bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of ribociclib and everolimus in children with newly diagnosed DIPG and high-grade glioma: A CONNECT pediatric neuro-oncology consortium report
Authors: DeWire Mariko , Lazow Margot , Campagne Olivia , Leach James , Fuller Christine , Senthil Kumar Shiva , Stanek Joseph , de Blank Peter , Hummel Trent R , Pillay-Smiley Natasha , Salloum Ralph , Stevenson Charles B , Baxter Patricia , Gass David , Goldman Stewart , Leary Sarah E S , Carle Adam , Mikael Leonie , Crabtree Dorothy , Chaney Brooklyn , Lane Adam , Drissi Rachid , Stewart Clinton F , Fouladi Maryam
Published: April 2022

Background

Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of CDK4/6 and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG.

Methods

Patients were enrolled according to a Rolling-6 design and received ribociclib and everolimus once daily for 21 and 28 days, respectively. All patients with HGG and biopsied DIPG were screened for retinoblastoma protein presence by immunohistochemistry. Pharmacokinetics were analyzed.

Results

Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each dose level 1 and 2 without dose-limiting toxicities (DLT). Thirteen patients were enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy before cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9 ± 0.9-fold higher than single-agent administration. Median overall survival for 15 patients with DIPG was 13.9 months; median event-free survival for four patients with HGG was 10.5 months. Two longer survivors had tumor molecular profiling identifying CDKN2A/B deletion and CDK4 overexpression.

Conclusion

The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m2 and everolimus 1.5 mg/m2. Results will inform a molecularly guided phase II study underway to evaluate efficacy.
Effector-mediated relocalization of a maize lipoxygenase protein triggers susceptibility toUstilago maydis
Authors: Saado Indira , Chia Khong-Sam , Betz Ruben , Alcântara André , Pettkó-Szandtner Aladár , Navarrete Fernando , D'Auria John C , Kolomiets Michael V , Melzer Michael , Feussner Ivo , Djamei Armin
Published: April 2022

As the gall-inducing smut fungus Ustilago maydis colonizes maize (Zea mays) plants, it secretes a complex effector blend that suppresses host defense responses, including production of reactive oxygen species (ROS) and redirects host metabolism to facilitate colonization. We show that the U. maydis effector ROS burst interfering protein 1 (Rip1), which is involved in pathogen-associated molecular pattern (PAMP)-triggered suppression of host immunity, is functionally conserved in several other monocot-infecting smut fungi. We also have identified a conserved C-terminal motif essential for Rip1-mediated PAMP-triggered suppression of the ROS burst. The maize susceptibility factor lipoxygenase 3 (Zmlox3) bound by Rip1 was relocalized to the nucleus, leading to partial suppression of the ROS burst. Relocalization was independent of its enzymatic activity, revealing a distinct function for ZmLox3. Most importantly, whereas Zmlox3 maize mutant plants showed increased resistance to U. maydis wild-type strains, rip1 deletion strains infecting the Zmlox3 mutant overcame this effect. This could indicate that Rip1-triggered host resistance depends on ZmLox3 to be suppressed and that lox3 mutation-based resistance of maize to U. maydis requires functional Rip1. Together, our results reveal that Rip1 acts in several cellular compartments to suppress immunity and that targeting of ZmLox3 by Rip1 is responsible for the suppression of Rip1-dependent reduced susceptibility of maize to U. maydis.
Development of the mentalizing network structures and theory of mind in extremely preterm youth
Authors: Fu Xiaoxue , Hung Andy , de Silva Aryanne D , Busch Tyler , Mattson Whitney I , Hoskinson Kristen R , Taylor Hudson Gerry , Nelson Eric E
Published: April 2022

Adolescents born preterm (<37 weeks of gestation) are at elevated risk for deficits in social cognition and peer relationships. Theory of Mind (ToM) is a complex form of social cognition important for regulating social interactions. ToM and the underlying mentalizing network continue to develop across adolescence. The present study recruited 48 adolescents (12–17 years old) who were either born extremely preterm (EPT; <28 weeks of gestation) or full-term (FT) at birth. Cortical thickness, gray matter volume and surface area were measured in four regions of the mentalizing network: the temporoparietal junction, anterior temporal cortex, posterior superior temporal sulcus and frontal pole (mBA10). We also assessed the adolescents’ performance on a ToM task. Findings revealed both group differences and group-by-age interaction effects in the gray matter indices within the temporal lobe regions of the mentalizing network. The EPT group also performed significantly worse than the FT group on the ToM task. The cortical structural measures that discriminated the EPT and FT groups were not related to ToM performance. These results highlight altered developmental changes in brain regions underlying mentalizing functions in EPT adolescents relative to FT controls.
Alpha-band EEG suppression as a neural marker of sustained attentional engagement to conditioned threat stimuli
Authors: Bacigalupo Felix , Luck Steven J
Published: April 2022

Attention helps us to be aware of the external world, and this may be especially important when a threat stimulus predicts an aversive outcome. Electroencephalogram (EEG) alpha-band suppression has long been considered as a neural signature of attentional engagement. The present study was designed to test whether attentional engagement, as indexed by alpha-band suppression, is increased in a sustained manner following a conditioned stimulus (CS) that is paired with an aversive (CS+) vs neutral (CS−) outcome. We tested 70 healthy young adults in aversive conditioning and extinction paradigms. One of three colored circles served as the CS+, which was paired in 50% of the trials with a noise burst (unconditioned stimulus, US). The other colored circles (CS−) were never paired with the US. For conditioning, we found greater alpha-band suppression for the CS+ compared to the CS−; this suppression was sustained through the time of the predicted US. This effect was significantly reduced for extinction. These results indicate that conditioned threat stimuli trigger an increase in attentional engagement as subjects monitor the environment for the predicted aversive stimulus. Moreover, this alpha-band suppression effect may be valuable for future studies examining normal or pathological increases in attentional monitoring following threat stimuli.
Probiotics Plus Dietary Fiber Supplements Attenuate Olanzapine-Induced Weight Gain in Drug-Naïve First-Episode Schizophrenia Patients: Two Randomized Clinical Trials
Authors: Huang Jing , Kang Dongyu , Zhang Fengyu , Yang Ye , Liu Chenchen , Xiao Jingmei , Long Yujun , Lang Bing , Peng Xingjie , Wang Weiyan , Wang Xiaoyi , Liu Fangkun , Davis John M , Zhao Jingping , Wu Renrong
Published: April 2022

Background and Hypothesis

Antipsychotic-induced weight gain is associated with alterations to the composition of the gut microbiota. The purpose of this study was to determine the effect of probiotics plus dietary fiber on antipsychotic-induced weight gain.

Study Design

Two sequential, randomized clinical trials were conducted. In Study 1, 90 drug-naïve, first-episode schizophrenia patients were randomized to receive either olanzapine plus probiotics or olanzapine monotherapy for 12 weeks. In Study 2, 60 drug-naïve, first-episode schizophrenia patients were randomly assigned to receive either olanzapine plus probiotics and dietary fiber or olanzapine monotherapy for 12 weeks.

Study Results

In Study 1, no significant differences in weight gain were observed between the two groups. The insulin resistance index (IRI) was lower in the olanzapine plus probiotics group compared with the olanzapine monotherapy group at week 12 (estimated mean difference, −0.65, [95% confidence interval (CI), −1.10 to −0.20]; p = .005). In Study 2, weight gain was lower in the probiotics plus dietary fiber group than in the olanzapine monotherapy group at week 12 (estimated mean difference −3.45 kg, [95% CI, −5.91 to −1.00]; p = .007). At week 12, IRI increased significantly in the olanzapine monotherapy group (mean, 1.74; standard deviation (SD) = 1.11, p < .001), but not in the olanzapine plus probiotics and dietary fiber group (mean 0.47, SD = 2.16, p = .35) with an estimated mean difference of −0.95 between the two groups [95% CI, −1.77 to −0.14]; p = .022).

Conclusions

These results provide support for the efficacy and safety of probiotics plus dietary fiber in attenuating antipsychotic-induced weight gain in drug-naïve, first-episode schizophrenia patients.
Embedded Distress: Social Integration, Gender, and Adolescent Depression
Authors: Copeland Molly
Published: April 2022

In adolescence, teens manage close friendships while simultaneously evaluating their social position in the larger peer context. Conceptualizing distinct local and global network structures clarifies how social integration relates to mental wellbeing. Examining local cohesion and global embeddedness in the context of key factors related to mental health, such as gender and friends’ depression, can further distinguish when the structure and content of social integration relate to higher and lower depressive levels. Analyses using survey data from PROSPER (n = 27,091, grades 9–12) indicate global embeddedness is generally protective, but for girls, greater global embeddedness when friends are more depressive is associated with increased depressive symptoms. For girls, greater local cohesion reduces associations between more depressive friends and increased depressive levels, while for boys, both local cohesion and friends’ depression are largely irrelevant. Results indicate the importance of considering both local and global network integration in tandem with gender and friends’ depression to understand how social integration relates to mental health.
Objective and subjective sleep and caregiving feelings in mothers of infants: a longitudinal daily diary study
Authors: Ran-Peled Dar , Bar-Shachar Yael , Horwitz Avel , Finkelstein Omer , Bar-Kalifa Eran , Meiri Gal , Tikotzky Liat
Published: April 2022

Study Objectives

This study explored the links between mothers’ objective and subjective sleep and their caregiving feelings toward their infant (i.e. patience for the infant, desire to be with the infant, and anger toward the infant), using a diary study design. We were particularly interested in examining whether nights of lower sleep quality within individual mothers predict more negative maternal caregiving feelings the following day.

Methods

The sample included 151 women, who were recruited during pregnancy. Data were collected at 4 and 8 months after delivery. Maternal sleep was monitored at home for seven nights using actigraphy and sleep diaries. Mothers rated their caregiving feelings each evening.

Results

Multilevel modeling (controlling for depressive symptoms, feeding method, and background variables) revealed that actigraphic and subjective sleep variables were associated with maternal caregiving feeling, both at the between- and within-person levels. For example, lower sleep percent predicted reduced levels of maternal patience for the infant at 4 and 8 months (between-person effect). Moreover, when a mother had a lower sleep percent on a given night (compared to her average), she reported lower levels of patience for her infant the following day (within-person prospective effect).

Conclusions

The findings demonstrate, for the first time, that maternal nightly variations in objective and subjective sleep quality predict daily changes in maternal feelings toward her infant at two different assessment points. Improving maternal sleep quality might be an important target for future interventions which may help mothers to feel more positively toward their infants.
Usefulness of the maintenance of wakefulness test in central disorders of hypersomnolence: a scoping review
Authors: Bijlenga Denise , Overeem Sebastiaan , Fronczek Rolf , Lammers Gert Jan
Published: April 2022

Study Objectives

To review the Maintenance of Wakefulness Test (MWT) as assessment of daytime sleepiness in the evaluation of treatment effects and driving fitness in central disorders of hypersomnolence (CDH).

Methods

We performed a scoping review of studies using the MWT in patients with CDH (i.e. narcolepsy types 1 and 2, and idiopathic hypersomnia). N = 20 articles were included, comprising 683 patients and 129 controls. MWT effect sizes were compared to the Clinical Global Impression (GCI) scale and the Epworth Sleepiness Scale (ESS). MWT sleep latency was correlated to objective driving performances. The role of motivation was evaluated by comparing MWTs of treatment studies (low motivation) to driving fitness studies (high motivation to stay awake). Healthy controls were compared to norm values.

Results

MWT and CGI were both impacted by the same treatment; however, the MWT has higher effect sizes and was more sensitive to measure these effects. The MWT correlated fairly to moderately (ρ = −0.26 to −0.56; p ≤ .05) to objective driving performance. Motivation played a major role on MWT sleep latencies (d = 0.76 to 1.43; p ≤ .001). Current norm values may not be valid, as sleep latency may be impacted by age.

Conclusions

The MWTs applicability to measure treatment effects in CDH was confirmed, but age-adjusted norm values are needed. For a more complete evaluation of EDS it should be combined with subjective measures. Its reliability for driving fitness evaluation is insufficient, and motivation plays a major role. To predict or monitor driving performance in CDH, valid and easy methods should be developed.
Motivating cascade testing for familial hypercholesterolemia: applying the extended parallel process model for clinician communication
Authors: Campbell-Salome Gemme , Walters Nicole L , Ladd Ilene G , Sheldon Amanda , Ahmed Catherine Davis , Brangan Andrew , McMinn Megan N , Rahm Alanna K , Schwartz Marci L B , Tricou Eric , Fisher Carla L , Sturm Amy C
Published: April 2022

Motivating at-risk relatives to undergo cascade testing for familial hypercholesterolemia (FH) is critical for diagnosis and lifesaving treatment. As credible sources of information, clinicians can assist in family communication about FH and motivate cascade testing uptake. However, there are no guidelines regarding how clinicians should effectively communicate with probands (the first person diagnosed in the family) and at-risk relatives. Individuals and families with FH can inform our understanding of the most effective communications to promote cascade testing. Guided by the extended parallel process model (EPPM), we analyzed the perspectives of individuals and families with FH for effective messaging clinicians can use to promote cascade testing uptake. We analyzed narrative data from interviews and surveys collected as part of a larger mixed-methods study. The EPPM was used to identify message features recommended by individuals and families with FH that focus on four key constructs (severity, susceptibility, response efficacy, self-efficacy) to promote cascade testing. Participants included 22 individuals from 11 dyadic interviews and 98 survey respondents. Participants described prioritizing multiple messages that address each EPPM construct to alert relatives about their risk. They illustrated strategies clinicians could use within each EPPM construct to communicate to at-risk relatives about the importance of pursuing diagnosis via cascade testing and subsequent treatment for high cholesterol due to FH. Findings provide guidance on effective messaging to motivate cascade testing uptake for FH and demonstrates how the EPPM may guide communication with at-risk relatives about genetic risk and motivate cascade testing broadly.
The Sociologist and the Subject: Two Historiographies of Post-war Social Science
Authors: Dubler Roslyn
Published: April 2022

There is not one historiography of post-war social science but two: one focused on the sociologists, the other on the people the sociologists studied. This second historiography peels back the abstractions of social scientists to reconstruct the everyday lives and the ‘vernacular’ speech of those studied. John Goldthorpe’s paper in this roundtable provides an opportunity to reflect on the historical concerns, methods, and future of the new literature on post-war sociology and social transcripts.
Seroprevalence and mutations in the major hydrophilic region of hepatitis B virus among pregnant women in Huzhou, China
Authors: Li Haiyan , Qian Fuchu , Zou Weihua , Jin Fang , Li Dongli , Zhang Yaqin
Published: April 2022

Background

Mother-to-child transmission (MTCT) is the main cause of hepatitis B virus (HBV) infections in China. However, there is a paucity of information on seroprevalence and mutations in HBV surface genes among pregnant women in Huzhou, China.

Methods

In this retrospective cross-sectional study, serum markers of 31 681 pregnant women were collected and analysed. The surface genes were amplified and directly sequenced. Mutations in the major hydrophilic region (MHR) were analysed in 171 randomly selected subjects.

Results

The seroprevalence of HBV infection was 3.32% (1053/31 681). The predominant HBV genotypes were B (57.4%) and C (42.6%). Pregnant women ≥30 y of age exhibited a higher hepatitis B surface antigen–positive rate than those <30 y of age. MHR mutations were found in 42.6% (72/169) of the subjects, several of which were escape mutations. The mutational frequencies in the a-determinant and first loop (AA124-137) were higher in genotype C than genotype B. Pregnant women with MHR mutations showed increased alanine transaminase, aspartate transaminase and gamma-glutamyl transpeptidase levels and decreased HBV loads.

Conclusions

The HBV seroprevalence among pregnant women in Huzhou was intermediate. MHR mutations occur and the risk of MTCT still persists. Therefore, early screening, intervention and care for HBV-infected pregnant women should be strengthened to minimize or prevent MTCT of HBV.
Characteristics of Patients with Hematologic Malignancies Without Seroconversion Post-COVID19 Third Vaccine Dosing
Authors: Hallmeyer Sigrun , Thompson Michael A , Fitzpatrick Veronica , Liao Yunqi Liao , Mullane Michael P , Medlin Stephen C , Copeland Kenneth , Weese James L
Published: April 2022

Patients with hematologic malignancies (HM) are at greater risk of severe morbidity and mortality caused by COVID19 and show a lower response to a two-dose COVID19 mRNA vaccine series. The primary objective of this retrospective cohort study is to explore the characteristics of the subset of patients with HM who had little to no change in SARS-CoV-2 spike antibody titer levels after a 3rd vaccine dose (3V) (-/-). As a secondary objective, we seek to compare the cohorts of patients who did and did not seroconvert post-3V to get a better understanding of the demographics and potential drivers of serostatus. A total of 625 patients with HM had two titer results at least 21 days apart pre- and post- the 3V dose. Among the participants who were seronegative prior to 3V (268), 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not. HM diagnosis was significantly associated with seroconversion status (P = .0003) with patients non-Hodgkin lymphoma 6 times the odds of not seroconverting compared to multiple myeloma patients (P = .0010). Among the cohort of patients who remained seronegative post-3V, 107 (90.0%) patients showed no reaction to 3V as indicated by pre- and post- 3V index values. This study focuses on an important subset of patients with HM who are not seroconverting after the COVID mRNA 3V, providing much needed data for clinicians to target and counsel this subset of patients.
Dose-response modelling of endemic coronavirus and SARS-CoV-2: human challenge trials reveal the individual variation in susceptibility
Authors: Miura Fuminari , Klinkenberg Don , Wallinga Jacco
Published: April 2022

We propose a mathematical framework to analyze and interpret the outcomes of human challenge trials. We present plausible infection risks with HCoV-229E and SARS-CoV-2 over a wide range of infectious dose, and suggest ways to improve the design of future trials and to translate its outcomes to the general population.

One sentence summary

We rephrase dose-response models in terms of heterogeneity in susceptibility in order to present the possible range of infection risks for endemic coronaviruses and SARS-CoV-2
Allelic expression imbalance in articular cartilage and subchondral bone refined genome-wide association signals in osteoarthritis
Authors: Coutinho de Almeida Rodrigo , Tuerlings Margo , Ramos Yolande , Den Hollander Wouter , Suchiman Eka , Lakenberg Nico , Nelissen Rob (RGHH) , Mei Hailiang , Meulenbelt Ingrid
Published: April 2022

Osteoarthritis (OA) is an age-related joint disease with a strong and complex genetic component. Genome-wide association studies (GWAS) discovered a large number of genomic regions associated with OA. Nevertheless, to link associated genetic variants affecting the expression of OA-risk genes in relevant tissues remains a challenge. Here, we showed an unbiased approach to identify transcript single nucleotide polymorphisms (SNPs) of OA risk loci by allelic expression imbalance (AEI). We used RNA sequencing of articular cartilage (N = 65) and subchondral bone (N= 24) from OA patients. AEI was determined for all genes present in the 100 regions reported by GWAS catalog. The count fraction of the alternative allele (φ) was calculated for each heterozygous individual with the risk-SNP or with the SNP in linkage disequilibrium (LD) with it. Furthermore, a meta-analysis was performed to generate a meta-φ (null hypothesis median φ=0.49) and P-value for each SNP. We identified 30 transcript SNPs subject to AEI (28 in cartilage and 2 in subchondral bone). Notably, 10 transcript SNPs were located in genes not previously reported in the GWAS catalogue, including two long intergenic non-coding RNAs (lincRNAs), MALAT1 (meta-φ=0.54, FDR=1.7×10−4) and ILF3-DT (meta-φ=0.6, FDR=1.75×10-5). Moreover, 14 drugs were interacting with 7 genes displaying AEI, of which 7 drugs has been already approved. By prioritizing proxy transcript SNPs that mark AEI in cartilage and/or subchondral bone at loci harboring GWAS signals, we present an unbiased approach to identify the most likely functional OA risk-SNP and gene. We identified 10 new potential OA risk genes ready for further, translation towards underlying biological mechanisms.
Monogenetic rare diseases in biomedical databases and text mining
Authors: Nesterova Anastasia , Klimov Eugene , Sozin Sergey , Sobolev Vladimir , Linsley Peter , Golovatenko-Abramov Pavel
Published: April 2022

1

Abstract

The testing of pharmacological hypotheses becomes faster and more accurate, but at the same time more difficult than even two decades ago. It takes more time to collect and analyse disease mechanisms and experimental facts in various specialized resources. We discuss a new approach to aggregating individual pieces of information about a single disease using Elsevier’s automated text mining technology. Developed algorithm allows for the collection of published facts in a unified format starting only with the name of the disease. The special template, which combines research and clinical descriptions of diseases was developed. The approach was tested, and information was collected for 55 rare monogenic diseases. Clinical, molecular, and pharmacological characteristics of diseases with supporting references from the literature are available in the form of tables and files. Manually curated templates for 10 rare diseases, including top ranked Cystic Fibrosis and Huntington’s disease, were published to demonstrate the results of the described approach.
Predictors of Developmental Defects of Enamel in the Primary Maxillary Central Incisors using Bayesian Model Selection
Authors: Reed Susan G. , Fan Sijian , Wagner Carol L. , Lawson Andrew B.
Published: April 2022

Localized non-inheritable developmental defects of tooth enamel (DDE) are classified as enamel hypoplasia (EH), opacity (OP) and post-eruptive breakdown (PEB) using the Enamel Defects Index. To better understand the etiology of DDE, and in particular possibly modifiable variables, we assessed the linkages amongst exposome variables during the specific time duration of the development of the DDE. In general, the human primary central maxillary incisor teeth develop between 13-14 weeksin uteroand 3-4 weeks’ postpartum of a full-term delivery, followed by tooth eruption at about 1 year of age. We utilized existing datasets of mother and child dyad data that encompassed 12 weeks’ gestation through birth and early infancy, and child DDE outcomes from digital images of the erupted primary maxillary central incisor teeth. We applied a Bayesian modeling paradigm to assess the important predictors of EH, OP, and PEB. The results of Gibbs variable selection showed a key set of predictors: mother’s pre-pregnancy body mass index (BMI); maternal serum levels of calcium and phosphorus at gestational week 28; child’s gestational age; and both mother’s and child’s functional vitamin D deficiency (FVDD). In this sample of healthy mothers and children, significant predictors for OP included the child having a gestational period > 36 weeks and FVDD at birth, and for PEB included a mother’s pre-pregnancy BMI < 21.5 and higher serum phosphorus level at week 28.
Disentangling the rhythms of human activity in the built environment for airborne transmission risk: an analysis of large-scale mobility data
Authors: Susswein Zachary , Rest Eva C. , Bansal Shweta
Published: April 2022

Background

Since the outset of the COVID-19 pandemic, substantial public attention has focused on the role of seasonality in impacting transmission. Misconceptions have relied on seasonal mediation of respiratory diseases driven solely by environmental variables. However, seasonality is expected to be driven by host social behavior, particularly in highly susceptible populations. A key gap in understanding the role of social behavior in respiratory disease seasonality is our incomplete understanding of the seasonality of indoor human activity.

Methods

We leverage a novel data stream on human mobility to characterize activity in indoor versus outdoor environments in the United States. We use an observational mobile app-based location dataset encompassing over 5 million locations nationally. We classify locations as primarily indoor (e.g. stores, offices) or outdoor (e.g. playgrounds, farmers markets), disentangling location-specific visits into indoor and outdoor, to arrive at a fine-scale measure of indoor to outdoor human activity across time and space.

Results

We find the proportion of indoor to outdoor activity during a baseline year is seasonal, peaking in winter months. The measure displays a latitudinal gradient with stronger seasonality at northern latitudes and an additional summer peak in southern latitudes. We statistically fit this baseline indoor-outdoor activity measure to inform the incorporation of this complex empirical pattern into infectious disease dynamic models. However, we find that the disruption of the COVID-19 pandemic caused these patterns to shift significantly from baseline, and the empirical patterns are necessary to predict spatiotemporal heterogeneity in disease dynamics.

Conclusions

Our work empirically characterizes, for the first time, the seasonality of human social behavior at a large scale with high spatiotemporal resolution, and provides a parsimonious parameterization of seasonal behavior that can be included in infectious disease dynamics models. We provide critical evidence and methods necessary to inform the public health of seasonal and pandemic respiratory pathogens and improve our understanding of the relationship between the physical environment and infection risk in the context of global change.

Funding

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM123007.
Addition of formaldehyde releaser imidazolidinyl urea and MOPS buffer to urine samples enables delayed processing for flow cytometric analysis of urinary cells
Authors: Freund Paul , Skopnik Christopher M. , Metzke Diana , Goerlich Nina , Klocke Jan , Grothgar Emil , Prskalo Luka , Hiepe Falk , Enghard Philipp
Published: April 2022

Kidney diseases are a major health concern worldwide. Currently there is a large unmet need for novel biomarkers to non-invasively diagnose and monitor kidney diseases. Urinary cells are promising biomarkers and their analysis by flow cytometry has demonstrated its utility in diverse clinical settings. However, up to date this methodology depends on fresh samples, as cellular event counts and the signal-to-noise-ratio deter over time.

Here we developed an easy-to-use two-step preservation method for conservation of urine samples for subsequent flow cytometry. The protocol utilizes a combination of the formaldehyde releasing agent imidazolidinyl urea (IU) and MOPS buffer, leading to gentle fixation of urinary cells. The preservation method increases acceptable storing time of urine samples from several hours to up to 6 days. Cellular event counts and staining properties of cells remain comparable to fresh untreated samples.

The hereby presented preservation method facilitates future investigations on flow cytometry of urinary cells as potential biomarkers and may enable broad implementation in clinical practice.
Microbiological risk ranking of foodborne pathogens and food products in scarce-data settings
Authors: Crotta Matteo , Prakashbabu Bhagyalakshmi Chengat , Holt Hannah , Swift Ben , Kaur Paviter , Bedi Jasbir Singh , Pedada Venkata Chaitanya , Shaik Thahir Basha , Tumati Srinivasa Rao , Guitian Javier
Published: April 2022

In the absence of epidemiological, microbiological or outbreak data, systematic identification of the hazards and food products posing the higher risk to the consumers is challenging. It is usually in Low- and Middle-Income Countries (LMICs), where the burden of foodborne disease is highest that data tend to be particularly scarce. In this study, we propose qualitative risk-ranking methods for pathogens and food products that can be used in settings where scarcity of data on the frequency/concentration of pathogens in foodstuff is a barrier towards the use of classical risk assessment frameworks. The approach integrates the existing knowledge on foodborne pathogens, manufacturing processes and intrinsic/extrinsic properties of food products with key context-specific information regarding the supply chain(s), characteristics of the Food Business Operators (FBOs) and cultural habits to identify: (i) the pathogens that should be considered as a “High” food safety priority and (ii) the food products posing the higher risk of consumer exposure to microbiological hazards via oral (ingestion) route. When applied to the dairy sector of Andhra Pradesh (India) as a case study, E. coli O157:H7, Salmonella spp., S. aureus and L. monocytogenes were identified as a “High” food safety priority across all FBOs, C. sakazakii a “High” priority for the FBOs producing infant formula/milk powder whilst Shigella spp. and Cryptosporidium spp. a “High” priority when considering the FBOs operating towards the informal end of the formal-informal spectrum. The risk ranking of dairy products was informed by a preliminary cluster analysis for early identification of products that are similar with regards to intrinsic/extrinsic features known to drive the microbiological risk. Products manufactured/retailed by FBOs in the informal market were considered as posing a “High” risk for the consumers due to a widespread lack of compliance to sanitary regulations. For dairy products produced by FBOs operating in the middle and formal end of the formal-informal spectrum, the risk of consumers exposure to microbiological hazards ranged from “Medium” to “Extremely low” depending on the FBO and the intrinsic/extrinsic properties of the products. While providing risk estimates of lower resolution if compared to data-driven risk assessments, the proposed method maximises the value of the information that can be easily gathered in LMICs and provide informative outputs to support food safety decision-making in contexts where resources to be allocated for prevention of foodborne diseases are limited and the food system is complex.
Heterologous Gam-COVID-Vac (Sputnik V) / mRNA-1273 (Moderna) vaccination induces a stronger humoral response than homologous Sputnik V in a real-world data analysis
Authors: Pereson Matías J. , Amaya Lucas , Neukam Karin , Bare Patricia , Echegoyen Natalia , Badano María Noel , Lucero Alicia , Martelli Antonella , Garcia Gabriel H. , Videla Cristina , Martínez Alfredo P. , Di Lello Federico A.
Published: April 2022

Introduction

Growing data are demonstrating safety and immunogenicity of heterologous vaccination schemes against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This strategy opens up the possibility of a shorter path towards the end of the pandemic.

Objective

To compare the homologous prime-boost vaccination scheme of Gam-COVID-Vac (Sputnik V, SpV) to its heterologous combination with mRNA-1273 (Moderna, Mod) vaccine.

Methods

SARS-CoV-2 anti-spike (S)-receptor binding domain (RBD) IgG concentration was assessed three to seven weeks after complete vaccination. Reactogenicity was evaluated by declared side events and medical assistance required until day 7 post-boost.

Results

Of 190 participants enrolled, 105 received homologous SpV/SpV and the remaining heterologous SpV/Mod vaccination scheme, respectively. Median (interquartile range, IQR) age was 54 (37-63) years, 132 (69.5%) were female and 46 (24.2%) individuals had a prior confirmed COVID-19. Anti-S-RBD IgG median (IQR) titers were significantly higher for SpV/Mod [2511 (1476-3992) BAU/mL] than for SpV/SpV [582 (209-1609) BAU/mL, p<0.001] vaccination scheme. In a linear model adjusted for age, gender, time to the serological assay and time between doses, SpV/Mod [4.154 (6.585-615.554), p<0.001] and prior COVID [3.732 (8.641-202.010), p<0.001] were independently associated with higher anti-S-RBD IgG values. A higher frequency of mild-moderate adverse effects was associated with the heterologous scheme, although it was well tolerated by all individuals and no medical assistance was required.

Conclusion

The heterologous SpV/Mod combination against SARS-CoV-2 is well tolerated and significantly increases humoral immune response as compared to the homologous SpV/SpV immunization.
Intellectual enrichment and genetic modifiers of cognitive function in Huntington’s disease
Authors: Papoutsi Marina , Flower Michael , Hensman Davina , Holmans Peter , Estevez-Fraga Carlos , Johnson Eileanor , Scahill Rachael I. , Rees Geraint , Langbehn Douglas , Tabrizi Sarah J. ,   the Track-HD Investigators
Published: April 2022

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle, and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track- HD, a multi-centre longitudinal study in Huntington’s disease gene-carriers, and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared to non-carriers, in agreement with its role in somatic expansion instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, ie. those who were better educated, had higher verbal IQ and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non- carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than non- carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their mechanism of action.
Multiple Cost Optimisation for Alzheimer’s Disease Diagnosis
Authors: McCombe Niamh , Ding Xuemei , Prasad Girijesh , Finn David P. , Todd Stephen , McClean Paula L. , Wong-Lin KongFatt ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2022

Current machine learning techniques for dementia diagnosis often do not take into account real-world practical constraints, which may include, for example, the cost of diagnostic assessment time and financial budgets. In this work, we built on previous cost-sensitive feature selection approaches by generalising to multiple cost types, while taking into consideration that stakeholders attempting to optimise the dementia care pathway might face multiple non-fungible budget constraints. Our new optimisation algorithm involved the searching of cost-weighting hyperparameters while constrained by total budgets. We then provided a proof of concept using both assessment time cost and financial budget cost. We showed that budget constraints could control the feature selection process in an intuitive and practical manner, while adjusting the hyperparameter increased the range of solutions selected by feature selection. We further showed that our budget-constrained cost optimisation framework could be implemented in a user-friendly graphical user interface sandbox tool to encourage non-technical users and stakeholders to adopt and to further explore and audit the model - a humans-in-the-loop approach. Overall, we suggest that setting budget constraints initially and then fine tuning the cost-weighting hyperparameters can be an effective way to perform feature selection where multiple cost constraints exist, which will in turn lead to more realistic optimising and redesigning of dementia diagnostic assessments.

Clinical Relevance

By optimising diagnostic accuracy against various costs (e.g. assessment administration time and financial budget), predictive yet practical dementia diagnostic assessments can be redesigned to suit clinical use.
Investigating direct and indirect genetic effects in attention deficit hyperactivity disorder (ADHD) using parent-offspring trios
Authors: Martin Joanna , Wray Matthew , Agha Sharifah Shameem , Lewis Katie J. S. , Anney Richard J. L. , O’Donovan Michael C. , Thapar Anita , Langley Kate
Published: April 2022

Background

Attention deficit hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e. direct) and non-transmitted (i.e. indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is over-transmitted to ADHD probands. We also tested for indirect or ‘genetic nurture’ effects, by examining whether non-transmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative.

Methods

Polygenic risk scores (PRS) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder (OCD), schizophrenia, Tourette’s syndrome, and cognitive ability were calculated in UK controls (N=5,081), UK probands with ADHD (N=857), and, where available, their biological parents (N=328 trios), and also a replication sample of 844 ADHD trios.

Results

ADHD PRS were over-transmitted and cognitive ability and OCD PRS were under-transmitted to probands. These results were independently replicated. Over-transmission of polygenic liability was not observed for other disorders. Non-transmitted alleles were not enriched for ADHD liability compared to controls. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status.

Conclusions

The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that non-transmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be non-random, in terms of demographic and clinical factors.
Domain expert evaluation of advanced visual computing solutions for the planning of left atrial appendage occluder interventions
Authors: Mill Jordi , Montoliu Helena , Moustafa Abdel H. , Olivares Andy L. , Albors Carlos , Aguado Ainhoa , Medina Elodie , Ceresa Mario , Freixa Xavier , Arzamendi Dabit , Cochet Hubert , Camara Oscar
Published: April 2022

Advanced visual computing solutions and 3D printing are starting to move from the engineering and development stage to being integrated into clinical pipelines for training, planning and guidance of complex interventions. Commonly, clinicians make decisions based on the exploration of patient-specific medical images in 2D flat monitors using specialised software with standard multi-planar reconstruction (MPR) visualisation. The new generation of visual computing technologies such as 3D imaging, 3D printing, 3D advanced rendering, Virtual Reality and in-silico simulations from Virtual Physiological Human models, provide complementary ways to better understand the structure and function of the organs under study and improve and personalise clinical decisions. Cardiology is a medical field where new visual computing solutions are already having an impact in decisions such as the selection of the optimal therapy for a given patient. A good example is the role of emerging visualisation technologies to choose the most appropriate settings of a left atrial appendage occluder (LAAO) device that needs to be implanted in some patients with atrial fibrillation having contraindications to drug therapies. Clinicians need to select the type and size of the LAAO device to implant, as well as the location to be deployed. Usually, interventional cardiologists make these decisions after the analysis of patient-specific medical images in 2D flat monitors with MPR visualisation, before and during the procedure, obtain manual measurements characterising the cardiac anatomy of the patient to avoid adverse events after the implantation. In this paper we evaluate several advanced visual computing solutions such as web-based 3D imaging visualisation (VIDAA platform), Virtual Reality (VRIDAA platform) and computational fluid simulations and 3D printing for the planning of LAAO device implantations. Six physicians including three interventional and three imaging cardiologists, with different level of experience in LAAO, tested the different technologies in preoperative data of 5 patients to identify the usability, friendliness, limitations and requirements for clinical translation of each technology through a qualitative questionnaire. The obtained results demonstrate the potential impact of advanced visual computing solutions to improve the planning of LAAO interventions but also a need of unification of them in order to be able to be uses in a clinical environment.
The incidence-based dynamic reproduction index: accurate determination, diagnostic sensitivity, and predictive power
Authors: Conradt Robert N. J. , Herminghaus Stephan
Published: April 2022

Two methods of calculating the reproduction index from daily new infection data are considered, one by using the generation time tG as a shift (RG), and an incidence-based method directly derived from the differential equation system of an SIR epidemic dynamics model (RI). While the former is shown to have few in common with the true reproduction index, we find that the latter provides a sensitive detection device for intervention effects and other events affecting the epidemic, making it well-suited for diagnostic purposes in policy making. Furthermore, we introduce a similar quantity, , which can be calculated directly from RG. It shows largely the same behaviour as RI, with less fine structure. However, it is accurate in particular in the vicinity of R = 1, where accuracy is important for the corrrect prediction of epidemic dynamics. We introduce an entirely new, self-consistent method to derive, from both quantities, an improved which is both accurate and contains the details of the epidemic spreading dynamics. Hence we obtain R accurately from data on daily new infections (incidence) alone. Moreover, by using RI instead of RG in plots of R versus incidence, orbital trajectories of epidemic waves become visible in a particularly insightful way, demonstrating that the widespread use of only incidence as a diagniostic tool is clearly inappropriate.

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