bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventing Potential Patient Harm Through Clinical Content Interventions During Oncology Clinical Trial Implementation
Authors: Loo Vivian C. , Kim Sarah , Johnson Lisa M. , Kay Howard , Yi Annie , Chen Jason , Asmar-Abdien Lisa O.
Published: August 2023

Objectives

Clinical trial documents are complex and may have inconsistencies, leading to potential site implementation errors and may compromise participant safety. This study characterizes the frequency and type of administrative and potential patient safety interventions (PPSIs) made during the review of oncology trial documents for clinical trial implementation by centralized clinical content specialists.

Methods

A dedicated group of centralized clinical content specialists reviewed trial documents, including the protocol, laboratory manual, and pharmacy/cellular therapy manual, and collected intervention data over a 1-year period. Each trial was categorized by study phase and sponsor type, and multiple interventions could be identified per trial. Interventions were deemed administrative or PPSIs, with PPSIs further subcategorized as medication, laboratory, procedure related, or other.

Results

Of 585 clinical trials reviewed, 269 (46%) required intervention(s). Among 1001 interventions, 171 (17.1%) were PPSIs. Most PPSIs were medication related (45.6%), with drug dosing interventions most frequently identified (53.8%). Phase 1 trials had the highest proportion of PPSIs (0.35:1) and administrative interventions (2:1) per trial compared with all other phases. Investigator-initiated trials saw the highest proportion of PPSIs per trial (0.44:1) of all sponsor types.

Conclusions

This study demonstrates a gap in patient safety when assessing trial documents for clinical trial implementation. One solution to address this gap is the utilization of a centralized team of clinical specialists to preemptively review trial documents, thereby enhancing patient safety during clinical trial conduct.
Global trends and current status of amputation: Bibliometrics and visual analysis of publications from 1999 to 2021
Authors: Liu Ze , Wang Min , Liu Qi , Huang Biling , Teng Yuanyuan , Li Mingliu , Peng Shuqin , Guo Hongbin , Liang Jieyu , Zhang Yi
Published: August 2023

Objective:

To generalize the research status, hotspots, and development trends of amputation-related research.

Methods:

The data from 1999 to 2021 were collected from the Web of Science core collection database, and analyzed through bibliometrics software (CiteSpace and VOSviewer) for the dual-map overlay of journals, top 25 references with the strongest citation bursts, top 25 keywords with the strongest citation bursts, and timeline of keywords.

Results:

A total of 8,588 literature studies were involved in this study. The United States ranks the first in terms of H-index, total number of publications, and total citations. US Department of Veterans Affairs, Veterans Health Administration, and University of Washington are the major contributors to amputation. Prosthetics and Orthotics International, Archives of Physical Medicine and Rehabilitation, and Journal of Rehabilitation Research and Development are the main publication channels for articles related to amputation. Geertzen JHB, Czerniecki J, and Dijkstra PU are major contributors to amputation. In addition, research on limb salvage treatment and surgical methods for amputation will become a hotspot in the future.

Conclusion:

The total number of publications for amputation has generally increased from 1999 to 2021. Our study is beneficial for scientists to specify the research hotspot and development direction of amputation.
Sex and Gender Disparities in Living Kidney Donation: A Scoping Review
Authors: Vilayur Eswari , van Zwieten Anita , Chen Mingxing , Francis Anna , Wyld Melanie , Kim Siah , Cooper Tess , Wong Germaine
Published: August 2023

Background.

Women are more likely than men to be living kidney donors. We summarized the evidence concerning the reasons behind sex and gender disparities in living kidney donation (LKD).

Methods.

A scoping review of quantitative and qualitative evidence on reasons for sex and gender disparities in LKD was conducted from inception to March 2023.

Results.

Of 1123 studies screened, 45 were eligible for inclusion. Most studies were from North America, Europe, and Central Asia (n = 33, 73%). A predominance of women as living donors (55%–65%) was observed in 15 out of 18 (83%) studies. Reasons for sex and gender disparities in LKD included socioeconomic, biological, and cognitive or emotional factors. A gendered division of roles within the families was observed in most studies, with men being the primary income earner and women being the main caregiver. Fear of loss of income was a barrier to male donation. Human leukocyte antigen sensitization through pregnancy in female recipients precluded male partner donation, whereas female donation was supported by altruism and a positive attitude toward LKD.

Conclusions.

Sex imbalance in LKD is prevalent, with a predominance of women as living donors. Such disparities are driven by societal and cultural perceptions of gender roles, pregnancy-induced sensitization, and attitudes toward donation and at least some of these factors are modifiable. Donor compensation to support predonation assessments and income loss, implementation of innovative desensitization treatments, promotion of paired kidney exchange program, and targeted educational initiatives to promote equitable living donation may help to close the gender gap in LKD.
International Variations in Dementia and Alzheimer Disease Diagnosis and Certification Habits and Their Associations With Dementia and Alzheimer Disease Mortality
Authors: Chi Ying-Chen , Chu Wei-Min , Chang Hsin-Yun , Lu Tsung-Hsueh
Published: August 2023

Objective:

To examine international variations in national diagnosis and certification habits prefer recording dementia (D) versus Alzhiemer disease (AD) as the underlying cause of death (UCOD) and their associations with mortality rates of dementia and AD.

Methods:

We calculated proportions of D/D+AD and AD/D+AD deaths as proxies of national diagnosis and certification habits. Pearson correlation coefficients (r) were estimated to assess the associations of proportions with the mortality rates of dementia or AD among adults aged 75 to 84 years across 38 countries.

Results:

The countries with a high preference for recording dementia as the UCOD were Taiwan and Latvia with proportion of D/D+AD deaths of 92% and 88%, respectively, and those with a high preference for recording AD as the UCOD were Slovenia, Turkey, and Poland with proportion of AD/D+AD deaths of 100%, 99%, and 89%, respectively. The r values for the proportions and mortality rate for dementia and AD were 0.67 (95% CI: 0.44-0.81) and 0.46 (95% CI: 0.16-0.68), respectively.

Conclusion:

We identified a small number of countries with obvious natonal diagnosis and certification habits preferring dementia or AD and had moderate effects on international variations in the mortality rates of dementia and AD.
Ensemble-Based Modeling of the SARS-CoV-2 Omicron BA.1 and BA.2 Spike Trimers and Systematic Characterization of Cryptic Binding Pockets in Distinct Functional States : Emergence of Conformation-Sensitive and Variant-Specific Allosteric Binding Sites
Authors: Verkhivker Gennady , Alshahrani Mohammed , Gupta Grace
Published: August 2023

A significant body of experimental structures of the SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity of the spike protein and emergence of druggable cryptic pockets. Understanding of the interplay of conformational dynamics changes induced by Omicron variants and identification of cryptic dynamic binding pockets in the S protein are of paramount importance as exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In the current study we explore conformational landscapes and characterize the universe of cryptic binding pockets in multiple open and closed functional spike states of the Omicron BA.1 and BA.2 variants. By using a combination of atomistic simulations, dynamics network analysis, and allostery-guided network screening of cryptic pockets in the conformational ensembles of BA.1 and BA.2 spike conformations, we identified all experimentally known allosteric sites and discovered significant variant-specific differences in the distribution of cryptic binding sites in the BA.1 and BA.2 trimers. This study provided in-depth structural analysis of the predicted allosteric site in the context of all available experimental information, revealing a critical role and effect of conformational plasticity on the distribution and function of allosteric binding sites. The results detailed how mutational and conformational changes in the BA.1 and BA.2 pike trimers can modulate the functional role of druggable allosteric pockets across different functional regions of the spike protein. The results of this study are particularly significant for understanding the universe of cryptic bindings sites and variant-specific preferences for druggable pockets. Exploring predicted druggable sites can present a new and previously underappreciated opportunity for therapeutic intervention of Omicron variants through conformation-selective and variant-specific targeting of functional sites involved in allosteric changes.
Safety and Immunogenicity of XBB.1.5-Containing mRNA Vaccines
Authors: Chalkias Spyros , McGhee Nichole , Whatley Jordan L. , Essink Brandon , Brosz Adam , Tomassini Joanne E. , Girard Bethany , Wu Kai , Edwards Darin K. , Nasir Arshan , Lee Diana , Avena Laura E. , Feng Jing , Deng Weiping , Montefiori David C. , Baden Lindsey R. , Miller Jacqueline M. , Das Rituparna
Published: August 2023

Background

Subvariants of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) omicron XBB-lineage have the potential to escape immunity provided by prior infection or vaccination. For Covid-19 immunizations beginning in the Fall 2023, the U.S. FDA has recommended updating to a monovalent omicron XBB.1.5-containing vaccine.

Methods

In this ongoing, phase 2/3 study participants were randomized 1:1 to receive 50-µg doses of mRNA-1273.815 monovalent (50-µg omicron XBB.1.5 spike mRNA) or mRNA-1273.231 bivalent (25-µg omicron XBB.1.5 and 25-µg omicron BA.4/BA.5 spike mRNAs) vaccines, administered as 5th doses, to adults who previously received a primary series and 3rd dose of an original mRNA coronavirus disease 2019 (Covid-19) vaccine, and a 4th dose of a bivalent (omicron BA.4/BA.5 and original SARS-CoV-2) vaccine. Interim safety and immunogenicity data 15 days post-vaccination are presented.

Results

In April 2023, participants received mRNA-1273.815 (n=50) and mRNA-1273.231 (n=51). The median intervals from the prior dose of BA.4/BA.5-containing bivalent vaccine were 8.2 and 8.3 months for the mRNA-1273.815 and mRNA-1273.231 groups, respectively. Both vaccines increased neutralizing antibody (nAb) geometric mean titers against all variants tested at day 15 post-booster nAb compared to pre-booster levels. Geometric mean fold-rises from pre-booster titers after the monovalent booster were numerically higher against XBB.1.5, XBB.1.16 and SARS-CoV-2 (D614G) than those of the bivalent booster and were comparable against BA.4/BA.5 and BQ1.1 variants for both vaccines. The monovalent vaccine also elicited nAb responses against omicron XBB.2.3.2, EG.5.1, FL.1.5.1 and BA.2.86 that were similar to those against XBB.1.5 in a subset (n=20) of participants. The occurrence of solicited adverse reactions and unsolicited adverse events were overall similar to those previously reported for the original mRNA-1273 50-µg and omicron BA.4/BA.5-containing bivalent mRNA-1273 vaccines.

Conclusion

In this interim analysis, XBB.1.5-containing monovalent and bivalent vaccines elicited potent neutralizing responses against variants of the omicron XBB-lineage (XBB.1.5, XBB.1.6, XBB.2.3.2, EG.5.1, and FL.1.5.1) as well as the recently emerged BA.2.86 variant. The safety profile of the XBB.1.5-containing vaccine was consistent with those of prior vaccines. These results overall indicate that the XBB.1.5-containing mRNA-1273.815 vaccine has the potential to provide protection against these emerging variants and support the Covid-19 vaccine update in 2023-2024 to a monovalent XBB.1.5-containing vaccine.
Identification of ade novomutation inTLK1associated with a neurodevelopmental disorder and immunodeficiency
Authors: Villamor-Payà Marina , Sanchiz-Calvo María , Smak Jordann , Pais Lynn , Sud Malika , Shankavaram Uma , Lovgren Alysia Kern , Austin-Tse Christina , Ganesh Vijay S , Gay Marina , Vilaseca Marta , Arauz-Garofalo Gianluca , Palenzuela Lluís , VanNoy Grace , O’Donnell-Luria Anne , Stracker Travis H.
Published: August 2023

Background

The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants are associated with ‘Intellectual Disability, Autosomal Dominant 57’ (MRD57), a neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown.

Methods

A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a novel, heterozygous variant in TLK1 (c.1435C>G, p.Q479E) by genome sequencing (GS). Single cell gel electrophoresis, western blot, flow cytometry and RNA-seq were performed in patient-derived lymphoblast cell lines. In silico, biochemical and proteomic analysis were used to determine the functional impact of the p.Q479E variant and previously reported NDD-associated TLK1 variant, p.M566T.

Results

Transcriptome sequencing in patient-derived cells confirmed expression of TLK1 transcripts carrying the p.Q479E variant and revealed alterations in genes involved in class switch recombination and cytokine signaling. Cells expressing the p.Q479E variant exhibited reduced cytokine responses and higher levels of spontaneous DNA damage but not increased sensitivity to radiation or DNA repair defects. The p.Q479E and p.M566T variants impaired kinase activity but did not strongly alter localization or proximal protein interactions.

Conclusion

Our study provides the first functional characterization of TLK1 variants associated with NDDs and suggests potential involvement in central nervous system and immune system development. Our results indicate that, like TLK2 variants, TLK1 variants may impact development in multiple tissues and should be considered in the diagnosis of rare NDDs.
Optimal tracheal tube rotation patterns for navigating through the glottis: an in-silico quantification
Authors: Schulz Erich B , Carra Schulz Lucy
Published: August 2023

Seeking to unpack some of the anaesthetists’ “knack” for intubation, this study examines the effect of various orientations of the tracheal tube on the anterior movement of the tube tip using a computerised 3D model of intubation.

The model used sets of coordinates for the upper incisor tip, lower incisor tip and vallecula extracted from mean values reported in a study of 16 volunteers predicted to have easy laryngoscopy and 16 predicted to have difficult laryngoscopy during both gentle laryngoscopy and laryngoscopy under 50N of lifting force, yielding a total of four sets of airway geometry.

Tube orientation was specified with the standard aviation terms pitch, roll and yaw. Observations were repeated across permutations of tube roll (0° to 45°) and yaw (0° to 15°) in all four geometric configurations.

Across all four geometries, the most favourable tip location was observed with close to 15° of yaw and 0° roll with an anterior tip movement at the level of the glottis observed between 19.2 and 26.6mm. Unsurprisingly given the curved shapes of the objects involved, incremental movement of the tip was greatest at extreme values of roll and yaw.

Both yaw and roll caused posterolateral movement of the maxillary teeth contact point. The posterior motion at the mouth enables the entire tube to pitch tip up. However, rolling the tube caused the tube tip to move posteriorly and the pivot point on the laryngoscope blade to move cephalad, nearly always negating what should be a favourable change in pitch allowed by the posterolateral maxillary dentition contact point.

Our analysis suggests that avoiding tube roll while maximising yaw at the time of glottic entrance may be a previously unrecognised manoeuvre to improve tracheal intubation success rate having implications for intubation teaching and simulation. Understanding the importance of posterolateral movement of the tube at the oral cavity also may provide new insights into the cause of some difficult intubations.
Two years of longitudinal measurements of human adenovirus group F, norovirus GI and GII, rotavirus, enterovirus, enterovirus D68, hepatitis A virus,Candida auris, and West Nile virus nucleic-acids in wastewater solids: A retrospective study at two wastewater treatment plants
Authors: Boehm Alexandria B. , Wolfe Marlene K. , White Bradley J. , Hughes Bridgette , Duong Dorothea
Published: August 2023

Wastewater monitoring for infectious disease targets is increasingly used to better understand circulation of diseases. The present study validated hydrolysis-probe digital droplet (reverse-transcriptase (RT))-PCR assays for important enteric viruses (rotavirus, adenovirus group F, norovirus GI and GII, and enteroviruses), outbreak or emerging viruses (hepatitis A and West Nile virus), and an emerging drug resistant fungal pathogen (Candida auris). We used the assays to retrospectively measure concentrations of the targets in wastewater solids. Viral and fungal nucleic-acid concentrations were measured in two wastewater solids samples per week at two wastewater treatment plants in the San Francisco Bay Area of California, USA for 26 months. We detected all targets in wastewater solids with the exception of West Nile virus. At both wastewater treatment plants, human adenovirus group F was detected at the highest concentrations, followed by norovirus GII, enteroviruses, norovirus GI, and rotavirus at the lowest concentrations. Hepatitis A andC. auriswere detected less consistently than the aforementioned viruses. Enterovirus D68 was detected in a limited time frame during fall 2022 at both sites. The measurements reported herein, and in some cases their seasonal trends, are consistent with previous reports of these targets in wastewater. These measurements represent some of the first quantitative measurements of these infectious disease targets in the solid fraction of wastewater. This study lays a foundation for the use of wastewater solids for the detection of specific infectious disease targets in wastewater monitoring programs aimed to better understand the spread of these diseases.
Temporal Trends in Lifestyle Modification of Patients with Hypertension in Korea, 1998–2021
Authors: Cho Jun Hwan , Park Gyu Tae , Park Kyung-Taek , Kim Hyue Mee , Cho Sungsoo , Lee Sang Yeub , Jeong Young-Hoon , Lee Wang-Soo , Kim Sang-Wook , Won Hoyoun
Published: August 2023

Background

Lifestyle modification is crucial in managing hypertension, independent of medical treatment. This study aimed to evaluate the implementation of lifestyle modifications and analyze the trends in lifestyle modification among patients with hypertension in Korea over the past two decades.

Methods

We analyzed data from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted between 1998 and 2021. The study included adults aged ≥ 20 years. Factors such as regular physical activity, smoking and alcohol abstinence, weight and stress management, and adherence to a healthy diet were analyzed.

Results

A significant threefold increase was observed in the proportion of patients with hypertension who adhered to sodium restriction compared with 20 years ago. However, 70% of patients with hypertension consume more sodium than recommended. Moreover, potassium intake has steadily decreased since 2014, with only 23.8% of patients with hypertension meeting the recommended intake. The body mass index (BMI) and waist circumference of patients with hypertension have gradually increased, with fewer patients maintaining an appropriate weight. The neglect of diet and weight control among young patients with hypertension who experience high stress levels poses challenges in modifying their lifestyles.

Conclusions

Patients with hypertension in Korea still consume high amounts of sodium, whereas potassium intake is gradually decreasing. Additionally, obesity rates have been increasing, especially among young patients with hypertension. Considering the increasing number of young patients with hypertension and the low control rate, the importance of lifestyle modifications should be further emphasized.
Integrating Patient Metadata and Genetic Pathogen Data: Advancing Pandemic Preparedness with a Multi-Parametric Simulator
Authors: Bonjean Maxime , Ambroise Jérôme , Orchard Francisco , Sentis Alexis , Hurel Julie , Hayes Jessica S , Connolly Máire A , Gala Jean-Luc
Published: August 2023

Training and practice are needed to handle an unusual crisis quickly, safely, and effectively. Functional and table-top exercises simulate anticipated CBRNe (Chemical, Biological, Radiological, Nuclear, and Explosive) and public health crises with complex scenarios based on realistic epidemiological, clinical, and biological data from affected populations. For this reason, the use of anonymized databases, such as those from ECDC or NCBI, are necessary to run meaningful exercises. Creating a training scenario requires connecting different datasets that characterise the population groups exposed to the simulated event. This involves interconnecting laboratory, epidemiological, and clinical data, alongside demographic information.

The sharing and connection of data among EU member states currently face shortcomings and insufficiencies due to a variety of factors including variations in data collection methods, standardisation practices, legal frameworks, privacy, and security regulations, as well as resource and infrastructure disparities.

During the H2020 project PANDEM-2 (Pandemic Preparedness and Response), we developed a multi-parametric training tool to artificially link together laboratory data and metadata. We used SARS-CoV-2 and ECDC and NCBI open-access databases to enhance pandemic preparedness.

We developed a comprehensive training procedure that encompasses guidelines, scenarios, and answers, all designed to assist users in effectively utilising the simulator.

Our tool empowers training managers and trainees to enhance existing datasets by generating additional variables through data-driven or random simulations. Furthermore, it facilitates the augmentation of a specific variable’s proportion within a given set, allowing for the customization of scenarios to achieve desired outcomes.

Our multi-parameter simulation tool is contained in the R packagePandem2simulator, available athttps://github.com/maous1/Pandem2simulator. A Shiny application, developed to make the tool easy to use, is available athttps://uclouvain-ctma.Shinyapps.io/Multi-parametricSimulator/. The tool runs in seconds despite using large data sets.

In conclusion, this multi-parametric training tool can simulate any crisis scenario, improving pandemic and CBRN preparedness and response. The simulator serves as a platform to develop methodology and graphical representations of future database-connected applications.
The ClpX chaperone and a hypermorphic FtsA variant with impaired self-interaction are mutually compensatory for coordinatingStaphylococcus aureuscell division
Authors: Henriksen Camilla , Bæk Kristoffer T. , Wacnik Katarzyna , Gallay Clement , Veening Jan-Willem , Foster Simon J. , Frees Dorte
Published: August 2023

Bacterial cell division requires the coordinated assembly and disassembly of a large protein complex called the divisome, however, the exact role of molecular chaperones in this critical process remains unclear. In the important pathogenic bacteriumStaphylococcus aureus, the ClpX chaperone is essential for growth at 30°C and microscopic analyses suggested that ClpX plays a temperature-dependent role in cell division. We here provide genetic evidence that ClpX unfoldase activity is a determinant for proper coordination of cell division by showing that a spontaneous G325V substitution in the ATP-binding domain of the essential FtsA cell division protein rescues growth and septum synthesis in aStaphylococcus aureus clpXmutant. The polymerization state of FtsA is thought to control initiation of bacterial septum synthesis and, while restoring the aberrant FtsA dynamics inclpXcells, the FtsAG325Vvariant displayed reduced ability to interact with itself and other cell division proteins. In wild-type cells, theftsAG325Vallele shared phenotypes withE. colisuperfissionftsAmutants and accelerated the cell cycle, increased the risk of daughter cell lysis, and conferred sensitivity to heat and antibiotics inhibiting cell wall synthesis. Strikingly, lethality was mitigated by spontaneous mutations that inactivate ClpX. Taken together, our results suggest that ClpX promotes septum synthesis by antagonizing FtsA interactions and illuminates the critical role of a protein unfoldase in coordinating bacterial cell division.

IMPORTANCE

Essential biological processes, such as cell division, are performed by multiple proteins working together in dynamic functional complexes. In eukaryotic cells, the disassembly of such molecular machines is often assisted by molecular chaperones capable of unfolding proteins. The ClpX unfoldase is conserved from bacteria to humans, however, the roles of ClpX in bacterial cell biology remain relatively unexplored. By combining genetic methods with super-resolution microscopy techniques, we show here that ClpX and a mutant variant of the essential cell division protein FtsA mutually compensate for each other in controlling cell division of the pathogenic bacteriumStaphylococcus aureus.The selected FtsAG325Vvariant has diminished self-interactions and restored the aberrant FtsA dynamics inclpXcells suggesting that ClpX promotes cell division by antagonizing FtsA protein interactions. This study, for the first time, illuminates the important role of protein unfoldases in the functioning of the divisome, a multienzyme complex fundamental to bacterial reproduction.
Pediatric and Adult Patients with ME/CFS following COVID-19: A Structured Approach to Diagnosis Using the Munich Berlin Symptom Questionnaire (MBSQ)
Authors: Peo Laura C. , Wiehler Katharina , Paulick Johannes , Gerrer Katrin , Leone Ariane , Viereck Anja , Haegele Matthias , Stojanov Silvia , Warlitz Cordula , Augustin Silvia , Alberer Martin , Hattesohl Daniel B. R. , Froehlich Laura , Scheibenbogen Carmen , Mihatsch Lorenz , Pricoco Rafael , Behrends Uta
Published: August 2023

Purpose

A subset of patients with post-COVID-19 condition (PCC) fulfill the clinical criteria of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). To establish the diagnosis of ME/CFS for clinical and research purposes, comprehensive scores have to be evaluated.

Methods

We developed the Munich Berlin Symptom Questionnaires (MBSQs) and supplementary scoring sheets (SSSs) to allow for a rapid evaluation of common ME/CFS case definitions. The MBSQs were applied to young patients with chronic fatigue and post-exertional malaise (PEM) who presented to the MRI Chronic Fatigue Center for Young People (MCFC). Trials were retrospectively registered (NCT05778006,NCT05638724).

Results

Using the MBSQs and SSSs, we report on ten patients aged 11 to 25 years diagnosed with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19. Results from their MBSQs and from well-established patient-reported outcome measures indicated severe impairments of daily activities and health-related quality of life.

Conclusions

ME/CFS can follow SARS-CoV-2 infection in patients younger than 18 years, rendering structured diagnostic approaches most relevant for pediatric PCC clinics. The MBSQs and SSSs represent novel diagnostic tools that can facilitate the diagnosis of ME/CFS in children, adolescents, and adults with PCC and other post-viral syndromes.

What is known

ME/CFS is a frequent debilitating illness. For diagnosis, an extensive differential diagnostic workup is required and the evaluation of clinical ME/CFS criteria. ME/CFS following COVID-19 has been reported in adults but not in pediatric patients younger than 19 years of age.

What is new

We present novel questionnairs (MBSQs), as tools to assess common ME/CFS case definitions in pediatric and adult patients with post-COVID-19 condition and beyond. We report on ten patients aged 11 to 25 years diagnosed with ME/CFS following asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19.
TFF1 – a new Biomarker in Liquid Biopsies of Retinoblastoma under Therapy
Authors: Busch Maike Anna , Haase André , Alefeld Emily , Biewald Eva , Jabbarli Leyla , Dünker Nicole
Published: August 2023

Effective management of retinoblastoma (RB), the most prevalent childhood eye cancer, depends on reliable monitoring and diagnosis. A promising candidate in this context is the secreted trefoil family factor peptide 1 (TFF1), recently discovered as a promising new biomarker in patients with a more advanced subtype of retinoblastoma. The present study investigated TFF1 expression within aqueous humor (AH) of enucleated eyes and compared TFF1 levels in AH and corresponding blood serum samples from RB patients undergoing intravitreal chemotherapy (IVC). TFF1 was consistently detectable in AH, confirming its potential as a biomarker. Crucially, our data confirmed that TFF1 secreting cells within the tumor mass originate from RB tumor cells, not from surrounding stromal cells. IVC therapy responsive patients exhibited remarkably reduced TFF1 levels post-therapy. By contrast, RB patients’ blood serum displayed low to undetectable levels of TFF1 even after sample concentration and no therapy-dependent changes were observed. Our findings suggest that compared to blood serum AH represents the more reliable source for TFF1 if used for liquid biopsy RB marker analysis in RB patients. Thus, analysis of TFF1 in AH of RB patients potentially provides a minimal invasive tool for monitoring RB therapy efficacy, suggesting its importance for effective treatment regimens.

Simple Summary

Effective management of retinoblastoma (RB), a common childhood eye cancer, requires accurate diagnosis and monitoring during therapy. In this study the liquid biopsy marker potential of the secreted trefoil family factor peptide 1 (TFF1), described as a biomarker of a more advanced RB subtype, was explored. TFF1 expression levels were investigated in aqueous humor (AH) of RB patients after enucleation and in RB patients undergoing intravitreal chemotherapy and compared with TFF1 expression levels in RB patients’ blood serum. AH showed consistent TFF1 levels in a subgroup of RB patients, remarkably decreasing post-therapy in responsive patients. Blood serum of RB patients only displayed low to non-detectable and therapy-independent TFF1 levels. The study suggests TFF1 expression in AH as a reliable biomarker, aiding RB diagnosis and treatment assessment and highlights it’s potential for non-invasive RB therapy monitoring.
Reference ranges for cardiovascular function during exercise: effects of aging and gender on performance
Authors: Schweitzer Ronny , de Marvao Antonio , Shah Mit , Inglese Paolo , Kellman Peter , Berry Alaine , Statton Ben , O’Regan Declan P
Published: August 2023

Purpose

Real-time (RT) exercise cardiac magnetic resonance imaging (exCMR) provides a highly reproducible and accurate assessment of cardiac volumes during maximal exercise. It has advantages over alternative approaches due to its high spatial resolution and use of physiological stress. Here we define the healthy response to exercise in adults and the effects of age and gender on performance.

Materials and Methods

Between 2018 and 2021, we conducted CMR evaluation on 169 healthy adults who had no known cardiovascular disease, did not harbour genetic variants associated with cardiomyopathy, and who completed an exCMR protocol using a pedal ergometer. Participants were imaged at rest and after exercise with left ventricular parameters measured using commercial software by two readers. Eight participants were excluded from the final analysis due to poor image quality and/or technical issues. Prediction intervals were calculated for each parameter.

Results

Exercise caused an increase in heart rate (64±9 bpm vs 133±19 bpm,P< 0.001), left ventricular end-diastolic volume (140±32 ml vs 148±35 ml,P< 0.001), stroke volume (82±18 ml vs 102±25 ml,P< 0.001), ejection fraction (59±6% vs 69±7%,P< 0.001), and cardiac output (5.2±1.1 l/min vs 13.5±3.9 l/min,P< 0.001), with a decrease in left ventricular end-systolic volume (58±18 ml vs 46±15 ml,P< 0.001). There was an effect of gender and age on response to exercise across most parameters. Measurements showed good to excellent intra- and inter-observer agreement.

Conclusion

In healthy adults, an increase in cardiac output after exercise is driven by a rise in heart rate with both increased ventricular filling and emptying. We establish normal ranges for exercise response, stratified by age and gender, as a reference for the use of exCMR in clinical practice.
Circulating ADAM17 is associated with COVID-19 severity
Authors: Pan Mengyu , Goncalves Isabel , Edsfeldt Andreas , Sun Jiangming , Swärd Per
Published: August 2023

Background

ADAM17 are emerging as an important role in the severe outcomes of COVID-19. This study aims to characterize causal relationship between ADAM17 and COVID-19.

Methods

Using mendelian randomization analyses, we examined the causal effects for circulating ADAM17 on COVID-19 outcomes using summary statistics from large genome wide association studies of ADAM17 (up to 35 559 individuals) from the Icelandic Cancer Project and deCODE genetics, critical COVID-19 (cases:13 769; controls:1 072 442), hospitalized COVID-19 (cases:32 519; controls: 2 062 805) and SARS-CoV-2 infection (cases:122 616; controls:2 475 240) from the COVID-19 Host Genetics Initiative.

Results

Mendelian randomization analyses demonstrated that 1 standard deviation increase of genetically determined circulating ADAM17 at extracellular domain were associated with increasing risk of developing critical COVID-19 (odds ratio [OR]=1.26, 95% CI 1.03-1.55). Multivariable MR analysis suggested a direct causal role of circulating ADAM17 at extracellular domain on the risk of critical COVID-19 (OR=1.09; 95% CI 1.01-1.17), accounting for body mass index. Casual effects for the cytoplasmic domain of ADAM17 on COVID-19 were not observed.

Conclusion

Our results suggest that the increased circulating ADAM17 at extracellular domain are associated with a high risk of critical COVID-19 strengthening that of ADAM17 may contribute to the risk stratification and a therapeutic option for severe COVID-19.

What is already known on this topic

Various inflammatory stimuli, as well as the SARS-CoV-2 S-protein, elevate the activity of a disintegrin and metalloproteinase 17 (ADAM17). Inhibition of ADAM17 activityin vitrohas illustrated the ability to effectively impede the infection caused by SARS-CoV-2. Nonetheless, the predictive capability of ADAM17 in predicting the severity of COVID-19 outcomes remains less certain within human populations.

What this study adds

Using large genome wide association studies, Mendelian randomization study demonstrated that genetic susceptibility to the increased circulating levels of ADAM17 (extracellular domain) were associated with critical COVID-19 but not SARS-CoV-2 infection or hospitalized COVID-19.

How this study might affect research, practice or policy

The study’s insights might pave the way for novel therapeutic strategies targeting ADAM17 activity. Patients with a genetic predisposition to higher ADAM17 activity might be identified and given tailored treatments.
Conserved and species-specific transcriptional responses to daily programmed resistance exercise in rat and mouse
Authors: Viggars Mark R , Sutherland Hazel , Cardozo Christopher P , Jarvis Jonathan C
Published: August 2023

Mice are often used in gain or loss of function studies to understand how genes regulate metabolism and adaptation to exercise in skeletal muscle. Once-daily resistance training with electrical nerve stimulation produces hypertrophy of the dorsiflexors in rat, but not in mouse. Using implantable pulse generators, we assessed the acute transcriptional response (1-hour post exercise) after 2, 10 and 20 days of training in free living mice and rats using identical nerve stimulation paradigms. RNA-sequencing revealed strong concordance in the timecourse of many transcriptional responses in the tibialis anterior muscles of both species including responses related to ‘stress responses/immediate-early genes’, and ‘collagen homeostasis’, ‘ribosomal subunits’, ‘autophagy’ and ‘focal adhesion’. However, pathways associated with energy metabolism including ‘carbon metabolism’, ‘oxidative phosphorylation’, ‘mitochondrial translation’, ‘propanoate metabolism’ and ‘valine, leucine and isoleucine degradation’ were oppositely regulated between species. These pathways were suppressed in the rat but upregulated in the mouse. Our transcriptional analysis suggests that although many pathways associated with growth show remarkable similarities between species, absence of an actual growth response in the mouse may be because the mouse prioritises energy metabolism, specifically replenishment of fuel stores and intermediate metabolites.
Neural specialization for ‘visual’ concepts emerges in the absence of vision
Authors: Hauptman Miriam , Elli Giulia , Pant Rashi , Bedny Marina
Published: August 2023

Vision provides a key source of information about many concepts, including ‘living things’ (e.g.,tiger) and visual events (e.g.,sparkle). According to a prominent theoretical framework, neural specialization for different conceptual categories is shaped by sensory features, e.g., living things are neurally dissociable from navigable places because living things concepts depend more on visual features. We tested this framework by comparing the neural basis of ‘visual’ concepts across sighted (n=22) and congenitally blind (n=21) adults. Participants judged the similarity of words varying in their reliance on vision while undergoing fMRI. We compared neural responses to living things nouns (birds, mammals) and place nouns (natural, manmade). In addition, we compared visual event verbs (e.g., ‘sparkle’) to non-visual events (sound emission, hand motion, mouth motion). People born blind exhibited distinctive univariate and multivariate responses to living things in a temporo-parietal semantic network activated by nouns, including the precuneus (PC). To our knowledge, this is the first demonstration that neural selectivity for living things does not require vision. We additionally observed preserved neural signatures of ‘visual’ light events in the left middle temporal gyrus (LMTG+). Across a wide range of semantic types, neural representations of sensory concepts develop independent of sensory experience.

Significance Statement

Vision offers a key source of information about major conceptual categories, including animals and light emission events. Comparing neural signatures of concepts in congenitally blind and sighted people tests the contribution of visual experience to conceptual representation. Sighted and congenitally blind participants heard ‘visual’ nouns (e.g., ‘tiger’) and verbs (e.g., ‘sparkle’), as well as less visual nouns (e.g., ‘barn’) and verbs (e.g., ‘squeak’) while undergoing fMRI. Contrary to previous claims, both univariate and multivariate approaches reveal similar representations of animals and light emission verbs across groups. Across a broad range of semantic types, ‘visual’ concepts develop independent of visual experience. These results challenge theories that emphasize the role of sensory information in conceptual representation.
Distributed representations of behavior-derived object dimensions in the human visual system
Authors: Contier O. , Baker C.I. , Hebart M.N.
Published: August 2023

Object vision is commonly thought to involve a hierarchy of brain regions processing increasingly complex image features, with high-level visual cortex supporting object recognition and categorization. However, object vision supports diverse behavioral goals, suggesting basic limitations of this category-centric framework. To address these limitations, we mapped a series of dimensions derived from a large-scale analysis of human similarity judgments directly onto the brain. Our results reveal broadly distributed representations of behaviorally-relevant information, demonstrating selectivity to a wide variety of novel dimensions while capturing known selectivities for visual features and categories. Behavior-derived dimensions were superior to categories at predicting brain responses, yielding mixed selectivity in much of visual cortex and sparse selectivity in category-selective clusters. This framework reconciles seemingly disparate findings regarding regional specialization, explaining category selectivity as a special case of sparse response profiles among representational dimensions, suggesting a more expansive view on visual processing in the human brain.
African bush pigs exhibit porous species boundaries and appeared in Madagascar concurrently with human arrival
Authors: Balboa Renzo F. , Bertola Laura D. , Brüniche-Olsen Anna , Rasmussen Malthe Sebro , Liu Xiaodong , Besnard Guillaume , Salmona Jordi , Santander Cindy G. , He Shixu , Zinner Dietmar , Pedrono Miguel , Muwanika Vincent , Masembe Charles , Schubert Mikkel , Kuja Josiah , Quinn Liam , Garcia-Erill Genís , Rakotoarivony Rianja , Henrique Margarida , Lin Long , Wang Xi , Heaton Michael P. , Smith Timothy P. L. , Hanghøj Kristian , Sinding Mikkel-Holger S. , Atickem Anagaw , Chikhi Lounès , Roos Christian , Gaubert Philippe , Siegismund Hans R. , Moltke Ida , Albrechtsen Anders , Heller Rasmus
Published: August 2023

Several African mammals exhibit a phylogeographic pattern where closely related taxa are split between West/Central and East/Southern Africa, but their evolutionary relationships and histories remain controversial. Bushpigs (Potamochoerus larvatus) and red river hogs (P. porcus) are recognised as separate species due to morphological distinctions, a perceived lack of interbreeding at contact, and putatively old divergence times, but historically, they were considered conspecific. Moreover, the presence of Malagasy bushpigs as the sole large terrestrial mammal shared with the African mainland raises intriguing questions about its origin and arrival in Madagascar. Analyses of 67 whole genomes revealed a genetic continuum between the two species, with putative signatures of historical gene flow, variableFSTvalues, and a recent divergence time (<500,000 years). Thus, our study challenges key arguments for splittingPotamochoerusinto two species and suggests their speciation might be incomplete. Our findings also indicate that Malagasy bushpigs diverged from southern African populations and underwent a limited bottleneck 1,000-5,000 years ago, concurrent with human arrival in Madagascar. These results shed new light on the evolutionary history of an iconic and widespread African genus and provide insight into the longstanding biogeographic puzzle surrounding the bushpig’s presence in Madagascar.
Absolute Quantification of Microbiota in Shotgun Sequencing Using Host Cells or Spike-Ins
Authors: Wallace Andrew , Ling Hong , Gatenby Sean , Pruden Seren , Neeley Catherine , Harland Chad , Couldrey Christine
Published: August 2023

Background

An ongoing challenge for DNA sequencing of samples containing microorganisms is the ability to meaningfully compare different samples and to connect the results back to clinically relevant disease states. The reads of DNA sequence from each sample do not, in and of themselves, give sufficient information to calculate the absolute abundances of each observed organism. Using relative abundances alone is insufficient to determine whether absolute abundances have increased or decreased in the organisms of interest from one sample to the next. This is a well-studied problem in 16S sequencing, but solutions in shotgun sequencing are lacking. Here we show how spike-ins can be used in shotgun sequencing to calculate absolute abundances of organisms present. We also propose the use of the host cells already in the sample as an alternative calculation method. Mammalian host cells are typically of sufficient size that they can be easily and cheaply counted prior to sequencing by a variety of methods and combining this with sequencing data provides sufficient information to calculate the absolute abundances of microbial organisms.

Results

Microbial abundances in the samples calculated via this method were consistent with manufacturer-stated values of microbial communities, with qPCR, and with our method tested against itself with regard the spike-in and host-cell based options.R2values on the log10scale in these tests ranged from 0.85 to 0.98, and the log10-RMSE ranged from 0.1 to 0.7.

Conclusions

The proposed method can consistently calculate absolute microbial abundances to within an order of magnitude. Both versions of the method, where spike-ins are added to the samples, or where host cells in the sample are counted, are viable. Calculating absolute abundances allows for direct comparisons to be made between different samples. If disease-thresholds have been identified, absolute abundances can quantify disease states.