bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative risk factors and cumulative incidence of temporary ileostomy non-closure after sphincter-preserving surgery for rectal cancer: a meta-analysis
Authors: He Fan , Tang Chenglin , Yang Fuyu , Chen Defei , Xiong Junjie , Zou Yu , Zhao Dongqin , Qian Kun
Published: April 2024

Background

Temporary ileostomy (TI) has proven effective in reducing the severity of anastomotic leakage after rectal cancer surgery; however, some ileostomies fail to reverse over time, leading to conversion into a permanent stoma (PS). In this study, we aimed to investigate the preoperative risk factors and cumulative incidence of TI non-closure after sphincter-preserving surgery for rectal cancer.

Materials and methods

We conducted a meta-analysis after searching the Embase, Web of Science, PubMed, and MEDLINE databases from their inception until November 2023. We collected all published studies on the risk factors related to TI non-closure after sphincter-preserving surgery for rectal cancer.

Results

A total of 1610 studies were retrieved, and 13 studies were included for meta-analysis, comprising 3026 patients. The results of the meta-analysis showed that the identified risk factors included older age (p = 0.03), especially > 65 years of age (p = 0.03), male sex (p = 0.009), American Society of Anesthesiologists score ≥ 3 (p = 0.004), comorbidity (p = 0.001), and distant metastasis (p < 0.001). Body mass index, preoperative hemoglobin, preoperative albumin, preoperative carcinoma embryonic antigen, tumor location, neoadjuvant chemoradiotherapy, smoking, history of abdominal surgery, and open surgery did not significantly change the risk of TI non-closure.

Conclusion

We identified five preoperative risk factors for TI non-closure after sphincter-preserving surgery for rectal cancer. This information enables surgeons to identify high-risk groups before surgery, inform patients about the possibility of PS in advance, and consider performing protective colostomy or Hartmann surgery.
Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods
Authors: Liu Yupeng , Ma Xue , Chen Zhehui , He Ruxuan , Zhang Yao , Dong Hui , Ma Yanyan , Wu Tongfei , Wang Qiao , Ding Yuan , Li Xiyuan , Li Dongxiao , Song Jinqing , Li Mengqiu , Jin Ying , Qin Jiong , Yang Yanling
Published: April 2024

Background

Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported.

Results

Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR.

Conclusions

Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.
CAPN2 correlates with insulin resistance states in PCOS as evidenced by multi-dataset analysis
Authors: Luo Xi , Dong Yunhua , Zheng Haishan , Zhou Xiaoting , Rong Lujuan , Liu Xiaoping , Bai Yun , Li Yunxiu , Wu Ze
Published: April 2024

Objective

IR emerges as a feature in the pathophysiology of PCOS, precipitating ovulatory anomalies and endometrial dysfunctions that contribute to the infertility challenges characteristic of this condition. Despite its clinical significance, a consensus on the precise mechanisms by which IR exacerbates PCOS is still lacking. This study aims to harness bioinformatics tools to unearth key IR-associated genes in PCOS patients, providing a platform for future therapeutic research and potential intervention strategies.

Methods

We retrieved 4 datasets detailing PCOS from the GEO, and sourced IRGs from the MSigDB. We applied WGCNA to identify gene modules linked to insulin resistance, utilizing IR scores as a phenotypic marker. Gene refinement was executed through the LASSO, SVM, and Boruta feature selection algorithms. qPCR was carried out on selected samples to confirm findings. We predicted both miRNA and lncRNA targets using the ENCORI database, which facilitated the construction of a ceRNA network. Lastly, a drug-target network was derived from the CTD.

Results

Thirteen genes related to insulin resistance in PCOS were identified via WGCNA analysis. LASSO, SVM, and Boruta algorithms further isolated CAPN2 as a notably upregulated gene, corroborated by biological verification. The ceRNA network involving lncRNA XIST and hsa-miR-433-3p indicated a possible regulatory link with CAPN2, supported by ENCORI database. Drug prediction analysis uncovered seven pharmacological agents, most being significant regulators of the endocrine system, as potential candidates for addressing insulin resistance in PCOS.

Conclusions

This study highlights the pivotal role of CAPN2 in insulin resistance within the context of PCOS, emphasizing its importance as both a critical biomarker and a potential therapeutic target. By identifying CAPN2, our research contributes to the expanding evidence surrounding the CAPN family, particularly CAPN10, in insulin resistance studies beyond PCOS. This work enriches our understanding of the mechanisms underlying insulin resistance, offering insights that bridge gaps in the current scientific landscape.
Probiotic supplementation and risk of necrotizing enterocolitis and mortality among extremely preterm infants—the Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial: study protocol for a multicenter, double-blinded, placebo-controlled, and registry-based randomized controlled trial
Authors: Kruth Sofia Söderquist , Willers Carl , Persad Emma , Sjöström Elisabeth Stoltz , Lagerström Susanne Rautiainen , Rakow Alexander
Published: April 2024

Background

Extremely preterm infants, defined as those born before 28 weeks’ gestational age, are a very vulnerable patient group at high risk for adverse outcomes, such as necrotizing enterocolitis and death. Necrotizing enterocolitis is an inflammatory gastrointestinal disease with high incidence in this cohort and has severe implications on morbidity and mortality. Previous randomized controlled trials have shown reduced incidence of necrotizing enterocolitis among older preterm infants following probiotic supplementation. However, these trials were underpowered for extremely preterm infants, rendering evidence for probiotic supplementation in this population insufficient to date.

Methods

The Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial is a multicenter, double-blinded, placebo-controlled and registry-based randomized controlled trial conducted among extremely preterm infants (n = 1620) born at six tertiary neonatal units in Sweden and four units in Denmark. Enrolled infants will be allocated to receive either probiotic supplementation with ProPrems® (Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus) diluted in 3 mL breastmilk or placebo (0.5 g maltodextrin powder) diluted in 3 mL breastmilk per day until gestational week 34. The primary composite outcome is incidence of necrotizing enterocolitis and/or mortality. Secondary outcomes include incidence of late-onset sepsis, length of hospitalization, use of antibiotics, feeding tolerance, growth, and body composition at age of full-term and 3 months corrected age after hospital discharge.

Discussion

Current recommendations for probiotic supplementation in Sweden and Denmark do not include extremely preterm infants due to lack of evidence in this population. However, this young subgroup is notably the most at risk for experiencing adverse outcomes. This trial aims to investigate the effects of probiotic supplementation on necrotizing enterocolitis, death, and other relevant outcomes to provide sufficiently powered, high-quality evidence to inform probiotic supplementation guidelines in this population. The results could have implications for clinical practice both in Sweden and Denmark and worldwide.

Trial registration

(Clinicaltrials.gov): NCT05604846
A theoretical study on toluene oxidization by OH radical
Authors: Mao Yumin , Yang Lijuan , Liu Siqi , Song Yunchang , Luo Mengchao , Guo Yongxue
Published: April 2024

Toluene, a prominent member of volatile organic compounds (VOCs), exerts a substantial adverse influence on both human life and the environment. In the context of advanced oxidation processes, the ·OH radical emerges as a highly efficient oxidant, pivotal in the elimination of VOCs. This study employs computational quantum chemistry methods (G4MP2//B3LYP/6-311++G(d,p)) to systematically investigate the degradation of toluene by ·OH radicals in an implicit solvent model, and validates the rationale of choosing a single-reference method using T1 diagnostics. Our results suggest three possible reaction mechanisms for the oxidation of toluene by ·OH: firstly, the phenyl ring undergoes a hydrogen abstraction reaction followed by direct combination with ·OH to form cresol; secondly, ·OH directly adds to the phenyl ring, leading to ring opening; thirdly, oxidation of sidechain to benzoic acid followed by further addition and ring opening. The last two oxidation pathways involve the ring opening of toluene via the addition of ·OH, significantly facilitating the process. Therefore, both pathways are considered feasible for the degradation of toluene. Subsequently, the UV-H2O2 system was designed to induce the formation of ·OH for toluene degradation and to identify the optimal reaction conditions. It was demonstrated that ·OH and 1O2 are the primary active species for degrading toluene, with their contribution ranking as ·OH > 1O2. The intermediates in the mixture solution after reactions were characterized using GC–MS, demonstrating the validity of theoretical predictions. A comparative study of the toluene consumption rate revealed an experimental comprehensive activation energy of 10.33 kJ/mol, which is consistent with the preliminary activation energies obtained via theoretical analysis of these three mechanisms (0.56 kJ/mol to 13.66 kJ/mol), indicating that this theoretical method can provide a theoretical basis for experimental studies on the oxidation of toluene by ·OH.
Integrative analysis of single-cell and bulk transcriptome data reveal the significant role of macrophages in lupus nephritis
Authors: Wei Shuping , Shen Haiyun , Zhang Yidan , Liu Chunrui , Li Shoushan , Yao Jing , Jin Zhibin , Yu Hongliang
Published: April 2024

Objective

We attempted to identify abnormal immune cell components and signaling pathways in lupus nephritis (LN) and to identify potential therapeutic targets.

Methods

Differentially expressed genes (DEGs) between LN and normal kidney tissues were identified from bulk transcriptome data, and functional annotation was performed. The phenotypic changes in macrophages and aberrant intercellular signaling communications within immune cells were imputed from LN scRNA-seq data using trajectory analysis and verified using immunofluorescence staining. Finally, lentivirus-mediated overexpression of LGALS9, the gene encoding Galectin 9, in THP-1 cells was used to study the functional effect of this gene on monocytic cells.

Results

From bulk transcriptome data, a significant activation of interferon (IFN) signaling was observed, and its intensity showed a significantly positive correlation with the abundance of infiltrating macrophages in LN. Analysis of scRNA-seq data revealed 17 immune cell clusters, with macrophages showing the highest enrichment of intercellular signal communication in LN. Trajectory analysis revealed macrophages in LN undergo a phenotypic change from inflammatory patrolling macrophages to phagocytic and then to antigen-presenting macrophages, and secrete various pro-inflammatory factors and complement components. LGALS9 was found significantly upregulated in macrophages in LN, which was confirmed by the immunofluorescence assay. Gene functional study showed that LGALS9 overexpression in THP-1 cells significantly elicited pro-inflammatory activation, releasing multiple immune cell chemoattractants.

Conclusion

Our results present an important pathophysiological role for macrophages in LN, and our preliminary results demonstrate significant pro-inflammatory effects of LGALS9 gene in LN macrophages.
Deregulation in adult IgA vasculitis skin as the basis for the discovery of novel serum biomarkers
Authors: Bajželj Matija , Hladnik Matjaž , Blagus Rok , Jurčić Vesna , Markež Ana , Toluay Tanya Deniz , Sodin-Šemrl Snežna , Hočevar Alojzija , Lakota Katja
Published: April 2024

Introduction

Immunoglobulin A vasculitis (IgAV) in adults has a variable disease course, with patients often developing gastrointestinal and renal involvement and thus contributing to higher mortality. Due to understudied molecular mechanisms in IgAV currently used biomarkers for IgAV visceral involvement are largely lacking. Our aim was to search for potential serum biomarkers based on the skin transcriptomic signature.

Methods

RNA sequencing analysis was conducted on skin biopsies collected from 6 treatment-naïve patients (3 skin only and 3 renal involvement) and 3 healthy controls (HC) to get insight into deregulated processes at the transcriptomic level. 15 analytes were selected and measured based on the transcriptome analysis (adiponectin, lipopolysaccharide binding protein (LBP), matrix metalloproteinase-1 (MMP1), C-C motif chemokine ligand (CCL) 19, kallikrein-5, CCL3, leptin, C-X-C motif chemokine ligand (CXCL) 5, osteopontin, interleukin (IL)-15, CXCL10, angiopoietin-like 4 (ANGPTL4), SERPIN A12/vaspin, IL-18 and fatty acid-binding protein 4 (FABP4)) in sera of 59 IgAV and 22 HC. Machine learning was used to assess the ability of the analytes to predict IgAV and its organ involvement.

Results

Based on the gene expression levels in the skin, we were able to differentiate between IgAV patients and HC using principal component analysis (PCA) and a sample-to-sample distance matrix. Differential expression analysis revealed 49 differentially expressed genes (DEGs) in all IgAV patient’s vs. HC. Patients with renal involvement had more DEGs than patients with skin involvement only (507 vs. 46 DEGs) as compared to HC, suggesting different skin signatures. Major dysregulated processes in patients with renal involvement were lipid metabolism, acute inflammatory response, and extracellular matrix (ECM)-related processes. 11 of 15 analytes selected based on affected processes in IgAV skin (osteopontin, LBP, ANGPTL4, IL-15, FABP4, CCL19, kallikrein-5, CCL3, leptin, IL-18 and MMP1) were significantly higher (p-adj < 0.05) in IgAV serum as compared to HC. Prediction models utilizing measured analytes showed high potential for predicting adult IgAV.

Conclusion

Skin transcriptomic data revealed deregulations in lipid metabolism and acute inflammatory response, reflected also in serum analyte measurements. LBP, among others, could serve as a potential biomarker of renal complications, while adiponectin and CXCL10 could indicate gastrointestinal involvement.
Cancer survivorship: understanding the patients’ journey and perspectives on post-treatment needs
Authors: Hussey Conor , Hanbridge Moira , Dowling Maura , Gupta Ananya
Published: April 2024

Background

Cancer treatments have many adverse effects on patient’s health leading to poor cardiorespiratory capacity, muscular- degeneration, fatigue, loss of strength and physical function, altered body-composition, compromised immune-function, peripheral neuropathy, and reduced quality of life (QOL). Exercise programs can significantly increase functional capacity when tailored to individual needs, thus improving health. Exercise interventions in cancer rehabilitation, when supported by appropriate nutrition can be effective in attaining a healthy weight and body-composition. The successful rehabilitation program should also include psycho-social education aimed to reduce anxiety and improve motivation.

Methods

The current study aimed to collect information on the post-treatment needs of cancer patients including barriers and expectations facing them, their caregivers and their families through consultation in focus group interviews. Cancer survivors living in the Republic of Ireland were recruited from the University Hospital Galway, community-based cancer centres, cancer support groups and social media platforms to participate in the study and attend a focus group interview. The focus group discussions were designed to obtain information on the collective views of cancer survivors on relevant topics selected. The topics were developed in consultation with a patient and public involvement (PPI) group supporting the study. The topics list was circulated to all participants prior to the focus group. The interviews were audio recorded and transcribed verbatim. Focus group transcripts were analysed subjected to a thematic framework analysis using NVivo.

Results

Thirty-six participants took part in 9 focus groups. Our analysis uncovered two main themes. The first theme ‘cast adrift with no direction’ was grouped into three sub-themes: everything revolves around treatment; panic and fear; and what exercise should I be doing? The second theme ‘everybody is different’ was clustered into two sub-themes: side effects get in the way; and personalised exercise program.

Conclusion

The study highlighted the lack of information and support needed by patients living with and beyond cancer. The study also highlighted the need for a personalised exercise programme designed to target the individual patient symptoms that would be ideal for the mitigation of long term symptoms and in improving QOL.
Pseudomonas fluorescens CRBSI outbreak: complying with the standardization of invasive procedures is a step ahead in the fight against antimicrobial resistance
Authors: Volkow Patricia , Chávez-Chávez Tania Guadalupe , García-Pineda Bertha , Velázquez-Acosta Consuelo , Carpio-Guadarrama Daniel , Vilar-Compte Diana , Ibanes-Gutiérrez Cyntia
Published: April 2024

In the healthcare sector, the implementation of standardized procedures, such as those commonly employed in franchises to ensure consistent quality, remains underprioritized. Within this framework, we focus on the importance of standardized central venous catheter (CVC) insertion procedures to prevent healthcare-associated outbreaks. While antimicrobial resistance (AMR) may still not be the most prevalent problem in some institutions, its increasing significance certainly underlines the urgency of infection prevention.

We aim to highlight this issue by describing and discussing an outbreak scenario of carbapenem-resistant (CR) Pseudomonas fluorescens bloodstream infections resulting from a deviation from the standardized CVC insertion procedure. This outbreak led to six episodes of catheter related bloodstream infection (CRBSI) in patients with hematologic malignancies, delaying their primary treatment. Nineteen patients were exposed, leading to an attack rate of 31.6%.
Dysregulation of neuroprotective lipoxin pathway in astrocytes in response to cytokines and ocular hypertension​
Authors: Karnam Shruthi , Maurya Shubham , Ng Elainna , Choudhary Amodini , Thobani Arzin , Flanagan John G , Gronert Karsten
Published: April 2024

Glaucoma leads to vision loss due to retinal ganglion cell death. Astrocyte reactivity contributes to neurodegeneration. Our recent study found that lipoxin B4 (LXB4), produced by retinal astrocytes, has direct neuroprotective actions on retinal ganglion cells. In this study, we aimed to investigate how the autacoid LXB4 influences astrocyte reactivity in the retina under inflammatory cytokine-induced activation and during ocular hypertension. The protective activity of LXB4 was investigated in vivo using the mouse silicone-oil model of chronic ocular hypertension. By employing a range of analytical techniques, including bulk RNA-seq, RNAscope in-situ hybridization, qPCR, and lipidomic analyses, we discovered the formation of lipoxins and expression of the lipoxin pathway in rodents (including the retina and optic nerve), primates (optic nerve), and human brain astrocytes, indicating the presence of this neuroprotective pathway across various species. Findings in the mouse retina identified significant dysregulation of the lipoxin pathway in response to chronic ocular hypertension, leading to an increase in 5-lipoxygenase (5-LOX) activity and a decrease in 15-LOX activity. This dysregulation was coincident with a marked upregulation of astrocyte reactivity. Reactive human brain astrocytes also showed a significant increase in 5-LOX. Treatment with LXB4 amplified the lipoxin biosynthetic pathway by restoring and amplifying the generation of another member of the lipoxin family, LXA4, and mitigated astrocyte reactivity in mouse retinas and human brain astrocytes. In conclusion, the lipoxin pathway is functionally expressed in rodents, primates, and human astrocytes, and is a resident neuroprotective pathway that is downregulated in reactive astrocytes. Novel cellular targets for LXB4’s neuroprotective action are inhibition of astrocyte reactivity and restoration of lipoxin generation. Amplifying the lipoxin pathway is a potential target to disrupt or prevent astrocyte reactivity in neurodegenerative diseases, including retinal ganglion cell death in glaucoma.
Development and validation of a Context-sensitive Positive Health Questionnaire (CPHQ): A factor analysis and multivariate regression study
Authors: Doornenbal Brian M. , van Zutphen Tim , Beumeler Lise F. E. , Vos Rimke C. , Derks Mark , Haisma Hinke , van den Akker-van Marle M. Elske , Kiefte-de Jong Jessica C.
Published: April 2024

Background

The concept of Positive Health (PH) has gained increasing attention as a way of measuring individuals’ ability to adapt in the face of contextual challenges. However, a suitable measurement instrument for PH that encompasses contextual factors has not yet been developed. This paper responds to this need by developing a Context-specific Positive Health (CPH) measurement instrument that aligns with the Capability Approach (CA).

Methods

The measurement instrument was developed and tested among a representative sample of 1002 Dutch internet survey panel members with diverse sociodemographic backgrounds. The instrument was developed in two stages: a preparation phase consisting of focus groups and expert consultations, and a validation among a representative panel of Dutch citizens. The goal of the preparation phase, was to pilot test and refine previously proposed Positive Health questionnaires into an initial version of the CPHQ. The validation phase aimed to examine the initial CPHQ’s factorial validity using Factor Analysis, and its concurrent validity using Multivariate Regression Analysis.

Results

The developed questionnaire demonstrated adequate factorial and concurrent validity. Furthermore, it explicitly includes an assessment of resilience, this being a key component of PH.

Conclusions

The introduced measurement tool, the CPHQ, comprises 11 dimensions that we have labeled as follows: relaxation, autonomy, fitness, perceived environmental safety, exclusion, social support, financial resources, political representation, health literacy, resilience, and enjoyment. In this article, we present four major contributions. Firstly, we embedded the measurement in a theoretical framework. Secondly, we focused the questionnaire on a key concept of Positive Health - the “ability to adapt.” Thirdly, we addressed issues of health inequality by considering contextual factors. Finally, we facilitated the development of more understandable measurement items.
Advances in laser-based diagnostic modalities for intraoperative tissue diagnosis in neurosurgery: current practices and future perspectives
Authors: Pierre Kevin , McCann U. George , Razavi Seyedeh Mehrsa Sadat , Patel Anjali , Acevedo Amanda , Cerillo John , Raviprasad Abheek , Zhou Joseph , Rashdan Dean , Lucke-Wold Brandon
Published: April 2024

This review assesses laser-based diagnostic modalities for intraoperative tissue diagnosis in neurosurgical oncology, emphasizing their utility in delineating tumor margins. Technologies such as optical coherence tomography, photoacoustic imaging, and confocal microscopy are scrutinized for their capability to enhance intraoperative discernment of neoplastic versus healthy tissue. We discuss the technical advancements, limitations related to depth penetration and resolution, and innovative approaches to mitigate these challenges. Economic and regulatory considerations pertinent to the clinical adoption of these technologies are also examined. The review highlights current clinical trials and research initiatives aiming to validate and standardize these applications. It concludes by highlighting the importance of ongoing research, cross-disciplinary cooperation, and professional training to integrate laser-based diagnostics into neurosurgical practice, with the ultimate goal of optimizing patient outcomes in brain tumor resection.
Role of interim positron emission tomography/computed tomography in assessment of lymphoma treatment response
Authors: Borg Salma M. , Saleh Gehad A. , Batouty Nihal M. , Mousa Amani Ezzat
Published: April 2024

Background

Lymphoma is the most common primary hematological malignancy. FDG PET/CT has recently become the standard imaging modality for clinical management owing to its ability to provide precise, non-invasive anatomical and functional data. The purpose of this study was to highlight the role of 18F FDG-PET/CT in the management of lymphoma by monitoring treatment response, providing a guide for response-adapted therapy, and predicting the final therapeutic outcome.

Methods

This was a prospective monocentric cohort observational study in which thirty-three patients with histopathologically proved lymphoma of different types performed FDG-PET/CT scanning several times throughout the 24-month duration of the study. Early-stage interim SUVmax of the most active lesion (both nodal and/or extra-nodal) was measured and statistically analyzed together with data of the international prognostic index parameters and score.

Results

Among the included 33 patients of lymphoma, international prognostic index parameters and score together with the early-stage interim SUVmax of the predominant nodal and extra-nodal sites showed statistical significance in predicting the initial as well as the final treatment response after 24 months. Using ROC analysis, we could obtain cutoff values of SUVmax of the predominant nodal lesion of 2.75 (AUC 72%, 95% CI 0.42–1.0) and SUVmax of the predominant extra-nodal lesion of 3 (AUC 70.8% and 95% CI 0.23–1.0); therefore, SUVmax of higher than these values was related to stable or progressive disease, and lower levels than these values were related to complete or partial metabolic response based on Deauville 5-point scale and Lugano response criteria.

Conclusions

Early-stage interim PET-CT SUVmax of the predominant nodal and extra-nodal lesion could be a reliable parameter in predicting initial and final therapeutic outcome in lymphoma patients.
Systematic Review of Cerebrospinal Fluid Biomarker Discovery in Neuro-Oncology: A Roadmap to Standardization and Clinical Application
Authors: Mikolajewicz Nicholas , Yee Patricia P. , Bhanja Debarati , Trifoi Mara , Miller Alexandra M. , Metellus Philippe , Bagley Stephen J. , Balaj Leonora , de Macedo Filho Leonardo J.M. , Zacharia Brad E. , Aregawi Dawit , Glantz Michael , Weller Michael , Ahluwalia Manmeet S. , Kislinger Thomas , Mansouri Alireza
Published: April 2024

Effective diagnosis, prognostication, and management of CNS malignancies traditionally involves invasive brain biopsies that pose significant risk to the patient. Sampling and molecular profiling of cerebrospinal fluid (CSF) is a safer, rapid, and noninvasive alternative that offers a snapshot of the intracranial milieu while overcoming the challenge of sampling error that plagues conventional brain biopsy. Although numerous biomarkers have been identified, translational challenges remain, and standardization of protocols is necessary. Here, we systematically reviewed 141 studies (Medline, SCOPUS, and Biosis databases; between January 2000 and September 29, 2022) that molecularly profiled CSF from adults with brain malignancies including glioma, brain metastasis, and primary and secondary CNS lymphomas. We provide an overview of promising CSF biomarkers, propose CSF reporting guidelines, and discuss the various considerations that go into biomarker discovery, including the influence of blood-brain barrier disruption, cell of origin, and site of CSF acquisition (eg, lumbar and ventricular). We also performed a meta-analysis of proteomic data sets, identifying biomarkers in CNS malignancies and establishing a resource for the research community.
Design and Implementation of an Opt-Out, End-to-End, Preemptive DPYD Testing Program for Patients Planned for a Systemic Fluoropyrimidine
Authors: Jacobson Joseph O. , Rompelman Garrett , Chen Angela , Morrison-Ma Samantha , Murray Lindsay , Ferzoco Maria , Bunnell Craig , Wagner Andrew J. , Roberts Daniel , Chan Jennifer , Block Caroline , Rubinson Douglas
Published: April 2024

PURPOSE

Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine.

METHODS

The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record–based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period.

RESULTS

At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non–fluoropyrimidine-based regimen was accomplished in 96%.

CONCLUSION

Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it.
Lessons From Prospective Longitudinal Follow-up of a French APECED Cohort
Authors: Humbert Linda , Proust-Lemoine Emmanuelle , Dubucquoi Sylvain , Kemp Elisabeth Helen , Saugier-Veber Pascale , Fabien Nicole , Raymond-Top Isabelle , Cardot-Bauters Catherine , Carel Jean-Claude , Cartigny Maryse , Chabre Olivier , Chanson Philippe , Delemer Brigitte , Do Cao Christine , Guignat Laurence , Kahn Jean Emmanuel , Kerlan Veronique , Lefebvre Herve , Linglart Agnès , Mallone Roberto , Reynaud Rachel , Sendid Boualem , Souchon Pierre-François , Touraine Philippe , Wémeau Jean-Louis , Vantyghem Marie-Christine
Published: April 2024

Background

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC) and nonendocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations, and to characterize immunological disturbances in a French cohort.

Patients and Methods

A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683).

Results

Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC.

Conclusion

This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.
Bisphosphonates Maintain BMD After Sequential Teriparatide and Denosumab in Premenopausal Women with Idiopathic Osteoporosis
Authors: Kamanda-Kosseh Mafo , Shiau Stephanie , Agarwal Sanchita , Kondapalli Ananya , Colon Ivelisse , Kil Nayoung , Bucovsky Mariana , Lappe Joan M , Stubby Julie , Shane Elizabeth , Cohen Adi
Published: April 2024

Context

We previously reported that sequential teriparatide followed by denosumab substantially increases bone mineral density (BMD) in premenopausal idiopathic osteoporosis (PremenIOP).

Objective

To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP

Design

Open-label extension study.

Participants

Twenty-four PremenIOP Teriparatide-Denosumab Study participants.

Interventions

Oral alendronate (ALN), 70 mg weekly, or intravenous zoledronic acid (ZOL), 5 mg once (patient choice), was administered 7 months (M) after final denosumab dose.

Outcomes

BMD by dual-energy x-ray absorptiometry and serum C-telopeptide (CTX) q6M; Vertebral Fracture Assessment (VFA), and high-resolution peripheral quantitative computed tomography (HR-pQCT) q12 M.

Results

Twenty-four women with PremenIOP (aged 43 ± 8 years), severely affected with low trauma adult fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases on sequential teriparatide-denosumab (spine: 25 ± 9%; total hip: 11 ± 6%). During the Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and not statistically significant at 6 or 12 M.

Women choosing ZOL (n = 6) vs ALN (n = 18) did not differ by baseline age, body mass index, fractures, BMD, or CTX. On ZOL, there were small lumbar spine BMD declines and CTX increases, particularly between 6 M and 12 M, while greater stability was observed on ALN.

Changes in BMD and CTX did not differ by duration of denosumab (36 M vs <36 M) or between 20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone loss. No new vertebral (clinical or vertebral fraction assessment screening) or nonvertebral fractures occurred.

Conclusion

BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.
Metabolic Effects of Testosterone Added to Intensive Lifestyle Intervention in Older Men With Obesity and Hypogonadism
Authors: Gonzalez-Gil Adrian M , Barnouin Yoann , Celli Alessandra , Viola Viola , Villarreal Marcos D , Duremdes Nava Maria Liza , Sciuk Adam , Qualls Clifford , Armamento-Villareal Reina , Villareal Dennis T
Published: April 2024

Background

Whether testosterone replacement therapy (TRT) conveys additional cardiometabolic benefit to an intensive lifestyle therapy (LT) in older men with obesity and hypogonadism remains unclear.

Objective

To determine whether TRT augments the effect of LT on metabolic outcomes in older men with obesity and hypogonadism.

Design

Secondary analysis of a randomized, double-blind, placebo-controlled trial.

Setting

Veterans Affairs Medical Center.

Participants

Eighty-three older (age ≥ 65 years) men with obesity (body mass index ≥ 30 kg/m2) and persistently low Am testosterone (< 10.4 nmol/L) associated with frailty.

Interventions

LT (weight management and exercise training) plus either testosterone (LT + TRT) or placebo (LT + Pbo) for 6 months.

Outcome Measures

The primary outcome was change in glycated hemoglobin (HbA1c). Secondary outcomes included changes in other glucometabolic and lipid profile components, liver enzymes, inflammatory markers, and adipokines; subcutaneous, visceral, intramuscular, and hepatic fat; blood pressure; and metabolic syndrome score.

Results

HbA1c decreased similarly in LT + TRT and LT + Pbo groups (−0.5 ± 0.1 vs −0.6 ± 0.1%, respectively; P = 0.35). While TRT showed no synergistic effect with LT on ameliorating secondary outcomes, it eliminated the augmentative effect of LT on high-density lipoprotein cholesterol concentration (5.4 ± 1.0 mg/dL in the LT + Pbo group vs 0.2 ± 1.1 mg/dL in the LT + TRT group, P = .01) and adiponectin levels (−408 ± 489 ng/mL in LT + TRT group vs 1832 ± 468 ng/mL in LT + Pbo group, P = .02).

Conclusion

In older men with obesity and hypogonadism, adding TRT for 6 months to LT does not result in further improved cardiometabolic profiles and could potentially blunt some of the metabolic benefits induced by LT.
Clomiphene Citrate Administered in Periconception Phase Causes Fetal Loss and Developmental Impairment in Mice
Authors: Chin Peck Y , Chan Hon Yeung , Kieffer Tom E C , Prins Jelmer R , Russell Darryl L , Davies Michael J , Robertson Sarah A
Published: April 2024

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated the consequences in mice for fetal development and pregnancy outcome of periconception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 hours after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in 3 independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30-hour average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed postweaning growth and development similar to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can compromise implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the periconception phase unless its use is well-supervised.
What Is This “Tranquility”? A Reply to Nelson
Authors: Cristiano Carlo
Published: April 2024

In a note appearing in the August 2024 issue of History of Political Economy (HOPE), Edward Nelson argues that a passage commenting on James Forder's Macroeconomics and the Phillips Curve Myth (2014) in a 2023 HOPE article by Carlo Cristiano titled “The Early Reception of the Phillips Curve in the United Kingdom” would provide a false characterization of the economic literature and claims priority in affirming that UK policymakers did not use the Phillips curve as a menu for policy. It is shown in this reply that Nelson's reading of Cristiano's 2023 article, and more specifically of the passage commenting on Forder's 2014 book, is based on a misunderstanding. The purpose of the 2023 article was not to show that UK policymakers did not use the Phillips trade-off as a menu for policy. In that article, consensus on this point is taken for granted. It is also argued in this reply that there is no need to mention Nelson's works to affirm that UK policymakers did not use the Phillips trade-off as a policy menu and that Nelson's works are indeed very relevant, but for other reasons.
The Making of Informational Efficiency: Information Policy and Theory in Interwar Agricultural Economics
Authors: Delcey Thomas , Noblet Guillaume
Published: April 2024

This article offers a historical analysis of American interwar agricultural economists and their interest in information. Believing that the main problem facing farmers was a lack of information, agricultural economists designed an information policy aiming to produce, format, and disseminate information. Using administrative archives, the article analyzes the motivations of these economists and the implementation of this policy. As the article shows, the policy was a prerequisite for theoretical discussions about information, and it established institutional tools that are still used today, such as the USDA market news service.
γ-TuRCs and the augmin complex are required for the development of highly branched dendritic arbors in Drosophila
Authors: Mukherjee Amrita , Andrés Jeske Yaiza , Becam Isabelle , Taïeb Anaelle , Brooks Paul , Aouad Joanna , Monguillon Clementine , Conduit Paul T.
Published: April 2024

Microtubules are nucleated by γ-tubulin ring complexes (γ-TuRCs) and are essential for neuronal development. Nevertheless, γ-TuRC depletion has been reported to perturb only higher-order branching in elaborated Drosophila larval class IV dendritic arborization (da) neurons. This relatively mild phenotype has been attributed to defects in microtubule nucleation from Golgi outposts, yet most Golgi outposts lack associated γ-TuRCs. By analyzing dendritic arbor regrowth in pupae, we show that γ-TuRCs are also required for the growth and branching of primary and secondary dendrites, as well as for higher-order branching. Moreover, we identify the augmin complex (hereafter augmin), which recruits γ-TuRCs to the sides of pre-existing microtubules, as being required predominantly for higher-order branching. Augmin strongly promotes the anterograde growth of microtubules in terminal dendrites and thus terminal dendrite stability. Consistent with a specific role in higher-order branching, we find that augmin is expressed less strongly and is largely dispensable in larval class I da neurons, which exhibit few higher-order dendrites. Thus, γ-TuRCs are essential for various aspects of complex dendritic arbor development, and they appear to function in higher-order branching via the augmin pathway, which promotes the elaboration of dendritic arbors to help define neuronal morphology.
A working model for the formation of Robertsonian chromosomes
Authors: Gerton Jennifer L.
Published: April 2024

Robertsonian chromosomes form by fusion of two chromosomes that have centromeres located near their ends, known as acrocentric or telocentric chromosomes. This fusion creates a new metacentric chromosome and is a major mechanism of karyotype evolution and speciation. Robertsonian chromosomes are common in nature and were first described in grasshoppers by the zoologist W. R. B. Robertson more than 100 years ago. They have since been observed in many species, including catfish, sheep, butterflies, bats, bovids, rodents and humans, and are the most common chromosomal change in mammals. Robertsonian translocations are particularly rampant in the house mouse, Mus musculus domesticus, where they exhibit meiotic drive and create reproductive isolation. Recent progress has been made in understanding how Robertsonian chromosomes form in the human genome, highlighting some of the fundamental principles of how and why these types of fusion events occur so frequently. Consequences of these fusions include infertility and Down's syndrome. In this Hypothesis, I postulate that the conditions that allow these fusions to form are threefold: (1) sequence homology on non-homologous chromosomes, often in the form of repetitive DNA; (2) recombination initiation during meiosis; and (3) physical proximity of the homologous sequences in three-dimensional space. This Hypothesis highlights the latest progress in understanding human Robertsonian translocations within the context of the broader literature on Robertsonian chromosomes.
Short Sleep Duration Disrupts Glucose Metabolism: Can Exercise Turn Back the Clock?
Authors: Maloney Alan , Kanaley Jill A.
Published: April 2024

Short sleep duration is prevalent in modern society and may be contributing to type 2 diabetes prevalence. This review will explore the effects of sleep restriction on glycemic control, the mechanisms causing insulin resistance, and whether exercise can offset changes in glycemic control. Chronic sleep restriction may also contribute to a decrease in physical activity leading to further health complications.