bluuebunny/crossref_metadata_2025 huggingface dataset:
Expansion of the Fertility Preservation Program to All Newly Diagnosed Prepubertal Patients with Cancer at a Pediatric Hospital
Authors: Leavitt Antonia P. , Albritton Karen H. , Cazzell Mary , Stevenson Eleanor
Published: March 2024

Background: As the majority of pediatric patients with cancer survive their disease, generating a population of over 500,000 childhood cancer survivors in the United States, it is imperative to minimize the lifelong consequences of treatment, which include temporary or permanent infertility caused by certain cancer treatments. A fertility consultation at diagnosis can provide patients and families with the opportunity to be informed regarding the likelihood of gonadal dysfunction and to consider fertility preservation. Method: After our pediatric hospital started to offer tissue cryopreservation, we initiated this evidence-based interventional quality improvement project. Our primary aim was to ensure that all newly diagnosed prepubertal patients with cancer who met the criteria for fertility tissue preservation were correctly identified and offered an educational consultation and preservation. Results: Between July 15, 2022 and October 30, 2022, 54 patients’ treatment plans were evaluated to determine treatment-related infertility risk using the Oncofertility Consortium Pediatric Initiative Network's Risk Assessment tool. Fifteen patients were at a high level of significantly increased risk and 13 were eligible for consultation. Seven (46%) patients and their families received a consultation. Initiation of treatment before referral was the primary reason for lack of consultation. Six of seven patients receiving consultation (86%) elected to undergo preservation. Preservation procedures did not cause a delay in starting treatment for those patients. Discussion: A fertility preservation program with established policies and processes can increase the likelihood that prepubertal patients at high risk for infertility are correctly identified, educated, and offered preservation.
From Return to Normal to a “New Normal”? A Call to Revive Music Teacher Motivation and Reflection
Authors: Cronenberg Stephanie
Published: March 2024

What might the field of music education do to learn, grow, and reinvent itself as we emerge from COVID-19 and virtual learning? Implied in the “return to normal” discourse, permeating all areas of music education in the year or more following virtual learning is the felt need to keep going and return to music education as usual. Yet significant changes, both positive and negative, occurred during virtual learning and music teachers have not received adequate time to reflect and consider new possibilities. In this article, I reject the idea of “return to normal” and call for a “new normal.” While this new normal might take many forms, I offer one possibility for middle level general music focused on student (as well as teacher) motivation. As music educators, we face a potentially exciting time to re-envision the future of music education—but only if we pause, reflect, and imagine a “new normal.”
Chloroplast genome of Calamus tetradactylus revealed rattan phylogeny
Authors: Zhang Haibo , Liu Peng , Zhang Yi , Sun Huayu , Wang Yue , Gao Zhimin , Liu Xin
Published: March 2024

Background

Calamus tetradactylus, a species primarily distributed in Vietnam, Laos, and southern China, is highly valued for its utilization as a small-diameter rattan material. While its physical and mechanical properties have been extensively studied, the genomic characteristics of C. tetradactylus remain largely unexplored.

Results

To gain a better understanding of its chloroplast genomic features and evolutionary relationships, we conducted sequencing and assembly of the chloroplast genome of C. tetradactylus. The complete chloroplast genome exhibited the typical highly conserved quartile structure, with specific variable regions identified in the single-copy region (like psbF-psbE, π = 0.10327, ndhF-rpl32, π = 0.10195), as well as genes such as trnT-GGU (π = 0.05764) and ycf1 (π = 0.03345) and others. We propose that these regions and genes hold potential as markers for species identification. Furthermore, phylogenetic analysis revealed that C. tetradactylus formed a distinct clade within the phylogenetic tree, alongside other Calamus species, and C. tetradactylus was most closely related to C. walkeri, providing support for the monophyly of the genus.

Conclusion

The analysis of the chloroplast genome conducted in this study provides valuable insights that can contribute to the improvement of rattan breeding programs and facilitate sustainable development in the future.
Estimating individualized treatment effects using an individual participant data meta-analysis
Authors: Bouvier Florie , Chaimani Anna , Peyrot Etienne , Gueyffier François , Grenet Guillaume , Porcher Raphaël
Published: March 2024

Background

One key aspect of personalized medicine is to identify individuals who benefit from an intervention. Some approaches have been developed to estimate individualized treatment effects (ITE) with a single randomized control trial (RCT) or observational data, but they are often underpowered for the ITE estimation. Using individual participant data meta-analyses (IPD-MA) might solve this problem. Few studies have investigated how to develop risk prediction models with IPD-MA, and it remains unclear how to combine those methods with approaches used for ITE estimation. In this article, we compared different approaches using both simulated and real data with binary and time-to-event outcomes to estimate the individualized treatment effects from an IPD-MA in a one-stage approach.

Methods

We compared five one-stage models: naive model (NA), random intercept (RI), stratified intercept (SI), rank-1 (R1), and fully stratified (FS), built with two different strategies, the S-learner and the T-learner constructed with a Monte Carlo simulation study in which we explored different scenarios with a binary or a time-to-event outcome. To evaluate the performance of the models, we used the c-statistic for benefit, the calibration of predictions, and the mean squared error. The different models were also used on the INDANA IPD-MA, comparing an anti-hypertensive treatment to no treatment or placebo ($$N = 40\,237$$

N
=
40

237

, 836 events).

Results

Simulation results showed that using the S-learner led to better ITE estimation performances for both binary and time-to-event outcomes. None of the risk models stand out and had significantly better results. For the INDANA dataset with a binary outcome, the naive and the random intercept models had the best performances.

Conclusions

For the choice of the strategy, using interactions with treatment (the S-learner) is preferable. For the choice of the method, no approach is better than the other.
Improvement of scoring system used before discharge to predict 30-day all-cause unplanned readmission in geriatric population: a prospective cohort study
Authors: Setiati Siti , Ardian Laurentius Johan , Fitriana Ika , Azwar Muhammad Khifzhon
Published: March 2024

Background

Data taken from tertiary referral hospitals in Indonesia suggested readmission rate in older population ranging between 18.1 and 36.3%. Thus, it is crucial to identify high risk patients who were readmitted. Our previous study found several important predictors, despite unsatisfactory discrimination value.

Methods

We aimed to investigate whether comprehensive geriatric assessment (CGA) -based modification to the published seven-point scoring system may increase the discrimination value. We conducted a prospective cohort study in July–September 2022 and recruited patients aged 60 years and older admitted to the non-surgical ward and intensive coronary care unit. The ROC curve was made based on the four variables included in the prior study. We conducted bivariate and multivariate analyses, and derived a new scoring system with its discrimination value.

Results

Of 235 subjects, the incidence of readmission was 32.3% (95% CI 26–38%). We established a new scoring system consisting of 4 components. The scoring system had maximum score of 21 and incorporated malignancy (6 points), delirium (4 points), length of stay ≥ 10 days (4 points), and being at risk of malnutrition or malnourished (7 points), with a good calibration test. The C-statistic value was 0.835 (95% CI 0.781–0.880). The optimal cut-off point was ≥ 8 with a sensitivity of 90.8% and a specificity of 54.7%.

Conclusions

Malignancy, delirium, length of stay ≥ 10 days, and being at risk of malnutrition or malnourished are predictors for 30-day all-cause unplanned readmission. The sensitive scoring system is a strong model to identify whether an individual is at higher risk for readmission. The new CGA-based scoring system had higher discrimination value than that of the previous seven-point scoring system.
Comment on “A novel
super-enhancer-related gene signature predicts prognosis and immune microenvironment for
breast cancer”
Authors: Chehelgerdi Matin , Khorramian-Ghahfarokhi Milad , Dehkordi Fereshteh Behdarvand , Chehelgerdi Mohammad
Published: March 2024

The primary aim of this study is to critically evaluate and comment on
the research presented in the article titled “A Novel Super-Enhancer-Related
Gene Signature Predicts Prognosis and Immune Microenvironment for Breast
Cancer” by Wu et al. Our specific objectives include assessing the
methodology employed by the authors, particularly in regard to the utilization of a
super-enhancer-related gene signature for breast cancer prognosis prediction. We
propose the necessity of subgroup analysis to effectively address the heterogeneity
in breast cancer subtypes, which is crucial for the applicability of the SERGs
across diverse breast cancer cases. Additionally, we suggest conducting a more
comprehensive immune panel study to deepen the understanding of how the immune
microenvironment impacts breast cancer prognosis. Our commentary seeks to provide
valuable insights into the strengths and weaknesses of the study, contributing to a
more comprehensive understanding of its findings and potential clinical
implications.
Management of corneal melting after collagen cross-linking for keratoconus: a case report and a review of the literature
Authors: Moramarco Antonio , di Geronimo Natalie , Gardini Lorenzo , Grendele Arianna , Fontana Luigi
Published: March 2024

Purpose

We describe the management of a case of severe corneal melting after corneal cross-linking (CXL) treated with a staged approach using a conjunctival flap followed by deep anterior lamellar keratoplasty (DALK).

Methods

A 12-year-old male developed severe corneal melting with pending perforation after an accelerated epithelium-off CXL protocol. We initially treated the patient with a conjunctival flap to prevent perforation. Three months later, we performed DALK to restore vision.

Results

Conjunctival flap surgery allowed us to avoid corneal perforation and penetrating keratoplasty (PK) à chaud. Once the inflammation had resolved, we recessed the conjunctiva and performed DALK for optical purposes. Twelve months later, the graft was clear and the corrected visual acuity was 20/25 (Snellen). No complications occurred after surgery.

Conclusions

Although CXL is considered a safe procedure, in rare cases it can lead to serious complications, such as corneal haze, infectious and non-infectious keratitis, stromal melting and perforation. Corneal melting and perforation are usually managed by emergency PK. Herein we suggest a staged approach involving an emergency conjunctival flap followed by DALK at a later time that allowed us to avoid PK à chaud.
Factors associated with antenatal depression among women attending antenatal care at Mubende Regional Referral Hospital: a cross-sectional study
Authors: Kasujja Musa , Omara Samuel , Senkungu Nasifu , Ndibuuza Shamim , Kirabira Joseph , Ibe Usman , Barankunda Lyse
Published: March 2024

Introduction

This study aimed to investigate the prevalence, severity, and factors associated with antenatal depression among women receiving antenatal care at Mubende Regional Referral Hospital (MRRH) in Uganda. Antenatal depression is a critical concern for maternal and child well-being, as it is associated with adverse outcomes such as preterm birth, abortion, low birth weight, and impaired maternal-infant bonding. Despite several international guidelines recommending routine screening for antenatal depression, local Ugandan guidelines often overlook this essential aspect of maternal care.

Methods

A cross-sectional study involving 353 pregnant women utilized the Patient Health Questionnaire 9 (PHQ-9) to assess antenatal depression. Participants were categorized as having antenatal depression if their total PHQ-9 score was ≥ 5 and met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for either major or minor depression. Psychosocial demographic and obstetric characteristics were recorded. Logistic regression analysis identified factors linked to antenatal depression.

Results

The burden of antenatal depression was notably high, affecting 37.68% of the participants. Among those with antenatal depression, the majority exhibited mild symptoms 94 (70.68%). The significant factors associated with antenatal depression, revealed by multivariate analysis, included younger age (≤ 20 years), older age (≥ 35 years), history of domestic violence, alcohol use, gestational age, history of abortion, history of preeclampsia, and unplanned pregnancies.

Conclusion

This study revealed a significantly high prevalence of antenatal depression, emphasizing its public health importance. Most cases were classified as mild, emphasizing the importance of timely interventions to prevent escalation. The identified risk factors included age, history of domestic violence, alcohol use, first-trimester pregnancy, abortion history, previous preeclampsia, and unplanned pregnancy.
Medical education during the COVID-19 pandemic: a reflection on the JHUSOM experience
Authors: Wade Sydney A. , Ali Iman , Milstone Aaron M. , Clever Sarah L. , Xiao Shaoming , Koontz Danielle Winner , Hansoti Bhakti
Published: March 2024

Background

We sought to understand the relative risk of COVID-19 infection and identify risk factors for infection to identify targets for mitigation among medical students.

Methods

An observational cohort study of Johns Hopkins School of Medicine students was conducted from June 2020 to July 2021. Blood samples were collected and tested at three visits to assess for antibodies against SARS-CoV-2. Additionally, a questionnaire was administered at each visit to collect demographic information and assess potential social and behavioral risk factors.

Results

264 students enrolled in the study, and 38 participants completed all study requirements by study end. Roughly 6% of the first- and second-year classes had a reported positive COVID-19 test compared to 5% of third- and fourth-year students. By visit 3, 92% of medical students had detectable antibodies against COVID-19 compared to 4% during the study enrollment period. From study enrollment to visit 3, there was a 10-fold increase in the percentage of students reporting attending large social gatherings and dining in restaurants.

Conclusions

Overall, few COVID-19 cases were found among medical students, even those on clinical rotations. As the study progressed, students reported engaging in higher-risk social behaviors in conjunction with increasing vaccination rates among students.
A novel large intragenic DPYD deletion causing dihydropyrimidine dehydrogenase deficiency: a case report
Authors: Malekkou Anna , Tomazou Marios , Mavrikiou Gavriella , Dionysiou Maria , Georgiou Theodoros , Papaevripidou Ioannis , Alexandrou Angelos , Sismani Carolina , Drousiotou Anthi , Grafakou Olga , Petrou Petros P.
Published: March 2024

Background

Dihydropyrimidine dehydrogenase (DPD), is the initial and rate-limiting enzyme in the catabolic pathway of pyrimidines. Deleterious variants in the DPYD gene cause DPD deficiency, a rare autosomal recessive disorder. The clinical spectrum of affected individuals is wide ranging from asymptomatic to severely affected patients presenting with intellectual disability, motor retardation, developmental delay and seizures. DPD is also important as the main enzyme in the catabolism of 5-fluorouracil (5-FU) which is extensively used as a chemotherapeutic agent. Even in the absence of clinical symptoms, individuals with either complete or partial DPD deficiency face a high risk of severe and even fatal fluoropyrimidine-associated toxicity. The identification of causative genetic variants in DPYD is therefore gaining increasing attention due to their potential use as predictive markers of fluoropyrimidine toxicity.

Methods

A male infant patient displaying biochemical features of DPD deficiency was investigated by clinical exome sequencing. Bioinformatics tools were used for data analysis and results were confirmed by MLPA and Sanger sequencing.

Results

A novel intragenic deletion of 71.2 kb in the DPYD gene was identified in homozygosity. The deletion, DPYD(NM_000110.4):c.850 + 23455_1128 + 8811del, eliminates exons 9 and 10 and may have resulted from a non-homologous end-joining event, as suggested by in silico analysis.

Conclusions

The study expands the spectrum of DPYD variants associated with DPD deficiency. Furthermore, it raises the concern that patients at risk for fluoropyrimidine toxicity due to DPYD deletions could be missed during pre-treatment genetic testing for the currently recommended single nucleotide polymorphisms.
Respiratory entrainment related reverse triggering in mechanically ventilated children
Authors: Blokpoel Robert G.T. , Brandsema Ruben B.R. , Koopman Alette A. , van Dijk Jefta , Kneyber Martin C.J.
Published: March 2024

Background

The underlying pathophysiological pathways how reverse triggering is being caused are not fully understood. Respiratory entrainment may be one of these mechanisms, but both terms are used interchangeably. We sought to characterize reverse triggering and the relationship with respiratory entrainment among mechanically ventilated children with and without acute lung injury.

Methods

We performed a secondary phyiology analysis of two previously published data sets of invasively mechanically ventilated children < 18 years with and without lung injury mechanically ventilated in a continuous or intermittent mandatory ventilation mode. Ventilator waveforms, electrical activity of the diaphragm measured with surface electromyography and oesophageal tracings were analyzed for entrained and non-entrained reverse triggered breaths.

Results

In total 102 measurements (3110 min) from 67 patients (median age 4.9 [1.8 ; 19,1] months) were analyzed. Entrained RT was identified in 12 (12%) and non-entrained RT in 39 (38%) recordings. Breathing variability for entrained RT breaths was lower compared to non-entrained RT breaths. We did not observe breath stacking during entrained RT. Double triggering often occurred during non-entrained RT and led to an increased tidal volume. Patients with respiratory entrainment related RT had a shorter duration of MV and length of PICU stay.

Conclusions

Reverse triggering is not one entity but a clinical spectrum with different mechanisms and consequences.

Trial registration

Not applicable.
rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC
Authors: Polcaro Giovanna , Liguori Luigi , Manzo Valentina , Chianese Annalisa , Donadio Giuliana , Caputo Alessandro , Scognamiglio Giosuè , Dell’Annunziata Federica , Langella Maddalena , Corbi Graziamaria , Ottaiano Alessandro , Cascella Marco , Perri Francesco , De Marco Margot , Col Jessica Dal , Nassa Giovanni , Giurato Giorgio , Zeppa Pio , Filippelli Amelia , Franci Gianluigi , Piaz Fabrizio Dal , Conti Valeria , Pepe Stefano , Sabbatino Francesco
Published: March 2024

Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.
Risk factors for Toxoplasma gondii infection in dogs: a serological survey
Authors: Dini Filippo Maria , Stancampiano Laura , Poglayen Giovanni , Galuppi Roberta
Published: March 2024

Background

Dogs, as well as a wide variety of other warm-blooded animals, act as intermediate host of Toxoplasma gondii. In dogs, most cases of toxoplasmosis are subclinical, although clinical disease has been sporadically reported. Beyond its role in diagnostic pathways, seropositivity also functions as a reflection of the parasite’s spread within the dog’s living environment. The aim of the present study was to evaluate the possible risk factor associated with seropositivity to T. gondii in dogs in Central-Northern Italy, analysing 120 dogs sera for the presence of IgG antibodies by indirect fluorescence antibody test (IFAT).

Results

The population examined was composed of 54.2% hunting dogs, 24.2% companion dogs, 14.2% truffle dogs and 7.5% watchdogs. Thirty-four (29.2%) dogs tested positive for T. gondii IgG, with titres ranging from 1:40 to 1:1280. Seroprevalence and antibodies titres were not related to dog gender, age or function. The logistic regression and ordered logistic regression results indicated that seroprevalence, and antibody titres were significantly higher in dogs cohabiting with cats, exhibiting coprophagy habits, and living constantly outdoors. Notably, the lifestyle factor showed the highest odds-ratios in the study: dogs living constantly outdoors were found to be at approximately 5 times greater risk of testing positive and having higher antibody titres compared to dogs living both indoors and outdoors.

Conclusion

Both logistic and ordered logistic regression results support the key role of living with cats, engaging in coprophagy behaviours, and maintaining an outdoor lifestyle in increasing the risk of T. gondii infection in dogs. These identified risk factors collectively suggest that both ingesting oocysts, as observed through cat cohabitation and coprophagy, and engaging in predatory behaviours, as possible for outdoor living dogs, are indicating likely sources of T. gondii infection in this host species.
Clinical and economic burden of respiratory syncytial virus in children aged 0–5 years in Italy
Authors: Dovizio Melania , Veronesi Chiara , Bartolini Fausto , Cavaliere Arturo , Grego Stefano , Pagliaro Romina , Procacci Cataldo , Ubertazzo Loredana , Bertizzolo Lorenzo , Muzii Barbara , Parisi Salvatore , Perrone Valentina , Baraldi Eugenio , Bozzola Elena , Mosca Fabio , Esposti Luca Degli
Published: March 2024

Background

Respiratory syncytial virus (RSV) is among the leading causes of hospitalization due to lower respiratory tract infections (LRTIs) in children younger than 5 years worldwide and the second cause of infant death after malaria. RSV infection occurs in almost all the infants before the second year of life with variable clinical severity, often requiring medical assistance. This analysis investigated patients aged 0–5 years with RSV infection focusing on epidemiology, clinical features, and economic burden of RSV-associated hospitalizations in a setting of Italian real clinical practice.

Methods

An observational retrospective analysis was conducted on administrative databases of healthcare entities covering around 2.6 million residents of whom 120,000 health-assisted infants aged < 5 years. From 2010 to 2018, pediatric patients were included in the presence of hospitalization discharge diagnosis for RSV infections, and RSV-related acute bronchiolitis or pneumonia. Epidemiology, demographics, clinical picture and costs were evaluated in RSV-infected patients, overall and stratified by age ranges (0–1, 1–2, 2–5 years) and compared with an age-matched general population.

Results

Overall 1378 RSV-infected children aged 0–5 years were included. Among them, the annual incidence rate of RSV-related hospitalizations was 175–195/100,000 people, with a peak in neonates aged < 1 year (689–806/100,000). While nearly 85% of infected infants were healthy, the remaining 15% presented previous hospitalization for known RSV risk factors, like preterm birth, or congenital heart, lung, and immune diseases. The economic analysis revealed that direct healthcare costs per patient/year were markedly higher in RSV patients than in the general population (3605€ vs 344€).

Conclusions

These findings derived from the real clinical practice in Italy confirmed that RSV has an important epidemiological, clinical, and economic burden among children aged 0–5 years. While the complex management of at-risk infants was confirmed, our data also highlighted the significant impact of RSV infection in infants born at term or otherwise healthy, demonstrating that all infants need protection against RSV disease, reducing then the risk of medium and long-term complications, such as wheezing and asthma.
Navigating uncharted territory with a borrowed map: lessons from setting up the BATH-OUT-2 randomised controlled trial in adult social care and housing services in English local authorities
Authors: McAnuff Jennifer , Rapley Tim , Rooney Leigh , Whitehead Phillip
Published: March 2024

Populations around the world are rapidly ageing and more people are living with multiple long-term conditions. There is an urgent need for evidence about high quality, cost-effective, and integrated systems of health and social care. Health research funders are now also prioritising research in adult social care and wider local authority settings, e.g. housing services.

Developing the evidence base for adult social care should include implementing randomised controlled trials, where appropriate. Within the UK, the clinical trial is the established road map for evaluating interventions in the National Health Service (NHS). However, adult social care and local authorities are relatively uncharted territory for trials. BATH-OUT-2 is one of the first clinical trials currently underway within adult social care and housing adaptations services in six English local authorities. It provides an opportunity to explore how the clinical trial road map fares in these settings.

Whilst setting up BATH-OUT-2, we encountered challenges with securing funding for the trial, lack of non-NHS intervention costs, using research and support costs as intended, gaining approvals, identifying additional trial sites, and including people who lack the mental capacity to provide informed consent. Overall, our experience has been like navigating uncharted territory with a borrowed map. In the UK, the clinical trial road map was developed for medical settings. Its key features are integrated within the NHS landscape but have been largely absent, unfamiliar, inaccessible, or irrelevant in social care and wider local authority terrain. Navigating the set-up of a clinical trial outside the NHS has been a complicated and disorientating journey.

BATH-OUT-2 highlights how local authorities generally and adult social care specifically are a relatively new and certainly different type of setting for trials. Whilst this poses a challenge for conducting trials, it also presents an opportunity to question longstanding assumptions within trials practices, reimagine the conventional clinical trial road map, and take it in new directions. As the UK research landscape moves forward and becomes better primed for randomised evaluations in local authorities, we propose several suggestions for building on recent progress and advancing trials within adult social care and across health and care systems.
Prospective virtual screening combined with bio-molecular simulation enabled identification of new inhibitors for the KRAS drug target
Authors: Ajmal Amar , Alkhatabi Hind A , Alreemi Roaa M. , Alamri Mubarak A. , Khalid Asaad , Abdalla Ashraf N. , Alotaibi Bader S. , Wadood Abdul
Published: March 2024

Lung cancer is a disease with a high mortality rate and it is the number one cause of cancer death globally. Approximately 12–14% of non-small cell lung cancers are caused by mutations in KRASG12C. The KRASG12C is one of the most prevalent mutants in lung cancer patients. KRAS was first considered undruggable. The sotorasib and adagrasib are the recently approved drugs that selectively target KRASG12C, and offer new treatment approaches to enhance patient outcomes however drug resistance frequently arises. Drug development is a challenging, expensive, and time-consuming process. Recently, machine-learning-based virtual screening are used for the development of new drugs. In this study, we performed machine-learning-based virtual screening followed by molecular docking, all atoms molecular dynamics simulation, and binding energy calculations for the identifications of new inhibitors against the KRASG12C mutant. In this study, four machine learning models including, random forest, k-nearest neighbors, Gaussian naïve Bayes, and support vector machine were used. By using an external dataset and 5-fold cross-validation, the developed models were validated. Among all the models the performance of the random forest (RF) model was best on the train/test dataset and external dataset. The random forest model was further used for the virtual screening of the ZINC15 database, in-house database, Pakistani phytochemicals, and South African Natural Products database. A total of 100 ns MD simulation was performed for the four best docking score complexes as well as the standard compound in complex with KRASG12C. Furthermore, the top four hits revealed greater stability and greater binding affinities for KRASG12C compared to the standard drug. These new hits have the potential to inhibit KRASG12C and may help to prevent KRAS-associated lung cancer. All the datasets used in this study can be freely available at (https://github.com/Amar-Ajmal/Datasets-for-KRAS).
Molecular characterization and zoonotic potential of Cryptosporidium spp. and Giardia duodenalis in humans and domestic animals in Heilongjiang Province, China
Authors: Hao Yaru , Liu Aiqin , Li He , Zhao Yiyang , Yao Lan , Yang Bo , Zhang Weizhe , Yang Fengkun
Published: March 2024

Background

Cryptosporidiosis and giardiasis are significant parasitic diseases shared between humans and domestic animals. Due to the close contact between humans and domestic animals in rural areas, it is important to consider the potential transmission of zoonotic parasites from infected domestic animals to humans. This investigation aimed to determine the prevalence and molecular characteristics ofCryptosporidiumspp. andGiardia duodenalisin domestic animals and villagers.

Methods

A total of 116 fecal samples from villagers and 686 fecal samples from domestic animals in Heilongjiang Province, China, were analyzed for two parasites using nested polymerase chain reaction (PCR) targeting various genetic loci and DNA sequence analysis of the PCR products.

Results

By sequence analysis of theSSUrRNA gene, the prevalence ofCryptosporidiumin humans was 0.9% (1/116), with one species ofC. parvum(n = 1) detected; among domestic animals, the prevalence was 2.6% (18/686), with five species identified:C. suis(n = 7) andC. scrofarum(n = 7) in pigs,C. meleagridis(n = 1) in chickens,C. andersoni(n = 1) in cattle, andC. canis(n = 2) in foxes.C. parvum and C. caniswere further subtyped as IIdA19G1 and XXa4 on the basis ofgp60gene. RegardingG. duodenalis, based on theSSUrRNA,bg,gdh, andtpigenes, the prevalence in domestic animals was 5.1% (31/608), with three assemblages identified: A (n = 1) in pigs, D (n = 1) in foxes, and E (n = 27) in geese, cattle, pigs, ducks, and sheep, along with mixed infection of A + E (n = 1) in one pig and B + E (n = 1) in one sheep. NoG. duodenaliswas detected in humans (0/116).

Conclusions

The present results show that no overlap of subtypes between animals and villagers was found inCryptosporidiumspp. andG. duodenalis, indicating a minor role of domestic animals in infecting humans in this population. However, the presence of zoonotic protozoa in domestic animals highlights the need for special attention to high-risk individuals during close contact with domestic animals.

Graphical Abstract
Head and neck cancer of unknown primary: unveiling primary tumor sites through machine learning on DNA methylation profiles
Authors: Stark Leonhard , Kasajima Atsuko , Stögbauer Fabian , Schmidl Benedikt , Rinecker Jakob , Holzmann Katharina , Färber Sarah , Pfarr Nicole , Steiger Katja , Wollenberg Barbara , Ruland Jürgen , Winter Christof , Wirth Markus
Published: March 2024

Background

The unknown tissue of origin in head and neck cancer of unknown primary (hnCUP) leads to invasive diagnostic procedures and unspecific and potentially inefficient treatment options for patients. The most common histologic subtype, squamous cell carcinoma, can stem from various tumor primary sites, including the oral cavity, oropharynx, larynx, head and neck skin, lungs, and esophagus. DNA methylation profiles are highly tissue-specific and have been successfully used to classify tissue origin. We therefore developed a support vector machine (SVM) classifier trained with publicly available DNA methylation profiles of commonly cervically metastasizing squamous cell carcinomas (n = 1103) in order to identify the primary tissue of origin of our own cohort of squamous cell hnCUP patient’s samples (n = 28). Methylation analysis was performed with Infinium MethylationEPIC v1.0 BeadChip by Illumina.

Results

The SVM algorithm achieved the highest overall accuracy of tested classifiers, with 87%. Squamous cell hnCUP samples on DNA methylation level resembled squamous cell carcinomas commonly metastasizing into cervical lymph nodes. The most frequently predicted cancer localization was the oral cavity in 11 cases (39%), followed by the oropharynx and larynx (both 7, 25%), skin (2, 7%), and esophagus (1, 4%). These frequencies concord with the expected distribution of lymph node metastases in epidemiological studies.

Conclusions

On DNA methylation level, hnCUP is comparable to primary tumor tissue cancer types that commonly metastasize to cervical lymph nodes. Our SVM-based classifier can accurately predict these cancers’ tissues of origin and could significantly reduce the invasiveness of hnCUP diagnostics and enable a more precise therapy after clinical validation.
A rare variant of mullerian agenesis: a case report and review of the literature
Authors: Tayade Shriya Devendra , Mehdi Nadia , Dube Rajani , Bose Vaishnavi , Ameer Ashna , Hakim Zainabsadat Tabatabaei , Wattiez Arnaud
Published: March 2024

Introduction

Menstruation is a developmental milestone and usually marks healthy and normal pubertal changes in females. Menarche refers to the onset of first menstruation in a female. The causes of primary amenorrhea include outflow tract abnormalities, resistant endometrium, primary ovarian insufficiency, and disorders of the hypothalamus, pituitary, or other endocrine glands. A rare variant of mullerian agenesis, which warrants an individualized approach to management, is presented here.

Case report

We present here the case of a 25-year-old Indian female with pain in the lower abdomen and primary amenorrhea. After a thorough history, clinical examination, imaging, and diagnostic laparoscopy, two small uteri, a blind upper half vagina, bilateral polycystic ovaries, and a blind transverse connection between the two uteri—a horseshoe band cervix—were detected, which confirmed the diagnosis of mullerian agenesis. There was evidence of adenomyosis in the mullerian duct element. This is a rare form of Müllerian abnormality with an unusual presentation.

Conclusion

Mullerian agenesis is the most common cause of primary amenorrhea with well-developed secondary sexual characteristics. There are various forms of mullerian agenesis. Most of the cases are managed by a multidisciplinary team. Rare variants warrant an individualized approach to management.
Recurrent severe hypocalcemia following chemotherapy regimen changes in advanced breast cancer: two case reports
Authors: Yanase Yurina , Bando Hiroko , Sato Riko , Matsuo Tomohei , Ueda Aya , Okazaki Mai , Hashimoto Sachie , Iguchi-Manaka Akiko , Hara Hisato
Published: March 2024

Background

As an oncologic emergency related to abnormalities in calcium metabolism, hypercalcemia associated with paraneoplastic syndrome and bone metastases is well known. Meanwhile, the incidence of hypocalcemia is low, except in cases associated with bone-modifying agents used for bone metastases. Hypocalcemia induced by bone-modifying agents typically occurs early after the initial administration, and its incidence can be significantly reduced by preventive administration of calcium and vitamin D3 supplements.

Case report

We report two cases of recurrent severe hypocalcemia occurring during chemotherapy for metastatic breast cancer with multiple bone metastases.

Case 1: A 35-year-old Japanese woman developed metastases in the bone, liver, and ovaries during postoperative endocrine therapy for invasive lobular carcinoma of the breast. She underwent chemotherapy and treatment with denosumab. She experienced recurrent episodes of severe hypocalcemia subsequent to a change in the chemotherapy regimen. Case 2: A 65-year-old Japanese woman encountered multiple bone metastases after postoperative anti-human epidermal growth factor receptor 2 therapy and during endocrine therapy for invasive ductal carcinoma of the breast. She underwent anti-human epidermal growth factor receptor 2 therapy and treatment with denosumab. She experienced recurrent severe hypocalcemia subsequent to a change in the chemotherapy regimen to letrozole + lapatinib, trastuzumab emtansine, and lapatinib + capecitabine.

Conclusions

We observed two cases of recurrent severe hypocalcemia in patients with advanced breast cancer and bone metastases after modifications to their therapy regimens. These cases differed from the typical hypocalcemia induced by bone-modifying agents. It is possible that antitumor drugs affect calcium and bone metabolism associated with bone metastases. While these cases are rare, it is crucial for oncologists to be aware of hypocalcemia not only at the initiation of bone-modifying agents but also throughout the entire antitumor therapy, as hypocalcemia can lead to fatal outcomes.
Strong convergence of split equality variational inequality, variational inclusion, and multiple sets fixed point problems in Hilbert spaces with application
Authors: Batra Charu , Chugh Renu , Kumar Rajeev , Suwais Khaled , Almanasra Sally , Mlaiki Nabil
Published: March 2024

This paper introduces an innovative inertial simultaneous cyclic iterative algorithm designed to address a range of mathematical problems within the realm of split equality variational inequalities. Specifically, the algorithm accommodates finite families of split equality variational inequality problems, infinite families of split equality variational inclusion problems, and multiple-sets split equality fixed point problems involving demicontractive operators in infinite-dimensional Hilbert spaces. The algorithm integrates well-established methods, including the cyclic method, the inertial method, the viscosity approximation method, and the projection method. We establish the strong convergence of this proposed algorithm, demonstrating its applicability in various scenarios and unifying disparate findings from existing literature. Additionally, a numerical example is presented to validate the primary convergence theorem.
Fostering idealogical and polical education via knowledge graph and KNN model: an emphasis on positive psychology
Authors: Chen Shuangquan , Ma Yu , Lian Wanting
Published: March 2024

As the primary domain of ideological and political education in higher education institutions, ideological and political courses must align with principles rooted in human psychology and education. Integrating educational psychology into ideological and political teaching in universities enhances the scientific, targeted, and forward-thinking nature of such education. The burgeoning exploration of knowledge graph applications has extended to machine translation, semantic search, and intelligent question answering. Diverging from traditional text matching, the knowledge spectrum graph transforms information acquisition in search engines. This paper pioneers a predictive system for delineating the relationship between educational psychology and ideological and political education in universities. Initially, it extracts diverse psychological mapping relationships of students, constructing a knowledge graph. By employing the KNN algorithm, the system analyzes psychological characteristics to effectively forecast the relationship between educational psychology and ideological and political education in universities. The system's functionality is meticulously detailed in this paper, and its performance is rigorously tested. The results demonstrate high accuracy, recall rates, and F1 values. The F1 score can reach 0.95enabling precise sample classification. The apex of the average curve for system response time peaks at approximately 2.5 s, maintaining an average response time of less than 3 s. This aligns seamlessly with the demands of practical online teaching requirements. The system adeptly forecasts the relationship between educational psychology and ideological and political education in universities, meeting response time requirements and thereby fostering the scientific and predictive nature of ideological and political teaching in higher education institutions.
Exploring the interplay between small and large scales movements in a neotropical small mammal
Authors: Brigatti E. , Ríos-Uzeda B. , Vieira M. V.
Published: March 2024

We record and analyze the movement patterns of the marsupial Didelphis aurita at different temporal scales. Animals trajectories are collected at a daily scale by using spool-and-line techniques and, with the help of radio-tracking devices, animals traveled distances are estimated at intervals of weeks. Small-scale movements are well described by truncated Lévy flight, while large-scale movements produce a distribution of distances which is compatible with a Brownian motion. A model of the movement behavior of these animals, based on a truncated Lévy flight calibrated on the small scale data, converges towards a Brownian behavior after a short time interval of the order of 1 week. These results show that whether Lévy flight or Brownian motion behaviors apply, will depend on the scale of aggregation of the animals paths. In this specific case, as the effect of the rude truncation present in the daily data generates a fast convergence towards Brownian behaviors, Lévy flights become of scarce interest for describing the local dispersion properties of these animals, which result well approximated by a normal diffusion process and not a fast, anomalous one. Interestingly, we are able to describe two movement phases as the consequence of a statistical effect generated by aggregation, without the necessity of introducing ecological constraints or mechanisms operating at different spatio-temporal scales. This result is of general interest, as it can be a key element for describing movement phenomenology at distinct spatio-temporal scales across different taxa and in a variety of systems.
Determining the destination: a co-designed chronic advanced cancer rehabilitation conceptual framework for engagement of individuals with lived experience in rehabilitation research
Authors: Dolgoy Naomi , Bernard Stephanie , Huang Fleur , Driga Amy , Hall-Lavoie Debra , Brown Adam , Pituskin Edith , Fairchild Alysa , McNeely Margaret L.
Published: March 2024

Background

Individuals living with chronic advanced cancer (CAC) often face distinct physical, functional, and cognitive issues. Their rehabilitation needs are not yet routinely met, warranting further CAC-specific rehabilitation-based research. Given the complexity of functional and symptom presentations, engagement of individuals living with CAC as partners in the research process is encouraged to better understand the lived perspective. Formal engagement requires both structured approaches and iterative processes. The aim was to co-design a conceptual framework to develop and integrate engagement strategies into rehabilitation research focused on CAC populations.

Methods

A multidisciplinary team of authors, including two individuals with lived experience, conducted an implementation-focused descriptive study to inform future research design, including: interviews and follow-up, review of current models and approaches, and development of a co-designed conceptual framework for engaging individuals with lived experience into CAC-specific rehabilitation research.

Results

Emergent themes include shared understanding, transparent appreciation, iterative processes and unique partnership needs. A definition, guiding principles and tools for engagement were identified. In consultation with individuals with lived experience, and application of the emergent themes in context, a conceptual framework to guide the engagement process was developed.

Conclusion

A novel conceptual framework for engaging individuals with lived experience with CAC as partners in rehabilitation research is proposed to facilitate implementation-focused team-based approaches for this population.