bluuebunny/crossref_metadata_2025 huggingface dataset:
Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody
Authors: Wang Lei , Feng Jin-Kai , Lu Chong-De , Wu Jia-Yi , Zhou Bin , Wang Kang , Wei Xu-Biao , Liang Chao , Zhou Hong-Kun , Shi Jie , Guo Wei-Xing , Lau Wan Yee , Yan Mao-Lin , Cheng Shu-Qun
Published: March 2024

Background

This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies.

Methods

The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT.

Results

Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS.

Conclusions

For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.
Regulatory loops between rice transcription factors OsNAC25 and OsNAC20/26 balance starch synthesis
Authors: Wang Juan , Zhang Haiqin , Wang Yuanjiang , Meng Shanshan , Liu Qing , Li Qian , Zhao Zhiwen , Liu Qiaoquan , Wei Cunxu
Published: March 2024

Several starch synthesis regulators have been identified, but these regulators are situated in the terminus of the regulatory network. Their upstream regulators and the complex regulatory network formed between these regulators remain largely unknown. A previous study demonstrated that NAM, ATAF, and CUC (NAC) transcription factors, OsNAC20 and OsNAC26 (OsNAC20/26), redundantly and positively regulate the accumulation of storage material in rice (Oryza sativa) endosperm. In this study, we detected OsNAC25 as an upstream regulator and interacting protein of OsNAC20/26. Both OsNAC25 mutation and OE resulted in a chalky seed phenotype, decreased starch content, and reduced expression of starch synthesis–related genes, but the mechanisms were different. In the osnac25 mutant, decreased expression of OsNAC20/26 resulted in reduced starch synthesis; however, in OsNAC25-overexpressing plants, the OsNAC25–OsNAC20/26 complex inhibited OsNAC20/26 binding to the promoter of starch synthesis–related genes. In addition, OsNAC20/26 positively regulated OsNAC25. Therefore, the mutual regulation between OsNAC25 and OsNAC20/26 forms a positive regulatory loop to stimulate the expression of starch synthesis–related genes and meet the great demand for starch accumulation in the grain filling stage. Simultaneously, a negative regulatory loop forms among the 3 proteins to avoid the excessive expression of starch synthesis–related genes. Collectively, our findings demonstrate that both promotion and inhibition mechanisms between OsNAC25 and OsNAC20/26 are essential for maintaining stable expression of starch synthesis–related genes and normal starch accumulation.
Chromosome ends initiate homologous chromosome pairing during rice meiosis
Authors: You Hanli , Tang Ding , Liu Huixin , Zhou Yue , Li Yafei , Shen Yi , Gong Zhiyun , Yu Hengxiu , Gu Minghong , Jiang Jiming , Zhang Tao , Cheng Zhukuan
Published: March 2024

During meiotic prophase I, chromosomes undergo large-scale dynamics to allow homologous chromosome pairing, prior to which chromosome ends attach to the inner nuclear envelope and form a chromosomal bouquet. Chromosome pairing is crucial for homologous recombination and accurate chromosome segregation during meiosis. However, the specific mechanism by which homologous chromosomes recognize each other is poorly understood. Here, we investigated the process of homologous chromosome pairing during early prophase I of meiosis in rice (Oryza sativa) using pooled oligo probes specific to an entire chromosome or chromosome arm. We revealed that chromosome pairing begins from both ends and extends toward the center from early zygotene through late zygotene. Genetic analysis of both trisomy and autotetraploidy also showed that pairing initiation is induced by both ends of a chromosome. However, healed ends that lack the original terminal regions on telocentric and acrocentric chromosomes cannot initiate homologous chromosome pairing, even though they may still enter the telomere clustering region at the bouquet stage. Furthermore, a chromosome that lacks the distal parts on both sides loses the ability to pair with other intact chromosomes. Thus, the native ends of chromosomes play a crucial role in initiating homologous chromosome pairing during meiosis and likely have a substantial impact on genome differentiation.
Subtilisin-like proteases from Fusarium graminearum induce plant cell death and contribute to virulence
Authors: Xiong Jiang , Luo Mingyu , Chen Yunshen , Hu Qianyong , Fang Ying , Sun Tongjun , Hu Guanjing , Zhang Cui-Jun
Published: March 2024

Fusarium head blight (FHB), caused by Fusarium graminearum, causes huge annual economic losses in cereal production. To successfully colonize host plants, pathogens secrete hundreds of effectors that interfere with plant immunity and facilitate infection. However, the roles of most secreted effectors of F. graminearum in pathogenesis remain unclear. We analyzed the secreted proteins of F. graminearum and identified 255 candidate effector proteins by liquid chromatography-mass spectrometry (LC-MS). Five subtilisin-like family proteases (FgSLPs) were identified that can induce cell death in Nicotiana benthamiana leaves. Further experiments showed that these FgSLPs induced cell death in cotton (Gossypium barbadense) and Arabidopsis (Arabidopsis thaliana). A signal peptide and light were not essential for the cell death-inducing activity of FgSLPs. The I9 inhibitor domain and the entire C-terminus of FgSLPs were indispensable for their self-processing and cell death-inducing activity. FgSLP-induced cell death occurred independent of the plant signal transduction components BRI-ASSOCIATED KINASE 1 (BAK1), SUPPRESSOR OF BIR1 1 (SOBIR1), ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1), and PHYTOALEXIN DEFICIENT 4 (PAD4). Reduced virulence was observed when FgSLP1 and FgSLP2 were simultaneously knocked out. This study reveals a class of secreted toxic proteins essential for F. graminearum virulence.
CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A
Authors: Feng Dandan , Gao Jie , Liu Ruiqiong , Liu Wei , Gao Tianyang , Yang Yunkai , Zhang Die , Yang Tianshu , Yin Xin , Yu Hefen , Huang Wei , Wang Yan
Published: March 2024

Coactivator-associated arginine methyltransferase 1 (CARM1) promotes the development and metastasis of estrogen receptor alpha (ERα)-positive breast cancer. The function of CARM1 in triple-negative breast cancer (TNBC) is still unclear and requires further exploration. Here, we report that CARM1 promotes proliferation, epithelial–mesenchymal transition, and stemness in TNBC. CARM1 is upregulated in multiple cancers and its expression correlates with breast cancer progression. Genome-wide analysis of CARM1 showed that CARM1 is recruited by hypoxia-inducible factor-1 subunit alpha (HIF1A) and occupy the promoters of CDK4, Cyclin D1, β-Catenin, HIF1A, MALAT1, and SIX1 critically involved in cell cycle, HIF-1 signaling pathway, Wnt signaling pathway, VEGF signaling pathway, thereby modulating the proliferation and invasion of TNBC cells. We demonstrated that CARM1 is physically associated with and directly interacts with HIF1A. Moreover, we found that ellagic acid, an inhibitor of CARM1, can suppress the proliferation and invasion of TNBC by directly inhibiting CDK4 expression. Our research has determined the molecular basis of CARM1 carcinogenesis in TNBC and its effective natural inhibitor, which may provide new ideas and drugs for cancer therapy.
N6-Methyladenosine (m6A) Sequencing Reveals Heterodera glycines-Induced Dynamic Methylation Promoting Soybean Defense
Authors: Qin Ruifeng , Huang Minghui , Jiang Ye , Jiang Dan , Chang Doudou , Xie Yifan , Dou Yuewen , Wu Lili , Wei Liuli , Wang Mingze , Tian Zhongyan , Li Chunjie , Wang Congli
Published: March 2024

Unraveling the intricacies of soybean cyst nematode ( Heterodera glycines) race 4 resistance and susceptibility in soybean breeding lines—11-452 (highly resistant) and Dongsheng1 (DS1, highly susceptible)—was the focal point of this study. Employing cutting-edge N6-methyladenosine (m6A) and RNA sequencing techniques, we delved into the impact of m6A modification on gene expression and plant defense responses. Through the evaluation of nematode development in both resistant and susceptible roots, a pivotal time point (3 days postinoculation) for m6A methylation sequencing was identified. Our sequencing data exhibited robust statistics, successful soybean genome mapping, and prevalent m6A peak distributions, primarily in the 3′ untranslated region and stop codon regions. Analysis of differential methylation peaks and differentially expressed genes revealed distinctive patterns between resistant and susceptible genotypes. In the highly resistant line (11-452), key resistance and defense-associated genes displayed increased expression coupled with inhibited methylation, encompassing crucial players such as R genes, receptor kinases, and transcription factors. Conversely, the highly susceptible DS1 line exhibited heightened expression correlated with decreased methylation in genes linked to susceptibility pathways, including Mildew Locus O-like proteins and regulatory elements affecting defense mechanisms. Genome-wide assessments, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, and differential methylation peak/differentially expressed gene overlap emphasized the intricate interplay of m6A modifications, alternative splicing, microRNA, and gene regulation in plant defense. Protein−protein interaction networks illuminated defense-pivotal genes, delineating divergent mechanisms in resistant and susceptible responses. This study sheds light on the dynamic correlation between methylation, splicing, and gene expression, providing profound insights into plant responses to nematode infection.
Maximizing Adherence and Minimizing Time to Antibiotics: A Multi-Disciplinary Institutional Trauma Bay Protocol for Single Antibiotic Prophylaxis in Open Fractures
Authors: Heiman Erick , Delaune Joss , Hong Ian S. , Lamb Matthew , Fisher Marissa , Molino Bruno , Moreau Sandy , Devivo Maria , Liporace Frank A. , Yoon Richard S. , Jankowski Jaclyn M.
Published: March 2024

Objectives:

To determine if a multi-disciplinary institutional protocol can optimize the time to antibiotic (Abx) administration for open fractures (openFx) and improve compliance with the administration of Abx prophylaxis during trauma activation.

Methods:

Design: Retrospective pre-post study design.

Setting:

Single Level II Trauma Center.

Patient Selection Criteria:

All patients that triggered a trauma activation with suspected openFx and were treated according to the institutional single antibiotic regimen were eligible for inclusion. Patients were excluded if fractures did not involve the appendicular skeleton. Patients treated prior to implementation of a standardized institutional protocol where premixed IV bags of antibiotics were stocked in automated dispensing systems within ED trauma bays (Jan 2021-Oct 2022) were defined as the “pre” group, and those treated following implementation the “post” group.

Outcome Measures and Comparisons: The primary outcome was time from trauma bay arrival to antibiotic aministration, measured in minutes, with comparisons made between pre- and post-protocol implementation. Secondary outcomes for comparison included rates (%) of time to Abx < 60 minutes, allergic reactions, acute kidney injury, ototoxicity, surgical site infection, multi-drug resistant organisms identified in blood or biopsy cultures in cases requiring reoperation, and Clostridium difficile infection in the gastrointestinal system, confirmed by stool test results, within 30 days.

Results:

Twenty-four patients (mean age 39.5±16.3) met the criteria after protocol implementation compared to 72 patients (mean age 34.3±14.8) prior to implementation. Implementation of the institutional protocol resulted in a significant reduction in the time to Abx administration for openFx from 87.9±104.6min to 22.2±12.8min in the post-protocol group (p<0.001). Additionally, only 53% in the pre-protocol group received Abx within 60 minutes compared to 97% in post-protocol group (p<0.001). Post-hoc power analysis revealed that the study was powered at 92% (effect size=0.72) to detect a significant difference between the pre- and post-protocol groups.

Conclusion:

This study provides evidence that a multi-disciplinary institutional protocol for the administration of Abx prophylaxis can be an effective strategy for optimizing the time to Abx administration in cases of suspected openFx. This protocol may be implemented in other trauma centers to optimize time to Abx administration for openFx.

Level of evidence:

III, Retrospective pre-post study.
Pediatric Type I Open Both Bone Forearm Fractures: Predicting Failure of Nonoperative Management
Authors: Noe McKenna C. , Link Robert C. , Warren Jonathan R. , Goodrich Ezra , Sinclair Mark , Tougas Caroline
Published: March 2024

Background:

In recent years, nonoperative treatment of pediatric type I open both bone forearm fractures (OBBFFs) with bedside irrigation, antibiotics, closed reduction, and casting has yielded low infection rates. However, risk factors for failure of type I OBBFF closed reduction have not been well described. Our purpose was to describe management of patients with type I OBBFFs at our institution and determine what factors are associated with failure of closed reduction in this population.

Methods:

This was a review of patients between 5 and 15 years of age who received initial nonoperative management for type I OBBFFs at one institution between 2015 and 2021. Primary outcome was success or failure of nonoperative management (defined as progression to surgical management). Secondary outcomes included infections, compartment syndromes, and neuropraxias. Other variables of interest were demographic information, prereduction and postreduction translation and angulation of the radius and ulna, cast index, and antibiotic administration.

Results:

Sixty-one patients (67.7% male) with 62 type I OBBFFs were included in this study. Following initial nonoperative management, 55 injuries (88.7%) were successfully treated in casts, while the remaining 7 (11.3%) required surgical intervention following loss of acceptable reduction in cast. Median cast index (0.84, IQR 0.8 to 0.9 vs. 0.75, IQR 0.7-0.8, P=0.020) and postreduction radius translation on anteroposterior films (32.0%, IQR 17.0% to 40.0% vs. 5.0%, IQR 0.0% to 26.0%, P=0.020) were higher among those who failed nonoperative management. Multivariable logistic regression models identified increased odds of failure for every SD (0.7) increase in cast index (OR 3.78, P=0.023, 95% CI: 1.4-14.3) and 25% increase in postreduction radius translation on anteroposterior films (OR 7.39, P=0.044, 95% CI 1.2-70.4). No infections or compartment syndromes and 2 transient ulnar neuropraxias occurred.

Conclusions:

Closed reduction of type I OBBFFs was successful in 88.7% of cases. There were no infections after nonoperative management. Increases in cast index of 0.7 and postreduction radius translation on anteroposterior radiographs of 25% were associated with increased likelihood of failure, thus requiring surgery; age was not.

Level of Evidence:

Level IV—retrospective comparative study.
Machine learning algorithms for predicting Cobb angle beyond 25 degrees in female adolescent idiopathic scoliosis patients
Authors: Ohyama Shuhei , Maki Satoshi , Kotani Toshiaki , Ogata Yosuke , Sakuma Tsuyoshi , Iijima Yasushi , Akazawa Tsutomu , Inage Kazuhide , Shiga Yasuhiro , Inoue Masahiro , Arai Takahito , Toshi Noriyasu , Tokeshi Soichiro , Okuyama Kohei , Tashiro Susumu , Suzuki Noritaka , Eguchi Yawara , Orita Sumihisa , Minami Shohei , Ohtori Seiji
Published: March 2024

Study Design:

Retrospective cohort study.

Objective:

To develop a machine learning (ML) model that predicts the progression of AIS using minimal radiographs and simple questionnaires during the first visit.

Summary of Background Data:

Several factors are associated with angle progression in patients with AIS. However, it is challenging to predict angular progression at the first visit.

Methods:

Among female patients with AIS treated at a single institution from July 2011 to February 2023, 1119 cases were studied. Patient data, including demographic and radiographic data based on anterior-posterior and lateral whole-spine radiographs, were collected at the first and last visits. The last visit was defined differently based on treatment plans. For patients slated for surgery or bracing, the last visit occurred just before these interventions. For others, it was their final visit before turning 18 years. Angular progression was defined as a Cobb angle greater than 25 degrees for each of the proximal thoracic (PT), main thoracic (MT), and thoracolumbar/lumbar (TLL) curves at the last visit. ML algorithms were employed to develop individual binary classification models for each type of curve (PT, MT, and TLL) using PyCaret in Python. Multiple models were explored and analyzed, with the selection of optimal models based on the area under the curve (AUC) and Recall scores. Feature importance was evaluated to understand the contribution of each feature to the model predictions.

Results:

For PT, MT, and TLL progression, the top-performing models exhibit AUC values of 0.94, 0.89, and 0.84, and achieve recall rates of 0.90, 0.85, and 0.81. The most significant factors predicting progression varied for each curve: initial Cobb angle for PT, presence of menarche for MT, and Risser grade for TLL.

Conclusions:

This study introduces an ML-based model using simple data at the first visit to precisely predict angle progression in female patients with AIS.
A Challenging Case of Thumb Replantation Aided by Intraoperative Indocyanine Green Fluorescence Angiography
Authors: Budini Valentina , Costa Alfio L. , Sofo Giuseppe , Bassetto Franco , Vindigni Vincenzo
Published: March 2024

Background:

This study presents a case of thumb replantation performed despite several risk factors: age, comorbidities, and trauma mechanism are major adverse prognostic factors directly impacting thumb replantation. Most of the literature backs up this claim that a thumb that works, even partially, is a better outcome for the patient than amputation.

Methods:

We performed thumb replantation on a 94-year-old patient with type 2 diabetes mellitus who arrived at the emergency department with a thumb avulsion due to a dog bite. The intraoperative indocyanine green fluorescence angiography method aided us in carrying out the operation.

Results:

We successfully used indocyanine green angiography intraoperatively to guide surgical debridement and evaluate the efficacy of anastomosis and reperfusion of the replanted segment during surgery. Two months after the operation, the patient had regained satisfactory hand function.

Conclusions:

Although indocyanine green angiography is not a technology created for revascularization procedures, it is instrumental in assessing vascular function and predicting a successful outcome. Given its undeniable potential, more research is needed on the possibility of widespread use in hand surgery and its indications.
Revision Rates in Cosmetic Plastic Surgery with and without Resident Involvement
Authors: Newman Ashley , Caudill Antonina R , Ball Eleanor , Davison Steven P.
Published: March 2024

Background:

Changes in surgical education have caused concern over residents’ preparedness for independent practice. As the field of otolaryngology requires such a wide breadth of expertise, ill preparation becomes especially costly. This study explores how the presence and participation of a postgraduate year 3 (PGY3) otolaryngology resident in surgery impacts revision rates and operating time as gauges for the resident competency and indirect training costs.

Methods:

A retrospective chart analysis of patients who underwent cosmetic plastic surgery at sites for PGY3 otolaryngology residents’ facial plastic surgery rotations was conducted. Residents performed one side of bilateral procedures (eg, blepharoplasties) and approximately 50% of midline procedures (eg, rhinoplasties). Chi-squared testing and odds/risk ratios were done to assess the effect of resident involvement on revision rates. Operating time was compared using t tests.

Results:

When a resident was involved in cosmetic surgery, the revision rate was 22.2% compared with 3.6% without. The likelihood of a future revision surgery was 7.57 times higher when a resident participated in the original operation. Resident involvement was not a statistically significant predictor of exceeding the allotted operating time.

Conclusions:

The revision rate of cosmetic surgery was much higher when a resident was involved. Otolaryngology residents would benefit from increased facial plastic and reconstructive surgery training. As a response to this analytical study, this clinical rotation was moved to be offered at a later stage of postgraduate surgical training to allow residents to gain more experience and be better set up for success in the rotation.
A blunted nocturnal blood pressure decline is associated with all-cause and cardiovascular mortality
Authors: de la Sierra Alejandro , Staplin Natalie , Ruilope Luis M. , Gorostidi Manuel , Vinyoles Ernest , Segura Julián , Baigent Colin , Williams Bryan
Published: March 2024

Objective:

It has been suggested that a blunted nocturnal blood pressure (BP) decline is associated with a poor prognosis. Nevertheless, it remains unclear if an abnormal dipping is deleterious per se or it merely reflects an elevated BP during sleep. We aimed to assess the prognostic value of nocturnal BP decline, with or without concomitant elevated nocturnal BP.

Methods:

Vital status and cause of death were obtained from death certificates in 59 124 patients, enrolled in the Spanish ABPM Registry between 2004 and 2014 (median follow-up: 10 years). The association between night-to-day ratio (NDR) and dipping patterns (extreme dippers, dippers, reduced dippers, and risers) with all-cause and cardiovascular mortality were evaluated by Cox-proportional models adjusted for clinical confounders and 24 h blood pressure.

Results:

NDR was associated with all-cause mortality [hazard ratio for 1SD change: 1.15; 95% confidence interval (CI) 1.13–1.17]. Reduced dippers (1.13; 1.06–1.20) and risers (1.41; 1.32–1.51) were associated with an increased risk of all-cause death, whereas extreme dippers (0.90; 0.79–1.02) were not. Elevated NDR (≥0.9) in the absence of elevated night SBP (<120 mmHg) was associated with an increased risk of death (1.13; 1.04–1.22), as well as elevated night SBP but normal NDR (1.38; 1.26–1.50), and the combination of both abnormalities (1.56; 1.46–1.66). Similar results were obtained for cardiovascular mortality.

Conclusion:

Abnormalities in the circadian pattern are associated with an increased risk of all-cause and cardiovascular mortality. This is maintained even in the absence of nocturnal BP elevation.
In vivo assessment of antimicrobial activity and toxicity of repeated 1% povidone–iodine applications vs a single 5% povidone–iodine application
Authors: Teren David , Neuman Gil , Abulafia Adi , Gelman Evgeny , Assayag Elishai , Hajj Abeer , Shwartz Orna , Zadok David
Published: March 2024

Purpose:

To demonstrate the noninferiority in antimicrobial effectiveness of thrice-repeated applications of 1% povidone–iodine (PI) compared with a single application of 5% PI on the ocular surface in vivo and to evaluate potential toxicity of PI to the corneal epithelium.

Setting:

Department of Ophthalmology, Shaare Zedek Medical Center, Jerusalem, Israel.

Design:

Prospective, randomized, double-blind study.

Methods:

Patients randomly received either a single application of 5% PI or repeated irrigations of 1% PI on the ocular surface preoperatively. Bacterial colony counts were quantitatively analyzed by taking standardized conjunctival swabs before and after irrigation, and differences in bacterial colony counts were compared between the 2 groups. The presence of superficial punctate keratopathy was evaluated in all patients by the National Eye Institute grading system.

Results:

The study comprised 102 eyes of 102 patients. Both 1% and 5% PI yielded a marked decrease in bacterial colonies compared with before application (P < .001). The repeated application of 1% PI showed a significantly lower bacterial count compared with the single application of 5% PI (P < .05) and resulted in significantly less damage to the corneal epithelium compared with a single 5% PI application (P < .001).

Conclusions:

Preoperative repeated applications of 1% PI effectively eradicated ocular surface bacteria equal to that of 5% PI with a less deleterious effect on the corneal epithelium. Our findings suggest that 1% PI may be a promising alternative to 5% PI.
Physiological Stress Responses to a Live-Fire Training Evolution in Career Structural Firefighters
Authors: Gonzalez Drew E. , Dillard Courtney C. , Johnson Sarah E. , Martin Steven E. , McAllister Matthew J.
Published: March 2024

Objective

This study assessed firefighters’ physiological stress response to a live fire training evolution (LFTE).

Methods

Seventy-six (n = 76) firefighters completed an LFTE. Salivary samples were collected pre-, immediately post, and 30-min post-LFTE and analyzed for α-amylase (AA), cortisol (CORT), and secretory immunoglobulin-A (SIgA).

Results

Concentrations of AA, CORT, and SIgA were elevated immediately post LFTE versus pre (P<0.001) and 30-min post (P<0.001). Cohen’s d effect size comparing pre and immediately-post means were 0.83, 0.77, and 0.61 for AA, CORT, and SIgA and were 0.54, 0.44, and 0.69 for AA, CORT, and SIgA, comparing immediately-post and 30-min post, respectively.

Conclusions

These data demonstrate the stress response and activation of the hypothalamic-pituitary-adrenal/sympathetic-adreno-medullar axis and immune system immediately after real-world firefighting operations. Future work is needed to understand the impact of elevated stress biomarkers on firefighter performance and disease risk.
Preoperative Imaging in Cochlear Implants
Authors: Lee Andrew Y. , Lee Diana Y. , Saunders James E.
Published: March 2024

Objective

To determine the utility of computed tomography (CT) and magnetic resonance imaging (MRI) in cochlear implant candidates.

Study Design

Retrospective case review.

Setting

Tertiary referral hospital.

Patients

A total of 207 cochlear implanted patients with CT and/or MRI

Intervention(s)

N/A.

Main Outcome Measure(s)

Age versus abnormal radiologic findings, imaging abnormality versus postoperative outcomes, postoperative outcomes versus electrode design, Cambridge Cochlear Implant Protocol (CCIP) status for imaging abnormalities, sensitivity and specificity of CT and MRI for round-window/cochlear occlusion, and MRI for incomplete partitions.

Results

A total of 207 patients with CT, MRI, or both were reviewed retrospectively. Less than half (15.5%) of CT scans had findings that might affect surgical intervention compared with 5.9% of MRI. No significant difference was found between children and adults for relevant imaging abnormalities (grade 4 or higher) with either CT (p= 0.931) or MRI (p= 0.606). CCIP status correlated with cochlear abnormalities (p= 0.040); however, only 46.2% of radiographic abnormalities on CT would be identified by these criteria. For detecting cochlear occlusion requiring surgical intervention, the sensitivity and specificity for CT were 40% (4 of 10; 95% confidence interval [CI], 12.16–73.76) and 95.73% (95% CI, 91.40–98.27), respectively. For MRI, the sensitivity and specificity were 33.33% (1 of 3; 95% CI, 0.84–90.57) and 96.97% (63 of 65; 95% CI, 89.32–99.63), respectively. There was no difference for postoperative AzBio scores for higher-grade imaging abnormalities (p= 0.6012) or for electrode designs (p= 0.3699).

Conclusions

Significant radiographic abnormalities were relatively uncommon in cochlear implant patients on either CT or MRI at our single-center institution. If present, abnormal imaging findings rarely translated to management changes. CCIP status does not reliably predict which patients are likely to have abnormalities. Both MRI and CT have low sensitivity for round-window or cochlear occlusion, but detection likely leads to changes in surgical management.
A rare case of essential thrombocythemia with pseudo-hyperkalemia
Authors: Kalan Ugur , Vardi Jale , Kaya Selin Kucukyurt , Gunes Ahmet Kursad
Published: March 2024

Essential thrombocythemia (ET) is a rare clonal stem cell disorder that affects the production of platelets in the bone marrow. This condition causes an overproduction of platelets, which can lead to blood clots and other complications. Potassium, on the other hand, is an essential mineral that plays a vital role in various bodily functions, including nerve impulses and muscle contractions. Here, in this case report, we investigated a case of pseudo-hyperkalemia caused by essential thrombocythemia in a 77-year-old woman with very high platelet counts. Moreover, this case report, which has no similar examples in the literature review, is important for clinicians.
Time trends in liver cancer mortality rates in Montenegro from 1990 to 2018
Authors: Vuković Mirjana Nedović , Jakšić Marina , Stojanović Danijela , Smolović Brigita
Published: March 2024

Objective

Liver cancer is the third most common cause of cancer-related deaths worldwide. Hepatitis B and C infections are the main factors affecting mortality. During recent years, Montenegro conducted activities on eradication of viral hepatitis according to the global strategy for the primary prevention of liver cancer mortality. The objective of this study was to assess the liver cancer mortality trend in Montenegro for the period of 1990–2018 using regression techniques.

Methods

liver cancer mortality data in Montenegro from 1990 to 2018 were collected. Mortality rates were age standardized to the World Standard Population. The joinpoint, linear and Poisson regressions were used to assess liver cancer mortality trends both overall and gender specific.

Results

The mortality trend was constant, with no significant increase or decrease in mortality rates both at the overall level and by gender. The number of cases, however, increases significantly at the overall level by an average of 1.4% per year [average annual percentage change (AAPC) (95% confidence interval, CI): 1.4 (0.5–2.3); P = 0.004] and in women by 1.9% per year [AAPC (95% CI): 1.9 (0.8–3.1); P = 0.002]. In men, there was no change in the number of cases. The three age groups most burdened by mortality from liver cancer were 65–74 (34.9%), 75–84 (26.6%) and 55–64 (25.8%).

Conclusion

The consistent implementation of prevention measures and hepatitis virus infection treatment has played a role in partially favorable liver cancer mortality trends in Montenegro. It is crucial to closely monitor guidelines for this cancer and give particular attention to the elderly population as the most affected.
Alport syndrome and Alport kidney diseases – elucidating the disease spectrum
Authors: Puapatanakul Pongpratch , Miner Jeffrey H.
Published: March 2024

Purpose of review

With the latest classification, variants in three collagen IV genes, COL4A3, COL4A4, and COL4A5, represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype–phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes “classic” Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called “Alport kidney diseases”.

Recent findings

Several research studies have focused on the genotype–phenotype correlation under the latest classification scheme of AS. The historic diagnoses of “benign familial hematuria” and “thin basement membrane nephropathy” linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression.

The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.
Fatal Iron Tablet Aspiration
Authors: Hojberg Yvonne , Abdeljaber Mahmuod , Milewski Yvonne , deJong Joyce , Prahlow Joseph A.
Published: March 2024

Pill aspiration is a significant source of foreign body aspiration in the United States and can occur without swallowing dysfunction or illness. Consequences depend on various factors, such as the pill's chemical composition, size, and diagnostic delay. Aspiration of iron tablets poses a higher risk because of hydroxyl radical formation and subsequent caustic burns, inflammation, obstruction, and/or necrosis. We present a case of a middle-aged obese woman who died 3 weeks after aspirating an iron tablet. Autopsy revealed morbid obesity, a necrotic focus in the right middle lobe of the lung, bronchiolar granulation tissue with iron staining foreign matter, extending into an adjacent arteriole, and mural perforation of the hilar right middle lobe. Despite seeking medical attention twice, the patient was only accurately diagnosed postmortem. This case highlights the importance of accurate and timely diagnosis in preventing fatal outcomes. To enhance diagnostic accuracy and reduce morbidity and mortality associated with pill aspiration, clinicians should maintain a high level of suspicion for foreign body aspiration in patients with persistent or worsening respiratory symptoms. Furthermore, it is crucial for forensic pathologists to have a high index of suspicion about the potential for lethal pill aspiration and complications days after the acute event.
The latest freshwater giants: a new
Peltocephalus
(Pleurodira: Podocnemididae) turtle from the Late Pleistocene of the Brazilian Amazon
Authors: Ferreira G. S. , Nascimento E. R. , Cadena E. A. , Cozzuol M. A. , Farina B. M. , Pacheco M. L. A. F. , Rizzutto M. A. , Langer M. C.
Published: March 2024

Overkill of large mammals is recognized as a key driver of Pleistocene megafaunal extinctions in the Americas and Australia. While this phenomenon primarily affected mega-mammals, its impact on large Quaternary reptiles has been debated. Freshwater turtles, due to the scarcity of giant forms in the Quaternary record, have been largely neglected in such discussions. Here we present a new giant podocnemidid turtle,
Peltocephalus maturin
sp. nov., from the Late Pleistocene Rio Madeira Formation in the Brazilian Amazon, that challenges this assumption. Morphological and phylogenetic analyses of the holotype, a massive partial lower jaw, reveal close affinities to extant Amazonian species and suggest an omnivorous diet. Body size regressions indicate
Pe. maturin
possibly reached about 180 cm in carapace length and is among the largest freshwater turtles ever found. This finding presents the latest known occurrence of giant freshwater turtles, hinting at coexistence with early human inhabitants in the Amazon.
Can institutions foster cooperation by wealth redistribution?
Authors: Chiba-Okabe Hiroaki , Plotkin Joshua B.
Published: March 2024

Theoretical models prescribe how institutions can promote cooperation in a population by imposing appropriate punishments or rewards on individuals. However, many real-world institutions are not sophisticated or responsive enough to ensure cooperation by calibrating their policies. Or, worse yet, an institution might selfishly exploit the population it governs for its own benefit. Here, we study the evolution of cooperation in the presence of an institution that is autonomous, in the sense that it has its own interests that may or may not align with those of the population. The institution imposes a tax on the population and redistributes a portion of the tax revenue to cooperators, withholding the remaining revenue for itself. The institution adjusts its rates of taxation and redistribution to optimize its own long-term, discounted utility. We consider three types of institutions with different goals, embodied in their utility functions. We show that a prosocial institution, whose goal is to maximize the average payoff of the population, can indeed promote cooperation—but only if it is sufficiently forward-looking. On the other hand, an institution that seeks to maximize welfare among cooperators alone will successfully promote collective cooperation even if it is myopic. Remarkably, even a selfish institution, which seeks to maximize the revenue it withholds for itself, can nonetheless promote cooperation. The average payoff of the population increases when a selfish institution is more forward-looking, so that a population under a selfish regime can sometimes fare better than under anarchy. Our analysis highlights the potential benefits of institutional wealth redistribution, even when an institution does not share the interests of the population it governs.
Language-based game theory in the age of artificial intelligence
Authors: Capraro Valerio , Di Paolo Roberto , Perc Matjaž , Pizziol Veronica
Published: March 2024

Understanding human behaviour in decision problems and strategic interactions has wide-ranging applications in economics, psychology and artificial intelligence. Game theory offers a robust foundation for this understanding, based on the idea that individuals aim to maximize a utility function. However, the exact factors influencing strategy choices remain elusive. While traditional models try to explain human behaviour as a function of the outcomes of available actions, recent experimental research reveals that linguistic content significantly impacts decision-making, thus prompting a paradigm shift from outcome-based to language-based utility functions. This shift is more urgent than ever, given the advancement of generative AI, which has the potential to support humans in making critical decisions through language-based interactions. We propose sentiment analysis as a fundamental tool for this shift and take an initial step by analysing 61 experimental instructions from the dictator game, an economic game capturing the balance between self-interest and the interest of others, which is at the core of many social interactions. Our meta-analysis shows that sentiment analysis can explain human behaviour beyond economic outcomes. We discuss future research directions. We hope this work sets the stage for a novel game-theoretical approach that emphasizes the importance of language in human decisions.
The scale of two cities: the geographies of Paris and London in the 1720s
Authors: Heffernan Michael
Published: March 2024

This essay considers an early eighteenth-century quarrel about the geographical dimensions of Paris and London. The dispute involved representatives of the Académie Royale des Sciences in Paris and the Royal Society in London. The three participants—Guillaume Delisle (1675–1726), Jean-Jacques Dortous de Mairan (1678–1771) and Peter Davall (?–1763)—were French, the first two resident in Paris, the third an exiled Huguenot based in London. From an initial, relatively trivial, confusion about trigonometrical calculations, this inconclusive debate ultimately embraced several wider questions about the nature of cities in classical antiquity and early eighteenth-century Europe, the changing meaning of urban life on the eve of the industrial age, the relationship between population size and urban space, and the relative economic, political and cultural vitality of Catholic absolutist France and Protestant Hanoverian England. Informed by rival claims promoted by Cartesians and Newtonians in London and Paris, the dispute also reflected a pre-existing tension within the Paris Academy about the remit of established and emerging scientific disciplines, specifically astronomy and geography. Subsequent cartographic representations of these two cities, including the Plan Turgot of Paris in the 1730s and the Rocque map of London in the 1740s, can be re-considered with reference to this now forgotten controversy.
IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer’s disease
Authors: Joshi Radhika , Brezani Veronika , Mey Gabrielle M , Guixé-Muntet Sergi , Ortega-Ribera Marti , Zhuang Yuan , Zivny Adam , Werneburg Sebastian , Gracia-Sancho Jordi , Szabo Gyongyi
Published: March 2024

The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D:IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer’s Disease, notablyapolipoprotein-e. Lastly, using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 as a target of IRF3 that is relevant across various neuroinflammatory disorders. Together, our results identify IRF3 as an important regulator of LPS-mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.
The molecules lost NEW COMPOUNDS BINDING AT THE HISTAMINE SITE OF THE NMDA RECEPTOR (NMDA(HA)R)
Authors: Armand V.
Published: March 2024

NMDA receptor ligands have been the target of intensive research for the treatment of psychotic diseases and central nervous system diseases. Our group published the characterization of the NMDA receptor histamine site. We developed modulators for this site, about 500 drugs were tested and we finally have a partial agonist FUBn293 with a nanomolar affinity and also an antagonist ST-579 with a nanomolar affinity. We suggest that agonists at the (NMDA(HA)R) constitute an innovative class of antipsychotics for the treatment of schizophrenia and other neurological or psychiatric disorders.
Integratedin vivofunctional screens and multi-omics analyses identify α-2,3-sialylation as essential for melanoma maintenance
Authors: Agrawal Praveen , Chen Shuhui , de Pablos Ana , Jame-Chenarboo Faezeh , Miera Saenz de Vega Eleazar , Darvishian Farbod , Osman Iman , Lujambio Amaia , Mahal Lara K. , Hernando Eva
Published: March 2024

Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma maintenance, we conducted anin vivogrowth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that α-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding α-2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growthin vivoandin vitro. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter Solute Carrier Family 3 Member 2 (SLC3A2/CD98hc). CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its pro-survival effect in melanoma are dependent upon α-2,3 sialylation mediated by ST3GAL1 and ST3GAL2. In summary, our studies reveal that α-2,3-sialosides functionally contribute to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as novel therapeutic targets in these tumors.
Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency
Authors: Pham Vi , Tricoli Lucas , Hong Xinying , Wongkittichote Parith , Castruccio Castracani Carlo , Guerra Amaliris , Schlotawa Lars , Adang Laura A. , Kuhs Amanda , Cassidy Margaret M. , Kane Owen , Tsai Emily , Presa Maximiliano , Lutz Cathleen , Rivella Stefano B. , Ahrens-Nicklas Rebecca C.
Published: March 2024

Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the geneSUMF1,encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplant withex vivo SUMF1lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that ourSUMF1lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation.In vivo, we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest thatSUMF1HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.