bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracorporeal Membrane Oxygenation and Reperfusion Strategies in High-Risk Pulmonary Embolism Hospitalizations
Authors: Farmakis Ioannis T. , Sagoschen Ingo , Barco Stefano , Keller Karsten , Valerio Luca , Wild Johannes , Giannakoulas George , Piazza Gregory , Konstantinides Stavros V. , Hobohm Lukas
Published: June 2024

OBJECTIVES:

To investigate the contemporary use of extracorporeal membrane oxygenation (ECMO) in conjunction with reperfusion strategies in high-risk pulmonary embolism (PE).

DESIGN:

Observational epidemiological analysis.

SETTING:

The U.S. Nationwide Inpatient Sample (NIS) (years 2016–2020).

PATIENTS:

High-risk PE hospitalizations.

MEASUREMENTS AND MAIN RESULTS:

Use of ECMO in conjunction with thrombolysis-based reperfusion (systemic thrombolysis or catheter-directed thrombolysis) or mechanical reperfusion (surgical embolectomy or catheter-based thrombectomy) with regards to in-hospital mortality and major bleeding. We identified high-risk PE hospitalizations in the NIS (years 2016–2020) and investigated the use of ECMO in conjunction with thrombolysis-based (systemic thrombolysis or catheter-directed thrombolysis) and mechanical (surgical embolectomy or catheter-based thrombectomy) reperfusion strategies with regards to in-hospital mortality and major bleeding. Among 122,735 hospitalizations for high-risk PE, ECMO was used in 2,805 (2.3%); stand-alone in 1.4%, thrombolysis-based reperfusion in 0.4%, and mechanical reperfusion in 0.5%. Compared with neither reperfusion nor ECMO, ECMO plus thrombolysis-based reperfusion was associated with reduced in-hospital mortality (adjusted odds ratio [aOR] 0.61; 95% CI, 0.38–0.98), whereas no difference was found with ECMO plus mechanical reperfusion (aOR 1.03; 95% CI, 0.67–1.60), and ECMO stand-alone was associated with increased in-hospital mortality (aOR 1.60; 95% CI, 1.22–2.10). In the cardiac arrest subgroup, ECMO was associated with reduced in-hospital mortality (aOR 0.71; 95% CI, 0.53–0.93). Among all patients on ECMO, thrombolysis-based reperfusion was significantly associated (aOR 0.55; 95% CI, 0.33–0.91), and mechanical reperfusion showed a trend (aOR 0.75; 95% CI, 0.47–1.19) toward reduced in-hospital mortality compared with no reperfusion, without increases in major bleeding.

CONCLUSIONS:

In patients with high-risk PE and refractory hemodynamic instability, ECMO may be a valuable supportive treatment in conjunction with reperfusion treatment but not as a stand-alone treatment especially for patients suffering from cardiac arrest.
Prenatal air pollution and children’s autism traits score: Examination of joint associations with maternal intake of vitamin D, methyl donors, and polyunsaturated fatty acids using mixture methods
Authors: Bragg Megan G. , Gorski-Steiner Irena , Song Ashley , Chavarro Jorge E. , Hart Jaime E. , Tabb Loni P. , Weisskopf Marc G. , Volk Heather , Lyall Kristen ,   the Early Autism Risk Longitudinal Investigation (EARLI) Team
Published: June 2024

Background:

Maternal nutrient intake may moderate associations between environmental exposures and children’s neurodevelopmental outcomes, but few studies have assessed joint effects. We aimed to evaluate whether prenatal nutrient intake influences the association between air pollutants and autism-related trait scores.

Methods:

We included 126 participants from the EARLI (Early Autism Risk Longitudinal Investigation, 2009–2012) cohort, which followed US pregnant mothers who previously had a child with autism. Bayesian kernel machine regression and traditional regression models were used to examine joint associations of prenatal nutrient intake (vitamins D, B12, and B6; folate, choline, and betaine; and total omega 3 and 6 polyunsaturated fatty acids, reported via food frequency questionnaire), air pollutant exposure (particulate matter <2.5 μm [PM2.5], nitrogen dioxide [NO2], and ozone [O3], estimated at the address level), and children’s autism-related traits (measured by the Social Responsiveness Scale [SRS] at 36 months).

Results:

Most participants had nutrient intakes and air pollutant exposures that met US standards. Bayesian kernel machine regression mixture models and traditional regression models provided little evidence of individual or joint associations of nutrients and air pollutants with SRS scores or of an association between the overall mixture and SRS scores.

Conclusion:

In this cohort with a high familial likelihood of autism, we did not observe evidence of joint associations between air pollution exposures and nutrient intake with autism-related traits. Future work should examine the use of these methods in larger, more diverse samples, as our results may have been influenced by familial liability and/or relatively high nutrient intakes and low air pollutant exposures.
Dynamic changes of serum α-fetoprotein predict the prognosis of bevacizumab plus immunotherapy in hepatocellular carcinoma
Authors: Yang Zhenyun , Fu Yizhen , Wang Qianyu , Pan Yangxun , Wang Juncheng , Chen Jinbin , Hu Dandan , Zhou Zhongguo , Chen Minshan , Zhang Yaojun
Published: June 2024

Background:

Alpha-fetoprotein (AFP) has been established as a biomarker for hepatocellular carcinoma (HCC); however, whether its dynamic changes could predict the response to systemic therapy remains elusive. This study explored the AFP trajectory and the association with survival in patients who received bevacizumab plus immunotherapy.

Materials and Methods:

We retrospectively enrolled 536 HCC patients who received bevacizumab plus immunotherapy between February 2021 and February 2023. Patients were divided into two groups according to AFP values before treatment (400 ng/ml). Dynamic changes of AFP were fitted using a latent class model to generate the AFP trajectories. Multivariable Cox models were utilized to compute hazard ratios (HRs) for survival. Inverse-probability-of-treatment weighted analyses were conducted to mitigate the influence of unmeasured confounding variables. The primary endpoint is progression-free survival (PFS). The second endpoint is overall survival (OS).

Results:

Three distinct trajectories were identified for AFP-low and AFP-high patients, respectively. In the AFP-low group, compared with the high-rising class (25%; n=69), HRs of PFS were 0.39 and 0.2 for the low-stable class (59.1%; n=163) and sharp-falling class (15.9%; n=44), after adjusting by tumor diameter, tumor number, and extra-hepatic metastasis. In the AFP-high group, compared with the high-stable class (18.5%; n=48), HRs of PFS were 0.3 and 0.04 for the middle-stable class (56.5%; n=147) and sharp-falling class (25%; n=65), after adjusting by tumor diameter, tumor number, and extra-hepatic metastasis. Furthermore, the AFP trajectories exhibited the utmost relative importance among all covariates regarding PFS and OS in the multivariable regression models.

Conclusion:

The AFP trajectories in HCC patients receiving bevacizumab and immunotherapy constituted an independent biomarker indicative of clinical outcomes. Findings from this study hold potential clinical utility in dynamically forecasting the prognosis of systemic therapy in HCC patients and facilitating clinical decision-making. Rapid reduction of AFP post-treatment can lead to favorable patient prognoses.
Diagnostic and prognostic value of heparin-binding protein in sepsis: A systematic review and meta-analysis
Authors: Taha Amira Mohamed , Najah Qasi , Omar Mohamed Mosad , Abouelmagd Khaled , Ali Mohammed , Hasan Mohammed Tarek , Allam Sahar A. , Hamam Yasser A. , Arian Roua , Abd-ElGawad Mohamed
Published: June 2024

Background:

Sepsis remains a leading cause of death worldwide. In this context, heparin-binding protein (HBP) has emerged as a possible biomarker, drawing significant attention for its diagnostic and prognostic usefulness in septic patients. Despite this advancement, the literature yields conflicting results. This study is intended to critically evaluate the diagnostic and prognostic value of HBP in critically ill septic patients.

Methods:

We searched multiple databases, including PubMed, SCOPUS, Web of Science, and EBSCO, to identify relevant studies on April 27, 2023. We included studies investigating sepsis or its severe outcomes that reported HBP levels and the required data to create 2 × 2 tables. We used R version 4.2.2 and R Studio to analyze the pooled diagnostic accuracy outcomes. The diagmeta package was utilized to calculate the optimum cutoff value.

Results:

In our meta-analysis, we incorporated 28 studies including 5508 patients. The analysis revealed that HBP has a sensitivity of 0.71 (95% CI: 0.60; 0.79) and a specificity of 0.68 (95% CI: 0.51; 0.81) in diagnosing sepsis, respectively. HBP demonstrated moderate prognostic accuracy for mortality at a cutoff value of 161.415 ng/mL, with a sensitivity and specificity of 72%, and for severe sepsis outcomes at a cutoff value of 58.907 ng/mL, with a sensitivity and specificity of 71%.

Conclusion:

Our findings indicate a relatively moderate diagnostic and prognostic accuracy of HBP for sepsis. Future studies are required to verify the accuracy of HBP as a biomarker for sepsis.
The success of SII, MII-1, MII-2, MII-3, and QT dispersion in predicting the walled-off pancreatic necrosis development in acute pancreatitis in the emergency department: An observational study
Authors: Çinaroğlu Osman Sezer , Acar Hüseyin , Çamyar Hakan , Bora Ejeder Saylav , Efgan Mehet Göktuğ , Korkmaz Uğur Bayram , Yurtsever Güner , Kanter Efe
Published: June 2024

walled-off pancreatic necrosis (WOPN) is one of the complications of acute pancreatitis (AP) with high mortality. A method to predict the development of WOPN in AP patients admitted to the emergency department may guide life-saving practices such as early initiation of antibiotic therapy and, when necessary, referral of the patient to a center where necrosectomy can be performed. This study is a prospective observational study. One hundred eleven AP patients who applied to the emergency department were included in the study. The mean of QT interval (QT) dispersion, systemic immune–inflammation Index (SII), multi-inflammatory index-I (MII-1), multi-inflammatory index-II (MII-2), and multi-inflammatory index-III (MII-3) were compared between patients who developed WOPN and patients who did not develop WOPN during their hospitalization. In the study, the mean of QT dispersion, SII, MII-1, MII-2, and MII-3 were significantly lower in the patient group who developed WOPN compared to those who did not develop WOPN. In the receiver operating characteristic analysis, all methods except SII were found to be successful in predicting WOPN. QT dispersion, SII, MII-1, MII-2, and MII-3 are valuable tools that provide rapid results and successfully predict the development of WOPN in AP. However, MII-2 and QT dispersion appears to be slightly more successful than the others.
Polycystic ovary syndrome and its multidimensional impacts on women’s mental health: A narrative review
Authors: Almhmoud Haya , Alatassi Lara , Baddoura Mouna , Sandouk Joudy , Alkayali Mohamad Zafer , Najjar Hasan , Zaino Basem
Published: June 2024

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects approximately 8% to 13% of women of reproductive age worldwide. It is characterized by a range of symptoms, including hirsutism, acne, and menstrual irregularities, and poses a significant psychological burden, including anxiety and depression. The evolving definition of PCOS, from the 1990 NIH conference to the 2003 Rotterdam conference, highlights its multifaceted nature, encompassing metabolic, reproductive, and psychological aspects. This overview aims to elucidate the complex interplay between PCOS’s physiological and psychological dimensions. It focuses on understanding the heightened risk of psychiatric disorders, including depression and anxiety, among women with PCOS and explores the contributing factors, such as obesity, body image issues, and stress. The etiology of PCOS involves a complex mixture of genetic, hormonal, and lifestyle factors that contribute to its pathophysiology and the associated mental health challenges. Stress, in various forms, including metabolic, inflammatory, oxidative, and emotional, is identified as a significant contributor to the pathogenesis of PCOS. Management strategies highlighted include lifestyle modifications, dietary and exercise interventions, and psychological therapies, underscoring the need for comprehensive and integrated care approaches that address the broad spectrum of PCOS effects. A multifaceted treatment approach that goes beyond just the physical symptoms of PCOS to also include its significant psychological effects is emphasized, reinforcing the necessity for a comprehensive, integrated care strategy to manage this complex condition effectively.
The struggle that is phenylketonuria: What do the patients and caregivers suffer from
Authors: Demirel Dilara , Sivri Serap
Published: June 2024

To assess stress levels and life hardships of patients with phenylketonuria and their parents. Between January 2020 and June 2020, 156 patients with PKU and their parents who arrived for regular examinations were included. Parents were asked to complete the parenting stress index, Zarit Burden Scale, and the Strengths and Difficulties Questionnaire (SDQ), and children over the age of 11 were asked to fill the Rosenberg Self-Esteem Scale, the State-Trait Anxiety Inventory, and the SDQ. We found a significant negative correlation between the Rosenberg Self-Esteem Scale and age at diagnosis (r= −0.27,P = .035), mother’s age (r= −0.33,P = .009), and father’s age (r= −0.38,P = .004). There was a significant positive correlation between the State-Trait Anxiety Inventory and patient’s age (r = 0.36,P = .006), mother’s age (r = 0.29,P = .031) and father’s age (r = 0.38,P = .024). In the child form of the SDQ, emotional problems were significantly positively correlated with serum phenylalanine (Phe) levels at diagnosis (r = 0.35,P = .036), total points were significantly positively correlated with serum Phe levels at clinical examination (r= −0.34,P = .004), and social problems were significantly negatively correlated with the father’s age (r= −0.34,P = .047). We found a significant positive correlation between the Zarit Burden Scale and number of siblings (r = 0.195,P = .023). In the parent form of the SDQ, emotional problems were significantly positively correlated with patient age (r = 0.217,P = .032), peer problems were significantly positively correlated with age at diagnosis (r = 0.211,P = .037), behavioral problems (r = 0.203,P = .045), and attention deficit and hyperactivity (r = 0.203,P = .045) were significantly positively correlated with serum Phe levels at diagnosis. Phenylketonuria is difficult to cope with both for the patients and their parents because of diet obligation, high expenditures for the formulas required for the diet, requirement of regular clinical examinations, and possible development of mental disability and psychiatric disorders. Patients and their families should be psychologically evaluated and support should be provided if needed.
Financial Toxicity in Patients With Chronic Pancreatitis
Authors: Choate Radmila , Wasilchenko Carrigan , Thakur Kshitij , Hill Rachel , Wright Elizabeth , Conwell Darwin L.
Published: June 2024

Objectives

Patients with chronic illnesses are susceptible to the financial burden of disease-related treatment costs. Financial toxicity is well researched in cancer and several chronic diseases. This review explores the financial challenges faced by patients with chronic pancreatitis and the impact of financial hardship on their well-being.

Materials and Methods

We performed a review of the published literature to summarize the body of existing research and to identify knowledge gaps related to the financial burden experienced by patients with chronic pancreatitis.

Results

Research on financial burden, cost-coping behaviors, cost-related nonadherence to prescribed medications, and social vulnerabilities in people with chronic pancreatitis is sparse. No studies have assessed the suitability and validity of instruments measuring subjective financial toxicity in a patient population with chronic pancreatitis.

Conclusions

There is a critical need for further studies of financial toxicity in the patient population with chronic pancreatitis, considering that if the sources of financial burden can be identified, opportunities emerge to dampen or mitigate their impact on patients with chronic pancreatitis.
Resilience and Self-Management of Hypertension in African American Adults Using a Conceptualized Resilience Framework
Authors: Still Carolyn Harmon , Ruksakulpiwat Suebsarn
Published: June 2024

Background

Hypertension rates have increased worldwide, with the most significant increase in morbidity and mortality observed among African Americans. Resilience is a potential factor influencing how individuals manage health-related challenges or self-management tasks for hypertension. Research is scarce related to resilience and self-management frameworks in African Americans with hypertension.

Objectives

We aimed to describe a conceptualized resilience framework and preliminary findings of the association among resilience precursors, stress response, hypertension self-management behaviors, and health outcomes in African Americans with hypertension.

Methods

This cross-sectional, descriptive-correlational study included African American adults with hypertension, aged 25 years and older, recruited from an academic university and surrounding urban communities in the Midwest. Participants completed standardized, validated questionnaires to examine the association among resilience precursors, stress response, hypertension self-management behaviors, health-related quality of life (HRQOL), and blood pressure at baseline. Descriptive statistics were used to describe the sample demographic characteristics, whereas Pearson's correlational and multiple regression analyses were conducted to determine the associations among the variables.

Results

African Americans with hypertension (N = 30) were included in this preliminary study, with a mean age of 59.17 years; 66.7% were female. The mean systolic blood pressure was 136 (SD = 16.8) mmHg; the mean diastolic blood pressure was 78.1 (SD = 13) mmHg. Pearson's correlation analysis revealed significant relationships between resilience precursors, stress response, hypertension self-management behaviors and capability, and health outcome components. Multiple regression analysis showed that poor perceived resilience significantly predicted depression. Low dispositional optimism and low perceived resilience were significant predictors of stress. Higher perceived resilience significantly predicted self-efficacy. Perceived stress was negatively and significantly associated with HRQOL. Finally, higher self-efficacy significantly predicted better HRQOL.

Discussion

This study underscores the significant association between resilience, stress, self-management behaviors, and health outcomes in African Americans with hypertension. Further research with larger sample sizes and longitudinal designs is warranted to confirm and expand upon these findings.
Point-of-care urine tenofovir test predicts future HIV preexposure prophylaxis discontinuation among young users
Authors: Martinson Tyler , Montoya Rikki , Moreira Carlos , Kuncze Karen , Sassaman Kevin , Heise Megan J. , Glidden David V. , Amico K. Rivet , Arnold Emily A. , Buchbinder Susan P. , Ewart Leah Davis , Carrico Adam , Wang Guohong , Okochi Hideaki , Scott Hyman M. , Gandhi Monica , Spinelli Matthew A.
Published: June 2024

Background:

Young men who have sex with men and transgender women (YMSM/TGW) have disproportionately high HIV incidence and lower preexposure prophylaxis (PrEP) adherence. Point-of-care (POC) urine tenofovir (TFV) rapid assay (UTRA) testing permits real-time monitoring for nonadherence within clinical settings. We performed UTRA testing among PrEP users to examine the relationship between low PrEP adherence and future PrEP discontinuation, and the accuracy of POC testing compared to gold-standard liquid chromatography tandem mass spectrometry (LC/MS/MS).

Methods:

YMSM/TGW participants (n = 100) were recruited during a daily PrEP visit. Logistic regression models analyzed the relationship between the primary predictor of urine POC assay results (cutoff 1,500 ng/ml) and the primary outcome of PrEP discontinuation, defined as no PrEP follow-up or prescription within 120 days.

Results:

Overall, 19% of participants had low urine TFV and 21% discontinued PrEP, while 11% of participants self-reported low PrEP adherence (<4 pills per week), which was only 43% sensitive/84% specific in predicting low TFV levels and was not associated with PrEP discontinuation. Low urine TFV level predicted PrEP discontinuation [adjusted odds ratio (AOR) 6.1; 95% confidence interval (CI): 1.4–11;P = 0.005] and was 71% sensitive/90% specific for discontinuation after 120 days. Compared to LC/MS/MS, UTRA testing had a 98% positive and 100% negative predictive value.

Conclusions:

In a sample of YMSM/TGW on daily PrEP, POC UTRA testing predicted PrEP discontinuation more accurately than self-reported adherence, with high predictive values compared to LC/MS/MS. UTRA testing may be a clinical tool for directing preventive interventions towards those likelier to discontinue PrEP despite ongoing HIV vulnerability.
Association of T-cell subtypes with macrophage-specific arterial infiltration in people with HIV
Authors: Schnittman Samuel R. , Talathi Ria , Wilks Moses Q. , Hedgire Sandeep , Lu Michael T. , Fourman Lindsay T. , Alagpulinsa David A. , Stockman Sara L. , White Kevin S. , Wallis Zoey K. , Autissier Patrick , Stanley Takara L. , Lee Hang , Honigberg Michael C. , El-Fakhri Georges , Williams Kenneth C. , Zanni Markella V. , Grinspoon Steven K. , Toribio Mabel
Published: June 2024

People with human immunodeficiency virus (HIV, PWH) face an increased risk of cardiovascular disease (CVD) compared to the general population. We previously demonstrated that people with (versus without) HIV have higher macrophage-specific arterial infiltration in relation to systemic monocyte activation. We now show that select T lymphocyte subpopulations (naïve CD4+, effector memory CD4+, and central memory CD8+) are differentially associated with macrophage-specific arterial infiltration among participants with versus without HIV, with evidence of interaction by HIV status. Our results suggest that among PWH, circulating T lymphocytes associate with macrophage-specific arterial infiltration, of relevance to atherogenesis and CVD risk.
The Draft genome sequence of Bacillus subtilis strain S2 Isolated from fermented bamboo drink.
Authors: Jain Priyanshi Mahendrakumar , Cheruvari Athira , Jenifer Helga Maria Tamilselvan , Kammara Rajagopal
Published: June 2024

This work reports the draft genome sequence of the fermented food probiotic Bacillus subtilis strain S2, which has antibacterial activity against Micrococcus luteus, Vibrio harveyi, Staphylococcus aureus, Listeria monocytogenes, and Streptococcus mutans. From the de novo assembly, a genome with 4,438 open reading frames and an approximate size of 4,208,679 bp was obtained. Phylogenetically, B. subtilis S2 and B. subtilis SRCM103571 are closely related. The organism is known to produce two bacteriocins (uniqueness), Sublancin and Subtilosin A, as per genome analyses by antiSMASH and BAGEL-4.
HIV-DRIVES: HIV Drug Resistance Identification, Variant Evaluation, & Surveillance Pipeline
Authors: Kanyerezi Stephen , Sserwadda Ivan , Ssemaganda Aloysius , Seruyange Julius , Ayitewala Alisen , Oundo Hellen Rosette , Tenywa Wilson , Kagurusi Brian A. , Tusabe Godwin , Were Stacy , Ssewanyana Isaac , Nabadda Susan , Namaganda Maria Magdalene , Mboowa Gerald
Published: June 2024

The global prevalence of resistance to antiviral drugs combined with antiretroviral therapy (cART) emphasizes the need for continuous monitoring to better understand the dynamics of drug-resistant mutations to guide treatment optimization and patient management as well as check the spread of resistant viral strains. We have recently, integrated next-generation sequencing (NGS) into routine HIV drug resistance (HIVDR) monitoring, with key challenges in the bioinformatic analysis and interpretation of the complex data generated while ensuring data security and privacy of patient information. To address these challenges, here, we present HIV-DRIVES (HIV Drug Resistance Identification, Variant Evaluation, and Surveillance), an NGS-HIVDR bioinformatics pipeline that has been developed and validated using Illumina short-reads, FASTA, and Sanger ab1.seq files.
Neurotransmitter release is triggered by a calcium-induced rearrangement in the Synaptotagmin-1/SNARE complex primary interface
Authors: Toulmé Estelle , Lázaro Andrea Salazar , Trimbuch Thorsten , Rizo Josep , Rosenmund Christian
Published: June 2024

The Ca2+sensor synaptotagmin-1 triggers neurotransmitter release together with the neuronal SNARE complex formed by syntaxin-1, SNAP25 and synaptobrevin. Moreover, synaptotagmin-1 increases synaptic vesicle priming and impairs spontaneous vesicle release. The synaptotagmin-1 C2B domain binds to the SNARE complex through a primary interface via two regions (I and II), but how exactly this interface mediates distinct functions of synaptotagmin-1, and the mechanism underlying Ca2+-triggering of release is unknown. Using mutagenesis and electrophysiological experiments, we show that region II is functionally and spatially subdivided: binding of C2B domain arginines to SNAP-25 acidic residues at one face of region II is crucial for Ca2+-evoked release but not for vesicle priming or clamping of spontaneous release, whereas other SNAP-25 and syntaxin-1 acidic residues at the other face mediate priming and clamping of spontaneous release but not evoked release. Mutations that disrupt region I impair the priming and clamping functions of synaptotagmin-1 while, strikingly, mutations that enhance binding through this region increase vesicle priming and clamping of spontaneous release, but strongly inhibit evoked release and vesicle fusogenicity. These results support previous findings that the primary interface mediates the functions of synaptotagmin-1 in vesicle priming and clamping of spontaneous release, and, importantly, show that Ca2+-triggering of release requires a rearrangement of the primary interface involving dissociation of region I, while region II remains bound. Together with modeling and biophysical studies presented in the accompanying paper, our data suggest a model whereby this rearrangement pulls the SNARE complex to facilitate fast synaptic vesicle fusion.

Significance statement

The synaptic SNARE complex and synaptotagmin-1 are required for fast neurotransmitter release. The functions of synaptotagmin-1 in preparing synaptic vesicles for fusion and executing the triggering step have been proposed to be regulated through interactions with the SNARE complex via the so-called primary interface. Using site-directed mutagenesis and functional analysis in neurons, we now show that synaptotagmin-1 mediates its release preparatory functions via two contact sites with the SNARE complex at this interface. During Ca2+triggering, synaptotagmin-1 continues to contact the SNAREs at one site but disconnects the other site. We propose that this switch generates a pulling force on the SNARE complex that in turn triggers release. Biochemical and modeling studies described in the accompanying paper support this hypothesis.
Variations in nonlocal interaction range lead to emergent chase-and-run in heterogeneous populations
Authors: Painter K. J. , Giunta V. , Potts J. R. , Bernardi S.
Published: June 2024

In a chase-and-run dynamic, the interaction between two individuals is such that one moves towards the other (the chaser), while the other moves away (the runner). Examples can be found in both interacting cells and interacting animals. Here we investigate the behaviours that can emerge at a population level, for a heterogeneous group that contains subpopulations of chasers and runners. We show that a wide variety of patterns can form, from stationary patterns to oscillatory and population-level chase-and-run, where the latter describes a synchronised collective movement of the two populations. We investigate the conditions under which different behaviours arise, specifically focusing on the interaction ranges: the distances over which cells or organisms can sense one another’s presence. We find that when the interaction range of the chaser is sufficiently larger than that of the runner – or when the interaction range of the chase is sufficiently larger than that of the run – population-level chase-and-run emerges in a robust manner. We discuss the results in the context of phenomena observed in cellular and ecological systems, with particular attention to the dynamics observed experimentally within populations of neural crest and placode cells.
Effect of Adjunctive Intraoral Balance Appliance in the Usual Care of Patients with Chronic Temporomandibular Joint Disorders using Korean Medicine: Study Protocol for a Randomized Controlled Trial
Authors: Shin Woo-Chul , Kim Se yun , Cho Whisung , Park Jaehyun , Kim Hyungsuk , Chung Won-Seok , Song Mi-Yeon , Cho Jae-Heung
Published: June 2024

Introduction

Temporomandibular disorders (TMD) are a group of conditions that affect the temporomandibular joint, masticatory muscles, and associated structures, often leading to pain, dysfunction, and a significant impact on quality of life. Epidemiological studies have estimated that up to 75% of the population in the United States exhibit at least one sign of TMD. Although conservative treatments such as acupuncture and occlusal splints have been recommended, evidence for their effectiveness remains inconclusive, and the combined effects of these interventions are not well understood.

This study aims to compare the efficacy of an intraoral balance appliance (IBA) combined with standard Korean medicine care versus Korean medicine care alone in patients with chronic, painful TMD with myalgia.

Materials and Methods

A single-center, two-arm, parallel, evaluator-blinded, randomized controlled trial (RCT) with a 1:1 allocation ratio will be designed to test the interventions. Seventy-six TMD patients with myalgia will be recruited and randomized. The Interventions will include manual acupuncture and physical therapy in both groups, with the addition of IBA in the treatment group.

Discussion

The outcomes will be measured using various scales such as the numeric rating scale for pain and bothersomeness, jaw functional limitation scale, and quality of life indicators.

Conclusion

The trial is expected to provide evidence of the efficacy of combining the usual Korean medicine care and IBA in managing chronic TMD myalgia. Despite certain limitations such as the short intervention period and lack of standardized splint therapy, this RCT will contribute valuable data to guide the future treatment of TMD with myalgia.

Trial registration

Clinical Research information Service (CRiS) ID: KCT0008906. Registered on October 30, 2023
Application of theAMOCATIR workflow to tumor transcriptomic data delineates the adverse effect of immune cell infiltration in immune-privileged organs
Authors: Régnier Paul , Cagnard Nicolas , Podsypanina Katrina , Darrasse-Jèze Guillaume
Published: June 2024

Immune cells are present inside tumor tissue and can alter tumor growth. Expression profiles of human tumors hold transcripts from cancer cells and their microenvironment, including the infiltrating immune cells. Few standardized methods examine tumor immunobiology relying only on tumor transcriptome data. Using a new in-house developed R analysis workflow calledAMOCATI, we classified 43 cancer types from 11,176 patients according to the degree of infiltration by 18 distinct immune cell subsets, measured by the abundance of their transcriptomic signature, and calculated its effect on the disease outcome. In about half of cancers affecting organs without immune privilege, immune cell infiltration has beneficial effects. In contrast, immune infiltration in cancers of immune-privileged organs (eye, testis and brain) confers poor prognosis. Moreover, transcriptional evidence of increased immune cell activity in immune-privileged cancer sites is associated with bad prognosis. Thus, our results suggest that the effect of immune infiltration may depend on the origin of the primary tumor.

SIGNIFICANCE

Our in-house developed computational R approachAMOCATIallows to easily download public transcriptomic and clinical data, classify and analyze them.

AMOCATI permitted us to define gene expression signatures associated with short- or long-term survival from 11,176 untreated patient unsorted biopsies in 43 types of cancer.

We present the level of infiltration of 18 types of immune cell subsets transcriptomic signatures and 50 immune-related pathways in all these cancers

Correlation between immune infiltration of the tumor and survival establishes a link between tumor tissue of origin and the overall effect of immune infiltration on survival.

Immune cell infiltration in tumors from ‘immune privileged organs’ correlate with shorter survival.

Contrary to what we observe in ‘hot’ tumors, biological pathways of immune response are associated with a short-term survival profile in these cancers.
Transcriptional pathobiology and multi-omics predictors for Parkinson’s disease
Authors: Hu Ruifeng , Wang Ruoxuan , Yuan Jie , Lin Zechuan , Hutchins Elizabeth , Landin Barry , Liao Zhixiang , Liu Ganqiang , Scherzer Clemens R. , Dong Xianjun
Published: June 2024

Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson’s disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson’s Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominalp< 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genesIKBIP,CXCR2, andNFKBIB. Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction.

Significance statement

Early and accurate diagnosis of Parkinson’s disease (PD) is urgently needed. However, biomarkers for early detection of PD are still lacking. Also, the limit of sample size remains one of the main pitfalls of current PD biomarker studies. We employed an analysis of large-scale whole-blood RNA-seq data. By identifying 1,111 significant marker RNAs, we establish a robust foundation for early PD detection, which implicated in neutrophil activation, degranulation, and TNF-alpha signaling, offer unprecedented insights into PD pathogenesis. Our multi-omics machine learning model, boasting an AUC of 0.89, outperforms previous studies, promising a transformative tool for precise PD diagnosis in clinical settings. This study marks a pivotal step toward enhanced biomarker development and early disease prediction.
E. colicells advance into phase-separated (biofilm-simulating) extracellular polymeric substance containing DNA, HU, and lipopolysaccharide
Authors: Gupta Archit , Guptasarma Purnananda
Published: June 2024

We have earlier shown that HU, a nucleoid-associated protein, uses its DNA-binding surfaces to bind to bacterial outer-membrane lipopolysachharide (LPS), with this explaining how HU act as a potential glue for the adherence of bacteria to DNA, e.g., in biofilms. We have also earlier shown that HU and DNA together condense into a state of liquid-liquid phase separation (LLPS) both within, and outside, bacterial cells. Here, we report that HU and free LPS also condense into a state of phase separation, with coacervates of HU, DNA and free LPS being less liquid-like than condensates of HU and DNA alone.E. colicells bearing surface LPS and also shedding LPS, are shown to adhere to (as well as enter into) condensates of HU and DNA. HU thus appears to play a role in maintaining both an intracellular state of phase separation involving genomic nucleoids that are phase-separated from the cytoplasm, and an extracellular state of phase separation involving coacervates of extracellular DNA, HU and LPS, in the extracellular polymeric substances (EPS) of biofilms, in which LPS content is shown to modulate liquidity.

Importance

Understanding biofilm genesis and nature are crucial to understanding how to deal with the bacterial resistance to antibiotics that develops eventually in persistent biofilms. This study, together with two other recent landmark studies from our group, elucidates a novel aspect of the extracellular polymeric substance (EPS) of anEscherichia colibiofilm, by creating a simulacrum of the EPS and demonstrating that its formation involves liquid-liquid phase separation (LLPS) by its component HU, DNA, and lipopolysaccharide (LPS), with LPS determining the liquidity of the EPS simulacrum. The findings provide insight into the physical nature of biofilms but also suggests that the interplay of HU, DNA, and LPS facilitates the structural integrity and functional dynamics of biofilms. These findings are a stepping stone to the eventual development of strategies to disrupt biofilm.
Mapping smartphone-based eye-tracking behavior across Japanese individuals on the pareidolia test
Authors: Revankar Gajanan S. , Furuya Kota , Mori Etsuro , Suzuki Maki , Nishio Yoshiyuki , Ogasawara Issei , Yamamoto Yuki , Aradhya Abhay M. , Salian Abhishek C. , Kajarekar Varad V. , Jagadeesh Ashwin M. , Revankar Seema S. , Revankar Arya A. , Yoshida Natsuki , Saeki Chizu , Ozono Tatsuhiko , Nakatani Daisaku , Mochizuki Hideki , Ikeda Manabu , Nakata Ken
Published: June 2024

Pareidolias are illusionary phenomena wherein ambiguous forms appear meaningful. In clinical research, pareidolias have been studied using paper or desktop test formats to deconstruct visuo-perceptual mechanisms. Translating this work on to an accessible, scalable setup such as smartphones is currently unknown. Here, we designed a smartphone-based pareidolia test to study visual processes affecting gaze behavior of cognitively healthy individuals using a standard, native front-facing camera. We optimized our system using machine learning and explored the challenges involved in user behavior, demographic specificity, and test functionality. We performed our experiments on 52 healthy Japanese adults, aged between 50 to 80 years who underwent MMSE and the smartphone test for pareidolias. Gaze movements on the 15-min, user-centric evaluation was calibrated to every individual. Results showed test responses with minimal differences with respect to age, sex, and completion time. Personalized calibrations improved the model’s prediction performance and quantification of gaze tracking metrics aligned with that of commercial grade eye-trackers. Our findings demonstrate the applicability and scalability of pareidolia testing on smartphone platforms.
Predicting IVF live birth probabilities using machine learning, center-specific models: validation results and potential benefits over national registry-based models
Authors: Nguyen Elizabeth T. , Retzloff Matthew G. , Gago L. April , Nichols John E. , Payne John F. , Ripps Barry A. , Opsahl Michael , Groll Jeremy , Beesley Ronald , Neal Gregory , Adams Jaye , Nowak Lorie , Swanson Trevor , Chen Xiaocong , Yao Mylene W. M.
Published: June 2024

Ongoing improvement of pretreatment live birth prognostication for in vitro fertilization (IVF) is critical for informing fertility patients’ treatment decisions, advocating for IVF coverage and supporting value-based IVF care. The US national registry Society for Assisted Reproductive Technology (SART) IVF live birth prediction (LBP) model (SART model) has been widely adopted for its prognostic support without external validation or utilization studies. We conducted a retrospective model validation study to compare the IVF LBP performance of machine learning, center-specific (MLCS) models versus the SART model in 6 unrelated US fertility centers using their respective center-specific test sets comprising an aggregate of 4,635 patients’ first-IVF cycle data. Compared to the SART model, MLCS2 showed higher median Precision Recall AUC at 0.75 (IQR 0.73, 0.77) vs. 0.69 (IQR 0.68, 0.71), p<0.05 and higher median F1 Score across LBP thresholds. Further, MLCS1 showed no evidence of data drift when validated using out-of-time test data from a later period. Reclassification analysis showed that MLCS2 models assigned more appropriate and higher IVF LBPs compared to the SART model, which underestimated patient prognoses (continuous net reclassification index: 18.3%, p<0.0001). Overall, MLCS2 and SART models assigned 30% of patients to differential prognostic groups, with MLCS2 assigning 26% of patients to a higher LBP category compared to the SART model. Importantly, MLCS2 models identified 11% of patients to have LBP ≥ 75%, whereas the SART model detected none. This group had a live birth rate of 81%. We recommend testing a larger sample of fertility centers to further evaluate MLCS model benefits and limitations.
Synchronous emergence ofStreptococcus pyogenes emmtype 3.93 with unique genomic inversion among invasive infections in the Netherlands and England
Authors: Davies Matthew A. , de Gier Brechje , Guy Rebecca L , Coelho Juliana , van Dam Alje P. , van Houdt Robin , Matamoros Sébastien , van den Berg Marit , Habermehl Patrick E. , Moganeradj Kartyk , Ryan Yan , Platt Steve , Hearn Henry , Blakey Eleanor , Chooneea Darren , Vlaminckx Bart J.M. , Lamagni Theresa , van Sorge Nina M.
Published: June 2024

A global increase in the incidence of invasive group A streptococcal (iGAS) infections was observed after lifting COVID-19-related restrictions in 2022 with dominance of M1UKin many countries. After seasonal declines in iGAS incidence during the summer of 2023, simultaneous, rapid expansion of a previously rareemmtype 3.93 was seen in both England and the Netherlands from November 2023, causing 20% and 60% of all iGAS cases, respectively, within 4 months.Emm3.93 was associated with iGAS in children 6-17 years of age and with increased risk of pneumonia/pleural empyema and meningitis in both countries. No significant excess risk of death was identified foremm3.93 compared to other types. Genomic analysis of historic and contemporaryemm3.93 isolates revealed the emergence of three new clades with a previously undescribed genomic inversion. Our findings underscore the value of molecular surveillance, including long-read sequencing, in identifying clinical and public health threats.
Impact of Chronic Kidney Disease on Clinical Outcomes after Percutaneous Coronary Intervention with Drug-Coated Balloons
Authors: Takahashi Tetsuya , Watanabe Tetsu , Toyoshima Mashu , Katawaki Wataru , Toshima Taku , Kumagai Yu , Yamanaka Tamon , Watanabe Masafumi
Published: June 2024

Background

Drug coated balloon (DCB) is an emerging treatment technology for percutaneous coronary intervention (PCI). However, the prognostic factors of PCI with DCB remain fully determined. Chronic kidney disease (CKD) is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD) who underwent PCI. The aim of the present study was to clarify the impact of CKD on prognosis in CAD patients who underwent PCI with DCB.

Methods

We enrolled 252 consecutive patients with CAD who underwent PCI with DCB from 2015 to 2023. The endpoints of this study were composite events including all-cause death, myocardial infarction, target vessel revascularization, stroke, and major bleeding.

Results

The prevalence rate of CKD was 48%. Patients with CKD were older and had higher prevalence of hypertension and diabetes mellitus than those without. Kaplan-Meier analysis revealed a significantly higher composite event rate in patients with CKD (log-rank test, P = 0.003). In the multivariate Cox proportional hazards analysis, CKD was independently associated with composite events after adjusting for confounding factors (adjusted hazard ratio 1.920, 95% confidence intervals 1.154-3.197, P = 0.012), mainly driven by all-cause deaths.

Conclusion

CKD was associated with unfavorable outcomes in CAD patients who underwent PCI with DCB.
The BRoccoli In Osteoarthritis (BRIO study) - A randomised controlled feasibility trial to examine the potential protective effect of broccoli bioactives, (specifically sulforaphane), on osteoarthritis
Authors: Davidson Rose K , Watts Laura , Beasy Gemma , Saha Shikha , Kroon Paul , Cassidy Aedin , Clark Allan , Fraser William , Mcnamara Iain , Kingsbury Sarah R , Conaghan Philip G , Clark Ian M , Macgregor Alex
Published: June 2024

Objective

The Broccoli in Osteoarthritis (BRIO Study) was conducted to determine whether dietary sulforaphane (SFN), consumed as broccoli, improves pain and/or physical function in participants with knee osteoarthritis (OA). This was a proof of principle study to test the feasibility of the trial to optimise the design of an appropriately powered study.

Design

Two-centre, double-blind, two-arm parallel, randomised placebo-controlled, dietary intervention feasibility trial. Patients with radiographic knee osteoarthritis (Kellgren-Lawrence score 2-3), with pain of at least 4 on a scale of 0-10 were recruited. The intervention was a high glucoraphanin broccoli, (source of SFN), or a matched placebo (no SFN) soup. Pain and measures of physical function were measured at baseline, 6 and 12 weeks.

Results

The mean WOMAC pain score (scale 0 - 20) was decreased by 4.2 (95% CI: 1.03,7.38) following intervention, Similar patterns of improvement were observed for other pain and function outcome measures. Study data, sample collections and intervention adherence were 100% compliant except where COVID restrictions applied. Acceptability for randomisation was 100% and acceptability for the intervention was 92%. There were three related adverse events, two of which were expected.

Conclusions

High glucosinolate broccoli soup is a novel approach to managing OA that is widely accessible and can be used on a large scale. This study shows that it is an acceptable way of delivering dietary bioactives and has potential for therapeutic benefit. The primary outcome of pain improved in the intervention group compared to the placebo and the confidence interval encompassed the minimal clinically important difference. The data provide justification for proceeding to a large scale, appropriately powered intervention trial.