bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of dose–TSH response effect of levothyroxine soft-gel formulation
Authors: Trimboli Pierpaolo , Piticchio Tommaso , Dadda Zeno , Stramazzo Ilaria , Gamarra Elena , Ruinelli Lorenzo , Virili Camilla
Published: February 2024

Background

Hypothyroidism is treated with daily levothyroxine (LT4). In recent years, soft gel caps of LT4 (LT4-C) have been commercialized, and their performance has been optimized. Since guidelines recommend dose LT4 according to the tablet preparation efficacy, the present study was undertaken to obtain data about the daily requirement, normalized per body weight, of LT4-C.

Methods

Patients undergoing LT4-C after total thyroidectomy and radioiodine treatment for differentiated thyroid carcinoma were selected. There was no specific indication of suppression of TSH (i.e., <0.5 or <0.1 mIU/L). Patients were required to maintain a stable LT4 dose during the study period. Patients with interfering factors were excluded from this study.

Results

Thirty patients were enrolled (18 females and 12 males; median age, 50 years; median body weight, 71 kg; median LT4-C dose, 1.71 µg/kg/day). The analysis of patient age did not reveal any differences. The LT4-C dose correlated with free-T4 p = 0.03), but not with TSH (p = 0.42) and free-T3 (p = 0.13). TSH was <1.0 mIU/L in 90% of the cases. The LT4-C dose–TSH response effect was analysed by probit regression model: the probability to achieve TSH <1.0 mIU/l was 99% with a dose of 1.84 (95%CI 1.57–2.12) µg/kg/day, 75% with a dose of 1.38 µg/kg/day (95%CI 1.17–1.59), and 50% with a dose of 1.20 (95%CI 0.96–1.43). At ROC curve analysis, the most accurate cut-off of LT4-C dose to achieve TSH <1.0 mIU/l was 1.53 ug/kg/day with 70% sensitivity and 100% specificity.

Conclusions

Athyreotic patients can be initially treated with an LT4-C dose lower than previously stated. Therefore, further prospective studies are warranted.
High mortality risk among women with acromegaly still persists
Authors: Găloiu Simona , Toma Iustin-Daniel , Tănasie Denisa Isabella , Bărbulescu Andreea , Baciu Ionela , Niculescu Dan Alexandru , Trifănescu Raluca Alexandra , Căpăţînă Cristina , Radian Şerban , Poiană Cătălina
Published: February 2024

Introduction

The mortality ratio in patients with acromegaly has improved over the last few decades. We aimed to determine the mortality rate and correlated factors in patients with acromegaly before and after the introduction of national protocols for treatment. In addition, we determined whether there are sex-related differences in mortality of patients with acromegaly.

Methods

This observational retrospective study included 399 consecutive patients with acromegaly between January 2001–December 2022. Paraclinical data included random growth hormone (GH) and insulin-like growth factor-I (IGF1) levels, maximal pituitary tumor diameter at diagnosis, first visit, and last evaluation. Standardized mortality ratio (SMR) was calculated by dividing the observed and expected mortality rates. Cox regression analysis revealed the independent factors associated with mortality.

Results

At the last visit, 31.07% (124) of patients were cured, 22.05% (88) had controlled acromegaly with medication, and 45.31% (181) had not controlled acromegaly. During follow-up (13.03 ± 5.65 years, 5216.62 person-years), 89 patients died (0.017%), resulting in an SMR of 1.18 [95% CI 0.95–1.45]. The independent factors associated with mortality were the last IGF1 level/last random GH level, absence of surgery, gonadotropin deficiency, and age. Patients with normal IGF1 after treatment showed an SMR of 0.71, whereas patients with IGF1 ratio > 1 showed SMR=1.51. Patients diagnosed between 1975–2007 and 2008–2022 had SMR = 1.25 [95% CI 0.97–1.58] and SMR = 1.09 [95% CI 0.68–1.65], respectively. In females with acromegaly, SMR was 1.63 [95% CI 1.24–2.11]; 1.76 [95% CI 1.30–2.34] in women diagnosed before 2008 and 1.33 [95% CI 0.69–2.33] in those diagnosed after 2008. Males with acromegaly had a mortality ratio similar to males from the general population (SMR = 0.99, [95% CI 0.66–1.41]).

Conclusion

Patients diagnosed with acromegaly in the last 15 years had lower mortality rates than those diagnosed before 2008, due to the availability of new medications, primarily somatostatin receptor analogs and to a higher proportion of patients undergoing surgery. Females still have a high mortality ratio owing to older age at diagnosis and higher risk of metabolic complications. Therefore, efforts should be made for early diagnosis of acromegaly in women.
Coordinated frequency support strategy for VSC-HVDC integrated offshore wind farm system
Authors: Li He , Li Yuekai , Meng Yao , Yan Kefei
Published: February 2024

The large-scale offshore wind power integrated into the onshore power grid through voltage source converter-based high voltage direct current (VSC-HVDC) system is unable to provide inertia response and frequency support to the onshore power grid. To improve the frequency characteristics of the receiving-end power grid, a coordinated frequency control strategy combining VSC-HVDC and offshore wind power is proposed. The onshore converter adopts virtual inertia control, which uses DC capacitors to absorb or release energy for inertia support after the receiving-end grid is disturbed. Wind-farm-side VSC (WFVSC) obtains the frequency signal of the receiving-end power grid by detecting the local DC voltage. The offshore wind farm (OWF) transfers the frequency deviation into an additional power signal and sends it to the power controller to adjust the output, thereby performing inertia and primary frequency response. In addition, a secondary frequency regulation strategy for wind farms has been designed to achieve non-difference frequency regulation of the receiving-end power grid. Finally, a simulation model of VSC-HVDC integrated OWF system is constructed to demonstrate the proposed coordinated frequency control strategy for VSC-HVDC and OWF. The results indicate that the proposed control strategy can effectively enhance the frequency support capability of the receiving-end power grid.
Factors that influence married/partnered women’s decisions to use contraception in Zambia
Authors: Chiziba Chilochibi , Chewe Mwimba , Hangoma Peter
Published: February 2024

According to the Demographic and Health Surveys (DHSs), Zambia has shown an increasing trend in the percentage of married women using contraceptives in the last three decades. As of 2018, this percentage increased from 34.2% in 2001 to 40.8% in 2007 and from 45% in 2013 to 48% in 2018. Despite the increasing trend in contraceptive use, the unmet needs remain relatively high. The low percentage of contraception use translates into 20% of women of reproductive age who are either married/partnered and want to stop or delay childbearing but are not using contraception. This study analyzed factors other than availability that influence women’s ability to make or influence the decision to use contraception using logistic regression using data from the Zambia 2013/2014 and 2018 DHSs. Furthermore, adjusted odds ratios and predicted probabilities were estimated using the fitted logistic regression. Data on 8,335 women were analyzed, and 13.7% (n = 1,145) had their husband as the sole decision maker for contraception use, while 86.3% (n = 7,189) made the decisions or participated in making the decision. Contrary to most literature, those with primary or secondary school education were less likely to decide than those without education. The data also associate women who contribute to daily household decisions to having a say in deciding to use contraception. Lastly, women using reversible contraception methods, other methods, hormonal methods, and fertility awareness were associated with less likelihood to decide on using contraceptives than those using barrier methods. Women with lower household decision-making powers are less likely to make or influence decisions to use contraception. Consequently, there is a need to prioritize such women in interventions aimed at increasing contraception use decision-making. Furthermore, more studies are required to investigate why uneducated women in Zambia are more likely to choose contraception. Also, the vast odds ratio difference between all other methods compared to barrier methods (condoms) indicates underlying factors that play a role, which warrants further studies.
A consensus statement on perinatal mental health during the COVID-19 pandemic and recommendations for post-pandemic recovery and re-build
Authors: Jackson Leanne , Greenfield Mari , Payne Elana , Burgess Karen , Oza Munira , Storey Claire , Davies Siân M. , De Backer Kaat , Kent-Nye Flora E. , Pilav Sabrina , Worrall Semra , Bridle Laura , Khazaezadeh Nina , Rajasingam Daghni , Carson Lauren E. , De Pascalis Leonardo , Fallon Victoria , Hartley Julie M. , Montgomery Elsa , Newburn Mary , Wilson Claire A. , Harrold Joanne A. , Howard Louise M. , Sandall Jane , Magee Laura A. , Sheen Kayleigh S. , Silverio Sergio A.
Published: February 2024

Introduction

The COVID-19 pandemic posed a significant lifecourse rupture, not least to those who had specific physical vulnerabilities to the virus, but also to those who were suffering with mental ill health. Women and birthing people who were pregnant, experienced a perinatal bereavement, or were in the first post-partum year (i.e., perinatal) were exposed to a number of risk factors for mental ill health, including alterations to the way in which their perinatal care was delivered.

Methods

A consensus statement was derived from a cross-disciplinary collaboration of experts, whereby evidence from collaborative work on perinatal mental health during the COVID-19 pandemic was synthesised, and priorities were established as recommendations for research, healthcare practice, and policy.

Results

The synthesis of research focused on the effect of the COVID-19 pandemic on perinatal health outcomes and care practices led to three immediate recommendations: what to retain, what to reinstate, and what to remove from perinatal mental healthcare provision. Longer-term recommendations for action were also made, categorised as follows: Equity and Relational Healthcare; Parity of Esteem in Mental and Physical Healthcare with an Emphasis on Specialist Perinatal Services; and Horizon Scanning for Perinatal Mental Health Research, Policy, & Practice.

Discussion

The evidence base on the effect of the pandemic on perinatal mental health is growing. This consensus statement synthesises said evidence and makes recommendations for a post-pandemic recovery and re-build of perinatal mental health services and care provision.
Case report: Complex evaluation of coagulation, fibrinolysis and inflammatory cytokines in a SARS-CoV-2 infected pregnant woman with fetal loss
Authors: Tóth Eszter Lilla , Orbán-Kálmándi Rita , Bagoly Zsuzsa , Lóczi Linda , Deli Tamás , Török Olga , Molnár Sarolta , Baráth Sándor , Singh Parvind , Hevessy Zsuzsanna , Katona Éva , Fagyas Miklós , Szabó Attila Ádám , Molnár Szabolcs , Krasznai Zoárd Tibor
Published: February 2024

Background

SARS-CoV-2 infection during pregnancy increases the risk of severe obstetrical complications. Detailed evaluation of COVID-19-associated coagulopathy in a pregnancy with stillbirth hasn’t been described so far. Besides knowledge gaps in the pathomechanism leading to stillbirth in COVID-19 pregnancies, currently, no prognostic biomarker is available to identify pregnant patients who are at imminent risk of COVID-19-associated maternal and fetal complications, requiring immediate medical attention.

Case

Here we report the case of a 28-year-old SARS-CoV-2 infected pregnant patient, admitted to our hospital at 28 weeks of gestation with intrauterine fetal loss. The presence of SARS-CoV-2 placentitis was confirmed by immunohistological evaluation of the placenta. She had only mild upper respiratory symptoms and her vital signs were within reference throughout labor and postpartum. The stillborn infant was delivered per vias naturales. Fibrinogen concentrate was administered before and after labor due to markedly decreased fibrinogen levels (1.49 g/l) at admission and excessive bleeding during and after delivery. Although coagulation screening tests were not alarming at admission, the balance of hemostasis was strikingly distorted in the patient. As compared to healthy age- and gestational age-matched pregnant controls, increased D-dimer, low FVIII activity, low FXIII level, marked hypocoagulability as demonstrated by the thrombin generation assay, together with shortened clot lysis and decreased levels of fibrinolytic proteins were observed. These alterations most likely have contributed to the increased bleeding observed during labor and in the early postpartum period. Interestingly, at the same time, only moderately altered inflammatory cytokine levels were found at admission. Serum ACE2 activity did not differ in the patient from that of age- and gestational age-matched healthy controls, suggesting that despite previous speculations in the literature, ACE2 may not be used as a potential biomarker for the prediction of COVID-19 placentitis and threatening fetal loss in SARS-CoV-2-infected pregnancies.

Conclusions

Although based on this case report no prognostic biomarker could be identified for use in pregnant patients with imminent risk of fetal loss associated with COVID-19 placentitis, the above-described hemostasis alterations warrant awareness of postpartum hemorrhagic complications and could be helpful to identify patients requiring intensified medical attention.
The nuclear pore protein NUP98 impedes LTR-driven basal gene expression of HIV-1, viral propagation, and infectivity
Authors: Chintala Kumaraswami , Yandrapally Sriram , Faiz Warisha , Kispotta Chhaya Rani , Sarkar Satarupa , Mishra Krishnaveni , Banerjee Sharmistha
Published: February 2024

Nucleoporins (NUPs) are cellular effectors of human immunodeficiency virus-1 (HIV-1) replication that support nucleocytoplasmic trafficking of viral components. However, these also non-canonically function as positive effectors, promoting proviral DNA integration into the host genome and viral gene transcription, or as negative effectors by associating with HIV-1 restriction factors, such as MX2, inhibiting the replication of HIV-1. Here, we investigated the regulatory role of NUP98 on HIV-1 as we observed a lowering of its endogenous levels upon HIV-1 infection in CD4+ T cells. Using complementary experiments in NUP98 overexpression and knockdown backgrounds, we deciphered that NUP98 negatively affected HIV-1 long terminal repeat (LTR) promoter activity and lowered released virus levels. The negative effect on promoter activity was independent of HIV-1 Tat, suggesting that NUP98 prevents the basal viral gene expression. ChIP-qPCR showed NUP98 to be associated with HIV-1 LTR, with the negative regulatory element (NRE) of HIV-1 LTR playing a dominant role in NUP98-mediated lowering of viral gene transcription. Truncated mutants of NUP98 showed that the attenuation of HIV-1 LTR-driven transcription is primarily contributed by its N-terminal region. Interestingly, the virus generated from the producer cells transiently expressing NUP98 showed lower infectivity, while the virus generated from NUP98 knockdown CD4+ T cells showed higher infectivity as assayed in TZM-bl cells, corroborating the anti-HIV-1 properties of NUP98. Collectively, we show a new non-canonical function of a nucleoporin adding to the list of moonlighting host factors regulating viral infections. Downregulation of NUP98 in a host cell upon HIV-1 infection supports the concept of evolutionary conflicts between viruses and host antiviral factors.
CLOINet: ocean state reconstructions through remote-sensing, in-situ sparse observations and deep learning
Authors: Cutolo Eugenio , Pascual Ananda , Ruiz Simon , Zarokanellos Nikolaos D. , Fablet Ronan
Published: February 2024

Combining remote-sensing data with in-situ observations to achieve a comprehensive 3D reconstruction of the ocean state presents significant challenges for traditional interpolation techniques. To address this, we developed the CLuster Optimal Interpolation Neural Network (CLOINet), which combines the robust mathematical framework of the Optimal Interpolation (OI) scheme with a self-supervised clustering approach. CLOINet efficiently segments remote sensing images into clusters to reveal non-local correlations, thereby enhancing fine-scale oceanic reconstructions. We trained our network using outputs from an Ocean General Circulation Model (OGCM), which also facilitated various testing scenarios. Our Observing System Simulation Experiments aimed to reconstruct deep salinity fields using Sea Surface Temperature (SST) or Sea Surface Height (SSH), alongside sparse in-situ salinity observations. The results showcased a significant reduction in reconstruction error up to 40% and the ability to resolve scales 50% smaller compared to baseline OI techniques. Remarkably, even though CLOINet was trained exclusively on simulated data, it accurately reconstructed an unseen SST field using only glider temperature observations and satellite chlorophyll concentration data. This demonstrates how deep learning networks like CLOINet can potentially lead the integration of modeling and observational efforts in developing an ocean digital twin.
Effect of deposition temperature on the tribo-mechanical properties of nitrogen doped DLC thin film
Authors: Shanmugasundar G. , Vanitha M. , Logesh K. , Cepova Lenka , Elangovan Muniyandy
Published: February 2024

The tribomechanical characteristics of diamond-like carbon (DLC) coatings are notably superior to other hard coatings, making them highly desirable for industrial applications. This study focuses on the synthesis of nitrogen-doped DLC (N-DLC) films through chemical vapor deposition (CVD) methods, with an emphasis on varying the deposition temperature. Comprehensive characterization techniques such as atomic force microscopy (AFM), scanning electron microscopy (SEM), and nanoindentation were employed to investigate the morphological and mechanical attributes of these coatings. The thickness of the films, measured using a Dektak profilometer, demonstrated an increase from 1.9 to 2.8 µm as the deposition temperature rose. Nanoindentation testing revealed that the film deposited at 900°C exhibited the highest hardness (H) and modulus of elasticity (E), measuring 21.95 and 208.3 GPa, respectively. Conversely, the film deposited at 1,000°C showed the lowest values, with H and E at 14.23a and 141.9 GPa, respectively. The H/E ratio of the coatings initially rose from 0.096 to 0.106 as the deposition temperature increased from 800°C to 900°C. However, for deposition temperatures exceeding 900°C the H/E ratio began to decline.
Transforming professional identity of medical teachers in Pakistan by a certificate program in health professions education: a thematic analysis of reflective essays
Authors: Kiran Faiza , Ayub Rukhsana , Rauf Ayesha , Zahoor Asiya
Published: February 2024

Introduction

A teacher’s professional identity development is a dynamic and continuous process that requires rigorous, longitudinal, faculty development initiatives which are designed to work on individual professional growth. Impact of such programs must be evaluated by qualitative means to identify the process of change; The purpose of our study was to investigate whether and how our thoughtfully designed 6-month certificate program has transformed the professional identity of medical teachers.

Methods

The study was conducted in National University of Medical Sciences, Pakistan using thematic analysis, wherein a weekly task of guided reflective writing, on Moodle, was given. Data was analyzed in six phases to achieve credibility and transferability.

Results

By analyzing 202 reflective writings, seven subthemes were identified which manifest transformation in certain aspects of identity of participants and grouped under three major themes. The seven subthemes represent transformative journey of participants and include recognizing millennial learners’ dilemma, identifying learning gaps and overcoming barriers, discovering a newer version of self, alternative frame of thinking, transforming traditional classroom, conducive learning environment and Community of Practice. Three major themes identified were Awareness, Modeling and Socialization which represent three processes bringing transformation in participants.

Conclusion

Our faculty development program has transformed certain aspects of professional identities of medical teachers by incorporating informal teaching strategies of experiential learning, professional socialization, reflections, and role modeling. Participants’ beliefs and practices on teaching were challenged by giving a disorienting dilemma of millennial learners and learning theories. They underwent critical discourse with professional peers and mentors in community of practice, reflected on their traditional teaching practices, acquired new insight, underwent self-discovery, and introduced digitalization and interactive learning strategies within their classrooms.
Association between sarcopenic obesity and mortality in patients on peritoneal dialysis: a prospective cohort study
Authors: Shen Yiwei , Su Xinyu , Yu Zanzhe , Yan Hao , Ma Dahua , Xu Yimei , Yuan Jiangzi , Ni Zhaohui , Gu Leyi , Fang Wei
Published: February 2024

Background

Whether sarcopenic obesity had unfavorable effect on survival of peritoneal dialysis (PD) patients is unknown. We aimed to investigate the association between sarcopenic obesity and survival in PD patients.

Methods

This was a prospective observational study. Eligible PD patients from November 2016 to December 2017 were enrolled and followed until August 31, 2023. Sarcopenia was defined following the recommendations of the Asian Working Group for Sarcopenia (AWGS) as low appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS). Obesity was defined using the percentage of body fat (PBF). Survival analysis was conducted using the Kaplan–Meier and log-rank test. The Cox regression and the cumulative incidence competing risk (CICR) analyzes were used to investigate the association between sarcopenic obesity and all-cause mortality.

Results

A total of 223 patients were enrolled with 133 (59.6%) males, a median age of 57.5 (44.6, 65.7) years, a median dialysis vintage of 20.3 (6.4, 57.7) months and 48 (21.5%) who had comorbid diabetes mellitus. Among them, 46 (20.6%) patients were sarcopenic, and 25 (11.2%) patients were diagnosed with sarcopenic obesity. After followed up for 51.6 (25.6, 73.9) months, the Kaplan–Meier curve showed the sarcopenic obesity (log-rank = 13.527, p < 0.001) group had significant lower survival rate compared to the nonsarcopenic non-obesity group. For multivariate analysis, the CICR method showed patients with sarcopenic obesity had significantly higher mortality rate (HR: 2.190, 95% CI: 1.011–4.743, p = 0.047) compared to those with nonsarcopenic non-obesity.

Conclusion

Sarcopenia is not uncommon in PD patients, with a considerable proportion having sarcopenic obesity. There is a significant association between sarcopenic obesity and an increased risk of mortality in PD patients.
Identification of closely related species in Aspergillus through Analysis of Whole-Genome
Authors: Qi Guihong , Hao Lijun , Gan Yutong , Xin Tianyi , Lou Qian , Xu Wenjie , Song Jingyuan
Published: February 2024

The challenge of discriminating closely related species persists, notably within clinical diagnostic laboratories for invasive aspergillosis (IA)-related species and food contamination microorganisms with toxin-producing potential. We employed Analysis of the whole-GEnome (AGE) to address the challenges of closely related species within the genus Aspergillus and developed a rapid detection method. First, reliable whole genome data for 77 Aspergillus species were downloaded from the database, and through bioinformatic analysis, specific targets for each species were identified. Subsequently, sequencing was employed to validate these specific targets. Additionally, we developed an on-site detection method targeting a specific target using a genome editing system. Our results indicate that AGE has successfully achieved reliable identification of all IA-related species (Aspergillus fumigatus, Aspergillus niger, Aspergillus nidulans, Aspergillus flavus, and Aspergillus terreus) and three well-known species (A. flavus, Aspergillus parasiticus, and Aspergillus oryzae) within the Aspergillus section. Flavi and AGE have provided species-level-specific targets for 77 species within the genus Aspergillus. Based on these reference targets, the sequencing results targeting specific targets substantiate the efficacy of distinguishing the focal species from its closely related species. Notably, the amalgamation of room-temperature amplification and genome editing techniques demonstrates the capacity for rapid and accurate identification of genomic DNA samples at a concentration as low as 0.1 ng/μl within a concise 30-min timeframe. Importantly, this methodology circumvents the reliance on large specialized instrumentation by presenting a singular tube operational modality and allowing for visualized result assessment. These advancements aptly meet the exigencies of on-site detection requirements for the specified species, facilitating prompt diagnosis and food quality monitoring. Moreover, as an identification method based on species-specific genomic sequences, AGE shows promising potential as an effective tool for epidemiological research and species classification.
Pan-genome analysis of Streptococcus suis serotype 2 highlights genes associated with virulence and antibiotic resistance
Authors: Zhou You , Tu Teng , Yao Xueping , Luo Yan , Yang Zexiao , Ren Meishen , Zhang Ge , Yu Yuanyuan , Lu Aiping , Wang Yin
Published: February 2024

Streptococcus suis serotype 2 (SS2) is a Gram-positive bacterium. It is a common and significant pathogen in pigs and a common cause of zoonotic meningitis in humans. It can lead to sepsis, endocarditis, arthritis, and pneumonia. If not diagnosed and treated promptly, it has a high mortality rate. The pan-genome of SS2 is open, and with an increasing number of genes, the core genome and accessory genome may exhibit more pronounced differences. Due to the diversity of SS2, the genes related to its virulence and resistance are still unclear. In this study, a strain of SS2 was isolated from a pig farm in Sichuan Province, China, and subjected to whole-genome sequencing and characterization. Subsequently, we conducted a Pan-Genome-Wide Association Study (Pan-GWAS) on 230 strains of SS2. Our analysis indicates that the core genome is composed of 1,458 genes related to the basic life processes of the bacterium. The accessory genome, consisting of 4,337 genes, is highly variable and a major contributor to the genetic diversity of SS2. Furthermore, we identified important virulence and resistance genes in SS2 through pan-GWAS. The virulence genes of SS2 are mainly associated with bacterial adhesion. In addition, resistance genes in the core genome may confer natural resistance of SS2 to fluoroquinolone and glycopeptide antibiotics. This study lays the foundation for further research on the virulence and resistance of SS2, providing potential new drug and vaccine targets against SS2.
Harnessing microRNA-enriched extracellular vesicles for liquid biopsy
Authors: Ko Song Yi , Lee WonJae , Naora Honami
Published: February 2024

Extracellular microRNAs (miRNAs) can be detected in body fluids and hold great potential as cancer biomarkers. Extracellular miRNAs are protected from degradation by binding various proteins and through their packaging into extracellular vesicles (EVs). There is evidence that the diagnostic performance of cancer-associated extracellular miRNAs can be improved by assaying EV-miRNA instead of total cell-free miRNA, but several challenges have hampered the advancement of EV-miRNA in liquid biopsy. Because almost all types of cells release EVs, cancer cell-derived EVs might constitute only a minor fraction of EVs in body fluids of cancer patients with low volume disease. Furthermore, a given cell type can release several subpopulations of EVs that vary in their cargo, and there is evidence that the majority of EVs contain low copy numbers of miRNAs. In this mini-review, we discuss the potential of several candidate EV membrane proteins such as CD147 to define cancer cell-derived EVs, and approaches by which subpopulations of miRNA-rich EVs in body fluids might be identified. By integrating these insights, we discuss strategies by which EVs that are both cancer cell-derived and miRNA-rich could be isolated to enhance the diagnostic performance of extracellular miRNAs.
Human stem cell transplantation models of Alzheimer’s disease
Authors: Ifediora Nkechime , Canoll Peter , Hargus Gunnar
Published: February 2024

Alzheimer’s disease (AD) is the most frequent form of dementia. It is characterized by pronounced neuronal degeneration with formation of neurofibrillary tangles and deposition of amyloid β throughout the central nervous system. Animal models have provided important insights into the pathogenesis of AD and they have shown that different brain cell types including neurons, astrocytes and microglia have important functions in the pathogenesis of AD. However, there are difficulties in translating promising therapeutic observations in mice into clinical application in patients. Alternative models using human cells such as human induced pluripotent stem cells (iPSCs) may provide significant advantages, since they have successfully been used to model disease mechanisms in neurons and in glial cells in neurodegenerative diseases in vitro and in vivo. In this review, we summarize recent studies that describe the transplantation of human iPSC-derived neurons, astrocytes and microglial cells into the forebrain of mice to generate chimeric transplantation models of AD. We also discuss opportunities, challenges and limitations in using differentiated human iPSCs for in vivo disease modeling and their application for biomedical research.
A selective defect in the glial wedge as part of the neuroepithelium disruption in hydrocephalus development in the mouse hyh model is associated with complete corpus callosum dysgenesis
Authors: Rodríguez-Pérez Luis-Manuel , López-de-San-Sebastián Javier , de Diego Isabel , Smith Aníbal , Roales-Buján Ruth , Jiménez Antonio J. , Paez-Gonzalez Patricia
Published: February 2024

Introduction

Dysgenesis of the corpus callosum is present in neurodevelopmental disorders and coexists with hydrocephalus in several human congenital syndromes. The mechanisms that underlie the etiology of congenital hydrocephalus and agenesis of the corpus callosum when they coappear during neurodevelopment persist unclear. In this work, the mechanistic relationship between both disorders is investigated in the hyh mouse model for congenital hydrocephalus, which also develops agenesis of the corpus callosum. In this model, hydrocephalus is generated by a defective program in the development of neuroepithelium during its differentiation into radial glial cells.

Methods

In this work, the populations implicated in the development of the corpus callosum (callosal neurons, pioneering axons, glial wedge cells, subcallosal sling and indusium griseum glial cells) were studied in wild-type and hyh mutant mice. Immunohistochemistry, mRNA in situ hybridization, axonal tracing experiments, and organotypic cultures from normal and hyh mouse embryos were used.

Results

Our results show that the defective program in the neuroepithelium/radial glial cell development in the hyh mutant mouse selectively affects the glial wedge cells. The glial wedge cells are necessary to guide the pioneering axons as they approach the corticoseptal boundary. Our results show that the pioneering callosal axons arising from neurons in the cingulate cortex can extend projections to the interhemispheric midline in normal and hyh mice. However, pioneering axons in the hyh mutant mouse, when approaching the area corresponding to the damaged glial wedge cell population, turned toward the ipsilateral lateral ventricle. This defect occurred before the appearance of ventriculomegaly.

Discussion

In conclusion, the abnormal development of the ventricular zone, which appears to be inherent to the etiology of several forms of congenital hydrocephalus, can explain, in some cases, the common association between hydrocephalus and corpus callosum dysgenesis. These results imply that further studies may be needed to understand the corpus callosum dysgenesis etiology when it concurs with hydrocephalus.
RETRACTED: Comparison of the effects of EGF, FGF-b, and NGF on the proliferation, migration, and reprogramming of primary rat Müller cells
Authors: Liao Yanying , Wu Miaoqin
Published: February 2024

Purpose

During the healing process of full-thickness macular holes (FTMHs), the closure and recovery of the hole depend on the migration, proliferation, and activation of Müller cells to promote the closure of holes and restoration of the photosensitive layer. In this study, we investigated the ability of the epidermal growth factor (EGF), fibroblast growth factor-basic (FGF-b), and nerve growth factor (NGF) to influence this process by regulating proliferation, migration, and reprogramming of primary rat Müller cells.

Methods

Cell proliferation was measured using CCK8 [2- (2-Methoxy-4-nitrophenyl)-3- (4-nitrophenyl)-5- (2,4-disulfophenyl)-2H-tetrazolium Sodium Salt] colorimetric assays and EdU [5-Ethynyl-2′-deoxyuridine] assays over 48 h. Cell migration was measured using scratch-wound assays and transwell migration assays over 48 h. In addition, we conducted Western blot assays and immunofluorescence assays on cells that were specially treated for 1, 3, and 5 days for cell reprogramming. The percentage of EdU-positive cells in Nestin-positive have also been tested by co-immunofluorescence (Co-IF) staining.

Results

EGF and FGF-b significantly promoted the proliferation of Müller cells (p < 0.05) at a concentration of 0–50 ng/mL, but NGF did not (p > 0.05), compared to untreated controls. Exogenous FGF-b and EGF promote the reprogramming of primary rat Müller cells, significantly enhancing the neural stem cell marker Nestin after stimulation on the 1st, 3rd, and 5th days, respectively. The expression of Müller cell marker Vimentin was significantly (p < 0.05) reduced during this period compared to the control group. However, there was no significant difference between the NGF and control groups. Furthermore, the EGF group expressed stronger Nestin expression than the SCM group. The Co-IF staining showed that early 50% of activated cells came from newly proliferating cells on the 5th day.

Conclusion

These observations suggest that FGF-b can promote the activation of Müller cells in a short time and enhance the possessive features of neural stem cells, while EGF may act for a longer period of time. This may further the understanding of growth factor therapy in treating FTMHs, and Müller glia may be promising candidates for cell replacement therapy.
Innate lymphoid cells in neuroinflammation
Authors: Kveštak Daria , Mihalić Andrea , Jonjić Stipan , Brizić Ilija
Published: February 2024

Innate lymphoid cells (ILCs) are largely tissue-resident cells that participate in the maintenance of tissue homeostasis and react early to inflammatory events. Mature ILCs are divided into three major groups based on the transcription factors required for their development and function. Under physiological conditions, ILCs are present within the choroid plexus and meninges while the CNS parenchyma is almost devoid of these cells. However, pathological conditions such as autoimmune neuroinflammation and viral infections of the CNS result in the infiltration of ILCs into parenchyma. In this article, we provide an overview of the involvement and function of the ILCs within the CNS during physiological conditions and in infections, autoimmune diseases, neurodegeneration, and injury.
Motor and neurocognitive profiles of children with symptomatic spinal muscular atrophy type 1 with two copies of SMN2 before and after treatment: a longitudinal observational study
Authors: Bitetti Ilaria , Manna Maria Rosaria , Stella Roberto , Varone Antonio
Published: February 2024

Introduction

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. In clinical studies, gene replacement therapy with onasemnogene abeparvovec (formerly AVXS-101, Zolgensma®, Novartis) was efficacious in improving motor functioning in children with SMA. However, its effects on cognitive and language skills are largely unknown.

Methods

This longitudinal observational study evaluated changes in motor and neurocognitive functioning over a 1-year period after administration of onasemnogene abeparvovec in 12 symptomatic SMA type 1 patients with two copies of SMN2 aged 1.7–52.6 months at administration. Motor functioning was measured using the Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) while neurocognitive assessment was measured using Griffiths III. Motor milestones and language ability were also assessed at each timepoint.

Results and discussion

Statistically significant increases in median CHOP-INTEND scores from baseline were observed at 1, 3, 6, and 12 months after onasemnogene abeparvovec administration (all p ≤ 0.005). Most (91.7%) patients were able to roll over or sit independently for >1 min at 12 months. Significant increases in the Griffiths III Foundations of Learning, Language and Communication, Eye and Hand Coordination, and Personal-Social-Emotional subscale scores were observed at 12-months, but not in the Gross Motor subscale. Speech and language abilities progressed in most patients. Overall, most patients showed some improvement in cognitive and communication performance after treatment with onasemnogene abeparvovec in addition to significant improvement in motor functioning and motor milestones. Evaluation of neurocognitive function should be considered when assessing the global functioning of patients with SMA.
Optimizing adjuvant treatment options for patients with glioblastoma
Authors: Zhu Enzhao , Wang Jiayi , Shi Weizhong , Jing Qi , Ai Pu , Shan Dan , Ai Zisheng
Published: February 2024

Background

This study focused on minimizing the costs and toxic effects associated with unnecessary chemotherapy. We sought to optimize the adjuvant therapy strategy, choosing between radiotherapy (RT) and chemoradiotherapy (CRT), for patients based on their specific characteristics. This selection process utilized an innovative deep learning method.

Methods

We trained six machine learning (ML) models to advise on the most suitable treatment for glioblastoma (GBM) patients. To assess the protective efficacy of these ML models, we employed various metrics: hazards ratio (HR), inverse probability treatment weighting (IPTW)-adjusted HR (HRa), the difference in restricted mean survival time (dRMST), and the number needed to treat (NNT).

Results

The Balanced Individual Treatment Effect for Survival data (BITES) model emerged as the most effective, demonstrating significant protective benefits (HR: 0.53, 95% CI, 0.48–0.60; IPTW-adjusted HR: 0.65, 95% CI, 0.55–0.78; dRMST: 7.92, 95% CI, 7.81–8.15; NNT: 1.67, 95% CI, 1.24–2.41). Patients whose treatment aligned with BITES recommendations exhibited notably better survival rates compared to those who received different treatments, both before and after IPTW adjustment. In the CRT-recommended group, a significant survival advantage was observed when choosing CRT over RT (p < 0.001). However, this was not the case in the RT-recommended group (p = 0.06). Males, older patients, and those whose tumor invasion is confined to the ventricular system were more frequently advised to undergo RT.

Conclusion

Our study suggests that BITES can effectively identify GBM patients likely to benefit from CRT. These ML models show promise in transforming the complex heterogeneity of real-world clinical practice into precise, personalized treatment recommendations.
Neuroinflammation and acquired traumatic CNS injury: a mini review
Authors: Theus Michelle H.
Published: February 2024

Acquired traumatic central nervous system (CNS) injuries, including traumatic brain injury (TBI) and spinal cord injury (SCI), are devastating conditions with limited treatment options. Neuroinflammation plays a pivotal role in secondary damage, making it a prime target for therapeutic intervention. Emerging therapeutic strategies are designed to modulate the inflammatory response, ultimately promoting neuroprotection and neuroregeneration. The use of anti-inflammatory agents has yielded limited support in improving outcomes in patients, creating a critical need to re-envision novel approaches to both quell deleterious inflammatory processes and upend the progressive cycle of neurotoxic inflammation. This demands a comprehensive exploration of individual, age, and sex differences, including the use of advanced imaging techniques, multi-omic profiling, and the expansion of translational studies from rodents to humans. Moreover, a holistic approach that combines pharmacological intervention with multidisciplinary neurorehabilitation is crucial and must include both acute and long-term care for the physical, cognitive, and emotional aspects of recovery. Ongoing research into neuroinflammatory biomarkers could revolutionize our ability to predict, diagnose, and monitor the inflammatory response in real time, allowing for timely adjustments in treatment regimens and facilitating a more precise evaluation of therapeutic efficacy. The management of neuroinflammation in acquired traumatic CNS injuries necessitates a paradigm shift in our approach that includes combining multiple therapeutic modalities and fostering a more comprehensive understanding of the intricate neuroinflammatory processes at play.
The efficacy of contralaterally controlled functional electrical stimulation compared to conventional neuromuscular electrical stimulation for recovery of limb function following a stroke: a systematic review and meta-analysis
Authors: Halawani Alhussain , Aljabri Ammar , Bahathiq Dena M. , Morya Roaa E. , Alghamdi Saeed , Makkawi Seraj
Published: February 2024

Introduction

Limb paresis following a stroke is a common sequela that can impact patients’ quality of life. Many rehabilitation strategies targeting the restoration of motor function exist. This systematic review and meta-analysis aim to evaluate the effects of contralaterally controlled functional electrical stimulation (CCFES) as a modality for limb rehabilitation. Unlike conventional neuromuscular electrical simulation (NMES), the contra-laterality in CCFES is achieved by two methods a bend angle sensor or an electromyographic bridge (EMGB) method, both of which targets signals from the unaffected limb.

Method

This review study was performed following the preferred reporting item for systematic review and meta-analysis (PRISMA) guidelines. Records that met the inclusion criteria were extracted from the following databases: Medline, Embase, and Cochrane Register of Controlled Trials (CENTRAL). Additional articles were also retrieved from clinicaltrials.gov and China/Asia on Demand (CAOD). Only randomized controlled studies (RCTs) were included.

Results

Sixteen RCTs met the inclusion criteria, and 14 of which were included in the quantitative analysis (meta-analysis). The results of the analysis show that when compared to conventional NMES, CCFES displayed a better improvement in the upper extremity Fugl–Meyer assessment (UEFMA) (SMD = 0.41, 95% CI: 0.21, 0.62, p-value <0.0001, I2 = 15%, GRADE: moderate), box and blocks test (BBT) (SMD = 0.48, 95% CI: 0.10, 0.86, p-value = 0.01, I2 = 0%, GRADE: very low), modified Barthel index (mBI) (SMD = 0.44, 95% CI: 0.16, 0.71, p-value = 0.002, I2 = 0%, GRADE: moderate), active range of motion (AROM) (SMD = 0.61, 95% CI: 0.29, 0.94, p-value = 0.0002, I2 = 23%, GRADE: moderate), and surface electromyography (sEMG) scores (SMD = 0.52, 95% CI: 0.14, 0.90, p-value = 0.008, I2 = 0%, GRADE: low). The results of the subgroup analysis for the type of sensor used in CCFES shows that an EMGB (SMD = 0.58, 95% CI: 0.33, 0.84, p-value <0.00001, I2 = 7%) is more effective than a bend angle sensor (SMD = 0.17, 95% CI: −0.12, 0.45, p-value = 0.25, I2 = 0%).

Conclusion

The results of this study provide strong evidence that shows CCFES being a better electrical stimulation modality compared to conventional NMES. This could be explained by the fact that CCFES is bilateral in nature which offers a platform for better neuroplasticity following a stroke. There is still a need for high-quality studies with a standardized approach comparing CCFES to other treatment modalities.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=342670, identifier CRD42022342670.
Comparing feature selection and machine learning approaches for predicting CYP2D6 methylation from genetic variation
Authors: Fong Wei Jing , Tan Hong Ming , Garg Rishabh , Teh Ai Ling , Pan Hong , Gupta Varsha , Krishna Bernadus , Chen Zou Hui , Purwanto Natania Yovela , Yap Fabian , Tan Kok Hian , Chan Kok Yen Jerry , Chan Shiao-Yng , Goh Nicole , Rane Nikita , Tan Ethel Siew Ee , Jiang Yuheng , Han Mei , Meaney Michael , Wang Dennis , Keppo Jussi , Tan Geoffrey Chern-Yee
Published: February 2024

Introduction

Pharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related toCYP2D6in children from the GUSTO cohort.

Methods

Buffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated withCYP2D6were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of theCYP2D6gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models’ performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites.

Results

Overall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model.

Discussion

The development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing.