , Qiu Rongli , Huang Yan , Zhou Zhuxiu , Yan Jin , Ou Qiaochan , Wei Donghui , He Jingxuan , Liang Yi , Du Xingyue , Yao Weifeng , Lu Tulin
Published: August 2024

Background

Aucklandiae Radix (CAR) and its roasted processed products (PAR) are extensively used in various Chinese patent medicines due to their diverse pharmacological activities. However, numerous side effects of CAR have been reported and the hepatotoxicity and the corresponding mechanisms have not been thoroughly investigated. Our study aims to explore the underlying mechanism of the hepatotoxic impacts of CAR.

Methods

In this study, metabolomic analysis was performed using liver tissue from the mice administered with different dosages of CAR/PAR extracts to examine the hepatotoxic impacts of CAR and elucidate the underlying mechanism. Network pharmacology was employed to predict the potential molecular targets and associated signaling pathways based on the distinctive compounds between CAR and PAR. A composition-target-GO-Bio process-metabolic pathway network was constructed by integrating the hepatotoxicity-related metabolic pathways. Finally, the target proteins related with the hepatotoxic effect of CAR were identified and validated in vivo.

Results

The metabolomics analysis revealed that 33 related metabolic pathways were significantly altered in the high-dose CAR group, four of which were associated with the hepatotoxicity and could be alleviated by PAR. The network identified NQO1 as the primary target of the hepatotoxic effect induced by CAR exposure, which was subsequently verified by Western Blotting. Further evidence in vivo demonstrated that Nrf2 and HO-1, closely related to NQO1, were also the main targets through which CAR induced the liver injury, and that oxidative stress should be the primary mechanism for the CAR-induced hepatotoxicity.

Conclusions

This preliminary study on the hepatic toxic injury of CAR provides a theoretical basis for the rational and safe use of CAR rationally and safely in clinical settings.
Original Research: Exploring Nurses' Use of Humor in the Workplace: A Thematic Analysis
Authors: Cadiz Edessa , Buxman Karyn , Angel Magda , Resseguie Carin , Wilder Carolyn , Chan Lilian , Bejar Jessica , Russe Jaclyn , Davidson Judy
Published: August 2024

Background:

The nursing work environment is often stressful and can lead to burnout. The use of humor may help nurses adapt and cope. Although most would agree that, in general, humor can help build camaraderie and ease tense situations, little is known about how nurses use humor in their professional lives.

Purpose:

The study's main purpose was to explore how humor is used and perceived by nurses in the workplace.

Methods:

A sample of LPNs, RNs, and advanced practice RNs was recruited in the United States. Participants were interviewed via the videoconferencing platform Zoom. Data from the video recordings, audio transcripts, and investigators' field notes were analyzed using reflexive thematic analysis.

Results:

Sixteen nurses were interviewed about their use of humor, whether intentional or spontaneous, in the workplace. Three main themes were identified: entertainment, influencing others, and well-being. Participants reported using humor with self and others, including patients, families, and colleagues. Reported benefits include emotional regulation, relationship building, and work enjoyment. Some participants noted feeling insecure over when and whether the use of humor was “appropriate.”

Conclusions:

The results indicate that nurses' use of humor in the workplace had many benefits. Participants reported that humor could relieve tension, create bonds and strengthen relationships, and enhance both learning and work environments. Many recognized that humor can also be maladaptive and harmful, and that sensitivity and caution are part of using humor skillfully. Still, the benefits of humor appear to outweigh the risks. We conclude that humor is a useful tool nurses can and should use to optimize their nursing experience.
Strengthening Nurses' Influence in Health Policy
Authors: Zalon Margarete L. , Ludwick Ruth , Patton Rebecca M.
Published: August 2024

With nurses at the forefront of health care, the need for their active engagement in policy has never been more urgent. Numerous national and global reports call for nurses to lead policy change. The Patton Zalon Ludwick Policy Assessment Framework is intended to answer this call by serving as a foundational guide to nurses' self-assessment of their health policy actions. It includes three dimensions: engagement, partnership, and reach, each with three levels. The levels of engagement are literacy, advocacy, and influence. The partnership levels are single unit or community group, interdisciplinary team(s), and broad-based coalitions. The reach levels are based on the location of policy work: local/unit/organization, regional/state, and national/global. The dimensions are interconnected, and the levels build upon one another but are not necessarily symmetrical, linear, or prescriptive. In this article, the authors describe each dimension and level in detail, and the accompanying tables provide examples of policy goals and actions. Nurses worldwide can use this framework to engage in self-reflection and envision actions to achieve their policy goals. It will enable nurses to evolve from being policy bystanders to becoming visible, credible policy leaders.
Application of Hyaluronic Acid/Alginate Sheet to Achilles Tendon Injuries to Prevent Peritendinous Adhesions
Authors: McCahon Joseph A.S. , Bridges Tiffany N. , Parekh Selene G.
Published: August 2024

Peritendinous adhesions is one of the most common complications following tendon injuries, resulting in limited joint motion and function. Interventions to optimize tendon gliding have been proposed—particularly the use of biological adjuncts such as hyaluronic acid. Several clinical and biomechanical studies have demonstrated improved tendon gliding and decreased excursion resistance with the use of a hyaluronic adjunct. We present a surgical technique using a hyaluronic acid/alginate sheet following acute repair of an Achilles tendon rupture to aid in tendon healing and prevent peritendinous adhesions.

Level of Evidence:

Diagnostic level IV.