bluuebunny/crossref_metadata_2025 huggingface dataset:
ER and COX2 expression in endometrial hyperplasia processes
Authors: Tsyndrenko Nataliia , Lyndіn Mykola , Sikora Kateryna , Wireko Andrew Awuah , Abdul-Rahman Toufik , Hyriavenko Nataliia , Romaniuk Anatolii
Published: August 2023

Endometrial hyperplastic processes (EHPs) encompass various morphological changes, characterized by an increased ratio of endometrial glands to stroma. These changes manifest as endometrial hyperplasia (EH) and endometrial polyps. The objective of this study was to investigate the expressions of ER and Cyclooxygenase-2 (COX2) in EH and endometrial polyps, and determine their correlation with histological and anthropometric parameters. Tissue samples were obtained during hysteroresectoscopy and divided into 3 groups: non-atypical EH, glandular EP, and glandular-fibrous EP. We examined the immunoprofile of epithelial and stromal cells using rabbit polyclonal anti-COX2 antibodies and rabbit monoclonal anti-ER antibodies (clone SP1). Our results indicate that there is no association between the expressions of ER and COX2 and the type of EHP. Furthermore, the expression levels of ER and COX2 are not influenced by the patients anthropometric parameters. However, tissues with EHPs exhibited significantly higher COX2 expression compared to intact tissues. We also observed a direct correlation between ER and COX2 expression in the endometrial epithelium. The variability in ER and COX2 expressions observed in hyperplastic processes of the endometrium potentially suggests their synergistic involvement in the initiation and progression of EHPs, as well as their potential role in subsequent tumor transformation.
Novel-fosfamide monotherapy or in combination with doxorubicin versus doxorubicin alone in patients with advanced soft tissue sarcoma: A pooled analysis of randomized clinical trials
Authors: Liu Xin-Xiu , Han Yan-Hong , Kuang Bo-Hua , Lin Guo-He , Wang Bi-Cheng
Published: August 2023

Background:

Novel-fosfamides (NFOs) belong to active metabolites of ifosfamide that bypass the generation of toxic byproducts. In this analysis, we aimed to comprehensively assess the benefits and risks of NFO monotherapy or in combination with doxorubicin (DOX) versus single-drug DOX in previously untreated patients with advanced soft-tissue sarcoma (ASTS).

Methods:

Online PubMed, Web of Science, Embase, and Cochrane CENTRAL databases were systematically searched on April 26, 2022. Objective response rate and disease control rate were primary outcomes. Overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events were secondary outcomes.

Results:

In all, 3 randomized clinical trials with a total of 1207 ASTS patients were eligible. DOX plus NFO combination therapy showed higher risk ratios of objective response rate (1.50, 95% CI 1.20–1.68, P = .0003) and disease control rate (1.15, 95% CI 1.05–1.27, P = .0030) compared with DOX monotherapy. Nevertheless, NFO-based monotherapy and combination therapy were found no improvements on OS (hazard ratio 0.93, 95% CI 0.52–1.65, P = .8050) and PFS (hazard ratio 0.88, 95% CI 0.54–1.43, P = .6088) against DOX. More incidences of grade 3 or worse anemia, thrombocytopenia, stomatitis, diarrhea, constipation, and febrile neutropenia were observed in NFO-based treatments.

Conclusion:

Adding NFO to DOX as first-line therapy improved the responses in ASTS patients but did not prolong OS and PFS. Grade 3 or worse treatment-related adverse events should be treated with caution during the NFO-based therapies.
Systematic reviews and meta-analyses on androgen administration in humans: an umbrella review
Authors: Chegeni Razieh , Pallesen Ståle , Weldemariam Hailemariam , Sagoe Dominic
Published: August 2023

Purpose of review

The present umbrella review systematically searches and synthesizes recent (2021–2023) systematic reviews and meta-analyses (SRMA) on androgen administration in humans.

Recent findings

Results from 19 SRMA are synthesized. Four themes were identified: market for androgens, prevalence of androgen abuse, psychological effects of androgens, and clinical/therapeutic effects of androgens. One of three androgens on the illicit market are fake or substandard. Whereas one of three androgen users experiences dependence and various serious disorders, only one of three androgen users seeks physician support. Additionally, androgen administration increases self-reported aggression in healthy male individuals, and abuse positively correlates with interpersonal violence. Furthermore, androgen therapy is beneficial in treating persons suffering from various chronic diseases.

In this umbrella review, we identified 19 SRMA on androgen use and abuse. Results show a high prevalence of fake androgens on the illicit market, a high prevalence of androgen abuse and dependence, and that a huge proportion of androgen users tend to avoid seeking support from clinicians. Also, androgen administration increases self-reported aggression among healthy male, and there is a positive correlation between androgen abuse and violent behavior. Finally, androgens have multiple therapeutic effects on various pathology.
Optimal combination therapy for metastatic hormone-sensitive prostate cancer: new evidence, challenges and unanswered questions
Authors: Zattoni Fabio , Rajwa Pawel , Gandaglia Giorgio
Published: August 2023

Purpose of review

To evaluate the evidence supporting treatment intensification in mHSPC, with a focus on possible indications for treatment in each clinical setting.

Recent findings

There is a growing armamentarium of treatment options for patients with metastatic hormone-sensitive prostate cancer (mHSPC). These include combinations of treatments such as androgen deprivation therapy (ADT), docetaxel, and new antiandrogenic therapies. Treatment intensification with chemotherapy or newer hormonal agents may improve patient's oncologic outcomes, but it can also come with additional toxicities and costs. Therefore, we need to take into account individual patient factors and preferences when deciding on the optimal combination therapy. Additionally, ongoing research is needed to identify biomarkers and new image techniques that can predict response to treatment and identify the best candidate for each treatment.

Challenges and unanswered questions regarding treatment intensification and de-intensification are still present. Further studies are still needed to identify which patients would benefit most from this approach to improve quality of life without compromising overall survival outcomes.
Effectiveness of Training: Airway Management of Tracheostomized Pediatric Patients by Pediatric Residents and Anesthesiology Residents
Authors: Duymaz Yasar Kemal , Bayram Furkan , Şahin Şamil , Erkmen Burak , Uzar Tuğçe , Önder Serap , Şahin Yilmaz Ayse A. , Tekin Ahmet M. , Bahşi İlhan
Published: August 2023

To evaluate the effect of training on increasing baseline knowledge of pediatrics and anesthesia residents about airway management of pediatric patients with tracheostomy. It is a prospective, descriptive, before and after survey study. A questionnaire was conducted to measure the baseline knowledge of pediatrics and anesthesia residents about airway management in patients with pediatric tracheotomy. The same questionnaire was repeated after the education. Of the 63 participants, 42 were pediatric residents and 21 were anesthesiology residents. While the number of participants who answered the cuff part, inner cannula part, obturator part and balloon part of the tracheostomy tube correctly before the training was 27, 4, 10, and 12, respectively, these numbers increased to 53, 52, 57, and 55 after the training. There was a statistically significant improvement after the training in the correct response of the cuff, inner cannula, obturator, and balloon sections. A statistically significant improvement was observed in the answers received after the training for all 7 questions regarding the clinical scenario of accidental decannulation and tracheostomy bleeding compared to the pre-training. There was a statistical improvement in part where the participants rated themselves. In conclusion, training increases the ability of healthcare professionals to cope with life-threatening complications related to pediatric tracheotomy. A standardized education program on pediatric tracheostomy should be included in the routine programs of associated departments such as emergency medicine, anesthesia, and pediatrics residencies.
Mineralocorticoid receptor antagonists in cardiovascular translational biology
Authors: Chilton Robert J. , Silva-Cardoso José
Published: August 2023

This review examines the role of mineralocorticoid receptor antagonists (MRAs) in cardiovascular biology and the molecular mechanisms involved in mineralocorticoid receptor antagonism. The data discussed suggest that MRAs can play an important role in decreasing the impact of inflammation and fibrosis on cardiorenal outcomes. Evidence derived from major randomized clinical trials demonstrates that steroidal MRAs reduce mortality in patients with heart failure and reduced ejection fraction. Initial positive findings observed in patients with chronic kidney disease and type 2 diabetes (T2D) indicate the possible mechanisms of action of nonsteroidal MRAs, and the clinical benefits for patients with cardiorenal disease and T2D. This article supports the application of basic science concepts to expand our understanding of the molecular mechanisms of action involved in pathophysiology. This approach encourages the development of treatment options before diseases clinically manifest.

Video Abstract: http://links.lww.com/CAEN/A42
Long-read sequencing resolves a complex structural variant inPRKNParkinson’s disease
Authors: Daida Kensuke , Funayama Manabu , Billingsley Kimberley J , Malik Laksh , Miano-Burkhardt Abigail , Leonard Hampton L. , Makarious Mary B. , Iwaki Hirotaka , Ding Jinhui , Gibbs J. Raphael , Ishiguro Mayu , Yoshino Hiroyo , Ogaki Kotaro , Oyama Genko , Nishioka Kenya , Nonaka Risa , Akamatsu Wado , Blauwendraat Cornelis , Hattori Nobutaka
Published: August 2023

Background

PRKNmutations are the most common cause of young onset and autosomal recessive Parkinson’s disease (PD).PRKNis located in FRA6E which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions ofPRKNare seldom reported, suggesting that there are potentially unrevealed complex pathogenicPRKNstructural variants.

Objectives

To identify complex structural variants inPRKNusing long-read sequencing.

Methods

We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read. We assessed the presence and frequency of complex inversions overlappingPRKNusing whole-genome sequencing data of AMP-PD and UK-Biobank datasets.

Results

Multiple ligation probe amplification identified a heterozygous exon 3 deletion inPRKNand long-read sequencing identified a large novel inversion spanning over 7Mb, including a large part of the coding DNA sequence ofPRKN. We could diagnose the affected subjects as compound heterozygous carriers ofPRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4,941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affectPRKNisoforms.

Conclusions

This is the first report describing a large 7Mb inversion involving breakpoints outside ofPRKN. This study highlights the importance of using long-read whole genome sequencing for structural variant analysis in unresolved young-onset PD cases.
Changes in an Enzyme Ensemble During Catalysis Observed by High Resolution XFEL Crystallography
Authors: Smith Nathan , Dasgupta Medhanjali , Wych David C. , Dolamore Cole , Sierra Raymond G. , Lisova Stella , Marchany-Rivera Darya , Cohen Aina E. , Boutet Sébastien , Hunter Mark S. , Kupitz Christopher , Poitevin Frédéric , Moss Frank R. , Brewster Aaron S. , Sauter Nicholas K. , Young Iris D. , Wolff Alexander M. , Tiwari Virendra K. , Kumar Nivesh , Berkowitz David B. , Hadt Ryan G. , Thompson Michael C. , Follmer Alec H. , Wall Michael E. , Wilson Mark A.
Published: August 2023

Enzymes populate ensembles of structures with intrinsically different catalytic proficiencies that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL) to observe catalysis in a designed mutant (G150T) isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations and formation of the thioimidate catalytic intermediate selects for catalytically competent substates. A prior proposal for active site cysteine charge-coupled conformational changes in ICH is validated by determining structures of the enzyme over a range of pH values. A combination of large molecular dynamics simulations of the enzyme in crystallo and time-resolved electron density maps shows that ionization of the general acid Asp17 during catalysis causes additional conformational changes that propagate across the dimer interface, connecting the two active sites. These ionization-linked changes in the ICH conformational ensemble permit water to enter the active site in a location that is poised for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.
Predicting risk of Alzheimer’s disease using polygenic risk scores developed for Parkinson’s disease
Authors: Graham Britney E. , Williams Scott M. , Moore Jason H.
Published: August 2023

Background and Objectives

The two most common neurodegenerative diseases are Alzheimer’s disease (AD) and Parkinson’s disease (PD), both related to age and affect millions of people across the world, especially as life expectancy increases in certain countries. Here, we explore the potential predictiveness of the genetic risk of AD and PD separately and then the extent of the underlying shared genetics of AD and PD.

Methods

The population genetic risk estimates for AD and PD were derived using a previously developed population specific polygenic risk score (psPRS) and regression-based SNP filtering method. To test the overlap between AD and PD, we ran a regression of the AD psPRSs versus the population PD prevalences for both the filtered and unfiltered AD PRS and vice versa. We then assessed gene-gene interaction and pathway involvement using the Alzheimer’s KnowledgeBase (AlzKB) and STRINGdb, respectively.

Results

The unfiltered PD psPRS was moderately predictive, while the AD psPRS was not. After filtering, both the AD and PD, psPRSs improved to strongly predictive, explained most of the genetic variation. The ability of the unfiltered AD psPRS to predict PD, and vice versa, is poor. However, the filtered AD, and PD, psPRS were highly predictive.

Discussion

Our results suggest that there is a correlation between AD, and PD, specific allele frequency and prevalence, as well as an overlap of AD and PD generally. However, the AD psPRS is a better predictor of PD, than the PD psPRS is of AD. Our results call for further research into the general overlap of Alzheimer’s disease and Parkinson’s disease, despite the previous lack of evidence.
Unraveling COVID-19: Descriptive Analytics in a Middle-Income Country, Paving the Path Forward
Authors: Bansilan Norvin P. , Rabajante Jomar F.
Published: August 2023

The outbreak of COVID-19 unleashed an unprecedented global pandemic, leaving a profound impact on lives and economies worldwide. Recognizing its severity, the World Health Organization swiftly declared it a public health emergency of international concern. Tragically, the Philippines reported the first death case outside China, leading to a surge in cases following the first instance of local transmission. In response to this crisis, collaborative efforts have been underway to control the disease and minimize its health and socio-economic impacts. The COVID-19 epidemic curve holds vital insights into the history of exposure, transmission, testing, tracing, social distancing measures, community lockdowns, quarantine, isolation, and treatment, offering a comprehensive perspective on the nation’s response. One approach to gaining crucial insights is through meticulous analysis of available datasets, empowering us to inform future strategies and responses effectively. This paper aims to provide descriptive data analytics of the COVID-19 pandemic in the Philippines, summarizing the country’s fight by visualizing epidemiological and mobility datasets, revisiting scientific papers and news articles, and creating a timeline of the key issues faced during the pandemic. By leveraging these multifaceted analyses, policymakers and health authorities can make informed decisions to enhance preparedness, expand inter-agency cooperation, and combat future public health crises effectively. This study seeks to serve as a valuable resource, guiding nations worldwide in comprehending and responding to the challenges posed by COVID-19 and beyond.
Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the likely disruption ofFOXA2
Authors: Laver Thomas W , Wakeling Matthew N , Caswell Richard C , Bunce Benjamin , Yau Daphne , Houghton Jayne AL , Hopkins Jasmin J. , Weedon Michael N , Saraff Vrinda , Kershaw Melanie , Honey Engela M , Murphy Nuala , Giri Dinesh , Nath Stuart , Saredo Ana Tangari , Banerjee Indraneel , Hussain Khalid , Owens Nick DL , Flanagan Sarah E
Published: August 2023

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene,FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent toFOXA2that encompasses multiple non-coding regulatory elements that are in conformational contact withFOXA2. Our data suggests that the deletions in these three patients may cause disease through the dysregulation ofFOXA2expression. These findings provide new insights into the regulation ofFOXA2in the beta-cell and confirm an aetiological role for chromosome 20p deletions in syndromic HI.
Trending Drugs Combination to Target Leukemia associated Proteins/Genes: using Graph Neural Networks under the RAIN Protocol
Authors: Boush Mahnaz , Kiaei Ali A. , Mahboubi Hossein
Published: August 2023

Background

Leukemia, a cancer impacting blood-forming tissues such as bone marrow and the lymphatic system, presents in various forms, affecting children and adults differently. The therapeutic approach is complex and depends on the specific leukemia type. Effective management is crucial as it disrupts normal blood cell production, increasing infection susceptibility. Treatments like chemotherapy can further weaken immunity. Thus, a patient’s healthcare plan should focus on comfort, reducing chemotherapy side effects, protecting veins, addressing complications, and offering educational and emotional support.

Method

This article reviews studies on the combined use of drugs for treating leukemia. Employing a mix of medicines might decrease the chances of tumor resistance. Starting multiple drugs concurrently allows for immediate application during disease onset, avoiding delays. Initial chemotherapy uses a drug combination to eliminate maximum leukemia cells and restore normal blood counts. Afterwards, intensification chemotherapy targets any residual, undetectable leukemia cells in the blood or bone marrow. To recommend a drug combination to treat/manage Leukemia, under first step of RAIN protocol, we have searched articles including related trend drugs using Natural Language Processing. In the second step, we have employed Graph Neural Network to pass information between these trending drugs and genes that act as potential targets for Leukemia.

Result

As a result, the Graph Neural network recommends combining Tretinoin, Asparaginase, and Cytarabine. The network meta-analysis confirmed the effectiveness of these drugs on associated genes.

Conclusion

The p-value between leukemia and the scenario that includes combinations of the mentioned drugs is almost zero, indicating an improvement in leukemia treatment. Reviews of clinical trials on these medications support this claim.

Highlights

Combined drugs that make p-value between Leukemia and target proteins/genes close to 1

Using Graph Neural network to recommend drug combination

A Network meta-analysis to measure the comparative efficacy

Considered drug interactions
Kinesiophobia and physical activity: A systematic review and meta-analysis
Authors: Goubran Miriam , Farajzadeh Ata , Lahart Ian M. , Bilodeau Martin , Boisgontier Matthieu P.
Published: August 2023

Objective

Physical activity contributes to the primary, secondary, and tertiary prevention of multiple diseases. However, in some patients, an excessive, irrational, and debilitating fear of movement (i.e., kinesiophobia) is thought to induce avoidance behaviors, contributing to decreased engagement in physical activity. The aim of this study was to examine whether kinesiophobia is negatively associated with physical activity in several health conditions and what factors may influence this relationship.

Methods

Five databases were searched for studies including both a measure of kinesiophobia and physical activity. Two reviewers screened articles for inclusion, assessed risk of bias, and extracted data from each study. Pearson product-moment correlations were pooled from eligible studies using the generic inverse pooling and random effects method to examine the relationship between kinesiophobia and physical activity.

Results

Seventy-four studies were included in the systematic review and 63 studies (83 estimates, 12,278 participants) in the main meta-analysis. Results showed a small-to-moderate negative correlation between kinesiophobia and physical activity (r = −0.19; 95% confidence interval: −0.26 to −0.13; I2= 85.5%; p < 0.0001). Funnel plot analysis showed evidence of publication bias, but p-curve analysis suggested that our results could not be caused by selective reporting. A subgroup meta-analysis showed that the correlation was statistically significant in patients with cardiac, rheumatologic, neurologic, or pulmonary conditions, but not in patients with chronic or acute pain.

Conclusion

Our results suggest that higher levels of kinesiophobia are associated with lower levels of physical activity in several health conditions that are not necessarily painful.

Impact

Kinesiophobia should be dissociated from pain and considered in relation to specific health conditions when implementing exercise therapy. Kinesiophobia may have prognostic implications in patients for whom physical activity contributes to prevent recurrence or worsening of their condition.
Antimicrobial activity of NK cells toTrypanosoma cruziinfected human primary Keratinocytes
Authors: Kroh Keshia , Barton Jessica , Fehling Helena , Lotter Hanna , Volkmer Beate , Greinert Rüdiger , Mhamdi-Ghodbani Mouna , Vanegas Andrea , Jacobs Thomas , Gálvez Rosa Isela
Published: August 2023

Infection with the protozoan parasiteTrypanosoma cruziis causative for Chagas disease, which is a highly neglected tropical disease prevalent in Latin America. Humans are primary infected through vectorial transmission by blood-sucking triatomine bugs. The parasite enters the human host through mucous membranes or small skin lesions. Since keratinocytes are the predominant cell type in the epidermis, they play a critical role in detecting disruptions in homeostasis and aiding in pathogen elimination by the immune system in the human skin as alternative antigen-presenting cells. Interestingly, keratinocytes also act as a reservoir forT. cruzi, as the skin has been identified as a major site of persistent infection in mice with chronic Chagas disease. Moreover, there are reports of the emergence ofT. cruziamastigote nests in the skin of immunocompromised individuals who are experiencing reactivation of Chagas disease. This observation implies that the skin may serve as a site for persistent parasite presence during chronic human infection too and underscores the significance of investigating the interactions betweenT. cruziand skin cells. Consequently, the primary objective of this study was to establish and characterize the infection kinetics in human primary epidermal keratinocytes (hPEK). Our investigation focused on surface molecules that either facilitated or hindered the activation of natural killer (NK) cells, which play a crucial role in controlling the infection. To simulate thein vivosituation in humans, an autologous co-culture model was developed to examine the interactions betweenT. cruziinfected keratinocytes and NK cells. We evaluated the degranulation, cytokine production, and cytotoxicity of NK cells in response to the infected keratinocytes. We observed a strong activation of NK cells by infected keratinocytes, despite minimal alterations in the expression of activating or inhibitory ligands on NK cell receptors. However, stimulation with recombinant interferon-gamma (IFN-γ), a cytokine known to be present in significant quantities during chronicT. cruziinfections in the host, resulted in a substantial upregulation of these ligands on primary keratinocytes. Overall, our findings suggest the crucial role of NK cells in controlling acuteT. cruziinfection in the upper layer of the skin and shed light on keratinocytes as potential initial targets of infection.
Glucose intolerance induces anxiety-like behaviors independent of obesity and insulin resistance in a novel model of nutritional metabolic stress
Authors: Al-Onaizi Mohammed , Braysh Kawthar , Alkefeef Selma , Altarrah Dana , Dannoon Shorouk , Alasousi Dalal , Adel Hawraa , Al-Ajmi Mariam , Kandari Anwar , Najem Rawan , Nizam Rasheeba , Williams Michayla R , John Sumi , Thanaraj Thangavel Alphonse , Ahmad Rasheed , Al-Hussaini Heba , Al-Mulla Fahd , Alzaid Fawaz
Published: August 2023

Type 2 diabetes (T2D) and its comorbidities are a major public health concern. In addition to peripheral tissues, T2D also impacts the central nervous system leading to neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we used a novel proprietary high-fat diet, in which glucose intolerance precedes weight gain, to decipher the metabolic determinants of neurocognitive affects. We show that this model exhibits anxiety-like behaviors, without eliciting depression nor recognition memory deficits. Long-term feeding leads to weight gain, brain glucose hypometabolism and impaired recognition memory alongside the early onset anxiety-like behavior. Using an established genetic model of T2D (db/db) and of diet-induced obesity we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. Our findings indicate that glucose intolerance alone can elicit anxiety-like behaviors. Through this study we also provide a novel nutritional model to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.
LPATH: A semi-automated Python tool for clustering molecular pathways
Authors: Bogetti Anthony T. , Leung Jeremy M. G. , Chong Lillian T.
Published: August 2023

The pathways by which a molecular process transitions to a target state are highly sought-after as direct views of a transition mechanism. While great strides have been made in the physics-based simulation of such pathways, the analysis of these pathways can be a major challenge due to their diversity and variable lengths. Here we present the LPATH Python tool, which implements a semi-automated method for linguistics-assisted clustering of pathways into distinct classes (or routes). This method involves three steps: 1) discretizing the configurational space into key states, 2) extracting a text-string sequence of key visited states for each pathway, and 3) pairwise matching of pathways based on a text-string similarity score. To circumvent the prohibitive memory requirements of the first step, we have implemented a general two-stage method for clustering conformational states that exploits machine learning. LPATH is primarily designed for use with the WESTPA software for weighted ensemble simulations; however, the tool can also be applied to conventional simulations. As demonstrated for the C7eqto C7axconformational transition of alanine dipeptide, LPATH provides physically reasonable classes of pathways and corresponding probabilities.

TOC Graphic
Effectiveness and residual activity of four common insecticides used in the Mississippi Delta to control tarnished plant bugs in cotton
Authors: Portilla Maribel , Little Nathan S. , Allen Clint , Zhu Yu Cheng
Published: August 2023

The tarnished plant bug, (TPB)Lygus lineolarisPalisot de Beauvois (Hemiptera: Miridae) is a key pest of cotton in the midsouth region and some areas of the eastern United States. Its control methods have been solely based on chemical insecticides which has contributed to insecticidal resistance and shortened residual periods for control of this insect pest. This study was conducted over a two-year period and examined the efficacy and residual effect of four commercial insecticides including lambda-cyhalothrin (pyrethroid), acephate (organophosphate), imidacloprid (neonicotinoid), and sulfoxaflor (sulfoxamine). The effectiveness and residual effects of these insecticides were determined by application on cotton field plots on four different dates during each season using three different concentrations (high: highest labeled commercial dose (CD), medium: 1/10 of the CD, low: 1/100 of the CD) on field cotton plots. Four groups of cotton leaves were randomly pulled from each treated plot and control 0-, 2-, 4-, 7-, and 9-days post treatment (DPT) and exposed to a lab colony of TPB adults. One extra leaf sample/ plot/ spray /DPT interval (0-2-4-7-9-11) during 2016 was randomly collected from the high concentration plots and sent to Mississippi State Chemical Laboratory for residual analysis. Mortality of TPB adults was greatest for those placed on leaves sprayed with the organophosphate insecticide with mortalities (%) of 81.7±23.4 and 63.3±28.8 (SE) 1-day after exposure (DAE) on leaves 0-DPT with the high concentration for 2016 and 2017, respectively, reaching 94.5±9.5 and 95.4±7.6 6-DAE each year. Mortality to all insecticides continued until 9 and 4-DPT for high and medium concentrations, respectively. However, organophosphate (39.4±28.6) and pyrethroid (24.4±9.9) exhibited higher mortality than sulfoxamine (10.6±6.6) and the neonicotinoid (4.0±1.5) 7-DAE on 9-DPT leaves with the high concentration. Based on our results using the current assay procedure, TPB adults were significantly more susceptible to contact than systemic insecticides and due to its residual effect, organophosphate could kill over 80% of the TPB population 7-DPT.
Revealing Complex Functional Topology Brain Network Correspondences Between Humans and Marmosets
Authors: Li Qiang , Calhoun Vince D. , Iraji Armin
Published: August 2023

Functional correspondences are known to exist within the brains of both human and non-human primates; however, our understanding of this phenomenon remains largely incomplete. The examination of the topological characteristics inherent in whole-brain functional connectivity bears immense promise in elucidating shared as well as distinctive patterns across different species. In this investigation, we applied topological graph analysis to brain networks and scrutinized the congruencies and disparities within the connectomes of human and marmoset monkey brains. The findings brought to light noteworthy similarities in functional connectivity patterns distributed across the entire brain, with a particular emphasis on the dorsal attention network, default mode network and visual network. Moreover, we discerned unique neural connections between humans and marmosets during both resting and task-oriented states. In essence, our study reveals a combination of shared and divergent functional brain connections underlying spontaneous and specific cognitive functions across these two species.
The role of neutrophil typing in homeostatic resilience protective model of inflammatory preconditioning
Authors: Li Liyuan , Zhang Xinfang , Yu Hongmei , Yan Chao , Sun Jicheng , Qi Yan , Gou Yawei , Zhang Mingming , Wang Shengnan , Li Haokun , Nie Wenying , Wang Renhao , Jiang Jiashan , Gao Feng , Li Xinyu , Shi Qinghong , Song Lina , Wang Fang , Xu Xuesong , Sun Wei
Published: August 2023

Sepsis is a systemic inflammatory response syndrome (SIRS) characterized by a dysregulated host response to infection that results in organ dysfunction. The response of neutrophils to early inflammation is critical, interferon regulatory factors 4 (IRF4) and interferon regulatory factors 5 (IRF5) are expressed in most cell types of the immune system, but the relationship between the role of IRF4 and IRF5 in preconditioning-protected septic peritonitis mouse model and neutrophils response remains unknown. In this study, we used anE.coli-induced septic peritonitis mouse model and zebrafish model to explore the relationship between neutrophil inflammation and IRF subtype changes in the process of septic peritonitis. Mechanistically, we found that the protein complex formed by polymorphonuclear neutrophils (PMN) and IRF5/MyD88 can secrete pro-inflammatory factors and directly kill invading bacteria.

Author Summary

Numerous animal and clinical sepsis studies have shown that markedly impaired recruitment of neutrophils to sites of infection and failure to clear bacteria contribute to excessive inflammation and increased mortality in sepsis. In our previous work, we established anEscherichia coli(E.coli) lethal septic peritonitis model and a preconditioning-protected septic peritonitis mouse model. In the early stage of septic peritonitis, a large number of PMN infiltrate the peritoneal cavity, which produces an inflammatory response to invasive bacteria. In this study, the switching process between pro-inflammatory and anti-inflammatory attracted our attention. Our research shows that IRF5-IRF4 regulatory axis leads to a PMN phenotype switch in sepsis and the expression of IRF5 and IRF4 was related to PMN pro-inflammatory (N1 type) and anti-inflammatory (N2 type) phenotypes, respectively.
Comparing Continuous versus Intermittent-Threshold Drainage Strategies for Spinal Perfusion Pressure Optimization in Patients with Acute Traumatic Spinal Cord Injuries
Authors: Lavadi Raj Swaroop , Shanahan Regan , Hamilton David Kojo , Buell Thomas James , Agarwal Nitin , Puccio Ava , Okonkwo David Okwudi , Fields Daryl Pinion
Published: August 2023

Study Design

A cross-sectional study.

Objective

The primary objective of this study is to compare the efficacy of continuous versus threshold drainage strategies for maintaining spinal cord perfusion pressure (SCPP) in patients with new traumatic spinal cord injuries (SCI).

Setting

Level 1 trauma center.

Methods

A retrospective study of 19 patients with traumatic SCIs. SCPP was optimized at the discretion of the managing clinician using either vasopressors to increase mean arterial pressure or cerebral spinal fluid (CSF) drainage to decrease intrathecal pressure. Six patients were managed with continuous drainage (CSF drained at regular intervals regardless of SCPP) and 13 had CSF drained only when SCPP fell below 65mmHg (i.e. threshold drainage). Intrathecal pressure, SCPP, mean arterial pressure, and vasopressor utilization were compared using univariate T-test statistical analysis.

Results

The cohort included over 1500 time points from 19 patients. While there was no difference in rates of sub-optimal SCPP (< 65mmHg; p = 0.257), patients managed with threshold drainage were more likely to exhibit critically-low SCPP (< 50 mmHg; p = 0.003) despite also having lower average intrathecal pressures (p < 0.001). There were no differences in average SCPP, MAP, or vasopressor utilization between the two groups (p > 0.05).

Conclusions

Acute SCI patients managed with continuous CSF drainage were less likely to exhibit critically-low SCPPs, previously shown to be associated with worse clinical recovery. A larger, prospective cohort is needed to validate the impact of CSF drainage strategies on long-term SCI outcomes.
Emergence of neutralizing antibodies associates with clearance of SARS-CoV-2 during HIV-mediated immunosuppression
Authors: Karim Farina , Bernstein Mallory , Jule Zesuliwe , Lustig Gila , Upton Janine-Lee , Ganga Yashica , Khan Khadija , Reedoy Kajal , Mazibuko Matilda , Govender Katya , Thambu Kershnee , Ngcobo Nokuthula , Venter Elizabeth , Makhado Zanele , Hanekom Willem , von Gottberg Anne , Karim Quarraisha Abdool , Abdool Karim Salim S. , Manickchund Nithendra , Magula Nombulelo , Gosnell Bernadett I. , Moore Penny L. , Lessells Richard J. , de Oliveira Tulio , Moosa Mahomed-Yunus S. , Sigal Alex
Published: August 2023

To design effective vaccines and other immune interventions against a pathogen, it is necessary to know which aspect of immunity associates with protection. We investigated whether neutralizing antibodies associate with infection clearance in long-term SARS-CoV-2 infection during HIV-mediated immunosuppression. We monitored neutralizing antibody activity against SARS-CoV-2 over 1 to 2 years in five participants with advanced HIV disease and delayed control of HIV viremia. These participants had persistent SARS-CoV-2 infection ranging from 110 to 289 days which was associated with low or undetectable neutralizing antibody responses. SARS-CoV-2 clearance was associated with the emergence of neutralizing antibodies and occurred in two participants before suppression of HIV viremia, but after some CD4 T cell reconstitution. Vaccination only further increased neutralizing antibody levels in the advanced HIV disease participants who achieved HIV suppression pre-vaccination. During the prolonged SARS-CoV-2 infection we observed widespread evolution which was particularly pronounced in one Delta variant infection. This resulted in high-level escape from Delta-elicited neutralizing antibodies and a virus antigenically distinct from both ancestral SARS-CoV-2 and Omicron XBB in hamster experimental infections. The results offer new evidence that neutralizing antibodies associate with SARS-CoV-2 clearance and argue that successful management of HIV may be necessary to curtail long-term infection and evolution of co-infecting pathogens.
Assessing ChatGPT’s Mastery of Bloom’s Taxonomy using psychosomatic medicine exam questions
Authors: Herrmann-Werner Anne , Festl-Wietek Teresa , Holderried Friederike , Herschbach Lea , Griewatz Jan , Masters Ken , Zipfel Stephan , Mahling Moritz
Published: August 2023

Introduction

Large language models (LLMs) such as GPT-4 are increasingly used in medicine and medical education. However, these models are prone to “hallucinations” – outputs that sound convincing while being factually incorrect. It is currently unknown how these errors by LLMs relate to the different cognitive levels defined in Bloom’s Taxonomy.

Methods

We used a large dataset of psychosomatic medicine multiple-choice questions (MCQ) (N = 307) with real-world results derived from medical school exams. GPT-4 answered the MCQs using two distinct prompt versions – detailed and short. The answers were analysed using a quantitative and qualitative approach. We focussed on incorrectly answered questions, categorizing reasoning errors according to Bloom’s Taxonomy.

Results

GPT-4’s performance in answering exam questions yielded a high success rate: 93% (284/307) for the detailed prompt and 91% (278/307) for the short prompt. Questions answered correctly by GPT-4 had a statistically significant higher difficulty compared to questions that GPT-4 answered incorrectly (p=0.002 for the detailed prompt and p<0.001 for the short prompt). Independent of the prompt, GPT-4’s lowest exam performance was 78.9%, always surpassing the pass threshold. Our qualitative analysis of incorrect answers, based on Bloom’s Taxonomy, showed errors mainly in the “remember” (29/68) and “understand” (23/68) cognitive levels. Specific issues arose in recalling details, understanding conceptual relationships, and adhering to standardized guidelines.

Discussion

GPT-4 displayed a remarkable success rate when confronted with psychosomatic medicine multiple-choice exam questions, aligning with previous findings. When evaluated against Bloom’s hierarchical framework, our data revealed that GPT-4 occasionally ignored specific facts (“remember”), provided illogical reasoning (“understand”), or failed to apply concepts to a new situation (“apply”). These errors, though confidently presented, could be attributed to inherent model biases and the tendency to generate outputs that maximize likelihood.

Conclusion

While GPT-4 mostly excels at medical exam questions, discerning its occasional cognitive errors is crucial.
Durability for 12 months of antibody response to a booster dose of monovalent BNT162b2 in adults who had initially received 2 doses of inactivated vaccine
Authors: Shiu Eunice Y. C. , Cheng Samuel M. S. , Martín-Sánchez Mario , Au Niki Y. M. , Chan Karl C. K. , Li John K. C. , Fung Lison W. C. , Luk Leo L. H. , Chaothai Sara , Kwan Tsz Chun , Ip Dennis K. M. , Leung Gabriel M. , Poon Leo L. M. , Peiris J. S. Malik , Leung Nancy H. L. , Cowling Benjamin J.
Published: August 2023

We administered BNT162b2 as a third dose to 314 adults ≥30 years of age who had previously received 2 doses of inactivated vaccine. We collected blood samples before the third dose and again after 1, 6 and 12 months, and found stable levels of antibody responses to the ancestral strain and Omicron BA.2 at 6-12 months after receipt of the BNT162b2 third dose, with increased antibody levels in individuals who also received a fourth vaccine dose or reported a SARS-CoV-2 infection during follow-up.
EXPRESSION OF VARIABILITY OF THE CYP2C19*2 GENE IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION FROM A SOUTH AMERICAN HOSPITAL AND ITS FUTURE RELEVANCE IN THE INTERACTION BETWEEN GENETICS AND CARDIOLOGY
Authors: Dulcey Sarmiento Luis Andres , Theran Leon Juan Sebastián , Gomez Jaime , Parales Strauch Rafael Guillermo , Caltagirone Raimondo , Blanco Pimiento Edgar Camilo , Ciliberti Artavia María Paula , Martinez Juan Camilo , Peña Valentina Cabrera , Amaya Maria Camila
Published: August 2023

Introduction

Some Polymorphisms of the CYP2C19 gene are associated with a decrease in the activity of the enzyme they encode, being the case of CYP2C19*2 in causing a lower generation of active metabolite of clopidogrel and therefore a low or null antiplatelet action depending on the genotype present. Antiplatelet therapy, mainly clopidogrel, is considered essential treatment in the management of acute coronary syndromes (ACS).

Target

The frequency of the CYPC19*2 polymorphism, identified as relevant in resistance to clopidogrel, is unknown in the population of this part of South America.

Methods

A descriptive, observational and cross-sectional study was designed to determine the frequency of the CYP2C19*2 allele in patients with ACS admitted to a South American hospital during the period between 2015-2016, being the first study to determine polymorphism in our population. fifty-nine adults patients diagnosed with ACS were included, 48 male (81.3%) and 11 female (18.7%), aged between 54 and 86 years. The genotype for the CYP2C19 gene was determined through the PCRRFLP (Restriction Fragments Length Polymorphism) technique from DNA extracted desde peripheral blood .

Results

The allelic frequency of the CYP2C19*2 polymorphism was 28.5%. Three subgroups of metabolizers were characterized : extensive (*1/*1) 40 (67.8%), intermediate (*1/*2) 17 (28.9%) and poor (*2/*2) 2 (3.3%).

Conclusions

This high number of carriers of the CYP2C19*2 polymorphism in the context of ACS is relevant due to its association with a lower responsiveness to clopidogrel and the possible involvement in the choice of antiplatelet therapy, for which characterization studies are required most appropriate to identify the best therapeutic strategies in our populations through pharmacogenomics.
Predicting the risk of diabetes complications using machine learning and social administrative data in a country with ethnic inequities in health: Aotearoa New Zealand
Authors: Nghiem Nhung , Wilson Nick , Krebs Jeremy , Tran Truyen
Published: August 2023

Background

In the age of big data, linked social and administrative health data in combination with machine learning (ML) is being increasingly used to improve prediction in cardiovascular diseases (CVD). We aimed to apply ML methods on extensive national-level health and social administrative datasets to predict future diabetes complications by ethnicity.

Methods

Five ML models were used to predict CVD events among all people with known diabetes in the population of New Zealand, utilizing national-level administrative data at the individual level.

Results

The Xgboost ML model had the best predictive power for predicting CVD events three years into the future among the population with diabetes. The optimization procedure also found limited improvement in AUC by ethnicity. The results indicated no trade-off between model predictive performance and equity gap of prediction by ethnicity. The list of variables of importance was different among different models/ethnic groups, for examples: age, deprivation, having had a hospitalization event, and the number of years living with diabetes.

Discussion and conclusions

We provide further evidence that ML with administrative health data can be used for meaningful future prediction of health outcomes. As such it could be utilized to inform health planning and healthcare resource allocation for diabetes management and the prevention of CVD events. Our results may suggest limited scope for developing prediction models by ethnic group and that the major ways to reduce inequitable health outcomes is probably via improved delivery of prevention and management to those groups with diabetes at highest need.
Real time quantification reveals novel dynamic processes in pancreatic lumenal network establishment and remodeling
Authors: Jackson Abigail Laura , Heilmann Silja , Ebeid Christine , Krivokapic Jelena Miskovic , Romero Herrera Jose Alejandro , Semb Henrik , Nyeng Pia
Published: August 2023

During embryogenesis dynamic changes in tissue architecture transform primitive anlages to functional organs. Here we document in real time how pancreatic lumens are derived and transformed using a new apical-polarity mouse reporter. Our 4D imaging data reveals dynamic remodeling of apical proteins and lumens to primarily drive each stage of pancreatic duct development. Furthermore, we pinpoint two unique transitions during lumenogenesis. Contrary to current “de novo” models of polarity acquisition, we show that expansion and rearrangement of the pre-existing central primary lumen drives early network growth. We also document how the endocrine promoting niche - a “plexus” of interconnected ducts - is resolved. We show that an arborized network forms by gradual closing of ductal loops, rather than via pruning. These novel tissue dynamics provide a new framework within which cell and molecular signaling can be investigated to better understand the interplay between organ architecture and cell fate.