bluuebunny/crossref_metadata_2025 huggingface dataset:
MASH clinical trials and drugs pipeline: An impending tsunami
Authors: Noureddin Mazen
Published: March 2024

Metabolic dysfunction–associated steatotic liver disease, formerly known as NAFLD, has ascended to prominence as the predominant chronic liver disease in Western countries and now stands as a leading cause of liver transplantations. In the more advanced stage, metabolic dysfunction–associated steatohepatitis (MASH) may lead to fibrosis, a gateway to cirrhosis, liver cancer, and liver failure. Despite extensive research and exploration of various drug mechanisms, the anticipation for the inaugural approved drug to materialize by 2024 is palpable, marking a significant milestone. Numerous pathways have been investigated for MASH treatment, exploring thyroid hormone receptors, glucagon-like peptides 1, peroxisome proliferator–activated receptors, and agents influencing hepatic steatosis synthesis, inflammatory pathways, genetic components, fibrosis mechanisms, and an array of other avenues. Over time, key regulatory directions have crystallized, now manifesting in 2 primary endpoints under investigation: resolution of steatohepatitis without worsening fibrosis and/or improvement of fibrosis stage without worsening of steatohepatitis, especially used in phase 3 clinical trials, while alternative noninvasive endpoints are explored in phase 2 trials. The prospect of proving efficacy in clinical trials opens doors to combination therapies, evaluating the ideal combination of drugs to yield comprehensive benefits, extending beyond the liver to other organs. Certain combination drug trials are already underway. In this review, we discuss the forefront of MASH drug research as of 2023/2024, illuminating mechanisms, outcomes, and future trajectories. Furthermore, we tackle the challenges confronting MASH trials and propose potential strategies for surmounting them.
Ambulatory blood pressure after 12 weeks of quadruple combination of quarter doses of blood pressure medication vs. standard medication
Authors: Nolde Janis M. , Atkins Emily , Marschner Simone , Hillis Graham S. , Chalmers John , Billiot Laurent , Nelson Mark R. , Reid Christopher M. , Hay Peter , Burke Michael , Jansen Shirley , Usherwood Tim , Rodgers Anthony , Chow Clara K. , Schlaich Markus P.
Published: March 2024

Background:

A combination of four ultra-low-dose blood pressure (BP) medications lowered office BP more effectively than initial monotherapy in the QUARTET trial. The effects on average ambulatory BP changes at 12 weeks have not yet been reported in detail.

Methods:

Adults with hypertension who were untreated or on monotherapy were eligible for participation. Overall, 591 participants were randomized to either the quadpill (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or monotherapy control (irbesartan 150 mg). The difference in 24-h, daytime, and night-time systolic and diastolic ambulatory BP at 12 weeks along further metrics were predefined secondary outcomes.

Results:

Of 576 participants, 289 were randomized to the quadpill group and 287 to the monotherapy group. At 12 weeks, mean 24-h ambulatory SBP and DBP were 7.7 [95% confidence interval (95% CI) 9.6–5.8] and 5.3 (95% CI: 6.5–4.1) mmHg lower in the quadpill vs. monotherapy group (P < 0.001 for both). Similar reductions in the quadpill group were observed for daytime (8.1/5.7 mmHg lower) and night-time (6.3/4.0 mmHg lower) BP at 12 weeks (all P < 0.001) compared to monotherapy. The rate of BP control (24-h average BP < 130/80 mmHg) at 12 weeks was higher in the quadpill group (77 vs. 50%; P < 0.001). The reduction in BP load was also more pronounced with the quadpill.

Conclusion:

A quadruple quarter-dose combination compared with monotherapy resulted in greater ambulatory BP lowering across the entire 24-h period with higher ambulatory BP control rates and reduced BP variability at 12 weeks. These findings further substantiate the efficacy of an ultra-low-dose quadpill-based BP lowering strategy.
Inverted Internal Limiting Membrane Flap Coverage with Autologous Blood Technique after Air–fluid Exchange and Silicone Oil Tamponade for Extensive Macular Hole Retinal Detachment in Highly Myopic Eyes
Authors: Tao Jiwei , Zhao Shixin , She Xiangjun , lv Zhe , Zhang Yun
Published: March 2024

Purpose

To report a technique consisting of inverted internal limiting membrane (ILM) flap coverage with autologous blood after air–fluid exchange and silicone oil tamponade in treating extensive retinal detachment (RD) secondary to a myopic macular hole (MH).

Methods

Retrospective case series. The technique was applied in 18 eyes with MH-RD extending beyond the equator with a minimum follow-up of 6 months. The procedures for pars plan vitrectomy (PPV) included the following:1) the ILM was peeled to the superior and inferior arcade margins, and except for the ILM in the temporal region, was hinged toward the edge of the MH. 2) Air–fluid exchange was then performed to drain the subretinal fluid (SRF) through the MH with a flute needle, ensuring that a small amount of SRF remained to facilitate ILM flap inversion. 3) The ILM flap was used to cover the MH with the assistance of autologous blood.

Results

Six months after surgery, the MH was successfully anatomically closed, and retinal reattachment was observed in all 18 eyes of 18 patients. The mean best-corrected visual acuity (BCVA, logMAR) improved from 2.03 ± 0.61 (ranging from hand motion [HM] [2.6] to finger counting [FC] [2.3]) to 1.23 ± 0.63 (ranging from HM [2.6] to 20/28 [0.15]) (P < 0.01) at 6 months.

Conclusion

This surgical technique using an inverted ILM flap combined with autologous blood provides an option for the treatment of extensive MHRD.
‘Legacy publication of a 2009 validation of the Riester Big Ben Square Desk aneroid device for blood pressure measurement according to the European Society of Hypertension International Protocol for validation of blood pressure measuring devices in adults (2002)’
Authors: McNally Ryan J. , Dunkerley Janette , Holland Maureen , Eatough Ruth , Lacy Peter , McManus Richard J. , Chapman Neil , Chowienczyk Philip J. , Lewis Philip , Clark Christopher E. , Denver Elizabeth , Neary Annette , McDonagh Sinead T.J. , Sheppard James P. ,   British and Irish Hypertension Society
Published: March 2024

Objective

To report a validation of the Riester Big Ben Square Desk Aneroid Sphygmomanometer according to the international protocol developed by the Working Group on Blood Pressure Monitoring of the European Society of Hypertension 2002 (ESH-IP 2002) in the interest of transparency. This legacy publication is intended to assure users that the device satisfied the requirements in place at that time.

Methods

Performance of the device was assessed by participants’ age, sex, arm circumference and entry SBP/DBP. Validation was performed in 33 participants. The sphygmomanometer was assessed according to the ESH-IP, which defines zones of accuracy compared to the mercury standard as ≤5, ≤10, ≤15 mmHg or more.

Results

The mean (± SD) age was 50.5 ± 13.0 years, range 29–71 years, entry SBP 142.6 ± 23.7 mmHg, entry DBP 89.0 ± 17.8 mmHg. The device passed all the requirements listed and the validation protocol. The Riester Big Ben Square Desk aneroid sphygmomanometer slightly underestimated the observer-measured SBP, yet slightly overestimated DBP. The observer-device disagreement was −0.8 ± 6.4 mmHg SBP and +0.6 ± 4.0 mmHg DBP.

Conclusion

These data show that the Riester Big Ben Square Desk aneroid sphygmomanometer fulfilled the ESH-IP 2002 requirements for the validation of BP monitors. It was on this basis that the British and Irish Hypertension Society recommended it for clinical use in the adult population.
The Journey and Experiences of Female Hispanic Nurse Leaders
Authors: Dolinta Jeniffer , Freysteinson Wyona M. , Nava Angeles , Clutter Paula
Published: March 2024

OBJECTIVE

This study aimed to understand the experience of female Hispanic nurses in formal leadership roles.

BACKGROUND

Research has identified that a diverse nursing leadership workforce is essential to providing optimal patient care. Little is known about the phenomenon of minority nurse leaders, particularly female Hispanic nurses in leadership roles.

METHODS

Ricoeur's hermeneutic phenomenology guided the interviews of 15 female Hispanic nurses in leadership roles.

RESULTS

Three themes were generated that described the environment in which leaders lived: family, culture, and healthcare organization. Four phenomenological themes were identified: weaving my life fabric, my inner dialogue, weight on my shoulders, and paving the way.

CONCLUSION

The study findings highlight the importance of a diverse and inclusive nursing leadership workforce. By proactively addressing equal opportunities, reducing barriers to career advancement, and developing strategies to support and encourage minority nurses, organizations and communities can recruit and retain qualified underrepresented minority nurse leaders.
Nurse Preceptor Burnout
Authors: Smith Maria , Rogers Allison , Fultz Julia , Davies Claire , Monroe Martha
Published: March 2024

OBJECTIVE

The aim of this study was to assess nurse preceptor burnout and examine related factors.

BACKGROUND

Nurse preceptors are essential to the provision of optimal hospital-based care. Preceptors guide and support nurses' transition from professional training to practice as well as movement within practice roles.

METHODS

As a component of the DevelopYou database, nurse preceptors (N = 210) were surveyed electronically using the BHLex Preceptor Role Questionnaire. Data retrieved from this data set were analyzed.

RESULTS

Twenty-eight percent (n = 60) of participants experienced burnout. Most (n = 203, 96.7%) enjoyed their role. Reasons for becoming a preceptor included a love for teaching, a desire to help others, and feelings of responsibility to the profession and the institution. Strategies to enable perceived value of the role focused on activities involving person-to-person interactions.

CONCLUSIONS

On the basis of the results of this analysis, it is apparent that nurse preceptors want to feel valued and supported by administration and have opportunities to interact regularly with colleagues.
Follow-Up of a Program to Improve Undergraduate and Graduate Nursing Student Diversity
Authors: Noone Joanne , Valenzuela Martinez Adriana
Published: March 2024

Background:

Underrepresented student recruitment is critical to resolve persistent gaps in workforce diversity in the United States.

Purpose:

Prenursing and nursing students participated in a nursing workforce diversity program designed to recruit and graduate underrepresented students, which provided academic and student support, financial support, and mentoring. A follow-up study was conducted to identify the impact of the program.

Methods:

Participants were surveyed about educational and employment information, perceptions about factors that contributed to success, benefits of the program, and educational experience. Descriptive summaries of data and thematic analysis of qualitative comments occurred.

Results:

Financial support, program quality, mentoring, career guidance, and meeting basic security needs were the strongest factors contributing to success. Program benefit themes included: feeling empowered, encouraging success, building confidence, and easing financial strain. Negative experiences with discrimination and bias were reported.

Conclusions:

Cocurricular support can help facilitate belonging. Scholarship awards communicate belief in student success, which impacts confidence and achievement.
Work With ChatGPT, Not Against
Authors: Simms Rachel Cox
Published: March 2024

Background:

Technological advances have expanded nursing education to include generative artificial intelligence (AI) tools such as ChatGPT.

Problem:

Generative AI tools challenge academic integrity, pose a challenge to validating information accuracy, and require strategies to ensure the credibility of AI-generated information.

Approach:

This article presents a dual-purpose approach integrating AI tools into prelicensure nursing education to enhance learning while promoting critical evaluation skills. Constructivist theories and Vygotsky’s Zone of Proximal Development framework support this integration, with AI as a scaffold for developing critical thinking.

Outcomes:

The approach involves practical activities for students to engage with AI-generated content critically, thereby reinforcing clinical judgment and preparing them for AI-prevalent health care environments.

Conclusions:

Incorporating AI tools such as ChatGPT into nursing curricula represents a strategic educational advancement, equipping students with essential skills to navigate modern health care.
Clinical Effectiveness of an Aquatic Exercise Program on Those With Visual Impairment: A Pilot Study
Authors: Rinehimer Maureen , Winton Clare , Ostrowski Marlena , Ertwine Kailey
Published: March 2024

Background and Purpose:

Visual impairments impact an individual’s ability to participate in certain activities, like exercise. Often, individuals with visual impairment have difficulty maintaining an active lifestyle, due to inopportunity and safety hazards. There is a lack of research on the use of aquatic exercise as a form of physical activity in those with visual impairments. The purpose of this study was to determine if this population can tolerate and benefit from an aquatic exercise program. Additionally, this study served to determine the effects of aquatic exercise on cardiovascular fitness, strength, and quality of life in individuals with visual impairment.

Methods:

This was a quasi-experimental study, evaluating participants with visual impairment aged 30 to 80 years, recruited from Northeast Sight Services in Exeter, PA. This study was reviewed and accepted by the Misericordia University Institutional Review Board. Eight participants were guided by physical therapy students and a primary researcher through a biweekly, 8-week aquatic exercise program at the Misericordia University Anderson Center Pool. This study utilized a pretest/post-test design to collect outcome measures. These included the 6-Minute Walk Test, 30-S Chair Stand Test, Modified Borg Ratings of Perceived Exertion (mRPE), the Modified Borg Dyspnea Scale, and the SF-36.

Results:

Paired t-tests and Cohen’s d were performed for the 6-Minute Walk Test (p = .04).953; Cohen’s d = 0.77, and the 30 Second Chair Stand Test (p = .02); Cohen’s d = 0.95 with large effect and significance. A Wilcoxon Signed Ranks and Cohen’s d were utilized for the mRPE 3 min, Cohen’s d = 0.27, Wilcoxon Signed Ranks 2.032 (p = .042), Borg RPE d = 1.054 and the SF-36 Cohen’s d = 2.3063.

Discussion and Conclusion:

This aquatic exercise program was tolerated well in this population and the results provide rehabilitation specialists an opportunity to promote health through aquatic programs for those with visual impairment. Furthermore, aquatic exercise was shown to be effective in improving lower extremity strength, cardiovascular endurance, and quality of life in participants, suggesting that aquatic exercise is a feasible intervention for this population.
Mortality of children and adolescents co-infected with tuberculosis and HIV: a systematic review and meta-analysis
Authors: Hu Fei-Hong , Tang Xiao-Lei , Ge Meng-Wei , Jia Yi-Jie , Zhang Wan-Qing , Tang Wen , Shen Lu-Ting , Du Wei , Xia Xiao-Peng , Chen Hong-Lin
Published: March 2024

Objective:

Children and adolescents with HIV infection are well known to face a heightened risk of tuberculosis. However, the exact mortality rates and temporal trends of those with HIV-tuberculosis (TB) co-infection remain unclear. We aimed to identify the overall mortality and temporal trends within this population.

Methods:

PubMed, Web of Science, and Embase were employed to search for publications reporting on the mortality rates of children and adolescents with HIV-TB co-infection from inception to March 2, 2024. The outcome is the mortality rate for children and adolescents with HIV-TB co-infection during the follow-up period. In addition, we evaluate the temporal trends of mortality.

Results:

During the follow-up period, the pooled mortality was 16% [95% confidence interval (CI) 13–20]. Single infection of either HIV or TB exhibit lower mortality rates (6% and 4%, respectively). We observed elevated mortality risks among individuals aged less than 12 months, those with extrapulmonary TB, poor adherence to ART, and severe immunosuppression. In addition, we observed a decreasing trend in mortality before 2008 and an increasing trend after 2008, although the trends were not statistically significant (P = 0.08 and 0.2 respectively).

Conclusions:

Children and adolescents with HIV-TB co-infection bear a significant burden of mortality. Timely screening, effective treatment, and a comprehensive follow-up system contribute to reducing the mortality burden in this population.
Effects of ovarian response prediction index and follicle-oocyte index on pregnancy outcomes: a retrospective cohort study of 12,218 fresh transfer cycles
Authors: Wang Mao , Tan Li , Ding Yu-Bin , Tang Xiao-Jun , Li Tian , Hu Xin-Yue , Zhong Hu-Cen , Wan Qi , Zhong Zhao-Hui
Published: March 2024

Objective:

To investigate the potential relationships among the ovarian response prediction index (ORPI), follicle-oocyte index (FOI), and clinical pregnancy rate (CPR) in women undergoing their first in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) fresh cycle transfer.

Methods:

In this retrospective cohort study, we included 12,218 women who underwent their first IVF/ICSI-ET cycle between December 2014 and January 2021. The primary and secondary outcomes of our study were CPR and cumulative live birth rate (CLBR), respectively. The data were divided into three groups according to the ORPI and FOI tertiles. Multivariate logistic regression analyses, stratification analyses, interaction, restricted cubic splines, and receiver operating characteristic (ROC) curves were constructed to identify the relationships among ORPI, FOI, and CPR.

Results:

A statistically significant increase in CPR was detected from the lowest to the highest tertile group (ORPI: 48.12%, 54.07%, and 53.47%, P <0.001; FOI: 49.99%, 52.95%, and 52.71%, P = 0.012). A higher CLBR was observed in the high group (ORPI: 38.63%, 44.62%, and 44.19%, P <0.001; FOI: 41.02%, 43.78%, and 42.59%, P = 0.039). Multivariate logistic regression analysis revealed no statistically significant differences between ORPI, FOI, and neither CPR (odds ratio [OR] [95% confidence interval {CI}], 0.99 [0.97–1.00] vs. [1.02 {0.84–1.24}]) nor CLBR (OR [95% CI], 0.99 [0.97–1.01] vs. 0.99 [0.81–1.20]). No significant association was found among FOI, ORPI, and CPR, even in the subgroups. Restricted cubic spline analyses indicated the existence of a non-linear relationship across the entire range of FOI and ORPI. The ORPI and FOI variables had poor predictive ability (AUC < 0.60) for CPR.

Conclusions:

Both ORPI and FOI are not reliable predictors of clinical pregnancy or live birth outcomes in fresh ETs. Clinicians and researchers should avoid using FOI and ORPI to assess pregnancy outcomes after fresh ET because of their limited relevance and predictive value.
Role of socioeconomic factors and interkingdom crosstalk in the dental plaque microbiome in early childhood caries
Authors: Khan Mohd Wasif , de Jesus Vivianne Cruz , Mittermuller Betty-Anne , Sareen Shaan , Lee Victor , Schroth Robert J. , Hu Pingzhao , Chelikani Prashen
Published: March 2024

Early childhood caries (ECC) is influenced by microbial and host factors, including social, behavioral, and oral health. In this cross-sectional study, we analyzed interkingdom dynamics in the dental plaque microbiome and its association with host variables. The samples collected from the preschool children underwent 16S rRNA and ITS1 rRNA gene sequencing. The questionnaire data were analyzed for social determinants of oral health. The results indicated a significant enrichment ofStreptococcus mutansandCandida dubliniensisin ECC samples, in contrast toNeisseria oralisin caries-free children. Our interkingdom correlation analysis revealed thatCandida dubliniensiswas strongly correlated with bothNeisseria bacilliformisandPrevotella veroralisin ECC. Additionally, ECC showed significant associations with host variables, including oral health status, age, place of residence, and mode of childbirth. This study provides empirical evidence associating the oral microbiome with socioeconomic and behavioral factors in relation to ECC, offering insights for developing targeted prevention strategies.

HIGHLIGHTS

Characterized interkingdom association between cariogenic species of genus Neisseria and Candida

Both bacterial and fungal species are important for caries status prediction using artificial intelligence

Socioeconomic index is associated with caries status and caries-associated microbial markers
Analytical and Clinical Validation of Direct Detection of Antimicrobial Resistance Markers by Plasma Microbial Cell-free DNA Sequencing
Authors: Christians Fred C. , Akhund-Zade Jamilla , Jarman Kristin , Venkatasubrahmanyam Shivkumar , Noll Nicholas , Blauwkamp Timothy A. , Bercovici Sivan , Zielinska Aga , Carr Amy L. , Craney Arryn , Pike Matthew , Farrell John Joseph , Dadwal Sanjeet , Wood James B. , Matkovich Efrat , McAdams Staci , Nolte Frederick S.
Published: March 2024

Sequencing of plasma microbial cell-free DNA (mcfDNA) has gained increased acceptance as a valuable adjunct to standard-of-care testing for diagnosis of infections throughout the body. Here we report the analytical and clinical validation of a novel application of mcfDNA sequencing, the non-invasive detection of seven common antimicrobial resistance (AMR) genetic markers in 18 important pathogens with potential to harbor these markers. The AMR markers include SCCmec,mecAandmecCfor methicillin,vanAandvanBfor vancomycin,blaCTX-Mfor oxyimino-cephalosporin and aztreonam, andblaKPCfor carbapenem resistance. The AMR markers are computationally linked to the pathogens detected, using a statistical model based on observed AMR gene and pathogen abundances. Analytical validation showed high reproducibility (100%), inclusivity (54 to100%), and exclusivity (100%), with limits of detection ranging from 425 to 6,107 pathogen mcfDNA molecules/μL for the different markers. Clinical accuracy was assessed with 115 unique plasma samples from patients at 7 study sites with concordant culture results for 12/18 (66.7%) target bacteria from a variety of specimen types and correlated with available phenotypic antimicrobial susceptibility test results and genotypic results when available. The positive percent agreement (PPA), negative percent agreement (NPA), overall percent agreement (OPA), and diagnostic yield (DY) were estimated for each AMR marker. The results for the combination of SCCmecandmecAfor staphylococci were PPA 19/20 (95.0%), NPA 21/22 (95.4%), OPA 40/42 (95.2%), DY 42/60 (70.0%);vanAfor enterococci were PPA 3/3 (100%), NPA 2/2 (100%), OPA5/5 (100%), DY 5/6 (83.3%);blaCTX-Mfor gram-negative bacilli were PPA 5/6 (83.3%), NPA 29/29 (100%), OPA34/35 (97.1%), DY 35/49 (71.4%); andblaKPCfor gram-negative bacilli were PPA 0/2 (0%), NPA: 23/23 (100%), OPA23/25 (92.3%), DY 25/44 (56.8%). The addition of AMR capability to plasma mcfDNA sequencing should provide clinicians with an effective new culture-independent tool for optimization of therapy.
Dynamics of Brain Connectivity across the Alzheimer’s Disease Spectrum: a magnetoencephalography study
Authors: Carrasco-Gómez Martín , García-Colomo Alejandra , Cabrera-Álvarez Jesús , Bruña Ricardo , Santos Andrés , Maestú Fernando
Published: March 2024

Alzheimer’s disease (AD) represents a major challenge in neurodegenerative disease research, as it is characterized by a complex pathophysiology that involves not only structural but also functional changes in the brain. While changes in static functional connectivity have already been linked to AD, there is still a lack of research studying dynamic functional connectivity (dFC) across the AD continuum, which could be crucial for identifying potential biomarkers for early diagnosis and tracking disease progression. This study leverages the high temporal resolution of MEG to dissect the dynamics of brain connectivity alterations across various stages of AD and their association with cognitive decline and structural brain changes.

321 participants were included in this study, categorized into healthy control, subjective cognitive decline (SCD), and mild cognitive impairment (MCI) groups. Amplitude envelope correlation with leakage correction was calculated over MEG signals using a sliding window, and the correlation across epochs was studied to assess dFC at whole-brain and node level. Finally, we explored dFC associations with cognitive scores, grey matter volume, and white matter fractal anisotropy.

The study unveils a significant reduction in whole-brain dFC, especially within the alpha and beta frequency bands, as individuals advance along the AD continuum. Notably, the frontal and temporal lobes, as well as regions within the default mode network, exhibited pronounced dFC reductions. Finally, dFC significantly correlated with cognitive performance and changes in structural brain, suggesting the potential of the proposed dFC metric as sensitive indicator for monitoring disease progression.

This investigation provides crucial insights into the temporal dynamics of brain connectivity alterations in the early stages of the AD spectrum, underlining the importance of dFC changes as reflective of cognitive and anatomical degeneration. The findings hint towards a strong relationship between connectivity profiles and white matter integrity, especially for high frequency activity in the association cortices.

Key Points

Dynamic functional connectivity declines over the AD spectrum.

Dynamic functional connectivity reductions are most prominent in orbitofrontal, temporal, and DMN-related areas.

Cognitive performance, brain volumetrics, and white matter integrity parameters positively correlate with dynamic functional connectivity over the whole AD spectrum, and most significantly among mild cognitive impairment participants.
Modulation of SARS-CoV-2 spike binding to ACE2 through conformational selection
Authors: Saha Prithwidip , Fernanadez Ignacio , Sumbul Fidan , Valotteau Claire , Kostrz Dorota , Meola Annalisa , Baquero Eduard , Sharma Arvind , Portman James R. , Stransky Francois , Boudier Thomas , Guardado Calvo Pablo , Gosse Charlie , Strick Terence , Rey Felix A. , Rico Felix
Published: March 2024

The first step of SARS-CoV-2 infection involves the interaction between the trimeric viral spike protein (𝑆) and the host angiotensin-converting enzyme 2 (𝐴𝐶𝐸2). The receptor binding domain (𝑅𝐵𝐷) of 𝑆 adopts two conformations: open and closed, respectively, accessible and inaccessible to 𝐴𝐶𝐸2. Therefore, 𝑅𝐵𝐷 motions are suspected to affect 𝐴𝐶𝐸2 binding; yet a quantitative description of the underlying mechanism has been elusive. Here, using single-molecule approaches, we visualize 𝑅𝐵𝐷 opening and closing and probe the 𝑆/𝐴𝐶𝐸2 interaction. Our results show that RBD dynamics affect 𝐴𝐶𝐸2 binding but not unbinding. The resulting modulation is quantitatively predicted by a conformational selection model in which each protomer behaves independently. Our work reveals a general molecular mechanism affecting binding affinity without altering binding strength, helping to understand coronavirus infection and immune evasion.
Bradyrhizobiumand the soybean rhizosphere: Species level bacterial population dynamics in established soybean fields, rhizosphere and nodules
Authors: Sarao Sukhvir K. , Boothe Vincent , Das Bikram K. , Gonzalez Hernandez Jose L. , Brözel Volker S.
Published: March 2024

Bradyrhizobiumfixes nitrogen symbiotically with soybean and is an agriculturally significant bacterium. Much is known about theBradyrhizobiumspecies that nodulate soybeans. Conversely, prevalence ofBradyrhizobiumin soil and the rhizosphere is known only to the genus level as culture independent approaches have provided only partial 16S rRNA gene sequences, so that nodulating and non-nodulating species could not be distinguished. To track which species in bulk soil proliferate in the rhizosphere, and then nodulate, we sought to study population dynamics ofBradyrhizobiumin soybean fields and rhizosphere at the species level. Recent advances in Oxford Nanopore Technologies provided us with higher fidelity and increased number of reads which enabled us to trackBradyrhizobiumpopulations at the species level. We found evidence for 74 species ofBradyrhizobiumwithin a community of 10,855 bacterial species in bulk soil and rhizosphere from three different soybean fields in South Dakota. The most predominant species in bulk soil and rhizosphere includedB. liaoningense, B. americanum,andB. diversitatus, however none of these were isolated from nodules. Isolates from nodules includedB. japonicum, B. elkaniiandB. diazoefficiens.These nodulators also maintained populations in bulk soil and rhizosphere, although they were not the most prevalentBradyrhizobium.Our findings reveal the rich diversity and community dynamics ofBradyrhizobiumspecies in soybean field soil as well as in the rhizosphere. Our results showed that many species of the genus maintain populations in soybean field soil, even in the long-term absence of potential nodulating partners.
Unraveling the Time-Frequency Features of Emotional Regulation: Based on an Interpretable XGBoost-SHAP Analytical Framework
Authors: Cheng Si
Published: March 2024

Negative emotions, while crucial for survival, can lead to adverse health effects if not managed properly. Our understanding of temporal EEG changes during emotion regulation is limited. To address this gap, this study employs interpretable machine learning techniques, XGBoost-SHAP model, to analyze EEG data. This study investigates the neural mechanisms underlying emotion regulation, with a focus on EEG oscillations in the lateral prefrontal area channels (F3, F4, F7, F8) across four specific frequency bands (Alpha, Beta, Theta, Delta). By identifying predictive features and patterns, this approach offers insights into the temporal dynamics of emotion regulation and the involvement of specific brain regions, enhancing our understanding of emotional processing and providing avenues for effective interventions. The findings reveal a significant relationship between specific EEG feature changes and emotional ratings during the emotion regulation process. The LPFC emerges as central in cognitive control and emotional regulation. These results highlight the LPFC's rapid and effective role in regulating complex emotional dynamics, crucial for understanding and treating emotional disorders. The study underscores the importance of machine learning in elucidating neural mechanisms and guiding personalized interventions for emotional well-being.
Spatial and temporal variation in respiratory syncytial virus (RSV) subtype RNA in wastewater, and relation to clinical specimens
Authors: Zambrana Winnie , Huang ChunHong , Solis Daniel , Sahoo Malaya K. , Pinsky Benjamin A. , Boehm Alexandria B.
Published: March 2024

Respiratory syncytial virus (RSV) causes a large burden of respiratory illness, globally. It has two subtypes, RSV A and RSV B, but little is known regarding the predominance of these subtypes during different seasons and their impact on morbidity and mortality. Using molecular methods, we quantified RSV A and RSV B RNA in wastewater solids across multiple seasons and metropolitan areas to gain insight into the predominance of RSV subtypes. We determined the predominant subtype for each group using the proportion of RSV A to total RSV (RSV A + RSV B) in each wastewater sample (PA,WW), and conducted a comparative analysis temporally, spatially and against clinical specimens. A median PA,WWof 0.00 in the first season and 0.58 in the second season indicated a temporal shift in the predominant subtype. Spatially, while we observed dominance of the same subtype, PA,WWwas higher in some areas (PA,WW= 0.58 to 0.88). The same subtype predominated in wastewater and clinical samples, but clinical samples showed higher levels of RSV A (RSV A positivity in clinical samples = 79%, median PA,WW= 0.58). These results suggest that wastewater, alongside clinical data, holds promise for enhanced subtype surveillance.

Importance

Respiratory syncytial virus (RSV) causes a large burden of respiratory illness, globally. It has two subtypes, RSV A and RSV B, but little is known regarding the predominance of these subtypes during different seasons and their impact on morbidity and mortality. The study illustrates that information on subtype predominance can be gleaned from wastewater. As a biological composite sample from the entire contributing population, wastewater monitoring of RSV A and B can complement clinical surveillance of RSV.
Heterogeneity in elevated glucose and A1C as predictors of the prediabetes to diabetes transition: Framingham Heart Study, Multi-Ethnic Study on Atherosclerosis, Jackson Heart Study, and Atherosclerosis Risk In Communities
Authors: Patel Chirag J. , Ioannidis John PA , Gregg Edward W. , Vasan Ramachandran S. , Manrai Arjun K.
Published: March 2024

Introduction

There are a number of glycemic definitions for prediabetes; however, the heterogeneity in diabetes transition rates from prediabetes across different glycemic definitions in major US cohorts has been unexplored. We estimate the variability in risk and relative risk of adiposity based on diagnostic criteria like fasting glucose and hemoglobin A1C% (HA1C%).

Research Design and Methods

We estimated transition rate from prediabetes, as defined by fasting glucose between 100-125 and/or 110-125 mg/dL, and HA1C% between 5.7-6.5% in participant data from the Framingham Heart Study, Multi-Ethnic Study on Atherosclerosis, Atherosclerosis Risk in Communities, and the Jackson Heart Study. We estimated the heterogeneity and prediction interval across cohorts, stratifying by age, sex, and body mass index. For individuals who were prediabetic, we estimated the relative risk for obesity, blood pressure, education, age, and sex for diabetes.

Results

There is substantial heterogeneity in diabetes transition rates across cohorts and prediabetes definitions with large prediction intervals. We observed the highest range of rates in individuals with fasting glucose of 110-125 mg/dL ranging from 2-18 per 100 person-years. Across different cohorts, the association obesity or hypertension in the progression to diabetes was consistent, yet it varied in magnitude. We provide a database of transition rates across subgroups and cohorts for comparison in future studies.

Conclusion

The absolute transition rate from prediabetes to diabetes significantly depends on cohort and prediabetes definitions.

Twitter Summary

New study finds variable diabetes risk in prediabetes across US cohorts. Results highlight obesity, Black race, and hypertension as key factors, emphasizing the need for precision in diabetes care. #DiabetesResearch
Identification of novel and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries
Authors: Akaberi Dario , Pourghasemi Lati Monireh , Krambrich Janina , Berger Julia , Neilsen Grace , Strandback Emilia , Turunen S. Pauliina , Wannberg Johan , Gullberg Hjalmar , Moche Martin , Chinthakindi Praveen Kumar , Nyman Tomas , G. Sarafianos Stefan , Sandström Anja , D. Järhult Josef , Sandberg Kristian , Lundkvist Åke , Verho Oscar , Lennerstrand Johan
Published: March 2024

In vitro screening of large compounds libraries with automated high-throughput screening is expensive, time consuming and requires dedicated infrastructures. Conversely, the selection of DNA-encoded chemical libraries (DECL) can be rapidly performed with routine equipment available in most laboratories. In this study we identified novel inhibitors of SARS-CoV-2 main protease (Mpro) through the affinity-based selection of the DELopen library (open access for academics), containing 4.2 billion compounds. The identified inhibitors were peptide-like compounds containing an N-terminal electrophilic group able to form a covalent bond with the nucleophilic Cys145 of Mpro, as confirmed by x-ray crystallography. This DECL selection campaign enabled the discovery of the unoptimized compound SLL11 displaying an IC50of 30 nM, proving that the rapid exploration of large chemical spaces enabled by DECL technology, allows for the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. Compound MP1, a close analogue of SLL11, showed antiviral activity against SARS-CoV-2 in the low micromolar range when tested in Caco-2 and Calu-3 (EC50= 2.3µM) cell lines. As peptide-like compounds can suffer from low cell permeability and metabolic stability, the cyclization of the compounds as well as the substitution of selected residues with D-enantiomers will be explored in the future to improve the antiviral activity of these novel compounds.
Applying health equity implementation science frameworks to population genetic screening
Authors: Rao Nandana D. , Fullerton Stephanie M. , Shirts Brian H. , Chen Annie T. , Henrikson Nora B.
Published: March 2024

Implementation science frameworks with a focus on health equity have emerged to help guide the introduction of new interventions into healthcare and community settings while limiting health disparities. The purpose of this research was to explore the applicability of such frameworks to guide the equitable implementation of population genetic screening programs. We searched PubMed and reference lists for relevant frameworks and examples of their use in health settings. We then assessed if and how selected frameworks provide guidance for different stages of population genetic screening: recruitment, sample collection, result return, follow-up care and prevention, and cascade screening. Findings were synthesized into a list of health equity considerations specific to each stage. We identified 5 implementation frameworks that focus on health equity. Guidance varied by framework type: determinant (explaining what affects implementation outcomes), process (translating research into practice), or evaluation (assessing implementation). Common characteristics included focusing implementation efforts on populations who have historically experienced health inequities and adapting interventions to fit local contexts. Process models also highlighted the importance of community partnerships. Overall, frameworks offered broad recommendations applicable to population genetic screening program implementation. However, gaps still exist in guidance provided for later stages of population genetic screening. To improve the equitable implementation of genetic screening, future programs may benefit from utilizing one or more of these frameworks or by incorporating the health equity considerations and outcomes compiled in this analysis.
Systematic comparison of quantity and quality of RNA recovered with commercial FFPE tissue extraction kits
Authors: Dube Sukoluhle , Al-Mannai Sharefa , Liu Li , Tomei Sara , Sanchez Apryl , Mifsud William , Bedognetti Davide , Hendrickx Wouter , Raynaud Christophe Michel
Published: March 2024

Background

FFPE tissue samples are commonly used in biomedical research and are a valuable source for next-generation sequencing in oncology, however, extracting RNA from these samples can be difficult the quantity and quality achieved can impact the downstream analysis. This study compared the effectiveness of seven different commercially available RNA extraction kits specifically designed for use with FFPE samples in terms of the quantity and quality of RNA recovered.

Methods

This study used 9 samples of FFPE tissue from three different types of tissue (Tonsil, Appendix and lymph node of B-cell lymphoma) to evaluate RNA extraction methods. Three sections of 20μm of each sample were combined per sample. The slices were distributed in a systematic manner to prevent any biases. Each of the 7 commercially available RNA extraction kits were used according to manufacturer’s instructions, with each sample being tested in triplicate resulting in a total of 189 extractions. The concentration, RNA integrity number (RIN) and DV200 of each extraction was analysed using a LabChip to determine the quantity and quality of the recovered RNA.

Results

This study found that despite processing the FFPE samples in the same standardized way, there were disparities in the quantity and quality of RNA recovered across the different tissue types. Additionally, the study found notable differences in the quantity of RNA recovered when using different extraction kits. In terms of quality, three of the kits performed better than the other four in terms of RNA integrity number (RIN) and DV200 values.

Conclusion

Though many laboratories have developed their own protocols for specific tissue types, using commercially available kits is still a popular option. Although these kits use similar processes and extraction procedures, the amount and quality of RNA obtained can vary greatly between kits. In this study, among the kits tested, while the Roche kit, provided a nearly systematic better-quality recovery than other kits, the ReliaPrep FFPE Total RNA miniprep from Promega yielded the best ratio of both quantity and quality on the tested tissue samples.
Estimating the selection pressure of tumor growth on tumor tissue microbiomes
Authors: Li Lianwei , Ma Zhanshan (Sam)
Published: March 2024

Background

The relationships between tumor and its microbiome are still puzzling, with possible bidirectional interactions. Tumor microbiomes may suppress or stimulate tumor growth on the one hand; on the other hand, tumor growth may exert selection pressure on its microbiomes. There is not any consensus on the mode and/or extension of the bidirectional interactions. The objective of this study is to estimate the selection pressure from the primary tumors on tumor microbiomes by comparing with the selection pressure from the solid normal tissues on their corresponding tissue microbiomes across 20+ cancer types.

Methods

We apply Sloan near neutral theory and big datasets of tumor tissue microbiomes from the TCGA (The Cancer Genome Atlas) databases to achieve the above objective. The near neutral theory model can determine the proportions of above-neutral, neutral and below-neutral species in microbial communities, corresponding with positive, neutral and negative selection pressures from host tissues. By comparing the proportions between the primary tumors and solid normal tissues, we can infer the selection pressure of tumor growth on tissue microbiomes.

Results

We find that approximately 65% of species in solid normal tissue microbiomes are neutral, and the proportion is only 40% in the primary tumor microbiomes. In contrast, the proportion of positively selected species exceeds 60% in the primary tumor microbiomes. Furthermore, simulations with neutral theory model reveal that most abundant species are mostly neutral, while non-neutral species are in the long tail of the species abundance distributions.

Conclusions

Tumor growth exerts strong positive selection on resident microbiomes, driving the abundances of certain species above the levels expected by the neutral process. Nevertheless, neutral species are still among the most abundant species, suggesting the necessity to pay close attention to the low-abundance or rare species because they are likely to play a critical role in oncogenesis.
Exploring Machine Learning Strategies in COVID-19 Prognostic Modelling: A Systematic Analysis of Diagnosis, Classification and Outcome Prediction
Authors: Najjar Reabal , Hossain Md Zakir , Ahmed Khandaker Asif , Hasan Md Rakibul
Published: March 2024

Background

The COVID-19 pandemic, which has impacted over 222 countries resulting in incalcu-lable losses, has necessitated innovative solutions via machine learning (ML) to tackle the problem of overburdened healthcare systems. This study consolidates research employing ML models for COVID-19 prognosis, evaluates prevalent models and performance, and provides an overview of suitable models and features while offering recommendations for experimental protocols, reproducibility and integration of ML algorithms in clinical settings.

Methods

We conducted a review following the PRISMA framework, examining ML utilisation for COVID-19 prediction. Five databases were searched for relevant studies up to 24 January 2023, resulting in 1,824 unique articles. Rigorous selection criteria led to 204 included studies. Top-performing features and models were extracted, with the area under the receiver operating characteristic curve (AUC) evaluation metric used for performance assessment.

Results

This systematic review investigated 204 studies on ML models for COVID-19 prognosis across automated diagnosis (18.1%), severity classification (31.9%), and outcome prediction (50%). We identified thirty-four unique features in five categories and twenty-one distinct ML models in six categories. The most prevalent features were chest CT, chest radiographs, and advanced age, while the most frequently employed models were CNN, XGB, and RF. Top-performing models included neural networks (ANN, MLP, DNN), distance-based methods (kNN), ensemble methods (XGB), and regression models (PLS-DA), all exhibiting high AUC values.

Conclusion

Machine learning models have shown considerable promise in improving COVID-19 diagnostic accuracy, risk stratification, and outcome prediction. Advancements in ML techniques and their integration with complementary technologies will be essential for expediting decision-making and informing clinical decisions, with long-lasting implications for healthcare systems globally.
GeneSurv: Multi-Gene Cancer Survival Analysis Tool
Authors: Xu Zikang , Wu Jamin , Shin Sung-young , Nguyen Lan K.
Published: March 2024

Traditional cancer survival analysis tools often restrict their analysis to single genes, thereby limiting their analytical scope. GeneSurv, a novel Web-Based Multi-Gene Cancer Survival Analysis Tool, addresses this limitation by enabling multi-gene analyses that correlates the expression of multiple genes, without restriction on their number, in various combinations, with patient survival outcomes. GeneSurv offers dynamic functionalities and an intuitive interface for flexible and precise adjustments of gene expression thresholds. Among its demonstrated applications, GeneSurv identified a significant association between high expression of CCND1 and CDK4 with poor breast cancer prognosis, and related the combined expression of five genes to patient survival, showcasing its capacity to unravel the complexities of genetic interactions and their impact on patient outcomes.

Conclusion

Available with user-friendly tutorials athttps://can-sat.erc.monash.edu/, GeneSurv is an invaluable addition to the existing suite of bioinformatic tools, significantly enhancing the investigation of cancer prognosis.