bluuebunny/crossref_metadata_2025 huggingface dataset:
Severity grading of unexpected events in paediatric surgery: evaluation of five classification systems and the Comprehensive Complication Index (CCI®)
Authors: Madadi-Sanjani Omid , Zoeller Christoph , Kuebler Joachim F , Hofmann Alejandro D , Dingemann Jens , Wiesner Soeren , Brendel Julia , Ure Benno M
Published: December 2021

Background

Postoperative adverse events may be associated with substantial morbidity and mortality. Numerous severity grading systems for these events have been introduced and validated but have not yet been systematically applied in paediatric surgery. This study aimed to analyse the advantages and disadvantages of these classifications in a paediatric cohort.

Methods

Unexpected events associated with interventional or organizational problems in the department of paediatric surgery during 2017–2020 were prospectively documented daily for all children. Events were classified according to the Clavien–Dindo grading system during monthly morbidity and mortality conferences. All events were also classified according to five additional grading systems: T92, contracted Accordion, expanded Accordion, Memorial Sloan Kettering Cancer Center, and Comprehensive Complication Index (CCI)®.

Results

Of 6296 patients, 673 (10.7 per cent) developed adverse events and 240 (35.7 per cent) had multiple events. Overall, 1253 adverse events were identified; of these, 574 (45.2 per cent) were associated with surgical or medical interventions and 679 (54.8 per cent) included organizational problems. The grading systems demonstrated high overall correlation (rpears = 0.9), with minor differences in sentinel events. The Clavien–Dindo classification offered the most detailed assessment. However, these details had only limited additional value. The CCI® scores were correlated with other grading systems (rpears = 0.9) and were useful in analysing multiple events within individual patients.

Conclusion

Grading systems demonstrated similar scoring patterns for minor and sentinel events, with none being superior for unexpected events in children. However, the CCI® can be a major improvement in assessing morbidity in patients with multiple events. Its use is therefore recommended in prospective studies on paediatric surgery.
Nanomaterials for the delivery of bioactive factors to enhance angiogenesis of dermal substitutes during wound healing
Authors: Weng Tingting , Wang Jialiang , Yang Min , Zhang Wei , Wu Pan , You Chuangang , Han Chunmao , Wang Xingang
Published: November 2021

Dermal substitutes provide a template for dermal regeneration and reconstruction. They constitutes an ideal clinical treatment for deep skin defects. However, rapid vascularization remains as a major hurdle to the development and application of dermal substitutes. Several bioactive factors play an important regulatory role in the process of angiogenesis and an understanding of the mechanism of achieving their effective delivery and sustained function is vital. Nanomaterials have great potential for tissue engineering. Effective delivery of bioactive factors (including growth factors, peptides and nucleic acids) by nanomaterials is of increasing research interest. This paper discusses the process of dermal substitute angiogenesis and the roles of related bioactive factors in this process. The application of nanomaterials for the delivery of bioactive factors to enhance angiogenesis and accelerate wound healing is also reviewed. We focus on new systems and approaches for delivering bioactive factors for enhancing angiogenesis in dermal substitutes.
A case report of pulmonary vein isolation performed in a patient with polysplenia and interrupted inferior vena cava
Authors: Kupics Kaspars , Jubele Kristine , Nesterovics Georgijs , Erglis Andrejs
Published: December 2021

Background

Pulmonary vein isolation (PVI) has entrenched itself as one of the main approaches for the treatment of paroxysmal symptomatic atrial fibrillation (AF). Pulmonary vein isolation prevents focal triggers from pulmonary veins from initiating AF paroxysms. As standard—PVI is performed through the inferior vena cava (IVC) approach, through the femoral vein. However, there are conditions when this approach is not appropriate or is not available.

Case summary

We report a case of a 53-year-old male who was referred to Pauls Stradins Clinical University Hospital for PVI due to worsening AF. Due to the rare anatomical variant of the venous system, the standard approach to PVI could not be applied. Interrupted cava inferior did not allow for femoral vein and IVC access. We had to figure out a different path—a combination of internal jugular and subclavian veins was used. Transseptal puncture was performed under transoesophageal echocardiography (TOE) control with a puncture needle stiletto. Pulmonary veins were isolated successfully, no complications were observed, and the patient was discharged in sinus rhythm.

Discussion

In some patients, PVI cannot be done through the standard IVC approach. In such cases, a different venous access must be chosen. Our patient had a rare variant of interrupted IVC and we had to use superior vena cava approach for the procedure. The difficulty of this approach is that procedure instruments are not designed for non-standard venous access; however, a combined use of TOE, general anaesthesia, and contact force-guided ablation has succeeded in isolating patients’ pulmonary veins.
Old stuff still trending: use of propafenone as a safety net until catheter ablation in a patient with documented pre-excited atrial fibrillation and Wolff–Parkinson–White syndrome – a classic case report
Authors: Karelas Dimitrios , Papanikolaou John , Kossyvakis Charalampos , Platogiannis Dimitrios
Published: December 2021

Background

Atrial fibrillation in Wolff–Parkinson–White syndrome may result in life-threateningly rapid antegrade conduction over a bypass tract, manifested by an irregular broad-complex (pre-excited) tachycardia that can degenerate to ventricular fibrillation. The shortest pre-excited RR interval below 250 ms during atrial fibrillation (AF) predicts increased risk of sudden cardiac death.

Case summary

We report a case of a 43-year-old man with unremarkable cardiac history who presented due to sudden-onset feeling of palpitations and pre-syncope after strenuous lifting. Electrocardiography depicted fast pre-excited AF. The shortest pre-excited RR interval was estimated at 160 ms, indicating an accessory pathway (AP) with short antegrade refractory period at risk for mediating sudden cardiac death. Direct current cardioversion restored sinus rhythm unravelling delta waves. The patient was put on propafenone 450 mg/day having an uneventful clinical course. On Day 10 post-admission, electrophysiological study induced rapid AF but the shortest pre-excited RR interval was substantially increased to 264 ms. A left anterolateral AP was ablated. The patient remained symptom free until his latest follow-up in the 3rd-month post-ablation without manifest pre-excitation on the surface electrocardiogram.

Discussion

Treatment options of pre-excited AF include anti-arrhythmic agents but mainly electrical cardioversion. Cardioversion can safely restore sinus rhythm, while use of anti-arrhythmics often requires intensive care unit monitoring due to the risk of QT prolongation. Catheter ablation is the mainstay of therapy for symptomatic patients. Our rare report highlights the direct impact of propafenone on prolonging the refractoriness of the AP, effectively and safely, and reappraises propafenone’s worthiness as a protective measure following pre-excited AF episode until ablation.
Symptomatic atherosclerotic plaque progression in a first-generation carotid stent: management and 5-year clinical and imaging outcome—a case report
Authors: Tekieli Lukasz , Mazurek Adam , Pieniazek Piotr , Musialek Piotr
Published: December 2021

Background

Restenosis in first-generation (single-layer) carotid stents (FGS) is believed to represent an exaggerated healing response of (neo)intimal hyperplasia (NIH) formation. Rather than NIH, we describe symptomatic in-FGS unstable plaque (neo)atherosclerosis mandating re-revascularization. To halt continued plaque evolution, we propose a novel treatment strategy involving a microNet-covered stent (MCS, second-generation carotid stent) to sequestrate the plaque from the vessel lumen. A durable long-term result is documented using multi-modal imaging.

Case summary

With a seemingly optimal result of FGS (Precise) symptomatic carotid lesion revascularization followed by optimal medical therapy, a late (≥3 years) progressive in-stent restenosis (ISR) arose. At Year 11, crescendo ipsilateral transient ischaemic attacks occurred. Angiography showed an ulcerated tight lesion throughout stent length. Intravascular ultrasound (IVUS) virtual histology imaging revealed thin-cap fibroatheroma. Reintervention was performed under distal protection. Undersized balloon predilatation to insert a stent caused symptomatic no-flow, and aspiration catheter was used to reduce the filter load. A MCS (CGuard) was implanted and post-dilated to ensure full lumen gain; IVUS confirmed complete plaque sequestration. The optimal anatomic result remained unchanged throughout 5 years (ultrasound and computed tomography verification); this was accompanied by clinical cure.

Discussion

This is the first demonstration of in-FGS (neo)atherosclerosis resolution using an MCS to sequestrate and insulate the atherosclerotic plaque. We show that ISR may be underlined by atherosclerotic plaque progression via the FGS single-layer stent struts that may show vulnerable plaque phenotype and may be associated with cerebral ischaemia. The anatomically and clinically effective exclusion of the atherosclerotic plaque by an MCS enabled lasting, optimal endovascular reconstruction and clinical cure.
Optical coherence tomographic insights of very late stent thrombosis of a second-generation drug-eluting stent: a case report
Authors: Otaal Parminder Singh , Gawalkar Atit A , Shunmugarajan Ajay
Published: December 2021

Background

Very-very late stent thrombosis (VVLST) occurring more than 5 years after implantation of drug-eluting stent (DES) is extremely rare, being restricted to few case reports. Mainly described with first-generation stents, this life-threatening complication has not been described with later-generation stents. We describe the first case of VVLST occurring 3309 days (>9 years) after implantation of second-generation DES.

Case summary

A 62-year-old man presented with the acute coronary syndrome. He has a history of percutaneous coronary intervention (PCI) to the right coronary artery using the three second-generation DES more than 9 years ago. Coronary angiogram revealed in-stent restenosis (ISR) with doubtful angiographic thrombus. Optical coherence tomography (OCT) confirmed the diagnosis of stent thrombosis (STh) localized to the stent overlap zone with underlying ISR. Patient underwent OCT-guided PCI with DES implantation and was discharged on dual antiplatelet therapy including ticagrelor. He is doing well on follow-up at 6 months.

Discussion

Stent thrombosis can occur in second-generation stents nearly a decade after implant. Stent overlap segment is more prone to neo-atheroma formation and vulnerable plaque leading to STh. In addition to confirming the diagnosis, OCT provides exciting insights into the underlying mechanism. This has implications for long-term antiplatelet therapy in patients implanted with multiple stents.
Development of a machine learning model using electrocardiogram signals to improve acute pulmonary embolism screening
Authors: Somani Sulaiman S , Honarvar Hossein , Narula Sukrit , Landi Isotta , Lee Shawn , Khachatoorian Yeraz , Rehmani Arsalan , Kim Andrew , De Freitas Jessica K , Teng Shelly , Jaladanki Suraj , Kumar Arvind , Russak Adam , Zhao Shan P , Freeman Robert , Levin Matthew A , Nadkarni Girish N , Kagen Alexander C , Argulian Edgar , Glicksberg Benjamin S
Published: December 2021

Aims

Clinical scoring systems for pulmonary embolism (PE) screening have low specificity and contribute to computed tomography pulmonary angiogram (CTPA) overuse. We assessed whether deep learning models using an existing and routinely collected data modality, electrocardiogram (ECG) waveforms, can increase specificity for PE detection.

Methods and results

We create a retrospective cohort of 21 183 patients at moderate- to high suspicion of PE and associate 23 793 CTPAs (10.0% PE-positive) with 320 746 ECGs and encounter-level clinical data (demographics, comorbidities, vital signs, and labs). We develop three machine learning models to predict PE likelihood: an ECG model using only ECG waveform data, an EHR model using tabular clinical data, and a Fusion model integrating clinical data and an embedded representation of the ECG waveform. We find that a Fusion model [area under the receiver-operating characteristic curve (AUROC) 0.81 ± 0.01] outperforms both the ECG model (AUROC 0.59 ± 0.01) and EHR model (AUROC 0.65 ± 0.01). On a sample of 100 patients from the test set, the Fusion model also achieves greater specificity (0.18) and performance (AUROC 0.84 ± 0.01) than four commonly evaluated clinical scores: Wells’ Criteria, Revised Geneva Score, Pulmonary Embolism Rule-Out Criteria, and 4-Level Pulmonary Embolism Clinical Probability Score (AUROC 0.50–0.58, specificity 0.00–0.05). The model is superior to these scores on feature sensitivity analyses (AUROC 0.66–0.84) and achieves comparable performance across sex (AUROC 0.81) and racial/ethnic (AUROC 0.77–0.84) subgroups.

Conclusion

Synergistic deep learning of ECG waveforms with traditional clinical variables can increase the specificity of PE detection in patients at least at moderate suspicion for PE.
Cognitive Performance in Remote Work: Evidence from Professional Chess
Authors: Künn Steffen , Seel Christian , Zegners Dainis
Published: December 2021

During the COVID-19 pandemic, traditional (offline) chess tournaments were prohibited and instead held online. We exploit this unique setting to assess the impact of remote work policies on the cognitive performance of individuals. Using the artificial intelligence embodied in a powerful chess engine to assess the quality of chess moves and associated errors, we find a statistically and economically significant decrease in performance when an individual competes remotely versus offline in a face-to-face setting. The effect size decreases over time, suggesting an adaptation to the new remote setting.
Contemporary surgical outcome and symptomatic relief following vascular ring surgery in children: effect of prenatal diagnosis
Authors: Swarnkar Parinita , Speggiorin Simone , Austin B Conal , Nyman Andrew , Salih Caner , Zidere Vita , Simpson John M , Vigneswaran Trisha V
Published: December 2021

OBJECTIVES

Our goal was to describe postoperative complications and outcomes in a large contemporary cohort of children with an isolated double aortic arch (DAA) or a right aortic arch (RAA) with left arterial ligament and to assess the impact of foetal diagnosis on outcomes.

METHODS

We performed a retrospective analysis of all patients who underwent surgery for DAA or RAA with left arterial ligament between 2005 and 2019.

RESULTS

A total of 132 children were operated on for a DAA (n = 77) or a RAA (n = 55). Prenatal diagnosis was made in 100/132 (75.8%). Median age at surgery for DAA was 5.0 (1.7–13.3) months and for RAA was 13.9 (6.4–20.1) months. There was no difference in the age at surgery between the prenatal and postnatal cases (8.6 [4.0–15.6] vs 5.4 months [1.8–17.7]; P = 0.37). No surgical deaths occurred. Vocal cord palsy was the most common complication, occurring in 12/132 (9%): of these, 11 resolved spontaneously and 1 required a temporary tracheostomy. Logistic regression demonstrated that older age at operation was the only predictor for a postoperative complication (P = 0.02). Overall, 21/67 (31%) of prenatally detected, symptomatic cases reported residual symptoms/signs 1 year after surgery compared to 18/28 (64%) of postnatally detected cases. Postnatal diagnosis was associated with persistent postoperative symptoms/signs [P = 0.006, odds ratio = 3.9 (95% confidence interval 1.5–9.4)].

CONCLUSIONS

Surgery to relieve a vascular ring resolves trache-oesophageal compressive symptoms in most cases, but parents/patients should be aware that symptoms/signs may persist in the first postoperative year despite effective release of the vascular ring. Earlier surgery and prenatal diagnosis may improve outcomes.
Construction of a gut microbiota-gene-pathway network to reveal the molecular mechanisms underlying right- and left-sided colorectal cancer
Authors: Du Kunli , Wang Xinyou , Li Shisen , Ren Jiahui , Li Ruikai , Wang Mian , Feng Fan , Du Hansong , Zheng Jianyong
Published: December 2021

Aiming to reveal the molecular mechanisms involved in right- and left-sided colorectal cancer (CRC) development, CRC gene expression data and a microorganism atlas were downloaded from The Cancer Genome Atlas and The Cancer Microbiome Atlas, respectively. The R package was used to screen differentially expressed genes (DEGs) between right- and left-sided CRC samples and identify those related to prognosis, a correlation analysis was performed between DEGs and prognosis-related microbiota, and an interaction network was created using Cytoscape. Finally, a taxon set enrichment analysis of the microbiota was performed and a gene-genus-pathway network was constructed after GO and KEGG analyses. In total, 9 out of 1557 identified DEGs had a significant correlation with prognosis, whereas 3 out of 211 bacterial genera (Fusobacterium, Bacteroides, and Parabacteroides) showed a significant correlation with prognosis. DEGs were mainly enriched in the PPAR pathway and vitamin metabolic and transport processes. According to a taxon set enrichment analysis, the microbes in the integrated network were significantly abundant in 28 host-intrinsic, 2 host-extrinsic, and 1 environment taxon sets. This study provides new insights for understanding the molecular mechanisms of left- and right- CRC.
Changes in fruit pigment accumulation, chloroplast development, and transcriptome analysis in the CRISPR/Cas9-mediated knockout of Stay-green 1 (slsgr1) mutant
Authors: Ma Liqun , Zeng Ni , Cheng Ke , Li Jinyan , Wang Keru , Zhang Chunjiao , Zhu Hongliang
Published: December 2021

The green-flesh (gf) mutant of the tomato fruit ripen to a muddy brown color and has been demonstrated previously to be a loss-of-function mutant. Here, we provide more evidence to support this view that SlSGR1 is involved in color change in ripening tomato fruits. Knocking out SlSGR1 expression using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 genome editing strategy showed obviously a muddy brown color with significantly higher chlorophyll and carotenoid content compared with wild-type (WT) fruits. To further verify the role of SlSGR1 in fruit color change, we performed transcriptome deep sequencing (RNA-seq) analysis, where a total of 354 differentially expressed genes (124/230 downregulated/upregulated) were identified between WT and slsgr1. Additionally, the expression of numerous genes associated with photosynthesis and chloroplast function changed significantly when SlSGR1 was knocked out. Taken together, these results indicate that SlSGR1 is involved in color change in ripening fruit via chlorophyll degradation and carotenoid biosynthesis.
Genome Sequence ofElaeagnus mollis, the First Chromosome-Level Genome of the Family Elaeagnaceae
Authors: Ren Baoqing , Ru Dafu , Chen Luqin , Duan Na , Li Yong , Shi Jianwei , Cao Jianting , Liu Bingbing
Published: November 2021

Elaeagnus mollis Diels (Elaeagnaceae) is a species of shrubs and/or dwarf trees that produces highly nutritious nuts with abundant oil and pharmaceutical properties. It is endemic to China but endangered. Therefore, to facilitate the protection of its genetic resources and the development of its commercially attractive traits we generated a high-quality genome of E. mollis. The contig version of the genome (630.96 Mb long) was assembled into 14 chromosomes using Hi-C data, with contig and scaffold N50 values of 18.40 and 38.86 Mb, respectively. Further analyses identified 397.49 Mb (63.0%) of repetitive sequences and 27,130 protein-coding genes, of which 26,725 (98.5%) were functionally annotated. Benchmarking Universal Single-Copy Ortholog assessment indicated that 98.0% of highly conserved plant genes are completely present in the genome. This is the first reference genome for any species of Elaeagnaceae and should greatly facilitate future efforts to conserve, utilize, and elucidate the evolution of this endangered endemic species.
100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes
Authors: Pearson James A , McKinney Eoin F , Walker Lucy S K
Published: December 2021

Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here, we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting.
The case for wearable proximity devices to inform physical distancing among healthcare workers
Authors: Keller Sara C , Salinas Alejandra B , Oladapo-Shittu Opeyemi , Cosgrove Sara E , Lewis-Cherry Robin , Osei Patience , Gurses Ayse P , Jacak Ron , Zudock Kristina K , Blount Kianna M , Bowden Kenneth V , Rock Clare , Sick-Samuels Anna C , Vecchio-Pagan Briana
Published: December 2021

Objective

Despite the importance of physical distancing in reducing SARS-CoV-2 transmission, this practice is challenging in healthcare. We piloted use of wearable proximity beacons among healthcare workers (HCWs) in an inpatient unit to highlight considerations for future use of trackable technologies in healthcare settings.

Materials and Methods

We performed a feasibility pilot study in a non-COVID adult medical unit from September 28 to October 28, 2020. HCWs wore wearable proximity beacons, and interactions defined as <6 feet for ≥5 s were recorded. Validation was performed using direct observations.

Results

A total of 6172 close proximity interactions were recorded, and with the removal of 2033 false-positive interactions, 4139 remained. The highest proportion of interactions occurred between 7:00 Am–9:00 Am. Direct observations of HCWs substantiated these findings.

Discussion

This pilot study showed that wearable beacons can be used to monitor and quantify HCW interactions in inpatient settings.

Conclusion

Technology can be used to track HCW physical distancing.
The role and clinical relevance of the ligamentum teres: long-term outcomes after hip arthroscopic surgery of cam-type femoroacetabular impingement
Authors: Lee Jeong-Kil , Hwang Deuk-Soo , Kim Sang-Bum , Kang Chan , Hwang Jung-Mo , Lee Gi-Soo , Park Eugene Jae-Jin
Published: December 2021

We aimed to compare clinical and radiologic outcomes in patients with cam-type femoroacetabular impingement (FAI), with and without a partial ligamentum teres (LT) tear, who underwent hip arthroscopy (HA) with ≥10 years of follow-up. Among the patients who underwent HA for a cam-type FAI diagnosis with a labral tear, 28 patients (28 hips) with a partial LT tear and 87 patients (99 hips) with an intact LT were assigned to Groups A and B, respectively. All patients underwent partial labral debridement and femoroplasty. Debridement and thermal shrinkage were performed for LT tears. The grade of chondral damage was measured intraoperatively. Clinical items were assessed preoperatively and at the last follow-up. Patients’ satisfaction with the surgery and changes in postoperative sports ability in those who had previously been active in sports were assessed at the last follow-up. The Tönnis grade was assessed preoperatively and at the last follow-up for radiologic evaluation. Chondral damage to the acetabular and femoral head detected intraoperatively was significantly different between the groups (P = 0.005 and P < 0.001). At the last follow-up, Group A patients experienced more difficulty performing sports activities than Group B patients (P = 0.056), and significantly, more Group A patients had stopped exercising despite their active participation in sports preoperatively (P = 0.002). Regarding the Tönnis grade, significant differences were found only at the final follow-up (P = 0.020). Patients with partial LT tear showed a higher grade of chondral damage, experienced decreased exercise capacity and had significantly worsened Tönnis grades, suggesting hip osteoarthritis progression compared to those with an intact LT.
Primary meningococcal septic arthritis associated with joint calcium oxalate crystals: A case report and review of the literature
Authors: Cimé-Aké Erik , Carranza-Enríquez Fabián , Hurtado-Arias José Joel , Muñoz-Castañeda Wallace Rafael A , Medina-Fonseca Benjamín , Barrera-Vargas Ana , Lizardo-Thiebaud María J , Saeb-Lima Marcela , Merayo-Chalico Javier
Published: December 2021

Primary meningococcal septic arthritis (PMSA) is an extremely rare local infection by Neisseria meningitidis in the absence of meningitis or meningococcaemia syndrome. A 30-year-old healthy, immunocompetent man presented with arthralgia, fever, chest rash, and significant swelling of the right knee. On admission, a disseminated maculopapular and purpuric rash, oligoarthritis, neutrophilia, and elevated acute phase reactants were documented. Following arthrocentesis of the right knee, isolation of N. meningitidis and the presence of calcium oxalate crystals in the synovial fluid were reported. The diagnosis of PMSA was made. Histological analysis of the skin lesion showed leucocytoclastic vasculitis. He was treated with intravenous ceftriaxone plus open surgical drainage and ambulatory cefixime with adequate response. After 1 month, he presented resolution of the pathological process. We performed an extensive review of the literature, finding that the key elements supporting the diagnosis of PMSA are prodromal upper respiratory tract symptoms and skin involvement prior to or synchronous with the arthritis. Also, the most frequently involved joint is the knee. This report is the first case of a patient presenting with PMSA associated with calcium oxalate crystals in the synovial fluid. Herein, we discuss the most frequent clinical manifestations, the unusual histological features, the recommended treatment, and the reported prognosis of this rare entity.
Misregulation of the expression and activity of DNA methyltransferases in cancer
Authors: Mensah Isaiah K , Norvil Allison B , AlAbdi Lama , McGovern Sarah , Petell Christopher J , He Ming , Gowher Humaira
Published: December 2021

In mammals, DNA methyltransferases DNMT1 and DNMT3’s (A, B and L) deposit and maintain DNA methylation in dividing and nondividing cells. Although these enzymes have an unremarkable DNA sequence specificity (CpG), their regional specificity is regulated by interactions with various protein factors, chromatin modifiers, and post-translational modifications of histones. Changes in the DNMT expression or interacting partners affect DNA methylation patterns. Consequently, the acquired gene expression may increase the proliferative potential of cells, often concomitant with loss of cell identity as found in cancer. Aberrant DNA methylation, including hypermethylation and hypomethylation at various genomic regions, therefore, is a hallmark of most cancers. Additionally, somatic mutations in DNMTs that affect catalytic activity were mapped in Acute Myeloid Leukemia cancer cells. Despite being very effective in some cancers, the clinically approved DNMT inhibitors lack specificity, which could result in a wide range of deleterious effects. Elucidating distinct molecular mechanisms of DNMTs will facilitate the discovery of alternative cancer therapeutic targets. This review is focused on: (i) the structure and characteristics of DNMTs, (ii) the prevalence of mutations and abnormal expression of DNMTs in cancer, (iii) factors that mediate their abnormal expression and (iv) the effect of anomalous DNMT-complexes in cancer.
RNA-Scoop: interactive visualization of transcripts in single-cell transcriptomes
Authors: Stephenson Maria , Nip Ka Ming , HafezQorani Saber , Gagalova Kristina K , Yang Chen , Warren René L , Birol Inanc
Published: December 2021

Recent advances in single-cell RNA sequencing technologies have made detection of transcripts in single cells possible. The level of resolution provided by these technologies can be used to study changes in transcript usage across cell populations and help investigate new biology. Here, we introduce RNA-Scoop, an interactive cell cluster and transcriptome visualization tool to analyze transcript usage across cell categories and clusters. The tool allows users to examine differential transcript expression across clusters and investigate how usage of specific transcript expression mechanisms varies across cell groups.
Structure-based deep learning for binding site detection in nucleic acid macromolecules
Authors: Kozlovskii Igor , Popov Petr
Published: December 2021

Structure-based drug design (SBDD) targeting nucleic acid macromolecules, particularly RNA, is a gaining momentum research direction that already resulted in several FDA-approved compounds. Similar to proteins, one of the critical components in SBDD for RNA is the correct identification of the binding sites for putative drug candidates. RNAs share a common structural organization that, together with the dynamic nature of these molecules, makes it challenging to recognize binding sites for small molecules. Moreover, there is a need for structure-based approaches, as sequence information only does not consider conformation plasticity of nucleic acid macromolecules. Deep learning holds a great promise to resolve binding site detection problem, but requires a large amount of structural data, which is very limited for nucleic acids, compared to proteins. In this study we composed a set of ∼2000 nucleic acid-small molecule structures comprising ∼2500 binding sites, which is ∼40-times larger than previously used one, and demonstrated the first structure-based deep learning approach, BiteNetN, to detect binding sites in nucleic acid structures. BiteNetN operates with arbitrary nucleic acid complexes, shows the state-of-the-art performance, and can be helpful in the analysis of different conformations and mutant variants, as we demonstrated for HIV-1 TAR RNA and ATP-aptamer case studies.
A review of neurotoxicities associated with immunotherapy and a framework for evaluation
Authors: Burton Leeann B , Eskian Mahsa , Guidon Amanda C , Reynolds Kerry L
Published: December 2021

Immuno-oncology agents, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T (CAR-T) cell therapies, are increasing in use for a growing list of oncologic indications. While harnessing the immune system against cancer cells has a potent anti-tumor effect, it can also cause widespread autoimmune toxicities that limit therapeutic potential. Neurologic toxicities have unique presentations and can progress rapidly, necessitating prompt recognition. In this article, we review the spectrum of central and peripheral neurologic immune-related adverse events (irAEs) associated with ICI therapies, emphasizing a diagnostic framework that includes consideration of the therapy regimen, timing of symptom onset, presence of non-neurologic irAEs, pre-existing neurologic disease, and syndrome specific features. In addition, we review the immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CAR-T cell therapy and address diagnostic challenges specific to patients with brain metastases. As immunotherapy use grows, so too will the number of patients affected by neurotoxicity. There is an urgent need to understand pathogenic mechanisms, predictors, and optimal treatments of these toxicities, so that we can manage them without sacrificing anti-tumor efficacy.
Preservation of neurocognitive function in the treatment of brain metastases
Authors: Parsons Michael W , Peters Katherine B , Floyd Scott R , Brown Paul , Wefel Jeffrey S
Published: December 2021

Neurocognitive function (NCF) deficits are common in patients with brain metastases, occurring in up to 90% of cases. NCF deficits may be caused by tumor-related factors and/or treatment for the metastasis, including surgery, radiation therapy, chemotherapy, and immunotherapy. In recent years, strategies to prevent negative impact of treatments and ameliorate cognitive deficits for patients with brain tumors have gained momentum. In this review, we report on research that has established the efficacy of preventative and rehabilitative therapies for NCF deficits in patients with brain metastases. Surgical strategies include the use of laser interstitial thermal therapy and intraoperative mapping. Radiotherapy approaches include focal treatments such as stereotactic radiosurgery and tailored approaches such as hippocampal avoidant whole-brain radiotherapy (WBRT). Pharmacologic options include use of the neuroprotectant memantine to reduce cognitive decline induced by WBRT and incorporation of medications traditionally used for attention and memory problems. Integration of neuropsychology into the care of patients with brain metastases helps characterize cognitive patterns, educate patients and families regarding their management, and guide rehabilitative therapies. These and other strategies will become even more important for long-term survivors of brain metastases as treatment options improve.
Advances in radiotherapy for brain metastases
Authors: Gondi Vinai , Meyer Jacquelyn , Shih Helen A
Published: December 2021

As novel systemic therapies yield improved survival in metastatic cancer patients, the frequency of brain metastases continues to increase. Over the years, management strategies have continued to evolve. Historically, stereotactic radiosurgery has been used as a boost to whole-brain radiotherapy (WBRT) but is increasingly being used as a replacement for WBRT. Given its capacity to treat both macro- and micro-metastases in the brain, WBRT has been an important management strategy for years, and recent research has identified technologic and pharmacologic approaches to delivering WBRT more safely. In this review, we outline the current landscape of radiotherapeutic treatment options and discuss approaches to integrating radiotherapy advances in the contemporary management of brain metastases.
Targeted therapy strategies for melanoma brain metastasis
Authors: Saberian Chantal , Sperduto Paul , Davies Michael A
Published: December 2021

Melanoma is the most aggressive of the common forms of skin cancer. Metastasis to the central nervous system is one of the most common and deadly complications of this disease. Historically, melanoma patients with brain metastases had a median survival of less than 6 months. However, outcomes of melanoma patients have markedly improved over the last decade due to new therapeutic approaches, including immune and targeted therapies. Targeted therapies leverage the high rate of driver mutations in this disease, which result in the activation of multiple key signaling pathways. The RAS-RAF-MEK-ERK pathway is activated in the majority of cutaneous melanomas, most commonly by point mutations in the Braf serine-threonine kinase. While most early targeted therapy studies excluded melanoma patients with brain metastases, subsequent studies have shown that BRAF inhibitors, now generally given concurrently with MEK inhibitors, achieve high rates of tumor response and disease control in Braf-mutant melanoma brain metastases (MBMs). Unfortunately, the duration of these responses is generally relatively short- and shorter than is observed in extracranial metastases. This review will summarize current data regarding the safety and efficacy of targeted therapies for MBMs and discuss rational combinatorial strategies that may improve outcomes further.
Homotopic functional connectivity disruptions in glioma patients are associated with tumor malignancy and overall survival
Authors: Daniel Andy G S , Hacker Carl D , Lee John J , Dierker Donna , Humphries Joseph B , Shimony Joshua S , Leuthardt Eric C
Published: December 2021

Background

Gliomas exhibit widespread bilateral functional connectivity (FC) alterations that may be associated with tumor grade. Limited studies have examined the connection-level mechanisms responsible for these effects. Given the typically strong FC observed between mirroring/homotopic brain regions in healthy subjects, we hypothesized that homotopic connectivity (HC) is altered in low-grade and high-grade glioma patients and the extent of disruption is associated with tumor grade and predictive of overall survival (OS) in a cohort of de novo high-grade glioma (World Health Organization [WHO] grade 4) patients.

Methods

We used a mirrored FC-derived cortical parcellation to extract blood-oxygen-level-dependent (BOLD) signals and to quantify FC differences between homotopic pairs in normal-appearing brain in a retrospective cohort of glioma patients and healthy controls.

Results

Fifty-nine glioma patients (WHO grade 2, n = 9; grade 4 = 50; mean age, 57.5 years) and 30 healthy subjects (mean age, 65.9 years) were analyzed. High-grade glioma patients showed lower HC compared with low-grade glioma patients and healthy controls across several cortical locations and resting-state networks. Connectivity disruptions were also strongly correlated with hemodynamic lags between homotopic regions. Finally, in high-grade glioma patients with known survival times (n = 42), HC in somatomotor and dorsal attention networks were significantly correlated with OS.

Conclusions

These findings demonstrate an association between tumor grade and HC alterations that may underlie global FC changes and provide prognostic information.
Landscape of driver gene events, biomarkers, and druggable targets identified by whole-genome sequencing of glioblastomas
Authors: van de Geer Wesley S , Hoogstrate Youri , Draaisma Kaspar , Robe Pierre A , Bins Sander , Mathijssen Ron H J , French Pim , van de Werken Harmen J G , de Vos Filip Y F
Published: December 2021

Background

The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy, and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve patient survival is urgently needed. Whole-genome sequencing (WGS) is the most comprehensive means to identify such DNA-level targets. We report a unique set of WGS samples along with comprehensive analyses of the glioblastoma genome and potential clinical impact of WGS.

Methods

Our cohort consisted of 42 glioblastoma tumor tissue and matched whole-blood samples, which were whole-genome sequenced as part of the CPCT-02 study. Somatic single-nucleotide variants, small insertions/deletions, multi-nucleotide variants, copy-number alterations (CNAs), and structural variants were analyzed. These aberrations were harnessed to investigate driver genes, enrichments in CNAs, mutational signatures, fusion genes, and potential targeted therapies.

Results

Tumor mutational burden (TMB) was similar to other WGS efforts (1–342 mutations per megabase pair). Mutational analysis in low TMB samples showed that the age-related CpG demethylation signature was dominant, while hyper- and ultramutated tumors had additional defective DNA mismatch repair signatures and showed microsatellite instability in their genomes. We detected chromothripsis in 24% of our cohort, recurrently on chromosomes 1 and 12. Recurrent noncoding regions only resulted in TERT promoter variants. Finally, we found biomarkers and potentially druggable changes in all but one of our tumor samples.

Conclusions

With high-quality WGS data and comprehensive methods, we identified the landscape of driver gene events and druggable targets in glioblastoma patients.
Rollback, scissor-like closure of the Mongol-Okhotsk Ocean and formation of an orocline: magmatic migration based on a large archive of age data
Authors: Wang Tao , Tong Ying , Xiao Wenjiao , Guo Lei , Windley Brian F , Donskaya Tatiana , Li Shan , Tserendash Narantsetseg , Zhang Jianjun
Published: November 2021

Tracing the closure of oceans with irregular margins and the formation of an orocline are crucial for understanding plate reconstruction and continental assembly. The eastern Central Asian Orogenic Belt, where the Mongol-Okhotsk orocline is situated, is one of the world's largest magmatic provinces. Using a large data set of U-Pb zircon ages, we updated the timing of many published igneous rocks, which allowed us to recognize tightly ‘folded’ linear Carboniferous-Jurassic magmatic belts that wrap around the Mongol-Okhotsk suture and their migrations both sutureward and suture-parallel. The new successive magmatic belts reveal a rollback, scissor-like (or zipper-like) closure of the Mongol-Okhotsk Ocean that was fundamentally controlled by coeval subduction rollback and rotation of the Siberian and Mongolian-Erguna blocks. This study also demonstrates the complex mechanisms and processes of the closure of an ocean with irregular margins and the formation of a consequent orocline.
Antibiotic Prophylaxis Prescribing Practice in Head and Neck Tumor Resection and Free Flap Reconstruction
Authors: Daly John Frederick , Gearing Peter Francis , Tang Nicholas Shi Jie , Ramakrishnan Anand , Singh Kasha Priya
Published: December 2021

Background

Adherence to guidelines for antibiotic prophylaxis is often poor and is an important target for antimicrobial stewardship programs. Prescribing audits that suggested poor adherence to guidelines in a plastic surgery department led to a targeted education program to bring antibiotic prescriptions in line with hospital guidelines. We reviewed whether this intervention was associated with changed perioperative prescribing and altered surgical outcomes, including the rate of surgical site infections, specifically looking at clean-contaminated head and neck tumor resections with free flap reconstruction.

Methods

A retrospective cohort study was performed on 325 patients who underwent clean-contaminated head and neck tumor resection and free flap reconstruction from January 1, 2013, to February 19, 2019. Patients were divided into 2 groups, those before (pre-intervention) and after (postintervention) the education campaign. We analyzed patient demographic and disease characteristics, intraoperative and postoperative factors, and surgical outcomes.

Results

Patients pre-intervention were prescribed longer courses of prophylactic antibiotics (median [interquartile range], 9 [8] vs 1 [1]; P < .001), more topical chloramphenicol ointment (21.82% vs 0%; P < .001), and more oral nystatin (36.9% vs 12.2%; P < .001). Patients postintervention had higher rates of recipient infections (36.11% vs 17.06%; P < .001) and donor site infections (6.94% vs 1.19%; P = .006).

Conclusions

Following the education campaign, patients were prescribed shorter courses of prophylactic antibiotics, more of the recommended cefazolin-metronidazole regimen, and fewer topical antibiotics. However, patients also had a higher rate of surgical site infections.
Invasive Mold Infections in Allogeneic Hematopoietic Cell Transplant Recipients in 2020: Have We Made Enough Progress?
Authors: Roth Romain Samuel , Masouridi-Levrat Stavroula , Chalandon Yves , Mamez Anne-Claire , Giannotti Federica , Riat Arnaud , Fischer Adrien , Poncet Antoine , Glampedakis Emmanouil , Van Delden Christian , Kaiser Laurent , Neofytos Dionysios
Published: December 2021

Background

Despite progress in diagnostic, prevention, and treatment strategies, invasive mold infections (IMIs) remain the leading cause of mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients.

Methods

We describe the incidence, risk factors, and mortality of allo-HCT recipients with proven/probable IMI in a retrospective single-center 10-year (01/01/2010–01/01/2020) cohort study.

Results

Among 515 allo-HCT recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%), and other molds (8/51, 15%). Overall, 35/51 (68.6%) breakthrough IMIs (bIMIs) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31–180, and >180 days post-HCT, respectively. Risk factors for IMI included prior allo-HCT (sub hazard ratio [SHR], 4.06; P = .004) and grade ≥2 acute graft-vs-host disease (aGvHD; SHR, 3.52; P < .001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (P = .02). Mortality predictors included disease relapse (hazard ratio [HR], 7.47; P < .001), aGvHD (HR, 1.51; P = .001), CMV serology–positive recipients (HR, 1.47; P = .03), and IMI (HR, 3.94; P < .001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (log-rank P = .47). At 1 year post–IMI diagnosis, 70.8% (34/48) of the patients were dead.

Conclusions

IA mortality has remained relatively unchanged during the last 2 decades. More than two-thirds of allo-HCT recipients with IMI die by 1 year post–IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.
Polymyxin B and low-dose hydrocortisone treatment in a patient with uroseptic shock in a rural health unit
Authors: Arai Toshio , Mori Yuichiro , Yoshizaki Saori , Ando Ryo , Natori Shunsuke , Morishita Shun , Otani Miyu , Numata Atsushi , Osanai Hiroaki
Published: December 2021

Sepsis has a high mortality rate; thus, in the intensive care unit, early diagnosis and adjunctive treatments are crucial. However, generally, most patients with sepsis from rural area initially visit the emergency department at a rural hospital and are managed in general medical wards in Japan. Here we report on an 81-year-old Japanese female manifesting septic shock caused by the upper urinary tract infection of extended-spectrum beta-lactamase-producing Escherichia coli secondary to the left ureter obstruction by the urothelial carcinoma. Broad-spectrum antibiotics were administered. Although critical for the source control of infection, drainage of the ureteropelvic junction could not be performed immediately because of catecholamine-resistant hypotension. Hence, we administered polymyxin B-immobilized fiber column direct hemoperfusion, followed by low-dose hydrocortisone administration. After 8 hours of infusion, she recovered from the septic shock and successfully underwent emergency percutaneous nephrostomy. This presented strategy may provide a new resolution of catecholamine-resistant patients in urosepsis.
Case report of primary CD20 negative diffuse large B-cell lymphoma
Authors: Devi Kanti , Ali Natashi , Ahmed Arsalan
Published: December 2021

Few groups of aggressive non-Hodgkin’s lymphomas (NHL) that are refractory to standard chemotherapy are rarely reported. Primary CD20 negative diffuse large B cell lymphoma (DLBCL) without human immunodeficiency virus infection is an uncommon presentation and this case report is challenging in terms of diagnosis and treatment as well.