bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrate reduction capacity of the oral microbiota is impaired in periodontitis: potential implications for systemic nitric oxide availability
Authors: Rosier Bob , Johnston William , Carda-Diéguez Miguel , Simpson Annabel , Cabello-Yeves Elena , Piela Krystyna , Reilly Robert , Artacho Alejandro , Easton Chris , Burleigh Mia , Culshaw Shauna , Mira Alex
Published: June 2023

Background

The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions, such as hypertension and diabetes. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with healthy conditions, but the impact of periodontitis on nitrate-reducing capacity and therefore nitric oxide availability has not been evaluated. The aim of the current study is to see assess how periodontitis and periodontal treatment affect the nitrate reduction capacity of the oral microbiota.

Methods

First, 16S rRNA sequencing data of five studies from different countries were analysed with the Dada2 pipeline to compare nitrate-reducing bacteria in health and periodontitis. Additionally, subgingival plaque, saliva and plasma samples from 42 periodontitis patients were collected before and after non-surgical periodontal therapy (NSPT). The subgingival plaque bacterial composition was determined using Illumina sequencing of the 16S rRNA gene and the quantity of the nitrate-reducing biomarker genusRothiawas determined by qPCR. Measurements of nitrate and nitrite in saliva and plasma were performed and the salivary nitrate reduction capacity (NRC) was determined after three hours of incubationin vitroand compared with the NRC of 15 healthy individuals.

Results

Nitrate-reducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals (p < 0.05 in all five datasets). After NSPT, nitrate-reducing bacteria increased in subgingival plaque (p < 0.05) and correlated negatively with periodontitis-associated bacteria (p < 0.001). A post-treatment increase in the genusRothiawas confirmed by qPCR (p < 0.05), as well as an increase in the salivary NRC (p < 0.05). No significant effect was found of NSPT on the plasma nitrate and nitrite levels in this population.

Conclusion

The levels of nitrate-reducing bacteria of the subgingival microbiota decrease in periodontitis and both their levels and the salivary NRC increase after NSPT. We hypothesize that an impaired NRC can affect nitric oxide availability and can therefore be an instrumental link between periodontitis and systemic conditions.
Characteristics of ictal thalamic EEG in pediatric-onset neocortical focal epilepsy
Authors: Edmonds Benjamin , Miyakoshi Makoto , Remore Luigi Gianmaria , Ahn Samuel , Phillips H. Westley , Daida Atsuro , Salamon Noriko , Bari Ausaf , Sankar Raman , Matsumoto Joyce H. , Fallah Aria , Nariai Hiroki
Published: June 2023

Objective:

To characterize ictal EEG change in the centromedian (CM) and anterior nucleus (AN) of the thalamus, using stereoelectroencephalography (SEEG) recordings

Methods:

Forty habitual seizures were analyzed in nine patients with pediatric-onset neocortical drug-resistant epilepsy who underwent SEEG (age 2-25 y) with thalamic coverage. Both visual and quantitative analysis was used to evaluate ictal EEG signal in the cortex and thalamus. The amplitude and cortico-thalamic latencies of broadband frequencies at ictal onset were measured.

Results:

Visual analysis demonstrated consistent detection of ictal EEG changes in both the CM nucleus and AN nucleus with latency to thalamic ictal EEG changes of less than 400ms in 95% of seizures, with low-voltage fast activity being the most common ictal pattern. Quantitative broadband amplitude analysis showed consistent power changes across the frequency bands, corresponding to ictal EEG onset, while while ictal EEG latency was variable from -18.0 seconds to 13.2 seconds. There was no significant difference between detection of CM and AN ictal activity on visual or amplitude analysis. Four patients with subsequent thalamic responsive neurostimulation (RNS) demonstrated ictal EEG changes consistent with SEEG findings.

Conclusions:

Ictal EEG changes were consistently seen at the CM and AN of the thalamus during neocortical seizures.

Significance:

It may be feasible to use a closed-loop system in the thalamus to detect and modulate seizure activity for neocortical epilepsy.
Thalamic connectivity topography in spina bifida newborns is linked to functional lesion level
Authors: Ji Hui , Payette Kelly , Speckert Anna , Tuura Ruth , Grehten Patrice , Kottke Raimund , Ochseinbein-Kölble Nicole , Hagmann Cornelia , Mazzone Luca , Meuli Martin , Padden Beth , Hackenberg Annette , Wille David-Alexander , Moehrlen Ueli , Latal Beatrice ,   SPINA BIFIDA STUDY GROUP ZURICH, Jakab Andras
Published: June 2023

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at two years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected p<0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.
Drivers of antibiotic use habits and animal disease incidence in smallholder livestock farms: evidence from a survey in Burkina Faso
Authors: Emes Eve , Kagambèga Assèta , Dione Michel
Published: June 2023

Reducing nontherapeutic antibiotic (ABU) use in livestock animals has been identified as an important way of curbing the growth of antimicrobial resistance (AMR). However, this ABU can be an important disease management tool, and farmers may not feel safe to reduce it without simultaneous interventions to safeguard animal health. It is therefore important to determine a) if nontherapeutic ABU is important for averting livestock animal disease, b) which factors can encourage farmers to improve antibiotic stewardship on their own terms, and c) which factors can be paired with ABU reduction in order to safeguard against any animal health risks.

We investigated these questions using data from the AMUSE survey, which is designed to evaluate knowledge, attitudes and practices relating to AMR in smallholder livestock farms. Our sample covered 320 animal herds from 216 smallholder livestock farms in Burkina Faso, with species including poultry, small ruminants, and cattle. The determinants of the likelihood of animal disease and nontherapeutic ABU were investigated using logistic regression.

We found that nontherapeutic ABU was positively associated with animal disease, although the potential endogeneity of this relationship should be investigated further. We also found that going primarily to a public veterinarian for animal health services was associated with a lower likelihood of nontherapeutic ABU. We also found some evidence that going to public veterinarians, and a higher level of formal education, were associated with a lower likelihood of animal disease.

These findings support the expansion of public veterinary services as a way to encourage antibiotic stewardship, and to safeguard against any animal health risks associated with ABU reduction.
Neisseria gonorrhoeaeMtrCDE Efflux Pump DuringIn VivoExperimental Genital Tract Infection in Men and Mice Reveals the Presence of Within-Host Colonization Bottleneck
Authors: Waltmann Andreea , Balthazar Jacqueline T. , Begum Afrin A. , Hua Nancy , Jerse Ann E. , Shafer William M. ,   UNC-Global Clinical Trials Unit/DMID 09-0106 Study Team, Hobbs Marcia M. , Duncan Joseph A.
Published: June 2023

The MtrCDE efflux pump ofNeisseria gonorrhoeaeexports a wide range of antimicrobial compounds that the gonococcus encounters at mucosal surfaces during colonization and infection. Here, we evaluate the role of this efflux pump system in strain FA1090 in human male urethral infection with a Controlled Human Infection Model. Using the strategy of competitive multi-strain infection with wild-type FA1090 and an isogenic mutant strain that does not contain a functional MtrCDE pump, we found that the presence of the efflux pump during human experimental infection did not confer a competitive advantage. This finding is in contrast to previous findings in female mice, which demonstrated that gonococci of strain FA19 lacking a functional MtrCDE pump had a significantly reduced fitness compared to the wild type strain in the lower genital tract of female mice. We conducted competitive infections in female mice with FA19 and FA1090 strains, including mutants that do not assemble a functional Mtr efflux pump, demonstrating the fitness advantage provided byt the MtrCDE efflux pump during infection of mice is strain dependent. Our data indicate that new gonorrhea treatment strategies targeting the MtrCDE efflux pump functions may not be universally efficacious in naturally occurring infections. Owing to the equal fitness of FA1090 strains in men, our experiments unexpectedly demonstrated the likely presence of an early colonization bottleneck ofN. gonorrhoeaein the human male urethra.

TRIAL REGISTRATION

Clinicaltrials.govNCT03840811.
Growing inequities by immigration group among older adults: Population-based analysis of access to primary care and return to in-person visits during the COVID-19 pandemic in British Columbia, Canada
Authors: Sierra-Heredia Cecilia , Tayyar Elmira , Bozorgi Yasmin , Thakore Padmini , Hagos Selamawit , Carrillo Ruth , Machado Stefanie , Peterson Sandra , Goldenberg Shira , Wiedmeyer Mei-ling , Lavergne Ruth
Published: June 2023

Background

The onset of the COVID-19 pandemic drove a rapid and widespread shift to virtual care, followed by a gradual return to in-person visits. Virtual visits may offer more convenient access to care for some, but others may experience challenges accessing care virtually, and some medical needs must be met in-person. Experiences of the shift to virtual care and benefits of in-person care may vary by immigration experience (immigration status and duration), official language level, and age. We examined use of virtual care and return to in-person visits in the Canadian province of British Columbia (BC), comparing patterns by age and across immigration groups, including length of time in Canada and language level (English) at time of arrival.

Methods

We used linked administrative health and immigration data to examine total primary care visits (virtual or in-person) and return to in-person visits during the COVID-19 pandemic (2019/20-2021/2) in BC. We examined the proportion of people with any primary care visits and with any in-person visit within each year as measures of access to primary care. We estimated the odds of any primary care visit and any in-person visit by immigration group and official language level assessed prior to arrival: non-immigrants, long-term immigrants, recent immigrants (<5 years) with high assessed English level and recent immigrants (<5 years) with low assessed English level, stratified by age.

Results

In general, changes in access to primary care (odds of any visit and odds of any in-person visit) were similar across immigration groups over the study period. However, we observed substantial disparities in access to primary care by immigration group among people aged 60+, particularly in recent immigrants with low official language level (0.42, 0.40-0.45). These disparities grew wider over the course of the pandemic.

Conclusion

Though among younger adults changes in access to primary care between 2019-2021 were similar across immigration groups, we observed significant and growing inequities among older adults, with particularly limited access among adults who immigrated recently and with low assessed English level. Targeted interventions to ensure acceptable, accessible care for older immigrants are needed.
Use of antimicrobials during the COVID-19 pandemic: a qualitative study among stakeholders in Nepal
Authors: Dhungel Binod , Shrestha Upendra Thapa , Adhikari Sanjib , Adhikari Nabaraj , Bhattarai Alisha , Pokharel Sunil , Karkey Abhilasha , Limmathurotsakul Direk , Ghimire Prakash , Rijal Komal Raj , Cheah Phaik Yeong , Pell Christopher , Adhikari Bipin
Published: June 2023

Introduction

The COVID-19 pandemic was a major public health threat and posed tremendous pressure to develop a cure for it. Apart from ongoing efforts in developing vaccines, a lot of empirical treatments were recommended, that may have expedited the use of antimicrobials. The main objective of this study was to explore if and how the pandemic posed pressure on antimicrobials in Nepal using semi-structured interviews (SSIs) among patients, clinicians and drug dispensers.

Methods

A total of 30 stakeholders (10 each among clinicians, dispensers and COVID-19 patients) were identified purposively and were approached for SSIs. Clinicians and dispensers working in three tertiary hospitals in Kathmandu were first approached and were asked for their support to reach out to COVID-19 patients who were on follow-up at their out-patient department. SSIs were audio recorded, translated and transcribed into English, and were analyzed for thematic synthesis.

Results

Over-the-counter (OTC) uses of antibiotics were widespread during the pandemic, and were mostly rooted to patients’ attempts to halt the potential severity due to respiratory like illnesses, and the fear of being identified as a COVID-19 patients. Being identified as a COVID-19 patient was feared because of the stigmatization and social isolation. Patients who visited the drug shops and physicians were reported to make demands on specific medicines including antibiotics that may have added pressure among physicians and dispensers. Clinicians reported a degree of uncertainty related to treatment and that may have added pressure to prescribe antimicrobials. All stakeholders, although mostly patients and dispensers with limited understanding of what constitutes antimicrobials and the mechanisms underpinning it reported that the pressure during the pandemic may have added to the adversities such as antimicrobials resistance.

Conclusions

COVID-19 added a pressure to prescribe, dispense and overuse antimicrobials and may have accentuated the pre-existing OTC use of antimicrobials. Future pandemics including infectious disease outbreaks are major public health incidents that warrant a special caution on inappropriate pressure on antimicrobials. Strict policies related to the use of antimicrobials are urgent to redress their use during normal and pandemic situations.
Clubfoot Twin Study with Wearable GaitUp Sensors and Footscan V9
Authors: Ursula Issler-Wüthrich , Christian Issler , Ulrich Exner G. , Peter Joller
Published: June 2023

Purpose

To control the therapeutic results in manual-dynamic physiotherapy for clubfeet we analyzed the gait pattern in children with clubfeet and their healthy twin siblings, aged between 3 and 13 years for GaitUp and 4 to 14 years for the footplate V9.

Methods

With the inertial GaitUp sensors and the footscan V9 pedobarographic plate the 11 twin-pairs were tested and statistically assessed. For the GaitUp sensors 22 parameters were considered and 10 parameters for the footplate V9. We analyzed the gait pattern for each child separately for both feet and in a second evaluation compared the affected feet with the ipsilateral feet of the healthy twins. The statistical comparisons were made with nonparametric methods. An additional twin girl treated with various therapies and her sister are included as a contrast.

Results

Especially in younger children, the gait pattern is not stabilized yet. Therefore, sometimes the healthy twins have inferior values in gait patterns than the affected siblings. Over the whole study there are only minor statistical differences between the affected group and the healthy group suggesting that with the manual-dynamic therapy the clubfeet children show a gait pattern statistically similar to the healthy group. Noteworthy are the less convincing results of the contrast twin.

Conclusion

Manual-dynamic physiotherapy can lead to a gait pattern equal to the one of unaffected children the same age. Our results do not support the statement that in one-sided clubfoot the other foot cannot be considered normal.

IMPLICATIONS FOR REHABILITATION

Clubfeet are a disabling birth defect affecting 1 to 3 babies per 1000 births.

The manual-dynamic physiotherapy for clubfeet starting at birth leads to a normal gait pattern.
Factors Influencing Job Satisfaction among Healthcare Providers in a Specialty Department: a cross-sectional study
Authors: Haider Tanvir , Efa Syeda Sumaiya , Hossain Md. Emam , Ara Shampa Shamima Gulshan , Mahdee Syed Nafi , Reza Rafsan , Al Fidah Md. Fuad
Published: June 2023

Background

Job satisfaction of professionals affects health, advancement, performance, and development, as well as the institution, employer, or organization. Healthcare professionals who are satisfied with their job have a higher probability of delivering excellent healthcare. In Bangladesh, the challenges of public health highlight the importance of having a competent healthcare workforce to provide an improved quality healthcare service.

Objectives

The objective of this study was to evaluate the degree of job satisfaction and identify the factors that contribute to it among healthcare providers employed in the BMT unit of DMCH.

Methods

This cross-sectional study was conducted for the period of six months, from July to December 2014. The study population was all the healthcare professionals at the BMT unit of DMCH, Bangladesh. and consisted of doctors (n=20), nurses (n=15), and laboratory technicians (n=5). A semi structured self-administered questionnaire was used to collect the preliminary data. All ethical issues were maintained strictly.

Results

Most (95.0%) of the study respondents were at or below the age of 40 years with a mean (±SD) of 30.1 (±7.92) years. Most of them were female (52.5%), and lab technician, nurse and doctors had a frequency of 12.5%, 37.5%, and 50.0% respectively. Among the study participants, 65.0% were satisfied with their jobs, 35% were dissatisfied. Statistically significant association was found between sex (p=0.011) and profession (p < 0.001) with level of job satisfaction among respondents.

Conclusion

Job satisfaction is important for healthcare professionals, patients, and institutions. Satisfied professionals provide better care, while low job satisfaction leads to turnover and decreased access to care. Individual, job-related, and workplace factors influence job satisfaction. This study evaluated job satisfaction among healthcare providers in Bangladesh and identified contributing factors to inform interventions.
A novel longitudinal rank-sum test for multiple primary endpoints in clinical trials: Applications to neurodegenerative disorders
Authors: Xu Xiaoming , Ghosh Dhrubajyoti , Luo Sheng
Published: June 2023

Neurodegenerative disorders such as Alzheimer’s disease (AD) present a significant global health challenge, characterized by cognitive decline, functional impairment, and other debilitating effects. Current AD clinical trials often assess multiple longitudinal primary endpoints to comprehensively evaluate treatment efficacy. Traditional methods, however, may fail to capture global treatment effects, require larger sample sizes due to multiplicity adjustments, and may not fully exploit multivariate longitudinal data. To address these limitations, we introduce the Longitudinal Rank Sum Test (LRST), a novel nonparametric rank-based omnibus test statistic. The LRST enables a comprehensive assessment of treatment efficacy across multiple endpoints and time points without multiplicity adjustments, effectively controlling Type I error while enhancing statistical power. It offers flexibility against various data distributions encountered in AD research and maximizes the utilization of longitudinal data. Extensive simulations and real-data applications demonstrate the LRST’s performance, underscoring its potential as a valuable tool in AD clinical trials. Nonparametrics, Global test, rank-sum-type test, U-Statistics.
Putting Bicarbonate on the spot. Implication for theratyping in Cystic Fibrosis
Authors: Zajac Miroslaw , Lepissier Agathe , Dréano Elise , Chevalier Benoit , Hatton Aurélie , Kelly Mairead , Guidone Daniela , Planelles Gabrielle , Edelman Aleksander , Girodon Emmanuelle , Hinzpeter Alexandre , Crambert Gilles , Pranke Iwona , Galietta Luis J.V. , Sermet-Gaudelus Isabelle
Published: June 2023

Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. CFTR controls chloride (Cl-) and bicarbonate (HCO3-) transport into the Airway Surface Liquid (ASL).We investigated the impact of F508del-CFTR correction on HCO3-secretion by studying transepithelial HCO3-fluxes.

HCO3-secretion was measured by pH-stat techniquein primary human respiratory epithelial cells from healthy subjects (WT) and people with CF (pwCF)carrying at least oneF508del variant.Its changes after CFTR modulation by the triple combination VX445/661/770 and in the context of TNF-α+IL-17 induced inflammation were related to ASL pH and transcriptionnal levels of CFTRand other HCO3-transporters ofairway epithelia such asSLC26A4 (Pendrin), SLC26A9 and NBCe1.

CFTR-mediated HCO3-secretion was not detected in F508del primary human respiratory epithelial cells. It was rescued up to ∼ 80% of the WT levelby VX-445/661/770. In contrast,TNF-α+IL-17 normalized transepithelial HCO3-transportand ASL acidic pH. This was related to anincrease in SLC26A4 and CFTR transcript levels.VX-445/661/770 induced an increase in pH only in the context of inflammation.Effects on HCO3-transport werenot differentbetween F508del homozygous and F508del heterozygous CF airway epithelia.

Our studies show that correction of F508del-CFTRHCO3-is not sufficient to buffer acidic ASL and that inflammation is a key regulator of HCO3-secretion in CF airways. Prediction of the response to CFTR modulators by theratyping should take into account airway inflammation.
Kidney Shape Statistical Analysis: Associations with Disease and Anthropometric Factors
Authors: Thanaj Marjola , Basty Nicolas , Cule Madeleine , Sorokin Elena P , Whitcher Brandon , Srinivasan Ramprakash , Lennon Rachel , Bell Jimmy D , Thomas E Louise
Published: June 2023

Background

Organ measurements derived from magnetic resonance imaging (MRI) have the potential to enhance our understanding of the precise phenotypic variations underlying many clinical conditions.

Methods

We applied morphometric methods to study the kidneys by constructing surface meshes from kidney segmentations from abdominal MRI data in 38,868 participants in the UK Biobank. Using mesh-based analysis techniques based on statistical parametric maps (SPMs), we were able to detect variations in specific regions of the kidney and associate those with anthropometric traits as well as disease states including chronic kidney disease (CKD), type-2 diabetes (T2D), and hypertension. Statistical shape analysis (SSA) based on principal component analysis was also used within the disease population and the principal component scores were used to assess the risk of disease events.

Results

We show that CKD, T2D and hypertension were associated with kidney shape. Age was associated with kidney shape consistently across disease groups. Body mass index (BMI) and waist-to-hip ratio (WHR) were also associated with kidney shape for the participants with T2D. Using SSA, we were able to capture kidney shape variations, relative to size, angle, straightness, width, length, and thickness of the kidneys, within disease populations. We identified significant associations between both left and right kidney length and width and incidence of CKD (hazard ratio (HR): 0.74, 95% CI: 0.61-0.90, p<0.05, in the left kidney; HR: 0.76, 95% CI: 0.63-0.92, p<0.05, in the right kidney) and hypertension (HR: 1.16, 95% CI: 1.03-1.29, p<0.05, in the left kidney; HR: 0.87, 95% CI: 0.79-0.96, p<0.05, in the right kidney).

Conclusions

The results suggest that shape-based analysis of the kidneys can augment studies aiming at the better categorisation of pathologies associated with acute and chronic kidney conditions.
A NOVEL ELECTROCARDIOGRAPHIC PREDICTION MODEL FOR DIAGNOSING CONCEALED BRUGADA SYNDROME: RESULTS FROM A CLINICAL TRIAL OF AJMALINE PROVOCATION IN HEALTHY SUBJECTS
Authors: Ensam Bode , Scrocco Chiara , Johnson David , Wijeyeratne Yanushi D. , Bastiaenen Rachel , Gray Belinda , Miles Chris , Ben-Haim Yael , Papatheodorou Stathis , Sharma Sanjay , Papadakis Michael , Devine Brian , Macfarlane Peter W. , Behr Elijah R.
Published: June 2023

Background

Clinical, electrocardiographic, and genomic factors have been associated with the drug-induced type 1 Brugada pattern (DI-T1BP), in response to sodium channel blocker provocation (SCBP). However, prior analyses have been concerned with prediction of the DI-T1BP rather than the validity of the diagnosis of concealed Brugada syndrome (BrS). We sought to analyse and compare the ECG response to SCBP with ajmaline in a cohort of healthy controls (HC) and a definite BrS group (Def-BrS) to develop a diagnostic score.

Methods

Healthy controls (HC) were systematically recruited as part of a clinical trial. Following comprehensive cardiovascular screening, eligible subjects underwent SCBP with ajmaline. We identified a Def-BrS cohort, defined as a DI-T1BP and a Shanghai Score (SS)>3.5, from consecutive patients with suspected BrS undergoing SCBP with ajmaline using the identical protocol. Def-BrS and HC were divided equally into discovery and validation cohorts. Digital ECG acquisition facilitated automated measurement of ECG parameters. A multivariable analysis compared ECG parameters between the HC and Def-BrS cohorts. A logistic regression analysis identified ECG characteristics that accurately predicted the diagnosis of Def-BrS. This model was then assessed in the validation cohort.

Results

Two-hundred-and-forty-eight volunteers completed an online questionnaire, 103 accepted an invitation to undergo further screening and 100 were recruited into the HC group. Three HCs developed a DI-T1BP. From 1241 patients undergoing SCBP, 166 were Def-BrS. There were no demographic differences between the HC discovery and validation groups or between the Def-BrS discovery and validation groups. Following multivariable logistic regression analysis, QRS duration, mean anterior lead ST segment amplitude at baseline, maximum change in QRS duration, anterior ST segment amplitude and QRS area after SCBP, were independently associated with Def-BrS. The combined model was an excellent discriminator for Def-BrS, with an area under the curve of 0.95 [95% confidence interval (CI) = 0.912 – 0.989], P<0.001 in the discovery groups and 0.97 [95% CI = 0.948 – 0.998], P<0.001 in the validation groups.

Conclusion

The yield of the DI-T1BP in HCs is 3%. However, there are distinct ECG parameters at baseline and in response to SCBP that favour a definite diagnosis of BrS. These observations permit the quantifiable refinement of the ECG diagnosis of concealed BrS, avoiding the pitfalls of relying upon the DI-T1BP alone.
Major bleeding increases the risk of subsequent cardiovascular events in patients with atrial fibrillation: Insights from the SAKURA AF registry and RAFFINE registry
Authors: Wada Hideki , Miyauchi Katsumi , Suwa Satoru , Miyazaki Sakiko , Hayashi Hidemori , Nishizaki Yuji , Yanagisawa Naotake , Yokoyama Katsuaki , Murata Nobuhiro , Saito Yuki , Nagashima Koichi , Matsumoto Naoya , Okumura Yasuo , Minamino Tohru , Daida Hiroyuki
Published: June 2023

Background

Bleeding events are one of the major concerns in patients using oral anticoagulants (OACs). We aimed to evaluate the association between major bleeding and long-term clinical outcomes in atrial fibrillation (AF) patients taking OACs.

Methods

We analyzed a database comprising two large-scale prospective registries of patients with documented AF: the RAFFINE and SAKURA registries. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of all-cause death, ischemic stroke, and myocardial infarction. Major bleeding was defined in accordance with the criteria of the International Society on Thrombosis and Haemostasis. Cox multivariate analysis was used to determine the impact of major bleeding on the incidence of MACCE.

Results

The median follow-up period was 39.7 months. Among 6,633 patients with AF who were taking OAC, 298 (4.5%) had major bleeding and 737 (11.1%) had MACCE. The incidence of MACCE was higher in patients with bleeding than in those without (18.33 and 3.22, respectively, per 100 patient-years; log-rank p <0.0001). Multivariate logistic regression analysis revealed older age, vitamin K antagonist use, and antiplatelet drug use as independent predictors of major bleeding. Multivariate Cox hazard regression analysis showed that the risk of MACCE was significantly higher in patients with major bleeding compared to those without (hazard risk, 4.64; 95% confidence interval, 3.62–5.94; p <0.0001).

Conclusions

Major bleeding was associated with long-term adverse cardiovascular events among AF patients taking OAC. Therefore, reducing the risk of bleeding is important for improving clinical outcomes in patients with AF.
An integrated model of the effects on fitness of beneficial, deleterious, and neutral mutations in sexual populations
Authors: Irlam Gordon
Published: June 2023

The fitness effects of beneficial, deleterious, and neutral mutations have historically been largely analyzed in isolation. Here, an integrated model of the fitness effects of mutations in sexual populations is assembled and analyzed. The model suggests the fitness effects associated with beneficial mutations can not be ignored simply because they are rare. The prospective load is defined as the genetic load associated with beneficial mutations that are feasible, but have yet to occur and begun the process of fixing. The optimal spontaneous mutation rate for a population is shown to occur when the prospective load is approximately equal to the mutational load. This population optimal mutation rate could be brought about through macroevolution. It differs from the as-small-as-possible rate that might be expected from microevolutionary considerations.
Morc1 re-establishes heterochromatin on activated transposons and shapes the host transcriptome in gonocytes
Authors: Uneme Yuta , Maeda Ryu , Nakayama Gen , Narita Haruka , Takeda Naoki , Hiramatsu Ryuji , Nishihara Hidenori , Nakato Ryuichiro , Kanai Yoshiakira , Araki Kimi , Siomi Mikiko C. , Yamanaka Soichiro
Published: June 2023

Following reprogramming of DNA methylation, numerous transposable elements (TEs) are transiently activated in male prenatal gonocytes. Persistent expression of such TEs to adulthood leads to arrest of germ cell development. However, how these TEs are re-silenced has been unexplored. Here, we found that DNA-binding protein Morc1 re-established H3K9me3-marked heterochromatin on activated TEs, which involved methyltransferase SetDB1. Although Morc1 also triggered DNA methylation, the types of Morc1-targeted TEs for each epigenetic modification were different, suggesting that these two mechanisms were largely independent of each other. Significant overlap between TEs targeted by Morc1 and those by Miwi2, a nuclear PIWI protein, indicated that piRNA-loaded Miwi2 conferred target specificity to Morc1. Activated TEs drove transcription of adjacent genes by acting as ectopiccis-regulatory elements. Such a disrupting effect of TEs on the transcriptome was compensated by Morc1. Thus, Morc1 ensures proper interactions of TEs with host genes through re-establishment of heterochromatin in gonocytes.
Simultaneous Multi-Omics Analysis by Direct Infusion Mass Spectrometry (SMAD-MS)
Authors: Jiang Yuming , Salladay-Perez Ivan , Momenzadeh Amanda , Covarrubias Anthony J. , Meyer Jesse G.
Published: June 2023

Combined multi-omics analysis of proteomics, polar metabolomics, and lipidomics requires separate liquid chromatography–mass spectrometry (LC–MS) platforms for each omics layer. This requirement for different platforms limits throughput and increases costs, preventing the application of mass spectrometry-based multi-omics to large scale drug discovery or clinical cohorts. Here, we present an innovative strategy for simultaneous multi-omics analysis by direct infusion (SMAD) using one single injection without liquid chromatography. SMAD allows quantification of over 9,000 metabolitem/zfeatures and over 1,300 proteins from the same sample in less than five minutes. We validated the efficiency and reliability of this method and then present two practical applications: mouse macrophage M1/M2 polarization and high throughput drug screening in human 293T cells. Finally, we demonstrate relationships between proteomic and metabolomic data are discovered by machine learning.
Detection of parasite DNA in soil samples from rural Yucatán, México
Authors: Villanueva-Lizama Liliana , Cruz-Coral Angela , Teh-Poot Christian , Cruz-Chan Vladimir , Mejia Rojelio
Published: June 2023

The soil is the primary environmental reservoir for many parasites transmitted to humans through the fecal-oral route, causing disease. Our environmental study used a high-throughput multi-parallel real-time quantitative PCR (qPCR) assay to detect parasites’ DNA in soil collected from the outdoor built environments of 34 houses. The total parasite prevalence wasAcanthamoeba spp. (53%),Blastocystisspp. (12%),Ascaris lumbricoides(12%),Toxocara canis(9%),Ancylostomaspp. (3%),Trichuris trichiura(3%),Entamoeba histolytica(3%) andGiardia intestinalis(3%). No DNA fromNecator americanus, Strongyloides stercoralis, Toxocara catis, andCryptosporidiumspp was detected. A total of 65% of houses were positive for at least one parasite, 15% had poly-parasites, and up to six different parasites were detected in a single sample. This is the first report of parasites-DNA detected in soil samples from a rural community in Yucatán and suggests higher rates of transmission of parasites with both a zoonotic and medical importance.
Highly divergent and diverse viral community infecting sylvatic mosquitoes from Northeast Brazil
Authors: da Silva Alexandre Freitas , Machado Laís Ceschini , da Silva Luisa Maria Inácio , Dezordi Filipe Zimmer , Wallau Gabriel Luz
Published: June 2023

Mosquitoes can transmit several pathogenic viruses to humans, but their natural viral community is also composed of a myriad of other viruses such as insect-specific viruses (ISV) and those that infect symbiotic microorganisms. Besides a growing number of studies investigating the mosquito virome the majority are focused on few urban species and relatively little is known about the virome of sylvatic mosquitoes particularly in high biodiverse brazilian biomes. Here, we characterized the RNA virome of 10 sylvatic mosquitos species from Atlantic forest remains at a sylvatic-urban interface in Northeast Brazil employing a metatranscriptomic approach. A total of 16 viral families were detected. The phylogenetic reconstructions of 14 viral families revealed that the majority of the sequences are putative ISVs. The phylogenetic positioning and, in most cases, the association with a high RdRp amino acid divergence from other known viruses suggests that the viruses characterized here represent at least 34 new viral species. Therefore, the sylvatic mosquitoes viral community is majorly composed of highly divergent viruses highlighting the limited knowledge we still have about the natural virome of mosquitoes in general. Moreover, we found that none of the viruses recovered were shared between the species investigated. These findings will help to understand the interactions and coevolution between mosquitoes and viruses in nature.

Importance

Mosquitoes are medically important insects as they transmit pathogenic viruses to humans and animals during blood feeding. However, their natural microbiota is also composed of a diverse set of viruses that cause no harm to the insect and other hosts, such as ISVs. In this study, we characterized the RNA virome of sylvatic mosquitoes from Northeast Brazil using unbiased metatranscriptomic sequencing and in depth bioinformatics approaches. Our analysis revealed that these mosquitoes species harbor a diverse set of highly divergent viruses and the majority comprises new viral species. Our findings revealed many new virus lineages characterized for the first time broadening our understanding about the natural interaction between mosquitoes and viruses. Lastly, it also provided several complete genomes that warrants further assessment for mosquito and vertebrate host pathogenicity and their potential interference with pathogenic arboviruses.
A shared linguistic space for transmitting our thoughts from brain to brain in natural conversations
Authors: Zada Zaid , Goldstein Ariel , Michelmann Sebastian , Simony Erez , Price Amy , Hasenfratz Liat , Barham Emily , Zadbood Asieh , Doyle Werner , Friedman Daniel , Dugan Patricia , Melloni Lucia , Devore Sasha , Flinker Adeen , Devinsky Orrin , Nastase Samuel A. , Hasson Uri
Published: June 2023

Effective communication hinges on a mutual understanding of word meaning in different contexts. The embedding space learned by large language models can serve as an explicit model of the shared, context-rich meaning space humans use to communicate their thoughts. We recorded brain activity using electrocorticography during spontaneous, face-to-face conversations in five pairs of epilepsy patients. We demonstrate that the linguistic embedding space can capture the linguistic content of word-by-word neural alignment between speaker and listener. Linguistic content emerged in the speaker’s brain before word articulation, and the same linguistic content rapidly reemerged in the listener’s brain after word articulation. These findings establish a computational framework to study how human brains transmit their thoughts to one another in real-world contexts.
Clinical Significance of the Stromatic Component in Ovarian Cancer: Quantity Over Quality in Outcome Prediction
Authors: Lou Emil , Clemente Valentino , Grube Marcel , Svedbom Axel , Nelson Andrew , Blome Freya , Staebler Annette , Kommoss Stefan , Bazzaro Martina
Published: June 2023

Background

The tumor stroma is composed of a complex network of non-cancerous cells and extracellular matrix elements that collectively are crucial for cancer progression and treatment response. Within the realm of ovarian cancer, the expression of the stromal gene cluster has been linked to poorer progression-free and overall survival rates. However, in the age of precision medicine and genome sequencing, the notion that the simple measurement of tumor-stroma proportion alone can serve as a biomarker for clinical outcome is a topic that continues to generate controversy and provoke discussion. Our current study reveals that it is the quantity of stroma, rather than its quality, that serves as a clinically significant indicator of patient outcome in ovarian cancer.

Methods

This study leveraged the High-Grade-Serous-Carcinoma (HGSC) cohort of the publicly accessible Cancer Genome Atlas Program (TCGA) along with an independent cohort comprising HGSC clinical specimens in diagnostic and Tissue Microarray formats. Our objective was to investigate the correlation between the Tumor-Stroma-Proportion (TSP) and progression-free survival (PFS), overall survival (OS), and response to chemotherapy. We assessed these associations using H&E-stained slides and tissue microarrays. Our analysis employed semi-parametric models that accounted for age, metastases, and residual disease as controlling factors.

Results

We found that high TSP (>50% stroma) was associated with significantly shorter progression-free survival (PFS) (p=0.016) and overall survival (OS) (p=0.006). Tumors from patients with chemoresistant tumors were twice as likely to have high TSP as compared to tumors from chemosensitive patients (p=0.012). In tissue microarrays, high TSP was again associated with significantly shorter PFS (p=0.044) and OS (p=0.0001), further confirming our findings. The Area Under the ROC curve for the model predicting platinum was estimated at 0.7644.

Conclusions

In HGSC, TSP was a consistent and reproducible marker of clinical outcome measures, including PFS, OS, and platinum chemoresistance. Assessment of TSP as a predictive biomarker that can be easily implemented and integrated into prospective clinical trial design and adapted to identify, at time of initial diagnosis, patients who are least likely to benefit long-term from conventional platinum-based cytotoxic chemotherapy treatment.
Implicit reward-based motor learning
Authors: van Mastrigt Nina M. , Tsay Jonathan S. , Wang Tianhe , Avraham Guy , Abram Sabrina J. , van der Kooij Katinka , Smeets Jeroen B. J. , Ivry Richard B.
Published: June 2023

Binary feedback, providing information solely about task success or failure, can be sufficient to drive motor learning. While binary feedback can induce explicit adjustments in movement strategy, it remains unclear if this type of feedback also induce implicit learning. We examined this question in a center-out reaching task by gradually moving an invisible reward zone away from a visual target to a final rotation of 7.5° or 25° in a between-group design. Participants received binary feedback, indicating if the movement intersected the reward zone. By the end of the training, both groups modified their reach angle by about 95% of the rotation. We quantified implicit learning by measuring performance in a subsequent no-feedback aftereffect phase, in which participants were told to forgo any adopted movement strategies and reach directly to the visual target. The results showed a small, but robust (2-3°) aftereffect in both groups, highlighting that binary feedback elicits implicit learning. Notably, for both groups, reaches to two flanking generalization targets were biased in the same direction as the aftereffect. This pattern is at odds with the hypothesis that implicit learning is a form of use-dependent learning. Rather, the results suggest that binary feedback can be sufficient to recalibrate a sensorimotor map.
Prediction tendency, eye movements, and attention in a unified framework of neural speech tracking
Authors: Schubert Juliane , Gehmacher Quirin , Schmidt Fabian , Hartmann Thomas , Weisz Nathan
Published: June 2023

Auditory speech comprehension is a multi-faceted process in which attention, prediction, and sensorimotor integration (via active sensing) interact with or complement each other. Although different conceptual models that focus on one of these aspects exist, we still lack a unified understanding of their role in speech processing. Here, we first replicated two recently published studies from our lab, confirming 1) a positive relationship between individual prediction tendencies and neural speech tracking, and 2) the phenomenon of ocular speech tracking – the tracking of attended speech by eye movements – and its shared contribution with neural activity to speech processing. In addition, we extended these findings with complementary analyses and investigated these phenomena in relation to each other in a multi-speaker paradigm with continuous, narrative speech. Importantly, prediction tendency and ocular speech tracking seem to be unrelated. In contrast to the shared contributions of oculomotor and neural activity to speech processing over a distributed set of brain regions that are critical for attention, individual prediction tendency and its relation to neural speech tracking seem to be largely independent of attention. Based on these findings, we propose a framework that aims to bridge the gaps between attention, prediction, and active (ocular) sensing in order to contribute to a holistic understanding of neural speech processing. In this speculative framework for listening, auditory inflow is, on a basic level, temporally modulated via active ocular sensing, and incoming information is interpreted based on probabilistic assumptions.
Stochastic coding: a conserved feature of odor representations and its implications for odor discrimination
Authors: Srinivasan Shyam , Daste Simon , Modi Mehrab , Turner Glenn , Fleischmann Alexander , Navlakha Saket
Published: June 2023

Sparse coding is thought to improve discrimination of sensory stimuli by reducing overlap between their representations. Two factors, however, can offset sparse coding’s advantages. Similar sensory stimuli have significant overlap, and responses vary across trials. To elucidate the effect of these two factors, we analyzed odor responses in the fly and mouse olfactory regions implicated in learning and discrimination — the Mushroom Body (MB) and the Piriform Cortex (PCx). In both species, we show that neuronal responses fall along a continuum from extremely reliable across trials to extremely variable or stochastic. Computationally, we show that the range of observed variability arises from probabilistic synapses in inhibitory feedback connections within central circuits rather than sensory noise, as is traditionally assumed. We propose this coding scheme to be advantageous for coarse– and fine-odor discrimination. More reliable cells enable quick discrimination between dissimilar odors. For similar odors, however, these cells overlap, and do not provide distinguishing information. By contrast, more unreliable cells are decorrelated for similar odors, providing distinguishing information, though this requires extended training with more trials. Overall, we have uncovered a stochastic coding scheme that is conserved in vertebrates and invertebrates, and we identify a candidate mechanism, based on variability in a winner-take-all inhibitory circuit, that improves discrimination with training.