bluuebunny/crossref_metadata_2025 huggingface dataset:
Vermiform appendix torsion complicated by postoperative venous pylephlebitis: a case report and review of literature
Authors: Nyssen Marie , Marliere Camille , Fobe Didier , Kothonidis Konstantinos
Published: May 2023

Vermiform appendix torsion is a rare condition that mimics acute appendicitis and is diagnosed during surgery. On the other hand, pylephlebitis (or septic thrombophlebitis) is a complication that occurs due to occlusive thrombosis of mesenteric venous system branches secondary to intra-abdominal infections. Although rare since the antibiotic era, it must be considered in the differential diagnosis of postoperative fever. We report the case of a 63-year-old man who was diagnosed with acute appendicitis. During laparoscopy, an anti-clockwise vermiform appendix torsion (360°) was identified. On postoperative day 3, the patient developed recurrent pyrexia related to ileocolic vein pylephlebitis, requiring specific management. Vermiform appendix torsion is a rare condition that is indistinguishable from acute appendicitis until an appendicectomy is performed. Whereas previous studies have reported an uneventful postoperative period in cases of vermiform appendix torsion, we present the first case of pylephlebitis as a rare complication and discuss adequate treatment.
Cauliflower mosaic virus disease spectrum uncovers novel susceptibility factorNCED9inArabidopsis thaliana
Authors: Hoffmann Gesa , Shukla Aayushi , López-González Silvia , Hafrén Anders
Published: May 2023

Viruses are intimately linked with their hosts and especially dependent on gene-for-gene interactions to establish successful infections. On the host side, defence mechanisms such as tolerance and resistance can occur within the same species, leading to differing virus accumulation in relation to symptomology and plant fitness. The identification of novel resistance genes against viruses and susceptibility factors is an important part of understanding viral patho­genesis and securing food production. The model plant Arabidopsis thaliana displays a wide symptom spectrum in response to RNA virus infections, and unbiased genome-wide association studies have proven a powerful tool to identify novel disease-genes. In this study we infected natural accessions of A. thaliana with the pararetrovirus cauliflower mosaic virus (CaMV) to study the phenotypic variations between accessions and their correlation with virus accumulation. Through genome-wide association mapping of viral accumulation differences, we identified several susceptibility factors for CaMV, the strongest of which was the abscisic acid synthesis gene NCED9. Further experiments confirmed the importance of abscisic acid homeostasis and its disruption for CaMV disease.
Secondary fibromyalgia: An entity to be remembered—A case series with axial spondyloarthritis
Authors: Yilmaz Ebru
Published: May 2023

Fibromyalgia (FM) is a clinical syndrome characterised by chronic widespread musculoskeletal pain, stiffness, and tenderness in addition to a variety of physical and mental symptoms such as fatigue, sleep disturbances, depression, anxiety, cognitive dysfunction, headaches, and digestive problems. FM can be associated with or coexist with other inflammatory rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and spondyloarthritis. This phenomenon is called secondary FM. Although FM cannot be considered an autoimmune disease, it may in some cases be an early sign of an autoimmune disease. Therefore, clinicians should be cautious in these situations. This case series presents three patients diagnosed with axial spondyloarthritis coexisted with FM symptoms.
Enhanced nonenzymatic RNA copying with in-situ activation of short oligonucleotides
Authors: Ding Dian , Zhang Stephanie J , Szostak Jack W
Published: May 2023

The nonenzymatic copying of RNA is thought to have been necessary for the transition between prebiotic chemistry and ribozyme-catalyzed RNA replication in the RNA World. We have previously shown that a potentially prebiotic nucleotide activation pathway based on phospho-Passerini chemistry can lead to the efficient synthesis of 2-aminoimidazole activated mononucleotides when carried out under freeze-thaw cycling conditions. Such activated nucleotides react with each other to form 5′–5′ 2-aminoimidazolium bridged dinucleotides, enabling template-directed primer extension to occur within the same reaction mixture. However, mononucleotides linked to oligonucleotides by a 5′–5′ 2-aminoimidazolium bridge are superior substrates for nonenzymatic primer extension; their higher intrinsic reactivity and their higher template affinity enable faster template copying at lower substrate concentrations. Here we show that eutectic phase phospho-Passerini chemistry efficiently activates short oligonucleotides and promotes the formation of monomer-bridged-oligonucleotide species during freeze-thaw cycles. We then demonstrate that in-situ generated monomer-bridged-oligonucleotides lead to efficient nonenzymatic template copying in the same reaction mixture. Our demonstration that multiple steps in the pathway from activation chemistry to RNA copying can occur together in a single complex environment simplifies this aspect of the origin of life.
Transcriptome sequencing suggests that pre-mRNA splicing counteracts widespread intronic cleavage and polyadenylation
Authors: Vlasenok Maria , Margasyuk Sergey , Pervouchine Dmitri D
Published: May 2023

Alternative splicing (AS) and alternative polyadenylation (APA) are two crucial steps in the post-transcriptional regulation of eukaryotic gene expression. Protocols capturing and sequencing RNA 3′-ends have uncovered widespread intronic polyadenylation (IPA) in normal and disease conditions, where it is currently attributed to stochastic variations in the pre-mRNA processing. Here, we took advantage of the massive amount of RNA-seq data generated by the Genotype Tissue Expression project (GTEx) to simultaneously identify and match tissue-specific expression of intronic polyadenylation sites with tissue-specific splicing. A combination of computational methods including the analysis of short reads with non-templated adenines revealed that APA events are more abundant in introns than in exons. While the rate of IPA in composite terminal exons and skipped terminal exons expectedly correlates with splicing, we observed a considerable fraction of IPA events that lack AS support and attributed them to spliced polyadenylated introns (SPI). We hypothesize that SPIs represent transient byproducts of a dynamic coupling between APA and AS, in which the spliceosome removes the intron while it is being cleaved and polyadenylated. These findings indicate that cotranscriptional pre-mRNA splicing could serve as a rescue mechanism to suppress premature transcription termination at intronic polyadenylation sites.
Refining the genomic determinants underlying escape from X-chromosome inactivation
Authors: Peeters Samantha , Leung Tiffany , Fornes Oriol , Farkas Rachelle A , Wasserman Wyeth W , Brown Carolyn J
Published: May 2023

X-chromosome inactivation (XCI) epigenetically silences one X chromosome in every cell in female mammals. Although the majority of X-linked genes are silenced, in humans 20% or more are able to escape inactivation and continue to be expressed. Such escape genes are important contributors to sex differences in gene expression, and may impact the phenotypes of X aneuploidies; yet the mechanisms regulating escape from XCI are not understood. We have performed an enrichment analysis of transcription factor binding on the X chromosome, providing new evidence for enriched factors at the transcription start sites of escape genes. The top escape-enriched transcription factors were detected at the RPS4X promoter, a well-described human escape gene previously demonstrated to escape from XCI in a transgenic mouse model. Using a cell line model system that allows for targeted integration and inactivation of transgenes on the mouse X chromosome, we further assessed combinations of RPS4X promoter and genic elements for their ability to drive escape from XCI. We identified a small transgenic construct of only 6 kb capable of robust escape from XCI, establishing that gene-proximal elements are sufficient to permit escape, and highlighting the additive effect of multiple elements that work together in a context-specific fashion.
Arena3Dweb: interactive 3D visualization of multilayered networks supporting multiple directional information channels, clustering analysis and application integration
Authors: Kokoli Maria , Karatzas Evangelos , Baltoumas Fotis A , Schneider Reinhard , Pafilis Evangelos , Paragkamian Savvas , Doncheva Nadezhda T , Jensen Lars Juhl , Pavlopoulos Georgios A
Published: May 2023

Arena3Dweb is an interactive web tool that visualizes multi-layered networks in 3D space. In this update, Arena3Dweb supports directed networks as well as up to nine different types of connections between pairs of nodes with the use of Bézier curves. It comes with different color schemes (light/gray/dark mode), custom channel coloring, four node clustering algorithms which one can run on-the-fly, visualization in VR mode and predefined layer layouts (zig-zag, star and cube). This update also includes enhanced navigation controls (mouse orbit controls, layer dragging and layer/node selection), while its newly developed API allows integration with external applications as well as saving and loading of sessions in JSON format. Finally, a dedicated Cytoscape app has been developed, through which users can automatically send their 2D networks from Cytoscape to Arena3Dweb for 3D multi-layer visualization. Arena3Dweb is accessible at http://arena3d.pavlopouloslab.info or http://arena3d.org
Prognostic evaluation of re-resection for recurrent glioblastoma using the novel RANO classification for extent of resection: A report of the RANO resect group
Authors: Karschnia Philipp , Dono Antonio , Young Jacob S , Juenger Stephanie T , Teske Nico , Häni Levin , Sciortino Tommaso , Mau Christine Y , Bruno Francesco , Nunez Luis , Morshed Ramin A , Haddad Alexander F , Weller Michael , van den Bent Martin , Beck Juergen , Hervey-Jumper Shawn , Molinaro Annette M , Tandon Nitin , Rudà Roberta , Vogelbaum Michael A , Bello Lorenzo , Schnell Oliver , Grau Stefan J , Chang Susan M , Berger Mitchel S , Esquenazi Yoshua , Tonn Joerg-Christian
Published: May 2023

Background

The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (1) explore the prognostic role of extent of re-resection using the previously proposed Response Assessment in Neuro-Oncology (RANO) classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (2) define factors consolidating the surgical effects on outcome.

Methods

The RANO resect group retrospectively compiled an 8-center cohort of patients with first recurrence from previously resected glioblastomas. The associations of re-resection and other clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to minimize confounding effects when comparing the different RANO classes.

Results

We studied 681 patients with first recurrence of Isocitrate Dehydrogenase (IDH) wild-type glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for molecular and clinical confounders on multivariate analysis; ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, “maximal resection” (class 2) had superior survival compared to “submaximal resection” (class 3). Administration of (radio-)chemotherapy in the absence of postoperative deficits augmented the survival associations of smaller residual CE tumors. Conversely, “supramaximal resection” of non-CE tumor (class 1) was not associated with prolonged survival but was frequently accompanied by postoperative deficits. The prognostic role of residual CE tumor was confirmed in propensity score analyses.

Conclusions

The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete resection according to RANO resect classes 1 and 2 is prognostic.
Radio-chemotherapy feasibility for biopsy-only unresectable IDH wild-type glioblastomas (BO-GBM)
Authors: Harlay Vincent , Appay Romain , Bequet Céline , Petrirena Gregorio , Campello Chantal , Barrié Maryline , Autran Didier , Graillon Thomas , Boissonneau Sébastien , Dufour Henry , Figarella-Branger Dominique , Padovani Laetitia , Barlier Anne , Nanni Isabelle , Tabouret Emeline , Chinot Olivier
Published: May 2023

Background

“Biopsy-only” glioblastoma (BO-GBM) is a heterogeneous, understudied group of patients associated with a poor outcome. Our objective was to explore the pattern of care and prognosis associated with BO-GBM in our center.

Methods

Patients with IDH wild-type BO-GBM included in a prospective regional cohort initiated in 2014 and closed in 2017 were retrospectively reviewed for patient characteristics, MRI findings, treatment allocation, and delivery.

Results

Of 535 patients included in the cohort, 137 patients were included in the present analysis. The median age was 66 years old and the median KPS was 70. Forty-six patients (33.6%) were referred to radiotherapy and chemotherapy (RT–TMZ) regimen, 75 (54.7%), considered unfitted for RT, received chemotherapy upfront (CT) and 16 (11.7%) were referred to palliative care (PC). Regarding the first group, 91% of patients completed the RT–TMZ. In the CT group, 11 of 75 patients (14.7%) underwent radiotherapy after chemotherapy upfront. Median overall survival was 12.3 months (95% CI, 15.30–24.16), 5.7 months (95% CI, 6.22–9.20), and 1.9 months (95% CI, 1.43–5.08) in RT–TMZ, CT, and PC groups, respectively. In multivariate analyses, progression-free survival was impacted by baseline KPS (P < .001) and MGMT status (P = .004). Overall survival was impacted by baseline KPS (P < .001) and age (P = .030).

Conclusion

BO-GBM constitute a large and heterogeneous population in which one-third of patients is amenable to the standard of care, with survival outcome close to one of the patients who underwent surgery. Reliable criteria are needed to help select patients for adequate treatment while new strategies are warranted for BO-GBM unfit for RT.
Pangenome-based trajectories of intracellular gene transfers in Poaceae unveil high cumulation in Triticeae
Authors: Chen Yongming , Guo Yiwen , Xie Xiaoming , Wang Zihao , Miao Lingfeng , Yang Zhengzhao , Jiao Yuannian , Xie Chaojie , Liu Jie , Hu Zhaorong , Xin Mingming , Yao Yingyin , Ni Zhongfu , Sun Qixin , Peng Huiru , Guo Weilong
Published: May 2023

Intracellular gene transfers (IGTs) between the nucleus and organelles, including plastids and mitochondria, constantly reshape the nuclear genome during evolution. Despite the substantial contribution of IGTs to genome variation, the dynamic trajectories of IGTs at the pangenomic level remain elusive. Here, we developed an approach, IGTminer, that maps the evolutionary trajectories of IGTs using collinearity and gene reannotation across multiple genome assemblies. We applied IGTminer to create a nuclear organellar gene (NOG) map across 67 genomes covering 15 Poaceae species, including important crops. The resulting NOGs were verified by experiments and sequencing data sets. Our analysis revealed that most NOGs were recently transferred and lineage specific and that Triticeae species tended to have more NOGs than other Poaceae species. Wheat (Triticum aestivum) had a higher retention rate of NOGs than maize (Zea mays) and rice (Oryza sativa), and the retained NOGs were likely involved in photosynthesis and translation pathways. Large numbers of NOG clusters were aggregated in hexaploid wheat during 2 rounds of polyploidization, contributing to the genetic diversity among modern wheat accessions. We implemented an interactive web server to facilitate the exploration of NOGs in Poaceae. In summary, this study provides resources and insights into the roles of IGTs in shaping interspecies and intraspecies genome variation and driving plant genome evolution.
Natural allelic variation in GRAIN SIZE AND WEIGHT 3 of wild rice regulates the grain size and weight
Authors: Bai Feng , Ma Huijin , Cai Yichang , Shahid Muhammad Qasim , Zheng Yuebin , Lang Chuan , Chen Zhixiong , Wu Jinwen , Liu Xiangdong , Wang Lan
Published: May 2023

Grain size is important for yield in rice (Oryza sativa L.). Although many genes involved in grain size have been isolated, few can be used in breeding due to their interactions and phenotypic effects. Here, we describe natural variation in the granule-type quantitative trait locus GRAIN SIZE AND WEIGHT 3 (GSW3) located on chromosome 3 in wild rice (Oryza rufipogon Griff.) that encodes a GTPase-regulated protein and negatively regulates grain length, grain width, and 1,000-grain weight. The insertion of a 232-bp fragment of the genomic sequence in the wild rice, a natural allelic variant gene (GSW3), increased the expression levels and reduced the grain length and width and 1,000-grain weight. Knockout of GSW3 in the wild rice inbred line Huaye 3 increased the grain length and width and 1,000-grain weight. Introducing GSW3Huaye3 into cultivated rice line KJ01 and overexpressing GSW3Huaye3 in Huaye 3 resulted in reduced grain length and width and 1,000-grain weight, and grain size and 1,000-grain weight changes were closely related to GSW3 expression levels. GSW3 regulated the grain length and width simultaneously by promoting grain glume cell division and longitudinal and transverse cell growth. GSW3 was also involved in regulating the gibberellic acid signaling pathway and negatively regulated plant growth. Furthermore, a critical SNP in the GSW3 coding region was obviously correlated with grain size variation in a core collection of cultivated rice. This SNP resulted in an amino acid substitution from Gln to Arg at position 161 in GSW3, which reduced the grain size. Our study shows that GSW3 negatively regulates the grain shape, which could explain different grain shapes in modern cultivars and wild rice. GSW3 may also be used for breeding rice varieties with improved grain shapes and higher yield.
Mortality in patients with incident rheumatoid arthritis and depression: a Danish cohort study of 11 071 patients and 55 355 comparators
Authors: Pedersen Jens K , Wang Lei , Risbo Nickolaj , Pedersen Alma B , Andersen Kjeld , Ellingsen Torkell
Published: May 2023

Objectives

In patients with RA, the association between mortality and depression has been investigated only in patients with prevalent RA. In this study, we estimated the mortality risk associated with depression, defined as the first filling of a prescription for antidepressants, in patients with incident RA and background population comparators.

Methods

From 2008 to 2018, we identified patients with incident RA in the nationwide Danish rheumatologic database, DANBIO. For each patient, we randomly selected five comparators. Participants were not treated with antidepressants or diagnosed with depression 3 years prior to the index date. From other registers we collected data on socioeconomic status, mortality and cause of death using unique personal identifiers. Using Cox models, we calculated hazard rate ratios (HRR) with 95% CI.

Results

In depressed patients with RA vs patients without depression, adjusted HRR for all-cause mortality was 5.34 (95% CI 3.02, 9.45) during 0–2 years and 3.15 (95% CI 2.62, 3.79) during the total follow-up period, and highest in patients <55 years with HRR 8.13 (95% CI 3.89, 17.02). In comparators with depression vs comparators without depression, the association with mortality was similar to that in patients with RA. There were no unnatural causes of death among depressed patients with RA. The most frequent natural causes of death were cancer, cardiovascular disease, stroke and pneumonia.

Conclusion

In patients with RA, depression was a predictor of death but with a strength similar to that in matched comparators.
Anti-citrullinated protein antibody profiles predict changes in disease activity in patients with rheumatoid arthritis initiating biologics
Authors: Aripova Nozima , Kremer Joel M , Pappas Dimitrios A , Reed George , England Bryant R , Robinson Bill H , Curtis Jeffrey R , Thiele Geoffrey M , Mikuls Ted R
Published: May 2023

Objectives

To determine whether an expanded antigen-specific ACPA profile predicts changes in disease activity in patients with RA initiating biologics.

Methods

The study included participants from a prospective, non-randomized, observational RA cohort. For this sub-study, treatment groups of interest included biologic-naïve initiating anti-TNF, biologic-exposed initiating non-TNF, and biologic-naïve initiating abatacept. ACPAs to 25 citrullinated peptides were measured using banked enrolment serum. Principal component analysis (PCA) was performed and associations of resulting principal component (PC) scores (in quartiles) and anti-CCP3 antibody (≤15, 16–250 or >250 U/ml) with EULAR (good/moderate/none) treatment response at 6 months were examined using adjusted ordinal regression models.

Results

Participants (n = 1092) had a mean age of 57 (13) years and 79% were women. At 6 months, 68.5% achieved a moderate/good EULAR response. There were three PCs that cumulatively explained 70% of variation in ACPA values. In models including the three components and anti-CCP3 antibody category, only PC1 and PC2 were associated with treatment response. The highest quartile for PC1 (odds ratio [OR] 1.76; 95% CI: 1.22, 2.53) and for PC2 (OR 1.74; 95% CI: 1.23, 2.46) were associated with treatment response after multivariable adjustment. There was no evidence of interaction between PCs and treatment group in EULAR responses (P-value for interaction >0.1).

Conclusion

An expanded ACPA profile appears to be more strongly associated with biologic treatment response in RA than commercially available anti-CCP3 antibody levels. However, further enhancements to PCA will be needed to effectively prioritize between different biologics available for the treatment of RA.
Investigating the effects of 7‐ketocholesterol on retinal pigment epithelium bioenergetics
Authors: Dey Sanchareeka , Catchpole Timothy , Takacs Alison , Csaky Karl G.
Published: May 2023

Age‐related macular degeneration (AMD) is associated with formation of drusen, clusters of lipids, and oxidized lipid products under the retinal pigment epithelium (RPE). 7‐Ketocholesterol (7KC) is a form of oxidized cholesterol present in drusen and is hypothesized to play a role in AMD pathogenesis. The association of 7KC with cellular toxicity and inflammation, key elements of AMD pathology, has been demonstrated. However, the effects of 7KC on altering RPE bioenergetics, a potentially important pathologic process in AMD, are unclear. Herein, we describe the effects of non‐lethal doses of 7KC on the bioenergetics and phenotype of RPE cells in culture. Metabolic analysis demonstrated a significant dose‐dependent increase in total ATP production rates that was driven primarily by an increase in glycolysis. The increase in glycolysis was accompanied by an increase in glucose uptake and increased expression of hexokinase 1. Increased levels of Translocase of Outer Mitochondrial Membrane 20 and NADH:Ubiquinone Oxidoreductase Core Subunit S1, Succinate dehydrogenase, Ubiquinol‐Cytochrome C Reductase Core Protein 2, Cytochrome C Oxidase II, and ATP synthase subunit beta, proteins involved in oxidative phosphorylation (OXPHOS), were also seen. However, specific electron transport chain activity remained unchanged. 7KC‐treated cells also demonstrated a change in cellular morphology with decreased expression of epithelial markers. In summary, 7KC has significant effects on the bioenergetics and morphology of RPE cells reflective of findings seen in clinical AMD.
METTL3‐mediated ANXA2 inhibition confers neuroprotection in ischemic stroke: Evidence from in vivo and in vitro studies
Authors: Liu Bin , Xing Zhiqun , Song Feng , Li Dejun , Zhao Bao , Xu Chunyang , Xia Wenjun , Ji Hongsheng
Published: May 2023

Given the important role of m6A, the most common and reversible mRNA modification, in the pathogenesis of ischemic stroke, this study investigates the mechanisms of m6A methyltransferase METTL3 in neuronal damage in ischemic stroke. In silico analysis was used to pinpoint the expression of ANXA2, which was verified in clinical peripheral blood samples. SD rats were used for middle cerebral artery occlusion (MCAO) establishment. The experimental data suggested that T lymphocytes were increased in peripheral blood samples of ischemic stroke patients and MCAO rats. The MCAO rats were treated with anti‐ANXA2 alone or combined with RP101075 (T lymphocyte infiltration inhibitor), followed by brain injury assessment. Oxygen–glucose deprivation/reoxygenation (OGD/R) was induced in primary cortical neurons, where shRNAs targeting ANXA2 or METTL3, or overexpression plasmids of METTL3 were introduced to verify the regulatory function for METTL3. Inhibition of T lymphocyte migration to the ischemic brain reduced brain injury in MCAO rats and neuronal damage in OGD/R‐exposed neurons. Ablation of ANXA2 in T lymphocytes inhibited the migration of T lymphocytes to the ischemic brain and reduced neuronal damage. Mechanistically, METTL3 reduced ANXA2 expression in T lymphocytes through m6A modification and inhibited p38MAPK/MMP‐9 pathway activation, exerting protective effects against neuronal damage in ischemic stroke. Overall, this study reveals the neuroprotective effects of METTL3‐mediated ANXA2/p38MAPK/MMP‐9 inhibition against ischemic stroke.
The plant‐derived alkaloid aloperine prevents ischemia/reperfusion injury‐induced sudden cardiac death
Authors: Hu Zhaoyang , Li Jiaxue , Liu Quanhua , Manville Rían W. , Abbott Geoffrey W.
Published: May 2023

Sudden cardiac death (SCD) remains a major cause of global mortality. In addition to modern interventions, botanical folk medicines have long been used to treat cardiovascular disease, although the efficacy and underlying mechanisms are often unresolved. Aloperine, a bioactive quinolizidine alkaloid isolated from Sophora alopecuroides plants, exhibits antioxidant, anti‐inflammatory, antitumor, and vasorelaxant properties, but possible antiarrhythmic effects of aloperine in SCD are unclear. Here, we examined whether aloperine protects against ischemia and reperfusion injury‐associated lethal ventricular arrhythmia and sudden cardiac death. Rats were divided into sham, control, and aloperine groups, and reperfusion‐provoked ventricular arrhythmogenesis, cardiac damage markers, and signaling pathways quantified following left main coronary artery ischemia and reperfusion. In vitro studies of effects of aloperine on hERG and Kv4.3 cardiac voltage‐gated potassium (Kv) channels were performed using two‐electrode voltage clamp analysis of cloned channels expressed in Xenopus laevis oocytes. Aloperine pretreatment (10 mg/kg) did not affect baseline cardiac electrical stability; yet, it reduced ventricular arrhythmogenesis and susceptibility to SCD (mortality rate: control: 64.3%; aloperine: 0%) induced by reperfusion injury. Aloperine also reduced serum levels of LDH, CK‐MB, α‐HBDH, and cTnI post‐I/R, and stimulated phosphorylation of ventricular ERK1/2 and STAT‐3, which are key components of RISK and SAFE signaling pathways. Inhibition of either ERK1/2 (with U0126) or STAT‐3 (with Ag490) abolished aloperine‐induced anti‐arrhythmic effects and ERK1/2 and STAT‐3 phosphorylation. Interestingly, while aloperine (100 μM) had no effect on cloned Kv4.3 activity, aloperine (1 μM and up) negative‐shifted the voltage dependence of hERG activation by ~10 mV and increased peak hERG current by 35%. Thus, aloperine exerts striking anti‐arrhythmic effects against myocardial ischemia and reperfusion injury‐induced severe lethal ventricular arrhythmia and sudden cardiac death via the ERK1/2/STAT‐3 signaling pathway, with potential additional contribution from increased cardiac myocyte repolarization capacity via augmented hERG activity.
A New Age of Health Promotion
Authors: Chu Charlene H. , Jibb Lindsay A. , MacInnes Neal , Beekhoo Zoraida D.
Published: May 2023

The COVID-19 pandemic has shifted how nursing education and information are delivered, with many classes being moved to an online platform. This opened opportunities to find creative ways to engage students. As a result, an entirely online infographic assignment for final-year baccalaureate nursing students was created. The focus of this assignment was to engage students to identify important health issues, consider multilevel solutions, and communicate information to relevant stakeholders using visual storytelling for maximum impact.
Routine Diaper Change Alters Kidney Oxygenation in Premature Infants
Authors: Marin Terri , Ghosh Santu , Cockfield Christie , Mundy Cynthia , Mansuri Asifhusen , Stansfield Brian K.
Published: May 2023

Background:

Reduction in oxygen delivery to developing kidneys of premature infants may be an important source for acute kidney injury in premature infants.

Purpose:

To describe changes in continuous kidney oxygenation (RrSO2) measures before, during, and after routine diaper changes.

Methods:

Non–a priori analysis of a prospective cohort that received continuous measurement of RrSO2 with near-infrared spectroscopy (NIRS) over the first 14 days of life demonstrating acute RrSO2 drops surrounding diaper changes.

Results:

In total, 26 of 38 (68%) infants (≤1800 g) from our cohort exhibited acute drops in RrSO2 that temporally correlated with diaper changes. Mean (SD) RrSO2 baseline prior to each diaper change event was 71.1 (13.2), dropped to 59.3 (11.6) during diaper change, and recovered to 73.3 (13.2). There was a significant difference between means when comparing baseline to diaper change (P < .001; 95% CI, 9.9 to 13.8) and diaper change to recovery (P < .001; 95% CI, −16.9 to −11.2). The mean decrease in RrSO2 during diaper change averaged 12 points (17%) below 15-minute RrSO2 mean prior to diaper change, with quick recovery to prediaper change levels. No decreases in SpO2, blood pressure, or heart rate were documented during the intermittent kidney hypoxic events.

Implications for Practice and Research:

Routine diaper changes in preterm infants may increase the risk for acute reductions in RrSO2 as measured by NIRS; however, the impact on kidney health remains unknown. Larger prospective cohort studies assessing kidney function and outcomes related to this phenomenon are needed.
Comparison of failure risk and outcome scores following meniscus repair among adolescent and adult patients
Authors: Martin Kyle , Magnussen Robert A. , Pappa Nicholas , DiBartola Alex C. , Duerr Robert A. , Kaeding Christopher C. , Flanigan David C.
Published: May 2023

Background:

There are few studies assessing the impact of age at time of surgery on meniscus repair failure risk and patient-reported outcome scores. We sought to determine whether age at time of meniscus repair surgery affects failure risk and patient-reported outcome scores.

Methods:

Patients who underwent meniscus repair during 2006-2013 were evaluated for meniscus repair failure and patient-reported outcome scores using the Knee Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) score, and Marx Activity score at mean follow-up 6.5±2.0 yr post-operative. A multivariable linear regression analysis was used to assess the influence of patient age on patient-reported outcome scores following meniscus repair.

Results:

A total of 170 patients with mean age 27.8±10.1 yr (59% male) were identified, including 29 patients age 18 and younger and 141 patients over 18. Increasing patient age was associated with significantly lower IKDC (P=0.027), KOOS-ADL (P=0.003), and Marx activity scores (P<0.001). Repair failure occurred in 46 patients (27.1%) overall, including 7 failures (24.1%) in patients 18 and under and 39 failures (27.7%) in patients over 18. The logistic regression analysis demonstrated no association between age and meniscus repair failure risk when controlled for ACL reconstruction and BMI (P=0.69).

Conclusion:

Increased age is associated with poorer IKDC, KOOS-ADL, and Marx Activity scores following meniscus repair. However, there is no difference in failure of healing of meniscus repair between adolescent patients and adults.

Level of Evidence:

III
Machine Learning for Benchmarking Adolescent Idiopathic Scoliosis Surgery Outcomes
Authors: Gupta Aditi , Oh Inez Y. , Kim Seunghwan , Marks Michelle C. , Payne Philip R.O. , Ames Christopher P. , Pellise Ferran , Pahys Joshua M. , Fletcher Nicholas D. , Newton Peter O. , Kelly Michael P. ,   Harms Study Group
Published: May 2023

Study Design.

Retrospective cohort.

Objective.

The aim of this study was to design a risk-stratified benchmarking tool for adolescent idiopathic scoliosis (AIS) surgeries.

Summary of Background Data.

Machine learning (ML) is an emerging method for prediction modeling in orthopedic surgery. Benchmarking is an established method of process improvement and is an area of opportunity for ML methods. Current surgical benchmark tools often use ranks and no “gold standards” for comparisons exist.

Materials and Methods.

Data from 6076 AIS surgeries were collected from a multicenter registry and divided into three datasets: encompassing surgeries performed (1) during the entire registry, (2) the past 10 years, and (3) during the last 5 years of the registry. We trained three ML regression models (baseline linear regression, gradient boosting, and eXtreme gradient boosted) on each data subset to predict each of the five outcome variables, length of stay (LOS), estimated blood loss (EBL), operative time, Scoliosis Research Society (SRS)-Pain and SRS-Self-Image. Performance was categorized as “below expected” if performing worse than one standard deviation of the mean, “as expected” if within 1 SD, and “better than expected” if better than 1 SD of the mean.

Results.

Ensemble ML methods classified performance better than traditional regression techniques for LOS, EBL, and operative time. The best performing models for predicting LOS and EBL were trained on data collected in the last 5 years, while operative time used the entire 10-year dataset. No models were able to predict SRS-Pain or SRS-Self-Image in any useful manner. Point-precise estimates for continuous variables were subject to high average errors.

Conclusions.

Classification of benchmark outcomes is improved with ensemble ML techniques and may provide much needed case-adjustment for a surgeon performance program. Precise estimates of health-related quality of life scores and continuous variables were not possible, suggesting that performance classification is a better method of performance evaluation.
Polyfunctionality of broadly neutralizing HIV-1 antibodies
Authors: Vrignaud Lou-Léna , Schwartz Olivier , Bruel Timothée
Published: May 2023

Purpose of review

The discovery of broadly neutralizing HIV-1 antibodies (bNAbs) has provided a framework for vaccine design and created new hope toward an HIV-1 cure. These antibodies recognize the HIV-1 Envelope and inhibit viral fusion with unprecedented breadth and potency. Beyond their unique neutralization capacity, bNAbs also activate immune cells and interfere with viral spread through nonneutralizing activities. Here, we review the landscape of bNAbs functions and their contribution to clinical efficacy.

Recent findings

Parallel evaluation of bNAbs nonneutralizing activities using in vivo and in vitro models have revealed how their importance varies across antibodies and strains. Nonneutralizing bNAbs functions target both infected cells and viral particles, leading to their destruction through various mechanisms. Reservoir targeting and prevention in context of suboptimal neutralization highly depends on bNAbs polyfunctionality. We recently showed that bNAbs tether virions at the surface of infected cells, impairing release and forming immune complexes, with consequences that are still to be understood.

Nonneutralizing activities of bNAbs target infected cells, virions, and immune complexes, promoting viral clearance and possibly improving immune responses. We review how these functions participate to the efficacy of bNAbs and how they can be manipulated to improve bNAbs therapies.
Radiation-Induced Eccrine Squamous Syringometaplasia With Perineural Invasion
Authors: Singh Neha S. , Phillips Mariana A. , Buhle Anna C. , Prickett Kyle , Grider Douglas J.
Published: May 2023

Eccrine squamous syringometaplasia (ESS) is a benign metaplastic reaction of eccrine ducts that occurs in response to injury and can be a histologic mimic of squamous cell carcinoma (SCC). Reported is an 82-year-old man undergoing Mohs surgery for presumed SCC diagnosed in a field of radiation dermatitis. After 3 Mohs stages, the peculiar squamous proliferation was recognized as ESS and the procedure was aborted. Complicating the interpretation of the Mohs frozen section was the presence of perineural invasion because perineural invasion has not been previously reported to occur with ESS. The histologic features used to distinguish ESS from SCC are discussed.
The Effect of Short-Term Acute Residential Treatment on Psychiatric Rehospitalization
Authors: Lichtenberg Pesach , Friedlander Avraham , Bergman-Levy Tal , Susser Ehud , Yoffe Rinat , Budowski Danny , Kodesh Arad , Tzur Bitan Dana , Weiser Mark
Published: May 2023

Short-Term Acute Residential Treatment (START) homes, located in the community and operating in noninstitutional atmospheres, seek to reduce rehospitalization. This report investigates whether these homes reduced rates and duration of subsequent inpatient stays in psychiatric hospitals. For 107 patients treated in START homes after psychiatric hospitalization, we compared the number and duration of psychiatric hospitalizations before and after their START stay. We found that, compared with the year before the START stay, in the year after the START stay, patients had fewer episodes of rehospitalization (1.60 [SD = 1.23] vs. 0.63 [SD = 1.05], t[106] = 7.097, p < 0.001) and a briefer accumulative duration of inpatient stays (41.60 days [SD = 49.4] vs. 26.60 days [SD = 53.25], t[106] = −2.32, p < 0.03). This suggests that START homes can reduce rehospitalization rates and should be considered a valid alternative to psychiatric hospitalization.
West Michigan Suicide Trends During the COVID-19 Pandemic
Authors: Workman Adrienne , deJong Joyce
Published: May 2023

The COVID-19 pandemic has resulted in increased concern regarding the mental health of individuals navigating this public health crisis. Various risk factors for suicide have increased during the pandemic, including isolation, depression, access to firearms, substance use, and loss of employment. However, the relationship between the COVID-19 pandemic and suicide rates in the United States remains unclear. In this retrospective study, we examined the relationship between suicide rates and COVID-19 cases in 11 West Michigan counties. Suicide rates in the prepandemic (January 2018 to February 2020) and pandemic (March 2020 to February 2022) months were compared after adjusting for seasonal and population size effects. A mixed effects model was used to assess the impacts of local COVID-19 rates and county on the ratio of pandemic to prepandemic monthly suicide rates. The model did not find a significant effect of COVID-19 case rates on suicide rates. Although this study does not find sufficient evidence for a statistical relationship between COVID-19 cases and suicide rates in West Michigan, close surveillance should continue and public health measures should be used because of the increased risk factors for suicide associated with the pandemic.
Assessing Oral Epithelial Dysplasia Risk for Transformation to Cancer: Comparison Between Histologic Grading Systems Versus S100A7 Immunohistochemical Signature-based Grading
Authors: Darling Mark Roger , Hwang Jason T.K. , Dickson Benjamin J. , Cutz Jean-Claude , Salama Samih , McCord Christina , Pritzker Kenneth P.H. , Mock David , Thompson Lester D.R.
Published: May 2023

While a 3-tier oral epithelial dysplasia grading system has been utilized for decades, it is widely recognized as a suboptimal risk indicator for transformation to cancer. A 2-tier grading system has been proposed, although not yet validated. In this study, the 3-tier and 2-tier dysplasia grading systems, and an S100A7 immunohistochemical signature-based grading system were compared to assess prediction of risk of transformation to oral cancer. Formalin-fixed, paraffin-embedded biopsy specimens with known clinical outcomes were obtained retrospectively from a cohort of 48 patients. Hematoxylin and eosin-stained slides were used for the 2- and 3-tier dysplasia grading, while S100A7 for biomarker signature-based assessment was based on immunohistochemistry. Inter-observer variability was determined using Cohen’s kappa (K) statistic with Cox regression disease free survival analysis used to determine if any of the methods were a predictor of transformation to oral squamous cell carcinoma. Both the 2- and 3-tier dysplasia grading systems ranged from slight to substantial inter-observer agreement (Kw between 0.093 to 0.624), with neither system a good predictor of transformation to cancer (at least P=0.231; (P>>>0.05). In contrast, the S100A7 immunohistochemical signature-based grading system showed almost perfect inter-observer agreement (Kw=0.892) and was a good indicator of transformation to cancer (P=0.047 and 0.030). The inherent grading challenges with oral epithelial dysplasia grading systems and the lack of meaningful prediction of transformation to carcinoma highlights the significant need for a more objective, quantitative, and reproducible risk assessment tool such as the S100A7 immunohistochemical signature-based system.
Hydroxychloroquine in the Diabetes Mellitus Complications.docx
Authors: Oliveira Andrade Luis Jesuino , Oliveira Luís Matos de , Bittencourt Alcina Maria Vinhaes , Oliveira Gabriela Correia Matos de
Published: May 2023

We submit the manuscript for evaluation and possible publication as a preprint.
Comparing Clinical and Aesthetic Outcomes of Digital Artery Flap using Nail Bed Graft for Fingertip Amputation with Replantation
Authors: Kuwahara Yutaro , Hara Tatsuya , Kurahashi Toshikazu , Takeshige Hiroki , Urata Shiro , Oguchi Takeshi
Published: May 2023

Background:

Digital artery flap (DAF) with nail bed graft is a simple method to preserve finger length for fingertip amputations. This study compared the clinical and aesthetic outcomes between replantation and DAF.

Methods:

Patients who underwent replantation or DAF for a single fingertip amputation (Ishikawa’s subzone II or III) at our hospital from 2013 to 2021 were retrospectively evaluated. The aesthetic and functional outcomes were finger length and nail deformity at the final follow-up, total active motion, grip strength, Semmes-Weinstein monofilament test (S-W), fingertip injuries outcome score (FIOS), and Hand20 scores.

Results:

Overall, for 74 analyzed cases (40, replantation; 34, DAF), the median operation time and the median length of hospital stay in replantation was longer than that in DAF (188 vs. 126 min, p<0.01; 15 vs. 4 days, p<0.01). The success rates of replantation and DAF were 82.5% and 94.1%, respectively. The rate of finger shortening in replantation was significantly lower than that in DAF (42.5% vs. 82.4%; p<0.01). There were fewer nail deformities in replantation than in DAF (45.0% vs. 67.6%, p=0.06). The proportion of patients who achieved excellent or good FIOS and the median Hand20 scores was not significantly different between the groups (89.5% vs. 85.3%, p=0.61; 8.0 vs. 13.5, p=0.42). The median postoperative S-W values were similar between the groups (3.61 vs. 3.61, p=0.23).

Conclusions:

In this retrospective study, DAF for fingertip amputations achieved equivalent postoperative functional outcomes and shorter intraoperative time and hospital stay, but worse aesthetic appearance compared with replantation.
Customized Orthosis for Nonsurgical Correction of Congenital Auricle Deformities in Newborns
Authors: Zhao Hui , Huang Shenghua , Li Suxia , Han Zhenyan , Huang Wenhua
Published: May 2023

A misshaped pinna, caused by extrinsic pressures such as birth canal extrusion or incorrect position, is a common congenital auricular deformity in newborns. Surgery is a routine option to address this deformity, but it is traumatic and may lead to unacceptable aesthetic outcomes. Commercial ear mold orthoses with uniform size have been used for nonsurgical orthotic treatment, but are not applicable in all cases, depending on the auricle morphology. The authors used computer-aided design and three-dimensional (3D) printing technology to develop a novel customized orthosis for congenital auricular deformities. 3D ear models were constructed using computer-aided design software and a novel customized orthosis model was established after a process of correction, adjustment, and construction, with precise matching to allow tight attachment to the outer ear free from uneven skin pressing. After 3D-printing a customized orthosis injection mold, medical silicone injection molding was used to produce customized orthoses. Clinical application was conducted in 3 newborns and achieved satisfactory results. This novel customized auricle orthosis is an effective option for nonsurgical correction of a misshaped pinna.
The Additional Cost of Perioperative Medication Errors
Authors: Langlieb Marin E. , Sharma Pranav , Hocevar Mark , Nanji Karen C.
Published: May 2023

The purpose of this report was to estimate the additional annual cost to the U.S. healthcare system attributable to preventable medication errors (MEs) in the operating room. The ME types were iteratively grouped by their associated harm (or potential harm) into 13 categories, and we determined the incidence of operations involving each ME category (number of operations involving each category/total number of operations): (1) delayed or missed required perioperative antibiotic (1.4% of operations); (2) prolonged hemodynamic swings (7.6% of operations); (3) untreated postoperative pain >4/10 (18.9% of operations); (4) residual neuromuscular blockade (2.9% of operations); (5) oxygen saturation <90% due to ME (1.8% of operations); (6) delayed emergence (1.1% of operations); (7) untreated new onset intraoperative cardiac arrhythmia (0.72% of operations); (8) medication documentation errors (7.6% of operations); (9) syringe swaps (5.8% of operations); (10) presumed hypotension with inability to obtain a blood pressure reading (2.2% of operations); (11) potential for bacterial contamination due to expired medication syringes (8.3% of operations); (12) untreated bradycardia <40 beats/min (1.1% of operations); and (13) other (13.0% of operations). Through a PubMed search, we determined the likelihood that the ME category would result in downstream patient harm such as surgical site infection or acute kidney injury, and the additional fully allocated cost of care (in 2021 U.S. dollars) for each potential downstream patient harm event. We then estimated the cost of the MEs across the U.S. healthcare system by scaling the number of MEs to the total number of annual operations in the United States (N = 19,800,000). The total estimated additional fully allocated annual cost of care due to perioperative MEs was $5.33 billion U.S. dollars.