bluuebunny/crossref_metadata_2025 huggingface dataset:
Curcumin-incorporated EGCG-based nano-antioxidants alleviate colon and kidney inflammation via antioxidant and anti-inflammatory therapy
Authors: Pan Qingqing , Xie Li , Zhu Huang , Zong Zhihui , Wu Di , Liu Rong , He Bin , Pu Yuji
Published: October 2024

Natural remedies are gaining attention as promising approaches to alleviating inflammation, yet their full potential is often limited by challenges such as poor bioavailability and suboptimal therapeutic effects. To overcome these limitations, we have developed a novel nano-antioxidant (EK) based on epigallocatechin gallate (EGCG) aimed at enhancing the oral and systemic bioavailability, as well as the anti-inflammatory efficacy, of curcumin (Cur) in conditions such as acute colon and kidney inflammation. EK is synthesized using a straightforward Mannich reaction between EGCG and L-lysine (K), resulting in the formation of EGCG oligomers. These oligomers spontaneously self-assemble into nanoparticles with a spherical morphology and an average diameter of approximately 160 nm. In vitro studies reveal that EK nanoparticles exhibit remarkable radical-scavenging capabilities and effectively regulate redox processes within macrophages, a key component in the body’s inflammatory response. By efficiently encapsulating curcumin within these EK nanoparticles, we create Cur@EK, a formulation that demonstrates a synergistic anti-inflammatory effect. Specifically, Cur@EK significantly reduces the levels of pro-inflammatory cytokines TNF-α and IL-6 while increasing the anti-inflammatory cytokine IL-10 in lipopolysaccharide-stimulated macrophages, highlighting its potent anti-inflammatory properties. When administered either orally or intravenously, Cur@EK shows superior bioavailability compared to free curcumin and exhibits pronounced anti-inflammatory effects in mouse models of ulcerative colitis and acute kidney injury. These findings suggest that the EK nano-antioxidant platform not only enhances the bioavailability of curcumin but also amplifies its therapeutic impact, offering a promising new avenue for the treatment and management of inflammation in both oral and systemic contexts.
FAM13A polymorphism is associated with a usual interstitial pneumonia pattern in patients with systemic sclerosis-associated interstitial lung disease
Authors: Bernstein Elana J , Boin Francesco , Elicker Brett , Luo Yiming , Ren Yawen , Zhang Meng , Varga John , Assassi Shervin
Published: October 2024

Objectives

The MUC5B promoter single nucleotide polymorphism (SNP) rs35705950 has been associated with idiopathic pulmonary fibrosis (IPF) and RA-related interstitial lung disease (ILD), but not with SSc-ILD. We hypothesized that the MUC5B promoter polymorphism or other IPF susceptibility loci are associated with an increased risk for the uncommon SSc-usual interstitial pneumonia (UIP) endophenotype, rather than SSc-ILD in general.

Methods

We performed a cross-sectional study of SSc-ILD patients from four US Scleroderma Programs to investigate the frequency of MUC5B rs35705950 and 12 additional IPF susceptibility loci. SSc-ILD patients were stratified by high resolution chest CT (HRCT) imaging findings into UIP and non-UIP groups. Analysis of HRCTs performed by a thoracic radiologist blinded to participants’ characteristics classified each scan as definite UIP, probable UIP, indeterminate or alternative diagnosis, according to American Thoracic Society criteria.

Results

Four-hundred and eighty-nine SSc-ILD patients were included; 80% were female and 75% were White. Twenty-three (4.7%) patients had a definite UIP pattern. The MUC5B SNP rs35705950 was not associated with a definite UIP pattern in SSc-ILD. In contrast, patients carrying two copies of the IPF risk gene FAM13A minor allele rs2609255 had significantly higher odds of a definite UIP pattern compared with the other patterns (odds ratio 3.40, 95% CI 1.19–9.70), and compared with an alternative diagnosis (odds ratio 3.65, 95% CI 1.25–10.65).

Conclusion

We demonstrated a novel association between FAM13A and SSc-UIP. Contrary to IPF and RA-ILD, the MUC5B promoter polymorphism was not associated with a definite UIP pattern in SSc-ILD.
Genomic epidemiology reveals the variation and transmission properties of SARS-CoV-2 in a single-source community outbreak
Authors: Zhao Ning , He Min , Wang HengXue , Zhu LiGuo , Wang Nan , Yong Wei , Fan HuaFeng , Ding SongNing , Ma Tao , Zhang Zhong , Dong XiaoXiao , Wang ZiYu , Dong XiaoQing , Min XiaoYu , Zhang HongBo , Ding Jie
Published: October 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic, which is still a global public health concern. During March 2022, a rapid and confined single-source outbreak of SARS-CoV-2 was identified in a community in Nanjing municipal city. Overall, 95 individuals had laboratory-confirmed SARS-CoV-2 infection. The whole genomes of 61 viral samples were obtained, which were all members of the BA.2.2 lineage and clearly demonstrated the presence of one large clade, and all the infections could be traced back to the original index case. The most distant sequence from the index case presented a difference of 4 SNPs, and 118 intrahost single-nucleotide variants (iSNVs) at 74 genomic sites were identified. Some minor iSNVs can be transmitted and subsequently rapidly fixed in the viral population. The minor iSNVs transmission resulted in at least two nucleotide substitutions among all seven SNPs identified in the outbreak, generating genetically diverse populations. We estimated the overall transmission bottleneck size to be 3 using 11 convincing donor–recipient transmission pairs. Our study provides new insights into genomic epidemiology and viral transmission, revealing how iSNVs become fixed in local clusters, followed by viral transmission across the community, which contributes to population diversity.
Eight novel diagnostic markers differentiate lineages of the highly invasive myrtle rust pathogen Austropuccinia psidii
Authors: Luo Zhenyan , Feng Jinghang , Bird Austin , Moeller Mareike , Tam Rita , Shepherd Luc , Murphy Lydia , Singh Lavi , Graetz Abigail , Amorim Lilian , Massola Júnior Nelson Sidnei , Prodhan M. Asaduzzaman , Shuey Louise S. , Beattie Douglas , Gonzalez Alejandro Trujillo , Tobias Peri , Padovan Amanda , Kimber Rohan Benjamin Essex , McTaggart A. R. , Kehoe Monica , Schwessinger Benjamin , Boufleur Thais Regina
Published: October 2024

Austropuccinia psidii is the causal agent of myrtle rust in over 480 species within the family Myrtaceae. Lineages of A. psidii are structured by their hosts in the native range, and some have success in infecting newly encountered hosts. For example, the pandemic biotype has spread beyond South America, and proliferation of other lineages is an additional risk to biodiversity and industries. Efforts to manage A. psidii incursions, including lineage differentiation, relies on variable microsatellite markers. Testing these markers is time-consuming, complex, and requires reference material that is not always readily available. We designed a novel diagnostic approach targeting eight selectively chosen loci including the fungal mating-type HD (homeodomain) transcription factor locus. The HD locus (bW1/2-HD1 and bE1/2-HD2) is highly polymorphic, facilitating clear biological predictions about its inheritance from founding populations. To be considered as potentially derived from the same lineage, all four HD alleles must be identical. If all four HD alleles are identical six additional markers can further differentiate lineage identity. Our lineage diagnostics relies on PCR amplification of eight loci in different genotypes of A. psidii followed by amplicon sequencing using Oxford Nanopore Technologies (ONT) and comparative analysis. The lineage-specific assay was validated on four isolates with existing genomes, uncharacterized isolates, and directly from infected leaf material. We reconstructed alleles from amplicons and confirmed their sequence identity relative to their reference. Genealogies of alleles confirmed the variations at the loci among lineages/isolates. Our study establishes a robust diagnostic tool for differentiating known lineages of A. psidii based on biological predictions and available nucleotide sequences. This tool is suited to detecting the origin of new pathogen incursions.
MOR23 deficiency exacerbates hepatic steatosis in mice
Authors: Kang Wesuk , Yang Suhjin , Roh Jiyun , Choi Dabin , Lee Han‐Woong , Lee Jae Hoon , Park Taesun
Published: October 2024

Hepatic steatosis, a common liver disorder, can progress to severe conditions such as nonalcoholic steatohepatitis and cirrhosis. While olfactory receptors are primarily known for detecting odorants, emerging evidence suggests that they also influence liver lipid metabolism. This study generated a mouse model with a specific knockout of olfactory receptor 23 (MOR23) to investigate its role in hepatic steatosis. MOR23 knockout mice on a normal diet showed a slight increase in liver weight compared to wild‐type (WT) mice. When fed a high‐fat diet (HFD), these knockout mice exhibited accelerated hepatic steatosis, indicated by increased liver weight and hepatic triglyceride levels. Our findings suggest that the cyclic adenosine monophosphate/protein kinase A/AMP‐activated protein kinase pathway is involved in the role of MOR23, leading to the upregulation of peroxisome proliferator‐activated receptor α, peroxisome proliferator‐activated receptor‐γ coactivator 1‐α, and their target β‐oxidation genes in the liver. MOR23 also appeared to regulate lipogenesis and free fatty acid uptake in HFD‐fed mice, potentially by influencing sterol regulatory element‐binding protein 1 activity. Notably, administering a potential MOR23 ligand, cedrene, attenuated hepatic steatosis in WT mice, but these effects were largely nullified in MOR23 knockout mice. These findings provide valuable insights into the in vivo role of MOR23 in hepatic steatosis development.
Control versus Choice in Deciding Career Pathway in Plastic Surgery: The Perfect Ratio
Authors: Davison Steven P. , Evans Gregory , Ball Eleanor , Newman Ashley , Sotile Wayne
Published: October 2024

Background:

The decisions and components of a career in medicine have changed. Historically, a career selection was often a decision between joining an institution or academic center versus the fiscal risks associated with private practice. This created a relatively simple risk versus reward equation: those in private practice made more money if it went well. The medical landscape has changed immensely, and priorities and remuneration have morphed, including concerns about promoting and sustaining well-being.

Methods:

The authors performed a systematic review of scholarly databases to identify relevant resources to the topic of study. Additionally, the authors relied on their own cumulative experience in the field, including the work of Dr. Wayne Sotile of the Sotile Center for Physician Resilience.

Results:

The first installment of this article proposes a new model in opposition to the current standard of “risk versus reward” where the tradeoff is instead “control versus choice,” where autonomy is the new risk.

Conclusions:

The five components that make up the majority of the ingredients in a plastic surgery career are clinical practice model, administrative duty, corporate support, academic involvement, and per diem or retainers. Much of finding or developing a practice model that suits the individual is figuring out an acceptable ratio of these ingredients. Inherent to this process is how much authority one has versus instituted control of any form, from hospital to university to insurance company.
Conservative treatment of iatrogenic tracheal injury: Our experience
Authors: Familiari Dario , Rizzo Rossana , Valenti Elena , Nunnari Flavia , Sibilio Michele , Marando Rosario , Pino Giancarlo , Monaco Francesco
Published: October 2024

Iatrogenic tracheal injury is a rare and potentially life-threatening condition that can occur after a healthcare procedure. In our experience in the last 5 years, we have seen 12 iatrogenic tracheal injury patients (five from other units of our hospital and seven from other hospitals of the province) as a consequence of endotracheal intubation using a single lumen tube, treated with conservative management. Conservative management is recommended for lesions of level I, II, and IIIA according to the classification of Cardillo et al. The 30-day morbidity and mortality rates were null; all injuries were completely healed at 1 month without any relapse at 3–6 months’ endoscopic follow-up.
THE FIGHT INHERITED RETINAL BLINDNESS! PROJECT
Authors: Simunovic Matthew P. , Moore Anthony T. , Grigg John , Sergouniotis Panagiotis , Mahroo Omar A. , Vincent Andrea , Singh Mandeep , Fischer M. Dominik , Edwards Thomas , Mack Heather , Hogden Michael , Chen Fred K. , Hewitt Alex , Ayton Lauren , Leroy Bart , Jamieson Robyn , Gillies Mark C. , Barthelmes Daniel
Published: October 2024

Purpose:

To design and build a new disease registry to track the natural history and outcomes of approved gene therapy in patients with inherited retinal diseases.

Methods:

A core committee of six members was convened to oversee the construction of the Fight Inherited Retinal Blindness! module. A further 11 experts formed a steering committee, which discussed disease classification and variables to form minimum datasets using a consensus approach.

Results:

The web-based Fight Inherited Retinal Blindness! registry records baseline demographic, clinical, and genetic data together with follow-up data. The Human Phenotype Ontology and Monarch Disease Ontology nomenclature were incorporated within the Fight Inherited Retinal Blindness! architecture to standardize nomenclature. The registry software assigns individual diagnoses to one of seven broad phenotypic groups, with minimum datasets dependent on the broad phenotypic group. In addition, minimum datasets were agreed on for patients undergoing approved gene therapy with voretigene neparvovec (Luxturna). New patient entries can be completed in 5 minutes, and follow-up data can be entered in 2 minutes.

Conclusion:

Fight Inherited Retinal Blindness! is an organized, web-based system that uses observational study methods to collect uniform data from patients with inherited retinal disease to track natural history and (uniquely) treatment outcomes. It is free to users who have control over their data.
Patient perspectives towards skin of color clinics: results from a survey study
Authors: Cao Severine , Thomas Reinie , Mansour Meghan , Ramirez Juliana L. , Hile Grace , Castanedo-Tardan Mari Paz , Eshaq Milad
Published: October 2024

Background:

Skin of color clinics (SOCCs) are dermatology clinics that provide specialized care for patients with melanated skin. Little is known about patient perceptions and attitudes toward these clinics.

Objective:

We sought to perform a survey study to assess the opinions of patients of color previously seen in our dermatology department toward SOCC.

Methods:

A 14-question survey was sent by email to patients of color seen at our institution between January 1, 2015 and December 31, 2021.

Results:

Out of 264 participants who completed the survey, 176 (66.7%) indicated they would prefer to be seen in a SOCC and 88 (33.3%) preferred to be seen in a general dermatology clinic (GDC). Clinic choice varied significantly by ethnicity, with Black/African American participants being the most likely to prefer SOCC over GDC than other races/ethnicities. Those interested in SOCC were primarily motivated by a search for expertise in the skin of color (SOC) and did not have a preference for the skin color of the SOCC dermatologist. Those interested in GDC were happy with their current care.

Limitations:

This study was limited by the single-center design and sample bias.

Conclusion:

Our results overall provide positive patient feedback for the creation of SOCCs as centers for expertise in SOC. The preference for SOCC varied by race/ethnicity, highlighting that clinic choice is best left to the patient.
The effect of PSMA PET/CT on clinical decision-making of radical prostatectomy and pelvic lymph node dissection
Authors: Özman Oktay , Veerman Hans , Hagens Marinus J. , van Leeuwen Pim J. , Vis André N. , van der Poel Henk G.
Published: October 2024

Objective

To evaluate the effect of prostate-specific membrane antigen (PSMA) PET/computed tomography (CT) on clinical decision-making of radical prostatectomy (RP) and pelvic lymph node dissection (PLND) after its utilization in daily clinical practice at an European high-volume cancer center.

Materials and methods

Patients who had unfavorable intermediate- and high-risk prostate cancer between 2017 and 2021 were included retrospectively and divided into two groups; those who staged using PSMA PET/CT (group 1) and those who staged using conventional modalities (group 2). Clinical decision-making of RP over nonsurgical treatments and f PLND were primary endpoints and evaluated using regression models.

Results

PSMA PET/CT claimed significantly more N1 (24.2% vs. 11.3%; P = 0.01; OR, 1.97; 95% CI, 1.18–3.28) but insignificantly more M1 disease (9.9% vs. 5.7%; P = 0.42; OR, 1.91; 95% CI, 0.39–9.23), compared with the conventional imaging modalities. miN0 stage was related to more RP decisions compared with cN0 stage (P < 0.001; OR, 1.91; 95% CI, 1.48–2.46). PLND decision-making was significantly driven by positive c\miN stage findings, which were more reliable when it was reported after a PSMA PET/CT examination (P < 0.001; OR, 35.55; 95% CI, 6.74–187.45 for conventional imaging modalities vs. P < 0.001; OR, 91.72; 95% CI, 11.25–747.56 for PSMA PET/CT).

Conclusions

Patients with no suspicion of lymph node invasion on molecular imaging (PSMA PET/CT) tended to be referred to RP more compared to radiological imaging. Also, the PLND decision was strongly driven by staging findings. Compared with conventional imaging, PSMA PET/CT findings were more reliable during PLND decision-making.
Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity
Authors: Davidson Michael H. , Hsieh Andrew , Kastelein John J.P.
Published: October 2024

Purpose of review

To review the evidence and describe the biological plausibility for the benefits of inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification of lipoprotein metabolism.

Recent findings

Results from observational studies, Mendelian randomization analyses, and randomized clinical trials support the potential of CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk through a reduction of apolipoprotein B-containing lipoproteins. In contrast, raising high-density lipoprotein (HDL) particles, as previously hypothesized, did not contribute to ASCVD risk reduction. There is also an expanding body of evidence supporting the benefits of CETP inhibition for safeguarding against other conditions associated with aging, particularly new-onset type 2 diabetes mellitus and dementia, as well as age-related macular degeneration, septicemia, and possibly chronic kidney disease. The latter are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.

At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.
Management of pediatric thyroid carcinoma
Authors: Dimachkieh Amy L. , Mahajan Priya
Published: October 2024

Purpose of review

The incidence of thyroid carcinoma is increasing among children and adolescents, particularly in female individuals. Children and adolescents require special considerations in management as the molecular genetics of pediatric thyroid tumors are inherently different from their adult counterparts. The increased risk of malignancy, nodal metastases, and pulmonary metastases in pediatric patients warrants pediatric-specific management recommendations and pediatric-specific multidisciplinary teams.

Recent findings

This article highlights the molecular origins of pediatric thyroid carcinoma and the implications of tumor genetics for the course of disease and treatment considerations. We highlight specific surgical considerations to optimize outcomes while minimizing lifelong risks of vocal paralysis and hypoparathyroidism. The landscape of treatment options is rapidly evolving with development of sophisticated molecular approaches to understand the genetic landscape, and this review features updated recommendations and systemic treatment options for the management of pediatric thyroid malignancy.

Pediatric thyroid carcinoma is a lifelong burden and the treatment tailored to optimize outcomes minimizes long-term risks of treatments, surgery, radiation and targeted systemic therapies. Multidisciplinary teams that treat pediatric thyroid carcinoma should focus surgical experience and use the most updated guidelines and treatments available, particularly considering the landscape of molecular genetics in pediatric thyroid carcinoma.
Superior retention of aged fat graft by supplementing young adipose-derived stromal cells in a murine model
Authors: Tran Vinh Vuong The , Jin Xian , Zhou Xin Ye , Hong Ki Yong , Chang Hak
Published: October 2024

Background:

In 2021, a meta-analysis showed fat graft retention varied from 26 to 83%. In a retrospective study including patients with Parry-Romberg syndrome, the younger age group had higher satisfaction scores (3.8 vs. 3.0) after fat grafting. Cell-assisted lipotransfer (CAL) could be an alternative to overcome the instability of volume loss; however, no study investigated its effect on old recipients.

Methods:

In an in vitro study, adipose-derived stromal cells (ASCs) from aged and young (52- and 8-weeks old) DsRed B6 mice were characterized by proliferation rates as percentages of Ki-67-positive cells. 68-week-old wild type B6 mice received 150 µL of green fluorescent protein fat (from 69-week-old B6 mice) mixed with saline, 3 x 105 aged or young DsRed ASCs (N, A, and Y groups, respectively) on the scalp (n = 6/group). After 8 weeks, graft volumes were evaluated using micro-computed tomography. Vessel densities were tracked by percentages of CD31 using immunofluorescence staining.

Results:

Young ASCs showed higher proliferation than the aged (47.1% and 26.2%, respectively, p < 0.05). The Y group showed the highest graft retention (median: N = 41.0%, A = 52.2%, Y = 65.2%, p < 0.05) and percentage of blood vessels (median: N = 27.7%, A = 43.5%, Y = 54.7%, p < 0.05) among the three groups.

Conclusions

CAL is effective with old recipients; higher effect was observed by supplementation with younger ASCs due to higher angiogenesis stimulation. However, this is autologous grafting model, further validation of safety, toxicity, and allogenic grafting is required.

Clinical Relevance Statement:

The results suggest that it is clinically possible to conduct CAL for old adults using autologous ASCs. However, further validation of using allogenic ASCs from young donors to improve graft retention in old adults is required.
Prenatal and postnatal antiviral therapies for the prevention and treatment of congenital cytomegalovirus infections
Authors: Chandrasekaran Preethi , Lee Han-Shin , Hui Lisa , Schleiss Mark R. , Sung Valerie
Published: October 2024

Purpose of review

Congenital cytomegalovirus infection (cCMV) is the leading infectious cause of sensorineural hearing loss and lifelong neurodevelopmental disabilities. Studies suggest antiviral therapy can prevent fetal infection after maternal primary infection, as well as halt the progression of hearing loss and neurodevelopmental disabilities in newborns with symptomatic cCMV. With growing worldwide momentum on early detection and diagnosis of cCMV, this review describes the exciting recent advances in antiviral therapies in CMV infected pregnant mothers and babies, as well as emerging evidence on anti-CMV vaccines.

Recent findings

New opportunities for prenatal and neonatal interventions have driven a rising interest in screening and identification of asymptomatic CMV infection. Routine screening of pregnant women to identify primary infection in first trimester is now advocated in Western Europe but has yet to be examined from a public health perspective in other regions. Evidence is emerging for maternal valaciclovir therapy to prevent fetal infection after a maternal primary CMV infection in the first trimester of pregnancy. For those infants who are born with symptomatic cCMV, a 6-month course of valganciclovir, started within the first 4 weeks of life, and possibly up to 13 weeks of life, is the current recommended therapy. However, there is unclear evidence for the benefit of treatment for asymptomatic cCMV and cCMV with isolated hearing loss. Research to identify more effective antivirals and an effective CMV vaccine continues.

More research is needed to determine the region-specific applicability of the new European recommendations for routine CMV screening in pregnancy. Areas of uncertainty in postnatal management include timing of initiation, duration of treatment and identifying pediatric subgroups that benefit from modification of the standard treatment recommendations.
Speech Outcomes After Primary Palatoplasty and Presurgical Cleft Characteristics: Is There a Predictive Association?
Authors: Moura Lucas B. , Antoneli Melissa Z. , Passaglia Igor R.G. , Yokoyama Flavio J. , Sampaio Emily C. da Fonseca , Alonso Nivaldo
Published: October 2024

Speech disorders related to cleft lip and palate exhibit different degrees of involvement and can occur even after primary palate repair. Hypernasality can be present as a result of velopharyngeal insufficiency, as well as nasal emission, weak pressure, articulatory errors and facial grimace, affecting speech intelligibility. Palatoplasty outcomes can be variable, and among the influencing factors are the surgical technique, the surgeon’s experience, the postoperative care, and the patient/cleft characteristics. The aim of this study was to correlate speech results after primary palate repair with surgical technique and cleft characteristics, using anthropometric measurements and speech assessment in patients diagnosed with cleft lip and palate. A longitudinal, retrospective study with patients who underwent primary palatoplasty between 2015 and 2019 and still attend Craniomaxillofacial Surgery Outpatient Clinic was conducted. Patients were operated on by a single surgeon using the intravelar technique veloplasty with maximal retropositioning of the soft palate elevator muscle. Patients who underwent primary palatoplasty after 2018 had the measurements before and immediately after palatoplasty recorded: length of palate, and the distances from cleft and uvula to posterior pharyngeal wall, and uvula to adenoid. Considering the total of 39 patients, 30 (76.9%) were male, with a mean age of 20.9 months (9–53 mo). All patients had their speech recorded between ages of 60 and 120 months. Speech samples were assessed by 3 different speech pathologists experienced in cleft speech, with an intrarater and inter-rater reliability >80%. The most frequent cleft type was unilateral complete cleft lip and palate (59%). One patient had mild hyponasality, 1 isolated obligatory disorder (nasal turbulence), and 3 patients presented compensatory articulation (2 isolated and 1 also presented obligatory disorder). Only 1 patient had marginal velopharyngeal insufficiency. Postoperatively, there was a mean increase in palate length from 5.4 to 5.6 cm, and a statistically significant decrease in the distance from the uvula to the pharynx wall, with a mean of 1.7 to 1.1 cm (P<0.001). In general, patients analyzed did not have significant alterations in speech assessment, which did not allow further comparisons and correlation. Therefore, regardless of the anatomic characteristics of the palate, it is possible to achieve good results depending on the handling experience and the technique used.
Epidemiological and virological characteristics of people living with HIV on antiretroviral treatment for more than six months in virological failure in Brazzaville, Republic of Congo
Authors: GOT Ferdinand Emaniel Brel , MALONGA Gervillien Arnold , MALANDA-KIMINOU Juthèce Privat , AKOLBOUT Maryse , LOUBANO-MVOUMBI Ghislain , EBOUROMBI Dagene , DIAFOUKA Merlin , ONDZOTTO Gontran
Published: October 2024

Introduction

Virological failure is one of the major causes of treatment failure, and better management of HIV infection requires understanding and controlling the factors that contribute to this phenomenon. The main objective was to characterize the patients of the active file of the Brazzaville Outpatient Treatment Center in virological failure in order to identify predictive factors that lead to virological failure.

Methods

This was a cross-sectional study conducted between June and December 2020. Patients enrolled were HIV-1 infected patients from the Brazzaville Outpatient Treatment Center receiving a potent combination therapy for at least 6 months but experiencing virological failure. Viral load was determined with the automated Abbott Real-time HIV-1 m2000rt System. Sociodemographic and clinical data were collected from a computerized patient record software called Santia. Statistical analysis was performed to identify independent predictors of virological failure.

Results

A total of 109 patients with virological failure were recruited. The median age of the patients was 45 years (IQR: 37-52 years) and women were more represented (74%). More than half of the patients had WHO stage IV HIV and the median duration on ARV treatment was 96 months. The most followed treatment regimen was AZT+3TC+EFV (or NVP) with 48% while the median viral load was 12,985 copies/mL.

Conclusion

In our study, we did not identify any sociodemographic or clinical variables predictive of virological failure. However, we felt that it would be desirable to carry out a study with temporal follow-up and the possibility of sequencing in order to identify the different circulating genotypes and resistance mutations.
Cystobactamid off-target profiling reveals favorable safety, superoxide reduction, and SCARB1 inhibition in eukaryotes
Authors: Risch Timo , Hellwinkel Benedikt , Mostert Dietrich , Kany Andreas M. , Solga Danny , Seedorf Tim , Heimann Dominik , Hoppstädter Jessica , Kohnhäuser Daniel , Hilgers Jil-Sophie , Fries Franziska , Deschner Felix , Brönstrup Mark , Kirschning Andreas , Sieber Stephan A. , Pietschmann Thomas , Kiemer Alexandra K. , Herrmann Jennifer , Müller Rolf
Published: October 2024

Antimicrobial resistance (AMR) poses a fundamental global threat, necessitating new strategies for effective therapies. Cystobactamids (CYS), a class of antibacterial agents targeting bacterial gyrase and topoisomerase IV, represent a non-traditional chemical scaffold with broad-spectrum activity. For toxicological de-risking, we performed a comprehensive profiling on eukaryotic cells, focusing on cytotoxicity, genotoxicity, and mitochondrial toxicity, demonstrating cellular safety and superoxide scavenging properties. Studies in zebrafish embryos assessed developmental, cardiovascular, and hepatic toxicity, indicating a favorablein vivosafety profile. Metabolism studies revealed glucuronidation and amide bond hydrolysis as key pathways, whereby CYS metabolic stability substantially improved by cobicistat co-treatment. Affinity-based protein profiling identified the cholesterol- and HCV-receptor scavenger receptor class B member 1 (SCARB1) as a primary eukaryotic off-target protein, with cystobactamids shown to inhibit SCARB1’s function, preventing hepatitis C virus pseudoparticle entry into cells. These findings suggest a high therapeutic potential for cystobactamids and highlight SCARB1 as a primary eukaryotic target.
Mapping the epigenomic landscape of post-traumatic stress disorder in human cortical neurons
Authors: Núñez-Ríos Diana L. , Nagamatsu Sheila T. , Martínez-Magaña Jose Jaime , Hurd Yasmin , Rompala Gregory , Krystal John H. ,   Traumatic Stress Brain Research Group, Montalvo-Ortiz Janitza L.
Published: October 2024

Most epigenetic research on post-traumatic stress disorder (PTSD) has primarily focused on DNA methylation (5mC) in peripheral tissues, particularly at CpG sites. DNA hydroxymethylation (5hmC) has been found to be highly enriched in the mammalian brain, while 5mC at non-CpG sites shows high enrichment in neurons. However, little is known about their role in PTSD. Here, we characterize genome-wide differential 5mC and 5hmC at both CpG and non-CpG sites in postmortem orbitofrontal neurons from PTSD cases and controls. Utilizing reduced-representation oxidative bisulfite sequencing, we found that genome-wide significant (GWS) differential CpGs were primarily hyper-5mC/5hmC, whereas GWS differential non-CpGs were hypo-5mC/5hmC. Compared with 5mC, we show that 5hmC is a more sensitive epigenetic mark in PTSD, with a higher number of differential 5hmC sites and a stronger significance in enriched pathways. Integrating other -omics data highlighted developmental processes as significant convergent pathways and revealed overlap of our GWS 5hmC findings with 50 previously reported PTSD-associated genes, including potential therapeutic targets such as CRHR1 and DRD4. This study underscores the importance of evaluating 5hmC in the human brain and our multi-omics integration provides insights into potential target genes for future therapeutic interventions in PTSD.

Graphical abstract

The study conducted a comprehensive genome-wide analysis of differential 5mC and 5hmC modifications at both CpG and non-CpG sites in postmortem orbitofrontal neurons from 25 PTSD cases and 13 healthy controls. It was observed that PTSD patients exhibit a greater number of differential 5hmC sites compared to 5mC sites. Specifically, individuals with PTSD tend to show hyper-5mC/5hmC at CpG sites, particularly within CpG islands and promoter regions, and hypo-5mC/5hmC at non-CpG sites, especially within intragenic regions. Functional enrichment analysis indicated distinct yet interconnected roles for 5mC and 5hmC in PTSD. The 5mC marks primarily regulate cell-cell adhesion processes, whereas 5hmC marks are involved in embryonic morphogenesis and cell fate commitment. By integrating published PTSD findings from central and peripheral tissues through multi-omics approaches, several biological mechanisms were prioritized, including developmental processes, HPA axis regulation, and immune responses. Based on the consistent enrichment in developmental processes, we hypothesize that if epigenetic changes occur during early developmental stages, they may increase the risk of developing PTSD following trauma exposure. Conversely, if these epigenetic changes occur in adulthood, they may influence neuronal apoptosis and survival mechanisms.
Fine-tuning and pre-training improve the predictive accuracy of large language models for rheumatoid arthritis disease activity
Authors: Honda Suguru , Ikari Katsunori , Fujisaki Mayuko , Tanaka Eiichi , Harigai Masayoshi
Published: October 2024

Objective

To evaluate whether the performance of the large language model (LLM) Llama2 improves with pre-training and fine-tuning, and to compare its predictive accuracy with that of a linear regression model for rheumatoid arthritis (RA) disease activity.

Methods

Clinical data from 11,865 patients in the cohort were used to predict disease activity at two years on four indices (Disease Activity Score (DAS) 28-Erythrocyte sedimentation rate (ESR), DAS28-C-reactive protein (CRP), Clinical Disease Activity Index (CDAI) or Japanese Health Assessment Questionnaire (J-HAQ)). Logistic regression was employed for the linear model for comparison. The predictive performance was assessed using area under the curve (AUC). Additional performance metrics including precision, recall, and F1 score were calculated.

Results

Pre-training significantly improved AUC of Meditron (Llama2 pre-trained with medical data) for DAS28-ESR >5.1, DAS28-ESR <2.6, DAS28-CRP <2.3, J-HAQ score >2.5, and J-HAQ score <0.5 (P<0.05). Fine-tuning resulted in significant improvements in AUC for Llama2 across all indices (P<0.05) except CDAI >22, and for Meditron in DAS28-ESR <2.6, DAS28-CRP >4.1, DAS28-CRP <2.3 and CDAI ≤2.8 (P<0.05). Both LLMs significantly outperformed linear regression in predicting DAS28-ESR <2.6, DAS28-CRP >4.1, DAS28-CRP <2.3, J-HAQ score >2.5, and J-HAQ score <0.5 (P<0.05). Furthermore, DAS28-CRP >4.1, DAS28-CRP <2.3, J-HAQ score >2.5 and J-HAQ score <0.5, Llama2 or Meditron consistently outperformed linear regression across all performance metrics.

Conclusion

Both pre-training and fine-tuning significantly improved the performance of Llama2. Both LLMs outperformed the linear regression model in predicting 5 out of the 8 categories of indices.
A Feasibility Study of Thermography for Detecting Pressure Injuries Across Diverse Skin Tones
Authors: Asare-Baiden Miriam , Sonenblum Sharon Eve , Jordan Kathleen , Chung Andrew , Gichoya Judy Wawira , Hertzberg Vicki Stover , Ho Joyce C
Published: October 2024

Pressure injury (PI) detection is challenging, especially in dark skin tones, due to the unreliability of visual inspection. Thermography may serve as a viable alternative as temperature differences in the skin can indicate impending tissue damage. Although deep learning models hold considerable promise toward reliably detecting PI, existing work fails to evaluate performance on diverse skin tones and varying data collection protocols. We collected a new dataset of 35 participants focused on darker skin tones where temperature differences are induced through cooling and cupping protocols. The dataset includes different cameras, lighting, patient pose, and camera distance. We compare the performance of three convolutional neural network (CNN) models trained on either the thermal or the optical images on all skin tones. Our results suggest thermography-based CNN is robust to data collection protocols. Moreover, the visual explanation often captures the region of interest without requiring explicit bounding box labels.
Non-lytic replicating viral delivery of an IL15 superagonist enhances antitumor immunity and extends survival in glioblastoma
Authors: Haddad Alexander F. , Saha Atul , Spatz Jordan , Collins Sara A. , Lovalvo Isabella , Gill Sabraj , Montoya Megan L. , Shukla Poojan , Hong Jinpyo , Wang Elaina , Chuntova Pavlina , Lad Meeki , Osorio Robert , Chen Jia-Shu , Jain Saket , Chalif Eric , Kasahara Noriyuki , Aghi Manish K.
Published: October 2024

Glioblastoma (GBM) is the most lethal primary brain neoplasm due to its highly immunosuppressive microenvironment and resistance to conventional therapies. To overcome this challenge, we engineered a replicating retrovirus (RRV) to deliver a superagonist interleukin-15 receptor-linked fusion protein (RLI) directly to tumor cells, engineering them into local immunotherapy biofactories. This strategy leverages the tumor-selective replication of RRV to achieve localized and sustained RLI expression within the tumor microenvironment. In two orthotopic poorly immunogenic GBM mouse models, intratumoral administration of RRV RLI significantly reduced tumor growth and prolonged survival compared to controls, with some mice achieving long-term remission and demonstrating immunologic memory upon rechallenge. Transcriptomic and flow cytometric analyses revealed that RRV RLI treatment enhanced infiltration and activation of CD8⁺ T cells, NK cells, and upregulated antigen presentation pathways within the tumor microenvironment. Depletion studies indicated that the therapeutic efficacy of RRV RLI is dependent on both CD4⁺ and CD8⁺ T cells. Notably, combining RRV RLI with the GBM standard of care chemotherapeutic agent temozolomide (TMZ) synergistically improved survival outcomes. Subsequent single-cell RNA and T cell receptor sequencing identified enhanced effector cell activation, antigen presentation, and clonal T cell expansion in the combination therapy group. Further T cell receptor analysis and clustering implied a tumor- specific immune response rather than one targeting the viral delivery vehicle, suggesting that this therapeutic approach could be reapplied without eliciting anti-vector immunity. Our findings suggest that RRV-mediated delivery of RLI effectively transforms GBM tumors into immunostimulatory hubs, eliciting a potent anti-tumor immune response. This novel viral immunotherapy holds significant promise for clinical translation in the treatment of GBM and other difficult-to-treat solid tumors.
Molecular basis of interchain disulfide-bond formation in BMP-9 and BMP-10
Authors: Schwartze Tristin A. , Morosky Stefanie A. , Rosato Teresa L. , Henrickson Amy , Lin Guowu , Hinck Cynthia S. , Taylor Alexander B. , Olsen Shaun K. , Calero Guillermo , Demeler Borries , Roman Beth L. , Hinck Andrew P.
Published: October 2024

BMP-9 and BMP-10 are TGF-β family signaling ligands naturally secreted into blood. They act on endothelial cells and are required for proper development and maintenance of the vasculature. In hereditary hemorrhagic telangiectasia, regulation is disrupted due to mutations in the BMP-9/10 pathway, namely in the type I receptor ALK1 or the co-receptor endoglin. It has been demonstrated that BMP-9/10 heterodimers are the most abundant signaling species in the blood, but it is unclear how they form. Unlike other ligands of the TGF-β family, BMP-9 and -10 are secreted as a mixture of monomers and disulfide-linked dimers. Here, we show that the monomers are secreted in a cysteinylated form that crystallizes as a noncovalent dimer. Despite this, monomers do not self-associate at micromolar or lower concentrations and have reduced signaling potency compared to dimers. We further show using protein crystallography that the interchain disulfide of the BMP-9 homodimer adopts a highly strained syn-periplanar conformation. Hence, geometric strain across the interchain disulfide is responsible for the reduced propensity to dimerize, not the cysteinylation. Additionally, we show that the dimerization propensity of BMP-9 is lower than BMP-10 and these propensities can be reversed by swapping residues near the interchain disulfide that form attractive interactions with the opposing monomer. Finally, we discuss the implications of these observations on BMP-9/10 heterodimer formation.
Role of AAA-ATPase Cdc48p in Peroxisomal Quality Control
Authors: Yusuf Ismaila Francis , Girzalsky Wolfgang , Erdmann Ralf
Published: October 2024

The majority of peroxisomal matrix proteins are equipped with a type 1 peroxisomal targeting signal (PTS1), which is recognized in the cytosol by the import receptor Pex5p and targeted to the peroxisomal membrane. After cargo translocation into the peroxisomal lumen, the receptor is monoubiquitinated and recycled to the cytosol in an ATP-dependent manner by the AAA-ATPases Pex1p and Pex6p. Defects in receptor recycling trigger a quality control process by which the receptor is polyubiquitinated, extracted from the membrane and targeted to the proteasome for degradation by the RADAR (Receptor Accumulation and Degradation in the Absence of Recycling)-pathway.

Although the RADAR-pathway is conserved among species, it seemed to be missing in baker’s yeast. We present the identification and characterization of the RADAR pathway inS. cerevisiaeand discover that the AAA-ATPases Msp1p and predominantly Cdc48p together with its co-factors Ufd1p/Npl4p are constituents of this pathway. In the RADAR-pathway, Cdc48p cooperates with the heterodimeric Ufd1p/Npl4p cofactor to pull misfolded, polyubiquitinated receptor out of the peroxisomal membrane for its subsequent degradation.
Pep2Vec: An Interpretable Model for Peptide-MHC Presentation Prediction and Contaminant Identification in Ligandome Datasets
Authors: Thrift William John , Broadwell Quade , Perera Jason , Lounsbury Nicolas W. , Chen Jieming , Jhunjhunwala Suchit
Published: October 2024

As personalized cancer vaccines advance, precise modeling of antigen presentation by MHC class I and II is crucial. High-quality training data is essential for clinical models. Existing deep learning models focus on prediction performance but lack interpretability. We introduce Pep2Vec, a modular, transformer-based model trained on MHC I and II ligandome data, transforming input sequences into interpretable vectors. This approach integrates source protein features and elucidates the source of its performance gains, revealing regions that correlate with gene expression and protein-protein interactions. Pep2Vec’s peptide latent space shows relationships between peptides of varying MHC class, allotype, lengths, and submotifs. This enables identifying four major contaminant types, constituting 5.0% of our data. Pep2Vec enhances MHC presentation prediction, achieving higher average precision on our presentation test set and immunogenicity datasets than existing models, and reducing contaminant-like peptide recommendations. Pep2Vec addresses a critical need for the development of more precise and effective applications of peptide MHC models, such as for cancer vaccines and antibody deimmunization.
SPLENDID incorporates continuous genetic ancestry in biobank-scale data to improve polygenic risk prediction across diverse populations
Authors: Chen Tony , Zhang Haoyu , Mazumder Rahul , Lin Xihong
Published: October 2024

Polygenic risk scores are widely used in disease risk stratification, but their accuracy varies across diverse populations. Recent methods large-scale leverage multi-ancestry data to improve accuracy in under-represented populations but require labelling individuals by ancestry for prediction. This poses challenges for practical use, as clinical practices are typically not based on ancestry. We propose SPLENDID, a novel penalized regression framework for diverse biobank-scale data. Our method utilizes ancestry principal component interactions to model genetic ancestry as a continuum within a single prediction model for all ancestries, eliminating the need for discrete labels. In extensive simulations and analyses of 9 traits from the All of Us Research Program (N=224,364) and UK Biobank (N=340,140), SPLENDID significantly outperformed existing methods in prediction accuracy and model sparsity. By directly incorporating continuous genetic ancestry in model training, SPLENDID stands as a valuable tool for robust risk prediction across diverse populations and fairer clinical implementation.