bluuebunny/crossref_metadata_2025 huggingface dataset:
Liver involvement with Langerhans cell histiocytosis in adults
Authors: Chang Long , Cai Hua-Cong , Lang Min , Lin He , Luo Ya-Ping , Duan Ming-hui , Zhou Dao-bin , Goyal Gaurav , Cao Xin-xin
Published: July 2024

Background and Aims

Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement.

Methods

We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022.

Results

Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18–66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%).

Outcomes

After a median 40 months’ follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550–7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy.

Conclusions

In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.
Immune-related adverse events requiring hospitalization in patients with lung cancer: implications and insights
Authors: Falade Ayo , Zubiri Leyre , Wu Chia-Yun , Perlman Katherine , Sun Joie , Hathaway Nora , Grealish Kelley , Lopiccolo Jackie , Reynolds Kerry , Mooradian Meghan J
Published: July 2024

Background

Immune checkpoint inhibitors (ICI) are associated with a distinct spectrum of toxicities. Data on irAE hospitalization rates and clinical course of patients with thoracic malignancies are lacking.

Methods

Patients with advanced thoracic malignancy treated with ICI (2/2016 to 6/2021) were retrospectively identified. Demographic and clinical data of confirmed irAE hospitalizations were extracted from the medical record and a descriptive analysis was performed.

Results

From February 2016 to June 2021, 1312 patients with thoracic malignancy received ICI (monotherapy, combination with 2nd ICI or other agents) with 102 patients (7.7%) hospitalized for irAEs. Treatment intent was first-line therapy in most patients (N = 50, 49%) with 9% (n = 9) receiving adjuvant ICI (N = 9). Sixty patients (59%) received ICI alone, 32% (N = 33) chemo plus immunotherapy, and 7% (N = 7) dual ICI. The median age on admission was 68 years. The median time between ICI initiation and admission was 64 days (1-935 days). Pneumonitis (32.3%; 33/102) was the most frequent indication for admission followed by gastroenterocolitis (19.6%; 20/102), hepatitis (12.7%; 13/102), myo/pericarditis (9.8%; 10/102), and endocrinopathies (9.8%; 10/102). Multi-organ toxicity occurred in 36% (N = 37) of patients. Overall, 85.2% (87/102) of patients received systemic corticosteroids and 17.6% (18/102) required additional lines of immunosuppression. The median length of hospitalization stay was 7 days (2-28 days) with a 25.5% (n = 26) readmission rate within 60 days and an 11.8% (n = 12) in house mortality rate.

Conclusions

Severe irAE requiring inpatient admission, although infrequent, results in considerable morbidity, mortality, and healthcare utilization. Pneumonitis was the most common irAE requiring inpatient management in our patient population with a significant risk of mortality despite the use of guideline-directed systemic immunosuppression. This study highlights the continued need for collaborative efforts amongst medical specialties for improving the diagnostic and therapeutic management of patients with irAEs.
ELONGATED HYPOCOTYL 5 regulates steroidal glycoalkaloid biosynthesis and fungal tolerance in tomato
Authors: Sinha Hiteshwari , Kumar Ravi Shankar , Datta Tapasya , Singh Deeksha , Srivastava Suchi , Trivedi Prabodh Kumar
Published: July 2024

Tomato (Solanum lycopersicum L.) is rich in nutrients and has been an important target for enhancing the accumulation of various metabolites. Tomato also contains cholesterol-derived molecules, steroidal glycoalkaloids (SGAs), which contribute to pathogen defense but are toxic to humans and considered antinutritional compounds. Previous studies suggest the role of various transcription factors in SGA biosynthesis; however, the role of light and associated regulatory factors has not been studied in tomatoes. Here, we demonstrated that SGA biosynthesis is regulated by light through the ELONGATED HYPOCOTYL 5 homolog, SlHY5, by binding to light-responsive G-boxes present in the promoters of structural and regulatory genes. SlHY5 complemented Arabidopsis (Arabidopsis thaliana) and tobacco (Nicotiana tabacum) hy5 mutants at molecular, morphological, and biochemical levels. CRISPR/Cas9-based knockout tomato plants, SlHY5CR, showed downregulation of SGA and phenylpropanoid pathway genes, leading to a significant reduction in SGA (α-tomatine and dehydrotomatine) and flavonol contents, whereas plants overexpressing SlHY5 (SlHY5OX) showed the opposite effect. Enhanced SGA and flavonol levels in SlHY5OX lines provided tolerance against Alternaria solani fungus, while SlHY5CR lines were susceptible to the pathogen. This study advances our understanding of the HY5-dependent light-regulated biosynthesis of SGAs and flavonoids and their role in biotic stress in tomatoes.
PTSD symptoms, pain catastrophizing, and pain outcomes after acute orthopedic injury
Authors: McDermott Katherine , Rush Christina , Pham Tony , Hooker Julia , Louis Courtney , Rochon Elizabeth A , Vranceanu Ana-Maria
Published: July 2024

Background

Posttraumatic stress disorder (PTSD) is associated with greater incidence of chronic pain. Pain catastrophizing often accounts for this association. Less is known about these relationships during the acute phase (1–2 months) following orthopedic traumatic injuries. We sought to understand which orthopedic traumatic injury-related PTSD symptoms were associated with acute pain and physical dysfunction and whether pain catastrophizing accounted for these associations.

Methods

This secondary analysis used baseline data from a multisite randomized controlled trial of an intervention for individuals with heightened pain catastrophizing or pain anxiety following acute orthopedic injury. We used partial correlations to examine associations between PTSD symptom clusters (re-experiencing, avoidance, negative alterations in cognitions and mood, and hyperarousal) and pain outcomes (pain intensity and physical dysfunction) controlling for pain catastrophizing. We used hierarchical regressions to evaluate unique associations between PTSD clusters and pain outcomes. In exploratory analysis, we examined the indirect effects of PTSD symptoms on pain outcomes through catastrophizing.

Results

Hierarchical linear regressions indicated that hyperarousal was uniquely associated with greater pain intensity with activity (β = 0.39, P < .001, ΔR2 = 0.06) and physical dysfunction (β = 0.22, P = 0.04, ΔR2 = 0.02). PTSD symptoms were still associated with pain with activity even with pain catastrophizing included in the models, and catastrophizing did not have a significant indirect effect on the relationship between PTSD and physical dysfunction (b = 0.06, SEBoot = 0.04, 95% CIBoot = [−0.003, 0.14]). Pain catastrophizing did largely account for the association between re-experiencing, avoidance, and negative alterations in cognitions and mood symptoms and pain at rest.

Conclusions

Pain catastrophizing interventions may be best suited for limiting the impact of PTSD symptoms on pain at rest, but catastrophizing alone may not fully explain the relationship between PTSD symptoms and physical dysfunction after acute orthopedic injury. To prevent the negative association of PTSD symptoms, especially hyperarousal, on physical outcomes in acute pain populations, interventions may require more than solely targeting pain catastrophizing.

Clinical trials registration

NCT04973696.
British Axial Spondyloarthritis Inception Cohort (BAxSIC): a protocol for a multicentre real-world observational cohort study of early axial spondyloarthritis
Authors: Weddell Jake , Harrison Stephanie R , Bennett Alexander N , Gaffney Karl , Jones Gareth T , Machado Pedro M , Packham Jonathan , Sengupta Raj , Zhao Sizheng Steven , Siebert Stefan , Marzo-Ortega Helena
Published: July 2024

Objectives

Timely diagnosis remains a challenge in axial SpA (axSpA). In addition, data are scarce on the impact of diagnostic delay and disease progression in affected individuals. The British Axial Spondyloarthritis Inception Cohort (BAxSIC) study aims to investigate the impact of newly diagnosed axSpA, the natural history of the disease and the effect of diagnostic delay on disease outcomes.

Methods

BAxSIC is a prospective, multicentre, observational study. Eligible participants are adults (≥16 years of age), with a physician-confirmed diagnosis of axSpA in the 6 months prior to study entry, recruited from secondary and tertiary rheumatology centres in the UK. Participants will be followed up for 3 years, with in-person visits at baseline and 24 months. In addition, patient self-reported assessments will be recorded remotely via the online electronic case report form (eCRF) at 6, 12, 18, 30 and 36 months.

Results

The first patient was enrolled in BAxSIC in June 2023. Recruitment is currently ongoing and is planned to end in June 2026. Initial results will be available in 2027. Since opening, the trial has undergone two protocol amendments.

Conclusion

The BAxSIC study is the first inception cohort designed to investigate the impact of diagnostic delay on clinical presentation and long-term functional outcomes in patients with axSpA in the UK. With an innovative, patient-led virtual longitudinal data collection model, data generated from this study will help inform and improve the care of people newly diagnosed with axSpA.

Trial registration

ClinicalTrials.gov (http://clinicaltrials.gov), NCT05676775.
Poetry, Patronage, and the Art of the Land-grab: A Newly Discovered Letter to Thomas Wyatt
Authors: Lazarus Micha , Brigden Susan
Published: July 2024

Between early summer 1540 and the new year of 1541, Alexander Nowell composed the only surviving Latin letter from England to Sir Thomas Wyatt. On behalf of the Dean and Chapter of Norwich Cathedral, he asks Wyatt, Sir Francis Bryan, and Henry Howard, Earl of Surrey, to help the new foundation resist the expropriation of its properties. The letter fills in several biographical lacunae for this prominent trio of courtiers. It provides primary evidence of Wyatt’s membership and sponsorship of English humanist networks. It offers the first sure evidence of Wyatt’s contact with Surrey, corroborating the evidence of Surrey’s poetry. It reveals the association of Wyatt, Surrey, and Bryan with evangelical figures: Nowell, later Dean of St Paul’s, was already a central figure in Oxford reform. And it presents an intricate example of the chains of patronage that reached, in the wake of the dissolution, across the universities, the new fleet of cathedral foundations, and the heights of the Henrician court.
The Role of Defeatist Performance Beliefs in State Fluctuations of Negative Symptoms in Schizophrenia Measured in Daily Life via Ecological Momentary Assessment
Authors: Luther Lauren , Raugh Ian M , Grant Paul M , Beck Aaron T , Strauss Gregory P
Published: July 2024

Background and Hypothesis: The Cognitive Model of Negative Symptoms is a prominent model that posits that defeatist performance beliefs (DPB) are a key psychological mechanism underlying negative symptoms in those with schizophrenia (SZ). However, the ecological validity of the model has not been established, and temporally specific evaluations of the model’s hypotheses have not been conducted. This study tested the model’s key hypotheses in real-world environments using ecological momentary assessment (EMA). Study Design: Fifty-two outpatients with SZ and 55 healthy controls (CN) completed 6 days of EMA. Multilevel models examined concurrent and time-lagged associations between DPB and negative symptoms in daily life. Study Results: SZ displayed greater DPB in daily life than CN. Furthermore, greater DPB were associated with greater concurrently assessed negative symptoms (anhedonia, avolition, and asociality) in daily life. Time-lagged analyses indicated that in both groups, greater DPB at time t led to elevations in negative symptoms (anhedonia, avolition, or asociality) at t + 1 above and beyond the effects of negative symptoms at time t. Conclusions: Results support the ecological validity of the Cognitive Model of Negative Symptoms and identify a temporally specific association between DPB and subsequent negative symptoms that is consistent with the model’s hypotheses and a putative mechanistic pathway in Cognitive Behavioral Therapy for negative symptoms. Findings suggest that DPB are a psychological factor contributing to negative symptoms in real-world environments. Implications for measuring DPB in daily life and providing just-in-time mobile health-based interventions to target this mechanism are discussed.
The origins of youth social citizenship in Europe: religion, trade unions and income support for young people
Authors: Chevalier Tom
Published: July 2024

This article is concerned with the development of young people’s access to income support in Europe. This access can be either ‘familialized’, where young people are seen as children, which leads low level of welfare generosity, or ‘individualized’, where they are seen as adults, with higher level of welfare generosity. I argue that two main factors can explain such cross-national variation. First, religion (and Protestantism is particular) is the main driver explaining the development of individualization, as opposed to familialization, through long-lasting institutional effects. Secondly, as outsiders on the labour market, the better represented young people are in trade unions, the more likely they are to access individualized generous social benefits. To test this argument, I rely on a multimethod research design: initially proceeding with time-series cross-sectional regressions across 18 countries, from 2001 to 2018, before turning to comparative historical case studies of youth social citizenship development in France, the UK and Sweden.
PlayDoc M.D.: Sexual Harassment and Discrimination in US Medical Schools in the 1960s and 1970s
Authors: Evens Elizabeth
Published: July 2024

Since women’s entrance the historically male-dominated medical profession in small numbers in the nineteenth century, they faced numerous exclusions and obstacles. In the 1960s and 1970s, as the number of women attending co-educational medical schools increased significantly, male students and faculty members responded with renewed opposition by deploying hypersexualised innuendo including references to Playboy magazine. This article brings together a range of material, including Playboy, student yearbooks, teaching materials, contemporary studies and oral histories, to document the masculine heterosexual peer culture that pervaded US medical schools, where sexual innuendo and centrefold-style images were commonplace. This learning environment influenced male students, perpetuating harmful views about women and fostering camaraderie at the expense of their female colleagues. These experiences also impacted female students, who confronted and negotiated encounters with sexual harassment, while balancing study, career ambitions and personal wellbeing.
Clinical and financial significance of insomnia within a large payor-provider health system
Authors: Karlin Bradley E , Anderson Ryan J , Rung Jillian M , Drury-Gworek Charlotte , Barrett Tyson S
Published: July 2024

Study Objectives

Insomnia has profound negative effects on behavioral health, physical health, and functional domains. Leveraging claims data from one of the nation’s largest payor-provider systems, the current study examined the real-world prevalence of insomnia, comorbidity of insomnia with behavioral health and other sleep disorders, and the impact of insomnia on total health care costs.

Methods

Prevalence and costs associated with insomnia were assessed by examining claims data on approximately 3 million insured members during the year 2022. Using propensity score matching, total health care expenditures were calculated and compared for members with insomnia relative to matched cohorts without insomnia. Generalized linear modeling tested for differences between the cohorts.

Results

Nine percent of members were identified as having insomnia; 64% of those also had depression, anxiety, and/or substance use disorder. Median total health care costs among individuals with insomnia were 4–6 times greater than among those without insomnia. A disproportionate amount (21.1%) of total claims spend came from members with insomnia.

Conclusions

Findings demonstrate a high degree of clinical need and behavioral health comorbidity associated with insomnia within a large insured cohort. Beyond the clinical significance, the current results demonstrate substantial financial need and opportunity for adequately treating insomnia. This is especially the case for the high proportion of members with insomnia and cooccurring depression, anxiety, and/or substance use disorders. Overall, the findings point to the important role payors and providers may have in promoting greater attention to sleep and insomnia.
Differences in impact of current and former shift work on cardiovascular risk factors, carotid atherosclerosis, and white matter integrity
Authors: Rimmele David Leander , Petersen Elina L , Affolderbach Sarah , Petersen Marvin , Cheng Bastian , Mayer Carola , Nägele Felix Leonard , Harth Volker , Terschüren Claudia , Kühn Simone , Zeller Tanja , Gerloff Christian , Thomalla Götz
Published: July 2024

Study Objectives

The association of shift work (SW) and disrupted circadian rhythm with markers of large artery atherosclerosis and cerebral small vessel disease is uncertain. We aimed to study the separate association of current and former SW with these markers.

Methods

We included participants from the population-based Hamburg City Health Study. SW was defined by monthly working hours between 06:00 pm and 07:00 am containing night shifts for at least 12 months. Cross-sectional data were obtained from structured questionnaires, laboratory analyses, physical examinations, brain magnetic resonance imaging, and carotid ultrasound. We performed multivariable regression analysis with carotid intima-media thickness (CIMT), and peak-width skeletonized mean diffusivity (PSMD) as dependent variables.

Results

Three hundred and forty-four current, 238 former, and 7162 never-shift workers were included. The median age was 60 years for both current and former shift workers, and total duration of SW was comparable for the two groups. Current shift workers were less frequently female (27.3% vs. 44.5%; p < .001), had more frequent hyperlipidemia (31.5% vs. 22.3%; p = .024), and diabetes (16.2% vs. 3.2%; p < .001). After adjustment for age and sex, reduced quality of sleep (β = 1.61, p = .001) and low education (β = 2.63, p < .001) were associated with current but not former SW. Adjusted for age and sex, the current SW was associated with higher CIMT (β = 0.02, p = .001) and PSMD (β = 9.06e-06, p = .006), whereas former SW was not. Adjusted for risk factors, current SW remained associated with PSMD (β = 9.91e-06, p = .006) but not with CIMT.

Conclusions

Current SW was associated with CIMT and with PSMD, with the latter association remaining after adjustment for risk factors. Former SW showed no associations with CIMT or PSMD. This may indicate that current SW is linked with increased neurovascular risk through disrupted circadian rhythms.

Trial Registration Information

The trial was submitted at http://www.clinicaltrials.gov, under NCT03934957 on January 4, 2019. The first participant was enrolled in February 2016.
Domestication of Information and Communication Technologies into Family Systems: A Conceptual Framework Evaluating Family Health
Authors: Purushothaman Nair Remesh Krishnan , Mengi Nancy , Jose Santhosh Adhikarathil
Published: July 2024

As the world undergoes its fourth industrial revolution, digital media are becoming more prevalent in both rural and urban communities. This shift has had a profound impact on our daily lives, transforming the way we live, work, and communicate. Although technology now plays a crucial role in our daily routine, it can lead to interference in human relationships, a phenomenon referred to as technoference. This interference has significant consequences, particularly in parent–child relationships, as it can adversely affect children’s emotional and behavioral development and the mental health and overall functioning of parents. Thus, for children to grow up healthy and for families to be harmoniously balanced, all the family subsystems need to be aligned in a healthy manner. This study conceptualizes how family health is affected when technological devices are brought as a subsystem into a family system. The researchers developed a conceptual multidimensional framework based on several interrelated theoretical concepts, and this framework is presented in three sequential frames for better comprehension, to identify how the interference, in particular, impacts the various dimensions of a healthy family system and contributes to dysfunctional family functioning and mental health issues in both parents and children.
Opening a 60-year time capsule: sequences of historical poliovirus cold variants shed a new light on a contemporary strain
Authors: Chesnais Morgane , Bujaki Erika , Filhol Typhaine , Caval Vincent , Joffret Marie-Line , Martin Javier , Jouvenet Nolwenn , Bessaud Maël
Published: July 2024

Polioviruses (PVs) are positive strand RNA viruses responsible for poliomyelitis. Many PVs have been isolated and phenotypically characterized in the 1940s–50s for the purpose of identifying attenuated strains that could be used as vaccine strains. Among these historical PVs, only few are genetically characterized. We report here the sequencing of four PV strains stored for more than 60 years in a sealed box. These PVs are cold variants that were selected by Albert Sabin based on their capacity to multiply at relatively low temperatures. Inoculation of permissive cells at 25°C showed that two of the four historical virus stocks still contained infectious particles. Both viruses reached titres that were higher at 25°C than at 37°C, thus demonstrating that they were genuine cold variants. We obtained sequences that span virtually all the genome for three out of the four strains; a short sequence that partly covers the 5ʹ untranslated region was recovered for the last one. Unexpectedly, the genome of one historical cold variant (which derives from PV-3 Glenn) displayed a very high nucleotide identity (above 95%) with that of a PV strain (PV-3 strain WIV14) sampled in China in 2014 and then classified as a highly evolved vaccine-derived PV. Our analyses made this hypothesis very unlikely and strongly suggested that Glenn and WIV14 shared a very recent common ancestor with one another. Some strains used to produce the inactivated polio vaccine were also very close to Glenn and WIV14 in the capsid-encoding region, but they had not been sequenced beyond the capsid. We therefore sequenced one of these strains, Saukett A, which was available in our collection. Saukett A and WIV14 featured an identity higher than 99% at the nucleotide level. This work provides original data on cold variants that were produced and studied decades ago. It also highlights that sequences of historical PV strains could be crucial to reliably characterize contemporary PVs in case of release from a natural reservoir or from a facility, which is of highest importance for the PV eradication program.
12Poetics
Authors: MacEachern Jessi
Published: July 2024

This chapter begins with a discussion of three works of poetics that emphasize local and material concerns from poets-theorists-activists engaged in collaborative and experimental writing practices. This openness in form and enquiry is further reflected in the major works published in 2023 that are under examination in the body of the review, which together attend to six major topics: (1) the formation of national poetries; (2) the role of the academy in preserving or destabilizing the lyric voice; (3) the intimate impasse of confessional and anthropocentric writing; (4) the sensorial body of hybrid writing; (5) the limiting structures of racial capitalism; and (6) the role of poetry in public life. Ending with a brief reflection on the immense influence of Lyn Hejinian, this chapter attests to the openness of enquiry that the aesthetic, philosophical, and political field of poetics permits from its discrete social locations and close attention to the page, the voice, and the body.
Towards Improved Nepovirus Detection and Identification in Xiphinema Nematodes
Authors: Everaert Ellen A. , Viaene Nicole , Quataert Paul , Haegeman Annelies , De Jonghe Kris
Published: July 2024

Several Xiphinema nematode species are vectors of regulated nepoviruses. The aim of this study was to develop an optimized method to detect virus-carrying Xiphinema specimens. The study compared various techniques for nematode extraction from soil (automated zonal centrifuging and the Flegg modified Cobb method), nematode cuticle disruption (slicing, bead beating, and bead beating with collagenase), RNA extraction (RNeasy Plant Mini Kit, cetyltrimethylammonium bromide [CTAB], and KingFisher MagMAX RNA Isolation Kit), and nepovirus detection (nepovirus generic subgroup and species-specific quantitative and conventional reverse transcription polymerase chain reaction [RT-(q)PCR] assays, as well as shotgun sequencing with Oxford nanopore sequencing technology using a MinION device). Based on this comparison, a diagnostic procedure is proposed including the best-performing methods: nematode extraction using automated zonal centrifugation, physical disruption of nematode cuticle using bead beating or slicing, and RNA extraction using either the KingFisher MagMAX or the RNeasy Plant Mini Kit method. While existing generic nepovirus subgroup reverse transcription polymerase chain reaction (RT-PCR) assays lacked sensitivity, species-specific RT-(q)PCR assays successfully detected Arabis mosaic virus (ArMV), grapevine fanleaf virus (GFLV), and tomato ringspot virus (ToRSV) in X. diversicaudatum, X. index, and X. americanum sensu stricto (s.s.), respectively. The reliability of nepovirus detection was higher with adults compared with juveniles. The minimum nematode quantity required varied depending on the specific nepovirus and the detection method used.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
The Importance of Discussing the History of Racism in Medical Student Education
Authors: Pleasant Versha , Kotian Alesha , Hammoud Maya M. , Maben-Feaster Rosalyn
Published: July 2024

Racial health disparities are tightly linked to the longstanding and pervasive institution of racism. Efforts to reverse disparities begin with awareness and accountability through education. The health care workforce must be formally educated about racist practices, tools, and ideologies that perpetuate poor health outcomes. This article explores prior efforts to integrate race didactics into medical school education, addresses current legislation, and illuminates lessons learned from a single institution pilot curriculum exploring the history of racism in the field of obstetrics and gynecology. Educating medical school students about the history of racism is an important and necessary tool for positive change.
Auditory Localization Performance in Cochlear Implant Recipients With Single-Sided Deafness: The Challenges and Limitations of Current Outcome Metrics
Authors: Anidi Chioma , Abdulrazzak Obada , Jones Gerilyn , Epperson Madison V. , Ibrahim Nadine I. , Banakis Hartl Renee M.
Published: July 2024

Hypothesis

Acoustic localization accuracy metrics currently employed in clinical literature both overestimate and underestimate performance benefit of cochlear implantation (CI) for single-sided deafness (SSD).

Background

Although localization in SSD with CI has been investigated, performance characterization has relied heavily on average error. Although attractively concise, this measure may misrepresent performance. Here, we characterize frequency-specific localization on a granular level in subjects with CI for SSD as a critical analysis of localization outcome metrics.

Methods

Eight CI recipients with SSD were recruited. Stimuli of broadband (BBN) and narrowband noise (NBN) at low (500 Hz), mid (1000 Hz), and high (4000 Hz) frequencies were presented in a semianechoic chamber. Localization accuracy was quantified in mean angular error (MAE) and linear regression slope.

Results

Use of a CI for SSD subjects improved localization performance by slope for all stimuli (p ≤ 0.0033) to a level that was equal to normal-hearing controls at 1 and 4 kHz (p ≥ 0.2281). MAE was also significantly improved for SSD subjects using CI for BBN stimuli (p ≪ 0.0001); however, no statistically significant improvement in MAE was seen for NBN (p ≥ 0.5773) with CI use. Descriptive analysis of individual subject performance highlights the reasons for contradictory results.

Conclusion

There is inherent challenge in characterizing localization benefit for individuals with CI for SSD. Our data demonstrate the limitations of utilization of average error as the sole metric for outcome benefit. We emphasize the importance of continued research investigating alternative outcome measures as we work toward a more refined understanding of the potential benefits and limitations of cochlear implantation for SSD.
Improving Evidence-based Management of Children and Adolescents with Elevated Blood Pressure during a Well-Child Encounter: A Quality Initiative
Authors: Ray Krista M. , Stille Christopher J. , Bunik Maya , Smith Hana , Lenssen Maureen , Fishbein Cassie
Published: July 2024

INTRODUCTION:

Pediatric hypertension requires accurate diagnosis and management to reduce the burden of cardiovascular disease across the lifespan. Despite national guidelines, hypertension (HTN) is one of the most frequently missed diagnoses within pediatric primary care. This quality improvement (QI) project aimed to improve the management of patients aged 3–18 years with elevated blood pressure (BP) by 25% during a well-child encounter.

METHODS:

Over one year, a single-center QI project was conducted at an academic general pediatrics center. Multidisciplinary interventions, including team education, workflow standardization, and clinical decision support tools, were implemented using Plan-Do-Study-Act cycles to improve adherence to evidence-based guidelines. Outcome measures were the percentage of youth with an elevated BP on screening who had documentation of provider actions. We used run charts to analyze the effect of interventions, and descriptive statistics for demographic data and process measures pre- and postintervention. Chi-square tests compared process measures pre- and postintervention and provider actions stratified by age.

RESULTS:

Key drivers of change were the percentage of documented confirmatory BPs, BP stage, and scheduled follow-up appointments. At baseline, 13% of children with elevated BP on screening had guideline-adherent provider actions documented. This increased to 40% postintervention; however, discrepancies in adherence stratified by age were observed. Youth 13 and older were significantly more likely to receive a provider action than younger children (P< 0.0001).

CONCLUSION:

BP management during a well-child encounter improved with multidisciplinary interventions that increased knowledge of evidence-based guidelines and standardized care.
On the resolution of sexual conflict over shared traits
Authors: Pennell Tanya M. , Mank Judith E. , Alonzo Suzanne H. , Hosken David J.
Published: July 2024

Anisogamy, different-sized male and female gametes, sits at the heart of sexual selection and conflict between the sexes. Sperm producers (males) and egg producers (females) of the same species generally share most, if not all, of the same genome, but selection frequently favours different trait values in each sex for traits common to both. The extent to which this conflict might be resolved, and the potential mechanisms by which this can occur, have been widely debated. Here, we summarize recent findings and emphasize that once the sexes evolve, sexual selection is ongoing, and therefore new conflict is always possible. In addition, sexual conflict is largely a multivariate problem, involving trait combinations underpinned by networks of interconnected genes. Although these complexities can hinder conflict resolution, they also provide multiple possible routes to decouple male and female phenotypes and permit sex-specific evolution. Finally, we highlight difficulty in the study of sexual conflict over shared traits and promising directions for future research.
Geometric morphometric analysis of an ontogenetic cranial series of the Permian dicynodont
Diictodon feliceps
Authors: Rabe Caitlin , Marugán-Lobón Jesús , Smith Roger M. H. , Chinsamy Anusuya
Published: July 2024

The Karoo Basin of South Africa is renowned for its abundance and diversity of therapsid fossils. Among the most ubiquitous and persistent of the Permian fauna is the small herbivorous dicynodont
Diictodon feliceps
. Intraspecific variation in
Diictodon
is historically confounding, and while ontogeny is frequently cited as a potential source of variation, observable developmental changes have never been calibrated. The present study revisits this issue, comparing three-dimensional landmark configurations of 82
Diictodon
crania to investigate the association between shape, size and dimorphism. Beyond the statistically significant relationship between shape and allometry, our results determine the shape differences between juvenile and adult skulls of
Diictodon
, aligned with common craniofacial features documented in other tetrapod taxa. Functionally, these changes are attributed to development of the jaw musculature for feeding on larger, tougher plant matter during later ontogeny. Cranial morphological variation owing to sexual dimorphism is negligible, but distinct differences are noted in the allometric trajectories of each morphotype. A component of non-allometric variation cannot be accounted for, and we propose that this represents natural variation, rather than an artefact of taphonomic deformation.
Virtual brain twins for stimulation in epilepsy
Authors: Wang Huifang E. , Dollomaja Borana , Triebkorn Paul , Duma Gian Marco , Williamson Adam , Makhalova Julia , Lemarecha Jean-Didier , Bartolomei Fabrice , Jirsa Viktor
Published: July 2024

Estimating the epileptogenic zone network (EZN) is an important part of the diagnosis of drug-resistant focal epilepsy and plays a pivotal role in treatment and intervention. Virtual brain twins based on personalized whole brain modeling provides a formal method for personalized diagnosis by integrating patient-specific brain topography with structural connectivity from anatomical neuroimaging such as MRI and dynamic activity from functional recordings such as EEG and stereo-EEG (SEEG). Seizures demonstrate rich spatial and temporal features in functional recordings, which can be exploited to estimate the EZN. Stimulation-induced seizures can provide important and complementary information. In our modeling process, we consider invasive SEEG stimulation as the most practical current approach, and temporal interference (TI) stimulation as a potential future approach for non-invasive diagnosis and treatment. This paper offers a virtual brain twin framework for EZN diagnosis based on stimulation-induced seizures. This framework estimates the EZN and validated the results on synthetic data with ground-truth. It provides an important methodological and conceptual basis for a series of ongoing scientific studies and clinical usage, which are specified in this paper. This framework also provides the necessary step to go from invasive to non-invasive diagnosis and treatment of drug-resistant focal epilepsy.
Autoantibodies towards HFE and SYT5 in anti-neutrophil cytoplasm antibody-associated vasculitis relapse
Authors: Bayati Shaghayegh , Nazeer Jamsheela , Ng James , Hayes Michael , Little Mark A. , Nilsson Peter , Pin Elisa
Published: July 2024

Objective

Identification of those at high and low risk of disease relapse is a major unmet need in the management of patients with ANCA-associated vasculitis (AAV). Precise stratification would allow tailoring of immunosuppressive medication. We profiled the autoantibody repertoire of AAV patients in remission to identify novel autoantibodies associated with relapse risk.

Methods

Plasma samples collected from AAV patients in remission were screened for novel autoantibodies using in-house generated protein arrays including 42,000 protein fragments representing 18,000 unique human proteins. Patients were categorized based on the occurrence and frequency of relapses. We modelled the association between these antibodies and relapse occurrence using descriptive and high dimensional regression approaches.

Results

We observed nine autoantibodies at higher frequency in samples from AAV patients experiencing multiple relapses compared to patients in long-term remission off therapy (LTROT). LASSO analysis identified six autoantibodies that exhibited an association with relapse occurrence after sample collection. Antibodies targeting HFE and SYT5 were identified as associated with relapse in both analyses.

Conclusion

Through a broad protein array-based autoantibody screening, we identified two novel autoantibodies as candidate biomarkers of relapse in AAV.

Key messages of this study

Our multi-step screening based on high-throughput and high-multiplexing protein arrays allowed to identify novel autoantibodies in AAV patients.

Our study identified two new autoantibodies as candidate biomarkers for predicting AAV patients at risk of relapse.

The risk of relapse may be better reflected by the presence of specific autoantibodies than by the overall autoantibody load in patients with AAV.
Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic bvFTD
Authors: Shen Ting , Vogel Jacob W. , Van Deerlin Vivianna M , Suh EunRan , Dratch Laynie , Phillips Jeffrey S. , Massimo Lauren , Lee Edward B. , Irwin David J. , McMillan Corey T.
Published: July 2024

Cortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness inC9orf72,GRNorMAPT-related bvFTD. Genes associated with cortical thinning inGRN-bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps. Previously identified genes linked to TDP-43 positive neurons were significantly overlapped with genes associated withC9orf72-bvFTD andGRN-bvFTD, but notMAPT-bvFTD providing specificity for our associations.C9orf72-bvFTD andGRN-bvFTD shared genes displaying consistent directionality of correlations with cortical thickness, whileMAPT-bvFTD displayed more pronounced differences in transcriptomic signatures with opposing directionality. Overall, we identified disparate and shared genes tied to regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression, illuminating intricate molecular underpinnings contributing to heterogeneities in bvFTD.
The effect of highly effective modulator therapy on systemic inflammation in cystic fibrosis
Authors: Maher Rosemary E , Cytlak-Chaudhuri Urszula , Aleem Saad , Barry Peter J , Brice Daniel , Caamaño-Gutiérrez Eva , Driver Kimberley , Emmott Edward , Rothwell Alexander , Smith Emily , Travis Mark , Lee Dave , McNamara Paul S , Waller Ian , Smith Jaclyn A , Jones Andrew M , Lord Robert W
Published: July 2024

Background

Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis established on Elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy.

Methods

We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age-matched healthy controls.

Results

Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift toward an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared to healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function.

Conclusions

Patients with CF show evidence of persisting systemic inflammation despite ETI therapy, this may have long term potentially adverse effects on respiratory and other organ systems.
Haploinsufficiency ofITSN1is associated with Parkinson’s disease
Authors: Spargo Thomas P. , Sands Chloe F. , Juan Isabella R. , Mitchell Jonathan , Ravanmehr Vida , Butts Jessica C. , De-Paula Ruth B. , Kim Youngdoo , Hu Fengyuan , Wang Quanli , Vitsios Dimitrios , Garg Manik , Messa Mirko , del Angel Guillermo , Calame Daniel G. , Saade Hiba , Robak Laurie , Hollis Ben , Zoghbi Huda Y. , Shulman Joshua , Petrovski Slavé , Al-Ramahi Ismael , Tachmazidou Ioanna , Dhindsa Ryan S.
Published: July 2024

Background

Despite its significant heritability, the genetic underpinnings of Parkinson disease (PD) remain incompletely understood, particularly the role of rare variants. Advances in population-scale sequencing now provide an unprecedented opportunity to uncover additional large-effect rare genetic risk factors and expand our understanding of disease mechanisms.

Methods

We leveraged whole-genome sequence data with linked electronic health records from 490,560 UK Biobank participants, identifying 3,809 PD cases and 247,101 controls without a neurological disorder. We performed both variant-and gene-level association analyses to identify novel genetic associations with PD. We analyzed two additional independent case-control cohorts for replication (totaling 3,739 cases and 58,156 controls). Additionally, we performed functional validation of a novel PD association in a human synuclein-expressingDrosophilamodel.

Findings

In the UK Biobank, we replicated associations in well-established loci includingGBA1andLRRK2.We also identified a novel association between protein-truncating variants (PTVs) inITSN1and an increased risk of PD, with an effect size exceeding those of established loci (Fisher’s Exact Test: p=6.1x10-7; Odds ratio [95% confidence interval] = 10.53 [5.20, 21.34]). We replicated theITSN1risk signal in a meta-analysis across all cohorts (Cochran-Mantel-Haenszel test p=5.7x10-9; Odds ratio [95% confidence interval] = 9.20 [4.66, 16.70]). InDrosophila, haploinsufficiency of theITSN1ortholog (Dap160) exacerbated α-synuclein-induced compound eye degeneration and motor deficits.

Interpretation

We establishITSN1as a novel risk gene for PD, with PTVs substantially increasing disease risk.ITSN1encodes a scaffold protein involved in synaptic vesicle endocytosis, a critical pathway increasingly recognized in PD pathogenesis. Our findings highlight the power of large-scale sequencing coupled with preclinical functional modeling to identify rare variant associations and elucidate disease mechanisms.
Leisure-time physical activity, sedentary behavior, and biological aging: evidence from genetic correlation and Mendelian randomization analyses
Authors: Zhao Xunying , Wu Xueyao , He Lin , Xiao Jinyu , Xiang Rong , Sha Linna , Tang Mingshuang , Hao Yu , Qu Yang , Xiao Changfeng , Qin Chenjiarui , Hou Jiaojiao , Deng Qin , Zhu Jiangbo , Zheng Sirui , Zhou Jinyu , Yu Ting , Yang Bin , Song Xin , Han Tao , Liao Jiaqiang , Zhang Tao , Fan Mengyu , Li Jiayuan , Jiang Xia
Published: July 2024

Physical inactivity and sedentary behavior are associated with higher risks of age-related morbidity and mortality. However, whether they causally contribute to accelerating biological aging has not been fully elucidated. Utilizing the largest available genome-wide association study (GWAS) summary data, we implemented a comprehensive analytical framework to investigate the causal relationships between moderate-to-vigorous leisure-time physical activity (MVPA), leisure screen time (LST), and four epigenetic age acceleration (EAA) measures: HannumAgeAccel, intrinsic HorvathAgeAccel, PhenoAgeAccel, and GrimAgeAccel. Shared genetic backgrounds across these traits were quantified through genetic correlation analysis. Overall and independent causal effects were assessed through univariable and multivariable Mendelian randomization (MR). A recently developed tissue-partitioned MR approach was further adopted to explore potential tissue-specific pathway that contributes to the observed causal relationships. Among the four EAA measures investigated, consistent results were identified for PhenoAgeAccel and GrimAgeAccel. These two measures were negatively genetically correlated with MVPA (rg=−0.18∼−0.29) and positively genetically correlated with LST (rg=0.22∼0.37). Univariable MR yielded a robust effect of genetically predicted LST on GrimAgeAccel (βIVW=0.69,P=1.10×10−7), while MVPA (βIVW=−1.02,P=1.50×10−2) and LST (βIVW=0.37,P=1.90×10−2) showed marginal causal effects on PhenoAgeAccel. Multivariable MR suggested an independent causal role of LST in GrimAgeAccel after accounting for effects of MVPA and other important confounders. Tissue-partitioned MR suggested skeletal muscle tissue associated variants be predominantly responsible for driving the effect of LST on GrimAgeAccel. Findings support sedentary lifestyles as a modifiable causal risk factor in accelerating epigenetic aging, emphasizing the need for preventive strategies to reduce sedentary screen time for healthy aging.