bluuebunny/crossref_metadata_2025 huggingface dataset:
P18.04.A APPLICATION OF THE PET RANO 1.0 CRITERIA IN DIFFUSE GLIOMA: RETROSPECTIVE SINGLE CENTER EXPERIENCE
Authors: Wiegand L , Barci E , Müller K J , Forbrig R , Brendel M , Preusser M , Schönecker S , Thon N , Harter P N , von Baumgarten L , Albert N L
Published: October 2024

BACKGROUND

Response evaluation and disease monitoring of gliomas relies on MRI in clinical routine and trials. Recently, novel response criteria utilizing amino acid PET (PET RANO 1.0) have been introduced. This study analyses longitudinal [18F]FET PET data of patients with diffuse glioma and applies the PET RANO 1.0 criteria to describe PET characteristics at baseline, response classes, and changes of individual parameters.

MATERIAL AND METHODS

In this retrospective single-center study, patients with diffuse glioma and a baseline as well as at least one follow-up [18F]FET PET scan were identified. PET analyses were performed according to the PET RANO 1.0 criteria and included the assessment of maximal and mean target-to-background ratios (TBRmax, TBRmean), PET volume, changes of these values between scans, and the presence of either measurable or no / non-measurable disease. Follow-up scans were classified as PET-based progressive disease (PET-PD), stable disease (PET-SD), partial response (PET-PR), or complete response (PET-CR) according to PET RANO 1.0.

RESULTS

A total of 475 scans in 148 patients were evaluated with a total of 228 treatment lines, defined as a baseline scan plus a series of one to four follow-up evaluations either with or without treatment. Overall, 164/228 baseline scans had measurable disease and 64/228 had non-measurable or no measurable disease. In the treatment lines, 4% of patients had PET-CR as best response, 23% had PET-PR, 37% had PET-SD, and 36% had PET-PD. PET-PD was determined based on significant volume changes and/or the occurrence of new lesions in the majority of cases (>90%), while significant increases of uptake intensity were found in 30% of cases. A sole increase of uptake intensity as determinant for PET-PD was only found in 8% of cases. PET-PR was determined based on volume reductions in 82% of cases (25% in combination with decreasing uptake intensity) and by a sole reduction of uptake intensity in 18% of cases. Treatment lines of glioblastoma had PET-PD as a best response in 56% of cases, while astrocytomas and oligodendrogliomas only had PET-PD in 44% and 35% of cases, respectively.

CONCLUSION

This study demonstrates that significant volume changes seem to be the major determinant for treatment response according to the PET RANO 1.0 criteria and are often accompanied by changes of uptake intensity, while sole uptake intensity changes determine response classes only in a subset of patients. Best responses in treatment lines classified with the new criteria varied based on tumor type with IDH-wildtype glioblastoma showing higher rates of PET-PD in comparison with IDH-mutant gliomas. In the future, response assessment from PET RANO 1.0 should be correlated with the MRI-based RANO 2.0 criteria, as well as the clinical outcome of patients.
P19.17.B THE PREOPERATIVE LEVELS OF CIRCULATING ERYTHROCYTIC HEMOGLOBIN ARE INDEPENDENT PREDICTORS FOR WHO GRADE 2-3 HISTOLOGY IN FALCINE AND PARASAGITTAL MENINGIOMAS
Authors: Gagliardi F , De Domenico P , Braga M , Barzaghi L R , Nocera G , Poliani P L , Mortini P , Roncelli F , Silvia S
Published: October 2024

BACKGROUND

Falcine and parasagittal lesions stand out among other intracranial meningiomas for their extreme histological heterogeneity, accounting for the highest rate of high-grade lesions. The ability to preoperatively estimate the lesion’s grade and its clinical outcome would be of great value in orienting and customizing the treatment approach in these patients. To date, no validated clinical or radiological predictive factors for tumoral grade and prognosis are available.

MATERIAL AND METHODS

This is a single-center, retrospective, clinical study designed to assess the diagnostic and prognostic role of pre-operative peripheral blood markers in patients harboring falcine (FM) and parasagittal (PM) high-grade meningiomas. A total of 121 patients undergoing surgical resection for a single FM/PM lesion at San Raffaele Hospital between November 2007 and April 2021 were included. A propensity score-matched analysis has been performed to account for gender imbalances in the low-grade (LG) vs high-grade (HG) cohorts.

RESULTS

A total of 75 tumors FM (62%), and 46 PM (38%) meningiomas were included. The median tumoral volume was 31.1 cm3 (IQR 17.1-65.4). Low-grade lesions comprised n=77 WHO grade 1 tumors, whereas the high-grade group (HG) included n=35 grade 2 (28.9%), and n=9 grade 3 lesions (7.4%). Patients harboring HG lesions showed significantly higher baseline Hb levels significantly compared to LG (mean 14.4 ± 1.59 vs 13.7 ± 1.25 g/dl, p=0.04). Preoperative Hb demonstrated a predictive value of lesional grade (OR 1.35, 95% CI: 1.01-1.85, p=0.04). Accordingly, patients showing increased Hb levels >15.4 g/dl achieved shorter OS (60.4 months, 95% CI: 14.7-106.1 vs 137.4 months, 95% CI: 111.2-163.6), p=0.0011 compared to patients with lower preoperative Hb values.

CONCLUSION

Increased levels of circulating erythrocytic hemoglobin might be independent predictors for high-grade histology, and correlate with shorter overall survival in falcine and parasagittal meningiomas.
P20.22.B STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMA - TUMOUR CONTROL AND TOXICITY OUTCOMES FROM THE EAST OF ENGLAND
Authors: Cullen K , Burton K , Jefferies S , Duke S
Published: October 2024

BACKGROUND

Stereotactic radiosurgery (SRS) is a standard of care for small to intermediate size vestibular schwannoma (VS). Having implemented this technique in our centre in 2017, we examined our tumour control and toxicity rates to audit against published data.

MATERIAL AND METHODS

We performed a retrospective review of all patients treated with linear accelerator based SRS (12Gy/1# delivered to 80% isodose) for VS in our centre. Patients were excluded from analysis if they had NF2 or had yet to receive a follow-up. Toxicity outcomes focussed on balance, hearing, and facial/trigeminal nerve symptoms; data was collected on a template within clinic letters. For tumour control, clinical progression requiring surgery was the primary outcome, with an exploratory endpoint of tumour growth (mm). Maximum tumour diameter was collected from radiology reports prior to starting treatment and years 1,2,3 & 5 post SRS. Radiotherapy dose metrics were obtained from radiotherapy plan data. Statistical tests used an unpaired T-test.

RESULTS

140 adult patients with VS were treated with SRS between 2017 and 2023. The mean age was 64. Mean cochlea, brainstem Dmax and trigeminal Dmax doses were 7.7Gy, 9.09Gy and 8.1Gy respectively. Median follow-up was 46 months (range 6 weeks-76 months). One patient was referred for surgery 31 months after treatment due to continued tumour growth. In the 1st year, the median change in tumour size = 0 mm (range -10 to 4), in the 2nd year it was -1 mm (range -1 to 5), in 3rd year 0 mm (range -10 to 3), and in the 4th & 5th years -1 mm (-4 to 0). The median rate of tumour size change was -0.67mm/year (range -6 to 3). 9.2% of patients experienced worsening facial/trigeminal nerve symptoms post-SRS with 90% improving within 2 years, 17% experienced decreased balance with 58% improving within 2 years and 25% experienced a subjective decrease in hearing with none improving within 2 years. 73% of patients with useful hearing retained it at most recent follow-up. There was no significant relationship between growth rate and age, tumour size, or tumour coverage. There was a relationship between higher cochlea dose and new balance problems (p=0.044). There was no significant relationship between symptom development and tumour growth, and many who had growth post-SRS had no new symptoms.

CONCLUSION

High rates of tumour control at early time points were seen as expected - only one patient (0.7%) needed surgery. While typically patients’ tumours shrunk or were stable, the inability to detect growth clinically, through symptom development, points towards the need for ongoing imaging follow-up. Although facial and trigeminal symptoms were uncommon and generally self-limiting, balance and hearing problems were more prevalent and persistent. This shows the need for following up these patients within a multi-disciplinary setting, reinforcing the case for our multi-disciplinary clinic.
P21.02.A GERMAN TRANSLATION AND CROSS-CULTURAL ADAPTATION OF THE VESTIBULAR SCHWANNOMA QUALITY OF LIFE INDEX (VSQOL)
Authors: Rutenkröger M , Wandke S , Gempt J , Dührsen L , Scheer M , Strauss C , Führes H
Published: October 2024

BACKGROUND

Vestibular schwannomas (VSs) are benign tumors of the vestibulocochlear nerve that often cause significant neurological and functional impairment. Patient-reported outcomes, including quality of life (QoL), are essential for understanding the overall impact of VS and its treatment. This study aimed to translate and culturally adapt the Vestibular Schwannoma Quality of Life (VSQOL) Index into German to expand its relevance to German-speaking populations.

MATERIAL AND METHODS

We used a qualitative approach including translation and cognitive interviews with 10 patients who underwent VS surgery. The translation process followed the TRAPD protocol to ensure linguistic and conceptual accuracy. Cognitive interviews assessed the comprehensibility and relevance of the translated questionnaire.

RESULTS

The translation showed remarkable consistency between translators, with minor discrepancies resolved by consensus. Cognitive interviews provided valuable insights that led to refinements in item wording and order. Participants emphasized the importance of an additional item on physician referrals, reflecting differences in health care systems between the United States and Germany.

CONCLUSION

The German VSQOL provides a comprehensive tool for assessing QoL in patients with VS that integrates patient-centered dimensions. A Validation study is underway to establish its reliability and validity.
P22.12.B PREDICTION OF QOL IN PATIENTS WITH IDH-MUTATED GLIOMAS, BEFORE AND ONE YEAR AFTER TREATMENT
Authors: Ryden I , Malmqvist S , Hellström P , Gomez Vecchio T , Smits A , Store Jakola A
Published: October 2024

BACKGROUND

IDH-mutated gliomas are primary brain tumours that typically affect relatively young individuals. As survival rates have increased due to changes in treatment strategies, maintaining health-related quality of life (HRQoL) has become more significant. This study will investigate factors influencing HRQoL in patients with IDH-mutated gliomas.

MATERIAL AND METHODS

Patients undergoing surgery (biopsy/resection) for a presumed IDH-mutated glioma between January 2017 to August 2024 were asked to do a neuropsychological assessment and fill out HRQoL questionnaires. As to this date, inclusion is not finished, and analyses based on molecular subgroups are not yet available. Results presented at the conference will be update. This abstract presents preliminary results for patients included so far (n=96). Two overlapping groups were created based on data availability: a preoperative (preop) group (n=85) and a 12-month postoperative (postop) group (n=71). HRQoL was assessed using the EORTC QLQ-C30 global health status. Tumour-specific, treatment-specific, cognitive, and psychological factors were identified as potential predictors, and hierarchical regression analysis was used for each group. Further analyses were conducted to compare HRQoL with the general population and to explore the most significant predictors.

RESULTS

In the preop group, anxiety levels (Hospital Anxiety and Depression Scale) were significantly associated with HRQoL, explaining 34 % of the variance. In the postop group, radiation therapy was initially associated with lower HRQoL, explaining 7 % of the variance, but this association was not significant in subsequent analyses. Instead, cognitive impairment (no/mild vs. moderate/severe) and anxiety levels were significant predictors of lower HRQoL, accounting for 61% of the variance, with anxiety being the stronger predictor. Compared to the general population (M = 76.3, SD = 21.8), HRQoL was significantly lower in both preop (M = 56.81, SD = 23.47, t = -7.38, p<.001, d = 0.86) and postop groups (M = 64.81, SD = 24.68, t = -3.98, p<.001, d = 0.50). A significant proportion of patients scored above the lower cut-off for anxiety: 53 % in the preop group (27 % above the pathological cut-off) and 30 % in the postop group (18 % above the pathological cut-off).

CONCLUSION

Patients with LGG reported lower HRQoL compared to the general population. Anxiety and cognitive impairment are key factors affecting HRQoL, with anxiety being the strongest predictor. These findings underscore the need to screen for psychological symptoms and evaluate cognitive functioning. In addition, they suggest key areas for rehabilitation to help improve HRQoL in patients with IDH-mutated gliomas.
P27.15.B OVERTREAMENT IN PATIENTS WITH AN UNRESECTABLE HIGH-GRADE GLIOMA IN DAILY CLINICAL PRACTICE
Authors: Claassen M
Published: October 2024

BACKGROUND

In unresectable high-grade glioma (HGG) patients, guidelines recommend a biopsy unless the prognosis is likely to be very unfavourable and best supportive care (BSC) should be advised. Estimating the prognosis is difficult in daily practice and poses the risk of overtreatment.

OBJECTIVE

In this study we assess the overtreatment of unresectable HGG patients.

MATERIAL AND METHODS

A retrospective analysis of patients with an unresectable HGG at the Amsterdam UMC, the Netherlands, between 2016 and 2022 was performed. Overtreatment was defined as not starting adjuvant treatment or survival < 3 months. Using patient (age, sex, Karnofsky Performance scale (KPS), American Society of Anesthesiologists (ASA) Physical Status Classification System) and tumor (multifocality and laterality) characteristics, a predictive model was created using logistic regression with backward elimination (P-removal = 0.05).

RESULTS

A total of 166 patients had an unresectable HGG of which 132 (80%) underwent a biopsy, and 33 (20%) received BSC. Overtreatment occurred in 57 (43%) biopsied patients, with 47 (82%) of these patients not starting adjuvant treatment and 10 (18%) patients surpassing within 3 months after the biopsy. Age ≥ 64.2 years (OR 2.739, p = 0.006) and a pre-biopsy KPS < 70 (OR 3.781, p = 0.006) were significant predictors of overtreatment. Biopsied patients had a longer survival than patients receiving BSC (respectively OS 8,6 and 3,8 months, p = < 0.001) However, survival of overtreated biopsy patients (OS 2,6 months) was shorter than in patients receiving BSC (p = 0.003).

CONCLUSION

Current decision-making in daily practice results in overtreatment in 43% of patients who are advised to undergo a biopsy. These patients have a shorter survival than those who receive BSC. Higher age and lower pre-biopsy KPS could help to identify these patients. Future research should aim to develop more robust markers to aid decision-making and prevent overtreatment of these vulnerable patients.
Data-driven discovery of Tsallis-like distribution using symbolic regression in high-energy physics
Authors: Makke Nour , Chawla Sanjay
Published: October 2024

The application of atificial intelligence (AI) in fundamental physics has faced limitations due to its inherently uninterpretable nature, which is less conducive to solving physical problems where natural phenomena are expressed in human-understandable language, i.e. mathematical equations. Fortunately, there exists a form of interpretable AI that aligns seamlessly with this requirement, namely, symbolic regression (SR), which learns mathematical equations directly from data. We introduce a groundbreaking application of SR on actual experimental data with an unknown underlying model, representing a significant departure from previous applications, which are primarily limited to simulated data. This application aims to evaluate the reliability of SR as a bona fide scientific discovery tool. SR is applied on transverse-momentum-dependent distributions of charged hadrons measured in high-energy-physics experiments. The outcome underscores the capability of SR to derive an analytical expression closely resembling the Tsallis distribution. The latter is a well-established and widely employed functional form for fitting measured distributions across a broad spectrum of hadron transverse momentum. This achievement is among the first instances where SR demonstrates its potential as a scientific discovery tool. It holds promise for advancing and refining SR methods, paving the way for future applications on experimental data.
A phylogenetics and variant calling pipeline to support SARS-CoV-2 genomic epidemiology in the UK
Authors: Colquhoun Rachel , O’Toole Áine , Hill Verity , McCrone J T , Yu Xiaoyu , Nicholls Samuel M , Poplawski Radoslaw , Whalley Thomas , Groves Natalie , Ellaby Nicholas , Loman Nick , Connor Tom , Rambaut Andrew
Published: October 2024

In response to the escalating SARS-CoV-2 pandemic, in March 2020 the COVID-19 Genomics UK (COG-UK) consortium was established to enable national-scale genomic surveillance in the UK. By the end of 2020, 49% of all SARS-CoV-2 genome sequences globally had been generated as part of the COG-UK programme, and to date, this system has generated >3 million SARS-CoV-2 genomes. Rapidly and reliably analysing this unprecedented number of genomes was an enormous challenge. To fulfil this need and to inform public health decision-making, we developed a centralized pipeline that performs quality control, alignment, and variant calling and provides the global phylogenetic context of sequences. We present this pipeline and describe how we tailored it as the pandemic progressed to scale with the increasing amounts of data and to provide the most relevant analyses on a daily basis.
Updates on pancreatic cancer treatment – invited special issue
Authors: Conlon Kevin , Coppola Roberto
Published: October 2024

Despite an increased understanding of the underlying biology of the disease, pancreatic ductal adenocarcinoma (PDAC) remains a challenging condition with poor outcomes and a 5-year survival rate, even at an early stage, of less than 10%. This dismal prognosis is due in part to biological aggressiveness, the lack of early diagnosis, suboptimal surgical selection, and the need for effective neoadjuvant and adjuvant therapies. However, progress is being made with significant advancements in the diagnosis, staging, and treatment of PDAC, with a focus on precision therapy, improved surgical care, and supportive care, coupled with a deeper understanding of PDAC’s biology. This Special Issue aims to provide an overview of these advancements, summarizing recent research key findings and contributions.
Student-Led Mobility Interventions for Hospitalized Adults
Authors: Crick James P. , Oberyszyn Alex , Alain Gabriel N. , Thomas Erin M. , Quatman Carmen E. , Quatman-Yates Catherine C.
Published: October 2024

Background:

Inactivity in hospitalized patients often leads to functional decline. We created an undergraduate course to promote mobilization, provide hands-on learning, and address staff shortages.

Purpose:

To assess the feasibility and acceptability of undergraduate students providing mobility-focused interventions for hospitalized adults.

Methods:

This mixed-methods study was conducted at a level 1 trauma academic center. We analyzed program feasibility and acceptability using quantitative data and thematic analysis of interviews and focus groups.

Results:

In total 47 individuals (n = 14 students, n = 9 patients, and n = 24 clinicians) were included. Students averaged 4.1 mobility sessions per 4-hour shift. All stakeholders agreed the program is acceptable, and 98.6% affirmed the program is feasible. The themes identified included positive impacts on patient care, enhanced student professional development, and practical implementation challenges.

Conclusions:

Student-led mobility interventions can be an acceptable strategy to mitigate immobility harm in hospitalized patients. The integration of students enhances patient care and provides valuable educational experiences.
MAiD in America
Authors: Grubbs Kathy Howard , Keinath Christiana M. , Bigger Sharon E.
Published: October 2024

The evolving legal landscape associated with medical assistance in dying (MAiD) may pose significant challenges for hospice and palliative care professionals. In the United States, 10 states and 1 jurisdiction have passed legislation allowing MAiD. National organizations, such as the Hospice and Palliative Nurses Association, have created position statements to serve as guides to care. Given the clinical and ethical challenges associated with MAiD, a rapid review was conducted to provide current evidence for policymakers, health care professionals, and researchers to use when considering care management and policy initiatives. Using a systematic approach, publications related to MAiD between 2019 and 2024 were extracted and synthesized. The review provides definitions of terms that differentiate between MAiD, euthanasia, physician-assisted suicide, medically assisted death of the nonterminal patient, and death with dignity. A total of 23 articles were included in the review and categorized into 4 themes: (1) legal, regulatory, and policy concerns; (2) health care professional experience of MAiD; (3) patient and caregiver experience of and communication about MAiD; and (4) disparate access to MAiD.
Uncovering the Motor Dynamics of Obsessive-Compulsive Rituals Through Cluster Analysis
Authors: Gambolò Luca , Ottoni Rebecca , Di Donna Anna , Marchesi Carlo , Tonna Matteo
Published: October 2024

Rituals represent a prominent human behavior in different contexts such as daily routines, life cycle stages, and psychopathology, for example, obsessive compulsive disorder (OCD) where they are referred to as compulsions. OCD compulsions differ from habitual behaviors and stereotypies regarding their formal features: acts repetition, the addition of nonfunctional acts, and attentional focus on basic motor units. This study aims to categorize OCD compulsions based on the motor patterns of acts repetition and inclusion of nonfunctional acts. We analyzed 28 video-recorded OCD compulsions; we adopted a cluster analytic model to identify distinct patterns within the data and determine cluster characteristics. Our findings revealed a moderate negative covariance between nonfunctionality and repetitiveness, indicating that as nonfunctionality increased, repetitiveness decreased. Three distinct clusters in OCD rituals were identified according to the motor pattern: “idiosyncratic rituals,” characterized by strong incorporation of nonfunctional acts; “iterative rituals” showing high repetitiveness; and “routines,” with minimal repetition and limited inclusion of nonfunctional acts. These motor patterns highlight evolutionarily conserved behavioral strategies aimed at coping with conditions of environmental unpredictability. The findings might allow fine-grained discrimination of ritual compulsions and help target personalized interventions.
Teamwork in Rural Emergency Health Care
Authors: Morian Hanna , Hultin Magnus , Lindkvist Marie , Creutzfeldt Johan , Dubois Hanna , Jonsson Karin , Amorøe Torben N. , Härgestam Maria
Published: October 2024

Introduction

Despite the increasing use of distributed healthcare teams, performance evaluation is largely lacking. This study examined rural emergency health care in Sweden to determine the effect of teams being either co-located or distributed with remote physicians accessible via telemedicine.

Method

In this crossover study, 17 three-person teams were video recorded during co-located and distributed simulated scenarios. Team performance in the video recordings was evaluated using the TEAM instrument.

Results

Co-located scenarios had significantly higher Total ratings for the instrument (items 1–11), in the teamwork domain (items 3–9), and in overall performance (item 12) compared with distributed scenarios (P < 0.005). Item-level analysis revealed that co-located teams were better at completing tasks on time (item 4) and showed greater adaptability to changing situations (item 7).

Conclusions

The higher rating of the performance of co-located teams underscores the challenges facing distributed teams. Given that distributed healthcare teams are a reality in rural areas in northern Sweden, education and training must be adapted to address these challenges. This adaptation is crucial for ensuring high-quality patient care by distributed teams.
Revisiting typing systems for group B Streptococcus prophages: an application in prophage detection and classification in group B Streptococcus isolates from Argentina
Authors: Kovacec Veronica , Di Gregorio Sabrina , Pajon Mario , Crestani Chiara , Poklepovich Tomás , Campos Josefina , Basit Khan Uzma , Bentley Stephen D. , Jamrozy Dorota , Mollerach Marta , Bonofiglio Laura
Published: October 2024

Group B Streptococcus (GBS) causes severe infections in neonates and adults with comorbidities. Prophages have been reported to contribute to GBS evolution and pathogenicity. However, no studies are available to date on the presence and diversity of prophages in GBS isolates from humans in South America. This study provides insights into the prophage content of 365 GBS isolates collected from clinical samples in the context of an Argentinean multicentric study. Using whole-genome sequence data, we implemented two previously proposed methods for prophage typing: a PCR approach (carried out in silico) coupled with a blastx-based method to classify prophages based on their prophage group and integrase type, respectively. We manually searched the genomes and identified 325 prophages. However, only 80% of prophages could be accurately categorized with the previous approaches. Integration of phylogenetic analysis, prophage group and integrase type allowed for all to be classified into 19 prophage types, which correlated with GBS clonal complex grouping. The revised prophage typing approach was additionally improved by using a blastn search after enriching the database with ten new genes for prophage group classification combined with the existing integrase typing method. This modified and integrated typing system was applied to the analysis of 615 GBS genomes (365 GBS from Argentina and 250 from public databases), which revealed 29 prophage types, including two novel integrase subtypes. Their characterization and comparative analysis revealed major differences in the lysogeny and replication modules. Genes related to bacterial fitness, virulence or adaptation to stressful environments were detected in all prophage types. Considering prophage prevalence, distribution and their association with bacterial virulence, it is important to study their role in GBS epidemiology. In this context, we propose the use of an improved and integrated prophage typing system suitable for rapid phage detection and classification with little computational processing.
Basic helix-loop-helix transcription factorBHLHE22monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, tone and movement abnormalities
Authors: Le Carolyn , Argilli Emanuela , George Elizabeth , Kalaycı Tuğba , Uyguner Zehra Oya , Karaman Birsen , Demirören Tanju , DiTroia Stephanie , Heron Delphine , Sabatier Isabelle , Rodan Lance H. , Girisha Katta Mohan , Radhakrishnan Periyasamy , Saunders Carol , Sullivan Bonnie , Fleming Emily , Alvi Javeria Raza , Sultan Tipu , Houlden Henry , Efthymiou Stephanie , Guillen Sacoto Maria J. , Goodman Melanie , Pierron Lucie , Sainte-Agathe Jean-Madeleine De , Durr Alexandra , Sherr Elliott H.
Published: October 2024

BHLHE22encodes a Class II basic helix-loop-helix transcription factor (bHLH). It is expressed exclusively in the retina and central nervous system (CNS), and functions as an important regulator of retinogenesis and neuronal differentiation. Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum. Here we report eleven individuals from nine unrelated families withBHLHE22variants, with a neurodevelopmental disorder presenting with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals have partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised of epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms. Four individuals carryde novomissense variants within the highly conserved helix-loop-helix domain while seven individuals from five unrelated families carry a recurrent homozygous frameshift variant, p.(Gly74Alafs*18). Our findings implicateBHLHE22variants in causing a previously unidentified autosomal dominant and recessive neurodevelopmental disorder associated with ACC, severe motor, language, and cognitive delays, abnormal tone, and involuntary movements. To our knowledge, this is the first report of Class II bHLH variants in humans shown to significantly disrupt brain development, cognition, and movement.
Development and qualification of an LC-MS/MS method for the quantification of MUC5AC and MUC5B mucins in spontaneous human sputum
Authors: Sun Weiwen , Mou Si , Huntington Catherine , Killick Helen , Scott Ian Christopher , Kelly Aoife , Gavala Monica , Larsson Jessica Holmen , Vakkalanka Deepika , Alexis Neil E , Wiley Walter , Wheeler Aaron , Shah Kumar , Yuan Moucun , Mylott William R. , Contrepois Kévin , Rosenbaum Anton I.
Published: October 2024

Aim

Airway mucins are promising biomarkers in respiratory diseases. In this study, we aimed to identify a suitable sputum collection and processing method, as well as qualify a bioanalytical method for soluble MUC5AC and MUC5B quantification in clinical samples.

Method

Mucins were quantified in induced and spontaneous sputum collected from the same COPD patients and following various sample processing procedures. Our LC-MS/MS method used truncated recombinant mucins as surrogate analytes and a surrogate matrix approach.

Results

Frozen spontaneous sputum was found to be a suitable and convenient matrix for mucin quantification and fit-for-purpose method qualification was performed.

Conclusion

Our methodology provides accurate and reliable MUC5AC and MUC5B quantification and facilitates multi-site clinical studies in COPD and potentially other respiratory diseases.
Religion, Politics, and Policy Related to Age-Adjusted Cancer, Heart Disease, Infant Mortality and COVID-19 Death Rates, U.S. States 2018-2021
Authors: Robertson Leon S.
Published: October 2024

The role of religion and politics in the responses to the coronavirus pandemic raises the question of their influence on the risk of other diseases. This study focuses on age-adjusted death rates of cancer, heart disease, and infant mortality per 1000 live births before the pandemic (2018-2019) and COVID-19 in 2020-2021. Seven hypothesized predictors of health effects were analyzed by examining their correlation to age-adjusted death rates among U.S. states – percent who pray once or more daily, Republican influence on state health policies as indicated by the percentage vote for Trump in 2016, median family income divided by a cost-of-living index, the Gini income inequality index, urban concentration of the population, physicians per capita, and public health expenditures per capita. Since many people practice religion independent of formal ceremonies, the percentage of people who claim to pray daily in each state was used as an indicator of potential religious influence. All of the death rates were higher in states where more people claim to pray daily and where Trump received a larger percentage of the vote. The rates were consistently lower in states where public health expenditures were higher. Only COVID-19 was correlated to physicians per capita, lower where there were more physicians. Corrected statistically for the other factors, income per cost of living explains no variance. Heart disease and COVID-19 death rates were higher in areas with more income inequality.
Outbreak of sexually transmittedS. sonnei blaCTX-M-15in England: an epidemiological and genomic investigation
Authors: Charles Hannah , Greig David R. , Swift Craig , Olonade Israel , Simms Ian , Sinka Katy , Baker Kate S , Godbole Gauri , Jenkins Claire
Published: October 2024

The diarrhoeal disease, shigellosis, can be sustained as a sexually transmissible enteric illness among gay, bisexual, and other men who have sex with men (GBMSM). Multiple extensively drug-resistant strains ofShigellahave been detected through genomic surveillance, which have typically been associated with plasmids carrying the gene variantblaCTX-M-27. We report an increase in likely sexually transmissible cases ofShigellacarryingblaCTX-M-15,which was previously associated with travel. In 2023, there were 117 cases belonging to the single 10-SNP single linkage cluster, t10.1814. While this cluster had been present in England since August 2019, genetic analyses revealed thatblaCTX-M-15entered the lineage on a novel resistance plasmid coincident with the first case of the outbreak. This highlights the shifting antimicrobial resistance landscape of sexually transmissibleShigellaand the parallel emergence of resistance determinants against third generation cephalosporins in sexual transmission networks suggests high levels of antimicrobial selection pressure among GBMSM.
SARS-CoV-2 outbreak in lions, tigers and hyenas at Denver Zoo
Authors: Gallichotte Emily N , Bashor Laura , Erbeck Katelyn , Croft Lara , Stache Katelyn , Long Jessica , VandeWoude Sue , Johnson James , Pabilonia Kristy , Ebel Gregory
Published: October 2024

In late 2019, SARS-CoV-2 spilled-over from an animal host into humans, where it efficiently spread, resulting in the COVID-19 pandemic. Through both natural and experimental infections, we learned that many animal species are susceptible to SARS-CoV-2. Importantly, animals in close proximity to humans, including companion, farmed, and those at zoos and aquariums, became infected, and many studies demonstrated transmission to/from humans in these settings. In this study, we first review the literature of SARS-CoV-2 infections in tigers and lions, and compare species, sex, age, virus and antibody detection assay, and types, frequency and length of clinical signs, demonstrating broad heterogeneity amongst infections. We then describe a SARS-CoV-2 outbreak in lions, tigers and hyenas at Denver Zoo in late 2021. Animals were tested for viral RNA (vRNA) for four months. Lions had significantly more viral RNA in nasal swabs than both tigers and hyenas, and many individual lions experienced viral recrudescence after weeks of undetectable vRNA. Infectious virus was correlated with high levels of vRNA and was more likely to be detected earlier during infection. Four months post-infection, all tested animals generated robust neutralizing antibody titers. Animals were infected with Delta lineage AY.20 identical to a variant circulating at less than 1% in Colorado humans at that time, suggesting a single spillover event from an infected human spread within and between species housed at the zoo. Better understanding of epidemiology and susceptibility of SARS-CoV-2 infections in animals is critical to limit the current and future spread and protect animal and human health.
Benchmarking Bayesian colocalization methods in validating Mendelian randomization-based target discoveries from circulating proteins for cardiometabolic diseases
Authors: Zhang Wenmin , Yoshiji Satoshi , Sladek Robert , Dupuis Josée , Lu Tianyuan
Published: October 2024

Background

Mendelian randomization (MR) is an important tool for identifying potential biomarkers and drug targets. Colocalization analysis is crucial for validating MR findings and guarding against potential confounding due to linkage disequilibrium. We aim to systematically benchmark the performance of four Bayesian colocalization methods in validating MR-based target discoveries from circulating proteins for cardiometabolic diseases.

Results

We conducted MR analyses to assess the associations between circulating levels of 1,535 proteins and five cardiometabolic traits, followed by colocalization analyses using coloc, coloc+SuSiE, PWCoCo and SharePro. All methods demonstrated well-controlled false discoveries in the colocalization analysis of 611 pairs of circulating proteins and cardiometabolic traits with a nominal p-value > 0.9 in MR. SharePro demonstrated the highest frequency in supporting 160 (79.6%) of the 201 Bonferroni-significant protein-trait associations identified by MR, compared to coloc (supporting 40.3% of these associations), coloc+SuSiE (46.8%), and PWCoCo (45.8%), and was robust to varying prior colocalization probabilities. Moreover, protein-trait associations identified by MR and supported by SharePro were more likely to agree with significant gene-level associations based on rare variants detected in exome-wide association studies and implicate known drug targets for cardiometabolic diseases. Eight protein-trait associations were exclusively supported by SharePro and did not demonstrate a high risk of horizontal pleiotropy, suggesting potential cardiometabolic biomarkers or drug targets, such as HSF1 and HAVCR2.

Conclusions

SharePro most often supports high-confidence associations identified through MR for cardiometabolic diseases. Combining multiple lines of evidence using different methods may substantially increase the yield of biomarker and drug target discovery programs.
DDX41 dissolves G-quadruplexes to maintain erythroid genome integrity and prevent cGAS-mediated cell death
Authors: Bi Honghao , Ren Kehan , Wang Pan , Li Ermin , Han Xu , Wang Wen , Yang Jing , Aydemir Inci , Tao Kara , Godley Lucy , Liu Yan , Shukla Vipul , Bartom Elizabeth T. , Tang Yuefeng , Blanc Lionel , Sukhanova Madina , Ji Peng
Published: October 2024

Deleterious germlineDDX41variants constitute the most common inherited predisposition disorder linked to myeloid neoplasms (MNs). The role of DDX41 in hematopoiesis and how its germline and somatic mutations contribute to MNs remain unclear. Here we show that DDX41 is essential for erythropoiesis but dispensable for the development of other hematopoietic lineages. Using stage-specific Cre models for erythropoiesis, we reveal that Ddx41 knockout in early erythropoiesis is embryonically lethal, while knockout in late-stage terminal erythropoiesis allows mice to survive with normal blood counts. DDX41 deficiency induces a significant upregulation of G-quadruplexes (G4), noncanonical DNA structures that tend to accumulate in the early stages of erythroid precursors. We show that DDX41 co-localizes with G4 on the erythroid genome. DDX41 directly binds to and dissolves G4, which is significantly compromised in MN-associatedDDX41mutants. Accumulation of G4 by DDX41 deficiency induces erythroid genome instability, defects in ribosomal biogenesis, and upregulation of p53. However, p53 deficiency does not rescue the embryonic death of Ddx41 hematopoietic-specific knockout mice. In parallel, genome instability also activates the cGas-Sting pathway, which is detrimental to survival since cGas-deficient and hematopoietic-specific Ddx41 knockout mice are viable without detectable hematologic phenotypes, although these mice continue to show erythroid ribosomal defects and upregulation of p53. These findings are further supported by data from aDDX41mutated MN patient and human iPSC-derived bone marrow organoids. Our study establishes DDX41 as a G4 dissolver, essential for erythroid genome stability and suppressing the cGAS-STING pathway.
Bringing Attomolar Detection to the Point-of-Care with Nanopatterned DNA Origami Nanoantennas
Authors: Yaadav Renukka , Trofymchuk Kateryna , Dass Mihir , Behrendt Vivien , Hauer Benedikt , Schütz Jan , Close Cindy , Scheckenbach Michael , Ferrari Giovanni , Maeurer Leoni , Sebina Sophia , Glembockyte Viktorija , Liedl Tim , Tinnefeld Philip
Published: October 2024

Creating increasingly sensitive and cost-effective nucleic acid detection methods is critical for enhancing point-of-care (POC) applications. This involves capturing all desired biomarkers in a sample with high specificity and transducing the capture events to a detector. However, the signal from biomarkers present at extremely low amounts often falls below the detection limit of typical fluorescence-based methods, making molecular amplification a necessary step. Here, we present a nucleic acid detection assay of a 151-nucleotide sequence specific to antibiotics-resistantKlebsiella pneumoniae, based on single-molecule fluorescence detection of non-amplified DNA down to the attomolar level, using Trident NanoAntennas with Cleared HOtSpots (NACHOS). Our NACHOS-diagnostics assay leverages a compact microscope with a large field-of-view and cost-efficient components, including microfluidic flow to enhance capturing efficiency. Fluorescence enhancement is provided by DNA origami NanoAntennas, arranged in a dense array using a combination of nanosphere lithography and site-specific DNA origami placement. Our method can detect 200 ± 50 out of 600 molecules in a 100 µL sample volume within an hour. This represents typical number of pathogens in clinical samples commonly detected by Polymerase Chain Reaction but without the need for molecular amplification. We achieve similar sensitivity in untreated human blood plasma, enhancing the practical applicability of the system. Our platform can be adapted to detect shorter nucleic acid fragments that are not compatible with traditional amplification-based technologies. This broadens its potential for diverse diagnostic and healthcare applications, providing a robust and scalable solution for sensitive nucleic acid detection in various clinical settings.
An iPSC model of fragile X syndrome reflects clinical phenotypes and reveals m6A- mediated epi-transcriptomic dysregulation underlying synaptic dysfunction
Authors: Lu Lu , Sarkar Avijite Kumer , Dao Lan , Liu Yanchen , Ma Chunlong , Thwin Phyo Han , Chang Xuyao , Yoshida George , Li Annie , Wang Cenjing , Westerkamp Crace , Schmitt Lauren , Chelsey Maag , Stephanie Monzon , Zhao Yu , Liu Yaping , Wang Xiong , Zhu Ling-Qiang , Liu Dan , Tchieu Jason , Miyakoshi Makoto , Zhu Haining , Gross Christina , Pedapati Ernest , Salomonis Nathan , Erickson Craig , Guo Ziyuan
Published: October 2024

Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises fromFMR1gene silencing and loss of the FMRP protein. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP is known to bind to and regulate the stability of m6A-containing transcripts. However, how loss of FMRP impacts on transcriptome-wide m6A modifications in FXS patients remains unknown. To answer this question, we generated cortical neurons differentiated from induced pluripotent stem cells (iPSC) derived from healthy subjects and FXS patients. In electrophysiology recordings, we validated that synaptic and neuronal network defects in iPSC-derived FXS neurons corresponded to the clinical EEG data of the patients from which the corresponding iPSC line was derived. In analysis of transcriptome-wide methylation, we show that FMRP deficiency led to increased translation of m6A writers, resulting in hypermethylation that primarily affecting synapse-associated transcripts and increased mRNA decay. Conversely, in the presence of an m6A writer inhibitor, synaptic defects in FXS neurons were rescued. Taken together, our findings uncover that an FMRP-dependent epi-transcriptomic mechanism contributes to FXS pathogenesis by disrupting m6A modifications in FXS, suggesting a promising avenue for m6A- targeted therapies.
Endurance exercise with reduced muscle glycogen content influences substrate utilization and attenuates acute mTORC1- and autophagic signaling in human type I and type II muscle fibers
Authors: Horwath O , Cornet L , Strömlind H , Moberg M , Edman S , Söderlund K , Checa A , Ruas J L , Blomstrand E
Published: October 2024

Background

Exercising with low muscle glycogen content can improve training adaptation, but the mechanisms underlying the muscular adaptation are still largely unknown. In this study, we measured substrate utilization and cell signaling in different muscle fiber types during exercise and investigated a possible link between these variables.

Methods

Five subjects performed a single leg cycling exercise in the evening (day 1) with the purpose of reducing glycogen stores. The following morning (day 2), they performed two-legged cycling at ∼70% of VO2peak for 1h. Muscle biopsies were taken from both legs pre- and post-exercise for enzymatic analyses of glycogen, metabolite concentrations using LC-MS/MS-based quantification, and protein signaling using Western blot in pools of type I or type II fibers.

Results

Glycogen content was 60-65% lower for both fiber types (P<0.01) in the leg that exercised on day 1 (low leg) compared to the other leg with normal level of glycogen (normal leg) before the cycling exercise on day 2. Glycogen utilization during exercise was significantly less in both fiber types in the low compared to the normal leg (P<0.05). In the low leg, there was a 14- and 6-fold increase in long-chain fatty acids conjugated to carnitine in type I and type II fibers, respectively, post-exercise. This increase was 3-4 times larger than in the normal leg (P<0.05). Post-exercise, mTORSer2448phosphorylation was increased in both fiber types in the normal leg (P<0.05) but remained unchanged in both fiber types in the low leg together with an increase in eEF2Thr56phosphorylation in type I fibers (P<0.01). Exercise induced a reduction in the autophagy marker LC3B-II in both fiber types and legs, but the post-exercise level was higher in both fiber types in the low leg (P<0.05). Accordingly, the LC3B-II/I ratio decreased only in the normal leg (75% for type I and 87% for type II, P<0.01).

Conclusions

Starting an endurance exercise session with low glycogen availability leads to profound changes in substrate utilization in both type I and type II fibers. This may reduce the mTORC1 signaling response, primarily in type I muscle fibers, and attenuate the normally observed reduction in autophagy.
PARMIK: PArtial Read Matching with Inexpensive K-mers
Authors: Baradaran Morteza , Layer Ryan M , Skadron Kevin
Published: October 2024

Environmental metagenomic sampling is instrumental in preparing for future pandemics by enabling early identification of potential pathogens and timely intervention strategies. Novel pathogens are a major concern, especially for zoonotic events. However, discovering novel pathogens often requires genome assembly, which remains a significant bottleneck. A robust metagenomic sampling that is directly searchable with new infection samples would give us a real-time understanding of outbreak origins dynamics. In this study, we propose PArtial Read Matching with Inexpensive K-mers (PARMIK), which is a search tool for efficiently identifying similar sequences from a patient sample (query) to a metagenomic sample (read). For example, at 90% identity between a query and a read, PARMIK surpassed BLAST, providing up to 21% higher recall. By filtering highly frequent k-mers, we reduced PARMIK's index size by over 50%. Moreover, PARMIK identified longer alignments faster than BLAST, peaking at 1.57x, when parallelizing across 32 cores.