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Sheehan’s Syndrome (SS) is a rare endocrine condition that presents with complex features in women with intrapartum or Postpartum Haemorrhage (PPH) seen in clinical practice. The spectrum of symptoms is diverse, and early detection with prompt treatment of this endocrinopathy is facilitated by a high index of suspicion, sound clinical acumen, and an appropriate diagnostic strategy by an astute physician. SS, which manifests as a major depressive disorder, but not accompanied with dyselectrolytaemia, is an interesting finding in the present case study. In fact, most of the time, it presents with non specific symptoms that delays the diagnosis and management. Hereby, the authors present the case of a 39-year-old multiparous woman who was diagnosed with depression for two months by the psychiatrist. Later, she developed symptoms including anorexia, for which she presented to the Medicine Department. On detailed examination, her vitals were poor. Again, she was evaluated in detail for her obstetric history presented as a history of agalactia and early amenorrhoea two years ago. Followed by the history, laboratory investigation and imaging techniques were done, and found to have thinned pituitary gland and flattened against the sella floor. With this prompt examination, diagnosed with SS due to PPH. Yet, her laboratory investigation resulted in abnormal electrolytes made the final diagnosis as SS with dyselectrolytaemia and depression as neuropsychiatric manifestations. She was treated with Hormone Replacement Therapy (HRT). Due to her financial constraints, her treatment switched to oral drugs and discharged Against Medical Advice (AMA) with follow-up advice.

There has been a rising trend in the number of histoplasmosis cases reported in the recent years. However, in southern India, the number of cases is relatively less. This report is about a 46-year-old Indian male from Tamil Nadu who presented with decreased appetite, vomiting, and giddiness. In view of persistent hyponatremia and hypotension, a work-up for adrenal insufficiency was done, and serum cortisol was found to be low. Contrast Enhanced Computed Tomography (CECT) showed bilateral adrenal enlargement with peripheral rim enhancement and hypodense areas within. There was a diagnostic dilemma between tubercular and fungal aetiology. Fine Needle Aspiration Cytology (FNAC) of the adrenal gland showed features suggestive of histoplasmosis. The patient was treated with itraconazole along with steroid replacement therapy, leading to marked improvement in his overall condition. In immunocompetent individuals, disseminated histoplasmosis with adrenal gland involvement is a rare occurrence. As an unusual presentation of histoplasmosis, this case adds to the body of literature available from Tamil Nadu, which is a non endemic region for histoplasmosis, with only 15 cases being reported as of 2018.

Introduction: There have been various inflammatory markers implicated in the pathogenesis of Acute Coronary Syndromes (ACS). However, the role of the Neutrophil Lymphocyte Ratio (NLR) and Platelet Lymphocyte Ratio (PLR) as prognostic markers in ST-elevation Myocardial Infarction (STEMI) remains poorly researched. Aim: To determine the prognostic value of NLR and PLR to predict the immediate outcomes in patients with acute STEMI, and if any association exists between NLR/PLR and Thrombolysis in Myocardial Infarction (TIMI) risk score. Materials and Methods: This was a cross-sectional study conducted at a tertiary care centre, Puducherry, India, where 190 patients who presented to casualty with STEMI were enrolled. The patient co-morbidities, personal and family history were obtained. The routine laboratory parameters including platelets, lymphocytes, neutrophils and their corresponding ratios were calculated. Patients were grouped into low and high NLR/PLR groups and were assessed for occurrence of in-hospital mortality or Major Adverse Cardiovascular Events (MACE). Analysis was made to see if there is an association between NLR/PLR and MACE. Chi-square test and one-way ANOVA test was used for statistical significance. Results: Among 190 subjects, 157 male and 33 female with mean age of 55.72±11.24 years were included. A total of 8.94% patients 8.94% had MACE. NLR was positively associated with MACE (p-value=0.0006), whereas PLR was not associated with MACE. Patients with high NLR had 1.45 times higher odds of having MACE. NLR was significantly associated with TIMI risk score. Both NLR (F ratio=6.341) and PLR (F ratio=4.600) showed significant association with Killip classification, however NLR showed higher association (p-value

Purpose: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing- and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the goals of the Registry is to continue to refine these guidelines as additional data become available., Experimental Design: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the NCI Natural History of DICER1 Syndrome study., Results: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed before 8 years of age, the current age of onset of pelvic surveillance. Additionally, 4% of Sertoli-Leydig cell tumors were diagnosed before 4 years of age., Conclusions: Ongoing data collection highlights the role of lung surveillance in the early detection of PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before 8 years of age, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant., (©2024 American Association for Cancer Research.)

Objective: Intradialytic hypotension (IDH), a common complication of hemodialysis (HD), is associated with increased cardiovascular risk, morbidity, and mortality. Fatigue is one of the most frequent symptoms of IDH, and deteriorates the quality of life of patients. This study aimed to evaluate the efficacy and safety of electronic moxibustion for improving IDH and its associated symptoms., Methods: We prospectively recruited 32 end-stage renal disease patients with IDH who underwent regular HD at our hospital's dialysis center between April 2019 and April 2020. A randomized, controlled, two-arm crossover trial was performed to evaluate the efficacy of adding one-hour electronic moxibustion during HD. The outcome measurements included patients' subjective assessment of the degree of fatigue, recovery time of fatigue from HD, cold intolerance before and after each intervention, frequency of IDH episodes and nursing interventions needed during HD, and blood pressure changes during HD., Results: Thirty (94%) patients completed the study. Intervention with electronic moxibustion improved the degree of fatigue (95% CI, -2.95 to -0.18, p = 0.027), specifically in patients prescribed with midodrine (95% CI, -4.20 to -0.53, p = 0.013). The short-term use of electronic moxibustion during HD did not significantly alter the frequency of IDH or reduce the degree of decrease in blood pressure. Serious adverse effects were not observed. One patient complained of heat, whereas two patients had local transient erythema and pruritus., Conclusion: Electronic moxibustion appears to be safe and efficacious for improving IDH-related fatigue, thus acting as an adjuvant therapy in HD units to enhance patient comfort and treatment adherence. Further studies with larger sample sizes are required to confirm the benefits of this novel technique., Competing Interests: The authors declare that they have no competing interests., (© 2024 Liu et al.)

Inhibition of immune checkpoint proteins is effective in adult cancers but has shown limited efficacy in pediatric cancers. While factors regulating expression of immune checkpoint proteins such as PD-L1 are well-documented in adult cancers, their regulation is poorly understood in pediatric cancers. Here, we show that PD-L1 is upregulated in distinct subsets of Wilms tumor, the most common pediatric kidney cancer. Specifically, chemotherapy-exposed Wilms tumor specimens exhibited higher levels of PD-L1 expression, and common chemotherapeutics upregulated PD-L1 in childhood cancer cell lines in vitro . Furthermore, mutations in CTNNB1 and DROSHA , the two most commonly mutated genes in Wilms tumor, correlated with higher PD-L1. Activation of Wnt/β-catenin signaling and knockdown of DROSHA or DICER1 both increase PD-L1 in vitro . Lastly, in adult cancers, DICER1 alterations are associated with immune gene expression signatures and improved survival in response to immune checkpoint inhibitors. Together, our results identify clinical and biological properties regulating PD-L1 in Wilms tumor that may inform precision therapy approaches in pediatric immuno-oncology.

Cultivated strawberry (Fragaria × ananassa) is a popular, economically important fruit. The ripening of the receptacle (pseudocarp), the main edible part, depends on endogenously produced abscisic acid (ABA) and is suppressed by the high level of auxin produced from achenes (true fruit) during early development. However, the mechanism whereby auxin regulates receptacle ripening through inhibiting ABA biosynthesis remains unclear. Here, we identified AUXIN RESPONSE FACTOR 2 (FaARF2), which showed decreased expression with reduced auxin content in the receptacle, leading to increased ABA levels and accelerated ripening. Dual-luciferase, yeast one-hybrid, and electrophoretic mobility shift assays demonstrated that FaARF2 could bind to the AuxRE element in the promoter of 9-CIS-EPOXYCAROT-ENOID DIOXYGENASE 1 (FaNCED1), a key ABA biosynthetic gene, to suppress its transcriptional activity. Transiently overexpressing FaARF2 in the receptacles decreased FaNCED1 expression and ABA levels, resulting in inhibition of receptacle ripening and of development of quality attributes, such as pigmentation, aroma, and sweetness. This inhibition caused by overexpressing FaARF2 was partially recovered by the injection of exogenous ABA; conversely, transient silencing of FaARF2 using RNA interference produced the opposite results. The negative targeting of FaNCED1 by FaARF2 is a key link between auxin-ABA interactions and regulation of strawberry ripening., Competing Interests: Conflict of interest statement. The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Information on the clinical outcomes of feline azotemia using ultrasound examinations is limited. This study aimed to understand the correlation between cortical anisotropy backscattering artifact (CABA) and serum creatinine (sCr) changes in feline azotemia after hospitalization and to investigate whether CABA is useful for predicting the clinical outcome of feline azotemia. Sixty-five hospitalized cats with azotemia, including 49 cats with moderate or severe azotemia (severe group) and 16 cats with mild azotemia (mild group). This retrospective study reviewed the CABA using ultrasound images of cats hospitalized with azotemia between 2016 and 2021. The correlation between CABA and the clinical outcomes of cats with azotemia was investigated using the chi-squared or Fisher's exact test, and the intra- and inter-observer agreements in CABA were assessed using McNemar's and Cohen's kappa tests. The presence of CABA was significantly positively correlated with the clinical outcomes of cats with azotemia only in the severe group ( p  = 0.0034, odds ratio = 8.57). There was no association between CABA and clinical outcomes in cats with mild azotemia ( p  = 0.75). CABA can be used for clinical outcome prediction in moderate and severe feline azotemia, with a sensitivity of 80.8% and a specificity of 73.9%. Also, satisfactory intra- and inter-observer agreements were revealed in the detection of CABA during ultrasound image review. Our study demonstrated that cats with moderate and severe azotemia with CABA observed during ultrasonography might have better clinical outcomes. These findings provide additional information on the prognosis and treatment of feline azotemia.

Recent progress in cancer cell-based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible RIPK3-driven necroptotic system that serves as a dual function of safety switch as well as inducing immunogenic cell death which in turn stimulates antitumor immune responses. We showed that activating RIPK3 safety switch triggered immunogenic responses marked by an increased release of adenosine triphosphate (ATP) and damage-associated molecular patterns (DAMPs). Compared to other existing safety switches, incorporating RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, RIPK3 system reinvigorated the TIME by promoting dendritic cell (DC) maturation, polarizing the macrophages towards the M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies.

Adult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. Conversely, we observed that overexpression of VEGF reduced microglial response to excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses widely throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Mutations in the microRNA processing genes DICER1 and DROSHA drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes. Pineal tumors driven by loss of Drosha or Dicer1 mimic tumors driven by Rb1 loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor Plagl2 , which regulates expression of pro-growth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation., Competing Interests: The authors have no competing interests to declare.

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.

Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. In this study, we used a "multiomics" approach to define the effects of DROSHA mutation in Wilms tumor. We categorized Wilms tumor mutations into four mutational subclasses with unique transcriptional effects: microRNA processing, MYCN activation, chromatin remodeling, and kidney developmental factors. In particular, we find that DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. We model these findings by inhibiting DROSHA expression in a Wilms tumor cell line, which led to upregulation of the cell cycle regulator cyclin D2 (CCND2). Furthermore, we observed that DROSHA mutations in Wilms tumor and DROSHA silencing in vitro were associated with a mesenchymal state with aberrations in redox metabolism. Accordingly, we demonstrate that Wilms tumor cells lacking microRNAs are sensitized to ferroptotic cell death through inhibition of glutathione peroxidase 4, the enzyme that detoxifies lipid peroxides. Implications: This study reveals genotype-transcriptome relationships in Wilms tumor and points to ferroptosis as a potentially therapeutic vulnerability in one subset of Wilms tumor., (©2024 American Association for Cancer Research.)

This study examines diatom assemblages in the Matsu Archipelago, an area influenced by Minjiang River runoff. It focuses on harmful algal blooms (HABs) that occurred between August 2021 and July 2022. Utilizing 18S rRNA metabarcoding and microscopic analysis, we observed a significant diatom bloom during early summer runoff, peaking at 5 × 10 5 cells L -1 . The research reveals dynamic community changes during the runoff season, with dominant genera including Pseudo-nitzschia, Chaetoceros, and Skeletonema. Skeletonema cell density correlated with NO 3 levels, Chaetoceros had a slight PO 4 affinity, and Pseudo-nitzschia showed a negative correlation with Skeletonema. Pseudo-nitzschia, which prefers high light and pH conditions, had notably high concentrations in the flood season and in the autumn. In both, it was dominated by potential toxin-producing species - P. multistriata and P. pungens during the flooding, and P. cuspidate in the autumn. These findings highlight the intricate relationship between diatom dynamics and environmental factors, providing essential insights for managing HABs, especially Pseudo-nitzschia species, amidst environmental changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear., Methods: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance., Results: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively., Conclusion: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors., (© 2024 Wiley Periodicals LLC.)

Auxin response transcription factors (ARFs) form a large gene family, many of whose members operate at the final step of the auxin signaling pathway. ARFs participate directly in many aspects of plant growth and development. Here we summarize recent advances in understanding the roles of ARFs in regulating aspects of fleshy fruit development and ripening. ARFs play a crucial role in regulating fruit size, color, nutrients, texture, yield, and other properties that ultimately influence the ripening and quality of important crops such as tomato, apple, strawberry, and peach. ARFs impact these processes acting as positive, negative, or bidirectional regulators via phytohormone-dependent or -independent mechanisms. In the phytohormone-dependent pathway, ARFs act as a central hub linking interactions with multiple phytohormones generating diverse effects. The three domains within ARFs, namely the DNA-binding domain, the middle region, and the carboxy-terminal dimerization domain, exhibit distinct yet overlapping functions, contributing to a range of mechanisms mediated by ARFs. These findings not only provide a profound understanding of ARF functions, but also raise new questions. Further exploration can lead to a more comprehensive understanding of the regulatory mechanisms of fleshy fruit development and ripening mediated by ARFs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Phosphorus (P) plays an important role in immobilizing heavy metals (HMs), thereby preventing their accumulation, especially in edible parts of crops. In this study, vermicompost (VM) and chemical fertilizers (CFs) were used as soil amendments to increase the available P concentration in soil contaminated with cadmium (Cd) and nickel (Ni), with the aim of reducing their bioavailability, uptake, and bioaccessibility. Using CF and VM as soil amendments substantially increased the available P and exchangeable potassium concentrations in the soil. Furthermore, VM addition led to an increase in OM content and in exchangeable calcium and magnesium, resulting in the improved growth of lettuce. It also reduced the uptake of Cd and Ni in the two lettuce cultivars tested in the study. However, CF addition boosted the accumulation of Cd and Ni by increasing the soil acidity. CF addition, and especially VM addition, altered the chemical forms of Cd and Ni from active to inactive. Overall, the results of this study underscore the positive impact of using VM as a soil amendment on lettuce growth and the prevention of HM accumulation in edible parts of lettuce. VM addition led to decreased bioavailability, uptake, and bioaccessibility of HMs in soil, which could improve food safety and reduce potential risks associated with HM contamination., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Vascular dementia (VaD) is a cognitive disorder characterized by a decline in cognitive function resulting from cerebrovascular disease. The hippocampus is particularly susceptible to ischemic insults, leading to memory deficits in VaD. Astaxanthin (AST) has shown potential therapeutic effects in neurodegenerative diseases. However, the mechanisms underlying its protective effects in VaD and against hippocampal neuronal death remain unclear. In this study, We used the bilateral common carotid artery occlusion (BCCAO) method to establish a chronic cerebral hypoperfusion (CCH) rat model of VaD and administered a gastric infusion of AST at 25 mg/kg per day for 4 weeks to explore its therapeutic effects. Memory impairments were assessed using Y-maze and Morris water maze tests. We also performed biochemical analyses to evaluate levels of hippocampal neuronal death and apoptosis-related proteins, as well as the impact of astaxanthin on the PI3K/Akt/mTOR pathway and oxidative stress. Our results demonstrated that AST significantly rescued memory impairments in VaD rats. Furthermore, astaxanthin treatment protected against hippocampal neuronal death and attenuated apoptosis. We also observed that AST modulated the PI3K/Akt/mTOR pathway, suggesting its involvement in promoting neuronal survival and synaptic plasticity. Additionally, AST exhibited antioxidant properties, mitigating oxidative stress in the hippocampus. These findings provide valuable insights into the potential therapeutic effects of AST in VaD. By elucidating the mechanisms underlying the actions of AST, this study highlights the importance of protecting hippocampal neurons and suggests potential targets for intervention in VaD. There are still some unanswered questions include long-term effects and optimal dosage of the use in human. Further research is warranted to fully understand the therapeutic potential of AST and its application in the clinical treatment of VaD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rapid advances in biological knowledge and technological innovation have greatly advanced the fields of stem cell and gene therapies to combat a broad spectrum of neurologic disorders. Researchers are currently exploring a variety of stem cell types (e.g., embryonic, progenitor, induced pluripotent) and various transplantation strategies, each with its own advantages and drawbacks. Similarly, various gene modification techniques (zinc finger, TALENs, CRISPR-Cas9) are employed with various delivery vectors to modify underlying genetic contributors to neurologic disorders. While these two individual fields continue to blaze new trails, it is the combination of these technologies which enables genetically engineered stem cells and vastly increases investigational and therapeutic opportunities. The capability to culture and expand stem cells outside the body, along with their potential to correct genetic abnormalities in patient-derived cells or enhance cells with extra gene products, unleashes the full biological potential for innovative, multifaceted approaches to treat complex neurological disorders. In this review, we provide an overview of stem cell and gene therapies in the context of neurologic disorders, highlighting recent advances and current shortcomings, and discuss prospects for future therapies in clinical settings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eva L. Feldman reports financial support was provided by National Institutes of Health. Kevin S. Chen reports financial support was provided by Alzheimer's Association. Kevin S. Chen reports financial support was provided by Frances and Kenneth Eisenberg Emerging Scholar Fund. Eva L. Feldman reports financial support was provided by Robert and Katherine Jacobs Environmental Health Initiative. Eva L. Feldman reports financial support was provided by Andrea and Lawrence A. Wolfe Brain Health Initiative. Eva L. Feldman reports financial support was provided by Richard and Jane Manoogian Foundation. Eva L. Feldman reports financial support was provided by Frank L. and Helen Gofrank Foundation Research Program in Alzheimer's Disease and Brain Health. Eva L. Feldman reports financial support was provided by Kiriluk Family Fund for Brain Health Research. Eva L. Feldman reports financial support was provided by Taubman Foundation. Eva L. Feldman reports financial support was provided by NeuroNetwork for Emerging Therapies. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The November 2013 online publication of ARUBA, the first multi-institutional randomized controlled trial for unruptured brain arteriovenous malformations (AVMs), has sparked over 100 publications in protracted debates METHODS: This study sought to examine inpatient management patterns of brain AVMs from 2009 to 2016 and observe if changes in U.S. inpatient management were attributable to the ARUBA publication using interrupted time series of brain AVM studies from the National Inpatient Sample data 2009-2016. Outcomes of interest were use of embolization, surgery, combined embolization and microsurgery, radiotherapy, and observation during that admission. An interrupted time series design compared management trends before and after ARUBA. Segmented linear regression analysis tested for immediate and long-term impacts of ARUBA on management. RESULTS: Elective and asymptomatic patient admissions declined 2009-2016. In keeping with the ARUBA findings, observation for unruptured brain AVMs increased and microsurgery decreased. However, embolization, radiosurgery, and combined embolization and microsurgery also increased. For ruptured brain AVMs, treatment modality trends remained positive with even greater rates of observation, embolization, and combined embolization and microsurgery occurring after ARUBA (data on radiosurgery were scarce). None of the estimates for the change in trends were statistically significant. CONCLUSIONS: The publication of ARUBA was associated with a decrease in microsurgery and increase in observation for unruptured brain AVMs in the US. However, inpatient radiotherapy, embolization, and combined embolization and surgery also increased, suggesting trends moved counter to ARUBA's conclusions. This analysis suggested that ARUBA had a small impact as clinicians rejected ARUBA's findings in managing unruptured brain AVMs., Competing Interests: Declaration of Competing Interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. The work presented in this manuscript was conducted while HV was at Brigham and Women’s Hospital., (Copyright © 2024. Published by Elsevier B.V.)

This study aimed to investigate how the decomposing scale effect, technique effect and composition effect of foreign direct investment (FDI) impact on carbon dioxide (CO 2 ) emissions for 115 nations spanning 1999 to 2019 by employing Generalised Method of Moments (GMM) model. The results indicated that FDI, real GDP per capita, capital-labor ratio, institutional quality and urbanization increase CO 2 emissions while the square of real GDP per capita and trade openness contributed to reducing CO 2 emissions. Also, our findings fail to support Environmental Kuznets Curve (EKC) theory. The outcomes of this research illustrated that scale effect dominates composition effect and followed by technique effect. The interaction effect of FDI and technique effect has the least influence on CO 2 levels in reducing the harmful effects of FDI on CO 2 . Furthermore, it should be highlighted that although FDI increases CO 2 emissions, its detrimental impact on CO 2 emissions is moderately mitigated by its interactions with three economic mechanisms. Therefore, it is necessary to enhance the technical processes of production as well as the development of modern technologies. We recommended that policymakers balance sustainable economic development with environmental sustainability by considering the indirect effects of factors on CO 2 emissions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT., Methods: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available., Results: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85)., Conclusion: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection., Competing Interests: Declaration of competing interest Dr. Hill is owner of ResourcePath LLC, a company which does research and development of laboratory tests including for DICER1 cancers. That work is unrelated to the information presented in this article. Dr. Stewart provides telegenetics services for Genome Medical, Inc., in accordance with relevant National Cancer Institute policies. The remaining authors have no conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Wilms tumor is the most common kidney cancer in children, and diffusely anaplastic Wilms tumor is the most chemoresistant histological subtype. Here we explore how Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell cycle progression. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Furthermore, the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment by inducing apoptosis both in vitro and in vivo . Lastly, we show that increased levels of proteasome components are associated with anaplastic histology and with worse prognosis in non-anaplastic Wilms tumor. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover., Competing Interests: The authors have no conflicts of interest to disclose.

Objective: This study aims to examine the trends in machine learning application to meningiomas between 2004 and 2023., Methods: Publication data were extracted from the Science Citation Index Expanded (SCI-E) within the Web of Science Core Collection (WOSCC). Using CiteSpace 6.2.R6, a comprehensive analysis of publications, authors, cited authors, countries, institutions, cited journals, references, and keywords was conducted on December 1, 2023., Results: The analysis included a total of 342 articles. Prior to 2007, no publications existed in this field, and the number remained modest until 2017. A significant increase occurred in publications from 2018 onwards. The majority of the top 10 authors hailed from Germany and China, with the USA also exerting substantial international influence, particularly in academic institutions. Journals from the IEEE series contributed significantly to the publications. "Deep learning," "brain tumor," and "classification" emerged as the primary keywords of focus among researchers. The developmental pattern in this field primarily involved a combination of interdisciplinary integration and the refinement of major disciplinary branches., Conclusion: Machine learning has demonstrated significant value in predicting early meningiomas and tailoring treatment plans. Key research focuses involve optimizing detection indicators and selecting superior machine learning algorithms. Future efforts should aim to develop high-performance algorithms to drive further innovation in this field., Competing Interests: The authors declare no conflict of interest related to the manuscript titled "Exploring the Research Trends in the Application of Machine Learning to Meningiomas (2004–2023)." The research conducted and presented in this manuscript is independent and impartial. The authors have no financial relationships with any organizations that might have an interest in the submitted work, nor were there any other relationships or activities that could appear to have influenced the submitted work. The data for the study was extracted from the Science Citation Index Expanded (SCI-E) within the Web of Science Core Collection (WOSCC), and the analysis was performed using CiteSpace 6.2.R6. The selection of data, process of analysis, and interpretation of results were conducted without any influence or input from these platforms. All authors have contributed significantly to the research and preparation of the manuscript and have approved the final version for submission to Heliyon. Additionally, all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This statement confirms the absence of any personal, financial, or other conflicts of interest that could be construed to influence the outcomes of this research study., (© 2024 The Authors. Published by Elsevier Ltd.)

We systematically reviewed the literature on the effects of the coronavirus disease 2019 (COVID-19) pandemic on the progression, prevalence, and incidence of myopia. A comprehensive literature search was performed on PubMed, Cochrane Central Register of Controlled Trials, and Scopus databases. Studies included in the review assessed myopia progression, prevalence, and/or incidence as the primary outcome. Of 523 articles yielded in the initial search, 23 studies (6 cross-sectional and 17 cohort) were eligible for inclusion. Sixteen of these were conducted in China and one each in Hong Kong, Turkey, Spain, Israel, India, Korea, and Tibet. Quality appraisals were conducted with the Joanna Briggs Institute Critical Appraisal Checklists. Of the included studies, a large majority reported a greater myopic shift and increase in myopia prevalence during the COVID-19 pandemic compared to the pre-COVID-19 years. All three studies on myopia incidence showed increased incidence during the COVID-19 pandemic. Myopia progression accelerated during the COVID-19 pandemic, even in individuals using low-concentration atropine eye drops in two studies but not in those using orthokeratology treatment in one study. Overall, the studies found that the COVID-19 pandemic and its associated home confinement measures generally increased myopia progression, prevalence, and incidence, even in individuals using low-concentration atropine eye drops., Competing Interests: The authors declare that there are no conflicts of interest in this paper., (Copyright: © 2024 Taiwan J Ophthalmol.)

Transcranial focused ultrasound stimulation (tFUS) has emerged as a promising neuromodulation technique that delivers acoustic energy with high spatial resolution for inducing long-term potentiation (LTP)- or depression (LTD)-like plasticity. The variability in the primary effects of tFUS-induced plasticity could be due to different stimulation patterns, such as intermittent versus continuous, and is an aspect that requires further detailed exploration. In this study, we developed a platform to evaluate the neuromodulatory effects of intermittent and continuous tFUS on motor cortical plasticity before and after tFUS application. Three groups of rats were exposed to either intermittent, continuous, or sham tFUS. We analyzed the neuromodulatory effects on motor cortical excitability by examining changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). We also investigated the effects of different stimulation patterns on excitatory and inhibitory neural biomarkers, examining c-Fos and glutamic acid decarboxylase (GAD-65) expression using immunohistochemistry staining. Additionally, we evaluated the safety of tFUS by analyzing glial fibrillary acidic protein (GFAP) expression. The current results indicated that intermittent tFUS produced a facilitation effect on motor excitability, while continuous tFUS significantly inhibited motor excitability. Furthermore, neither tFUS approach caused injury to the stimulation sites in rats. Immunohistochemistry staining revealed increased c-Fos and decreased GAD-65 expression following intermittent tFUS. Conversely, continuous tFUS downregulated c-Fos and upregulated GAD-65 expression. In conclusion, our findings demonstrate that both intermittent and continuous tFUS effectively modulate cortical excitability. The neuromodulatory effects may result from the activation or deactivation of cortical neurons following tFUS intervention. These effects are considered safe and well-tolerated, highlighting the potential for using different patterns of tFUS in future clinical neuromodulatory applications., Competing Interests: H.-L.L. served as a technical consultant at NaviFUS Corp., Taipei, Taiwan and currently holds several therapeutic ultrasound-related patents; P.-C.C. concurrently served as a part-time research and development scientist at NaviFUS Corp., Taiwan.

Formosan serows are endemic to the mountainous regions of Taiwan. This crossover study aimed to assess and compare the anesthetic induction and recovery using either dexmedetomidine-tiletamine-zolazepam (DZ) or dexmedetomidine-ketamine (DK) by intramuscular injection from a blow-dart in a zoo environment. Ten anesthetic procedures were performed with five adult Formosan serows. Each participant was anesthetized with both combinations at least once with a minimal 12-month washout. The average dosages were 22.6 ± 8.3 µg/kg and 35.8 ± 2.5 µg/kg for dexmedetomidine and 185.6 ± 123.6 and 357.8 ± 25.2 µg/kg for atipamezole for the DZ and DK groups, respectively. The doses of tiletamine-zolazepam and ketamine were 2.1 ± 0.25 mg/kg and 3.6 ± 0.3 mg/kg, respectively, in the DZ and DK groups. All participants were induced within 10 min (median: 8 min for both groups), except one serow in the DK group with an induction time of 22 min. Serows in the DZ group had a lower respiratory rate ( p = 0.016) and lower rectal temperature ( p = 0.008) than those in the DK group. The quality of recovery was poor for DZ because of paddling, prolonged recovery, and ataxia after antagonism of dexmedetomidine with atipamezole. The induction of anesthesia with dexmedetomidine-tiletamine-zolazepam was uneventful and rapid. However, recovery from this combination was not smooth.

Pediatric pial arteriovenous shunts in the brain and spine are challenging to understand because of low incidence, variable presentation, and associations with genetic syndromes. What is known about their natural history comes from reviews of small series. To better understand the natural history and role for intervention, two cases are presented followed by a review of the literature. In the first case, an infant with a prior history of intracranial hemorrhage from a ruptured pial fistula returns for elective embolization for a second pial fistula which was found to be spontaneously thrombosed 2 weeks later. In the second case, a 5-year-old with a vertebro-vertebral fistula, identified on work up for a heart murmur and documented with diagnostic angiography, is brought for elective embolization 6 weeks later where spontaneous thrombosis is identified. In reviewing the literature on pediatric single-hole fistulae of the brain and spine, the authors offer some morphologic considerations for identifying which high-flow fistulae may undergo spontaneous thrombosis to decrease the potentially unnecessary risk associated with interventions in small children., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A 9 yr old male miniature poodle presented with acute diarrhea, vomiting, and a distended abdomen. A large and firm mass was palpated in the caudal abdomen. Radiography showed a large soft-tissue mass in the mid ventral abdomen. The mass was mildly contrast-enhancing and in contact with the right cranial aspect of the bladder on computed tomography. The mass was heterogeneous with minimal blood flow on Doppler examination. Surgery confirmed its origin of the urinary bladder, and it was diagnosed leiomyosarcoma on pathology. This is the first report of extraluminal leiomyosarcoma of the bladder wall with imaging characteristics using various modalities., (© 2024 by American Animal Hospital Association.)

Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024;95:635-652., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The Childhood Autism Rating Scale™, Second Edition (CARS™-2) and Social Responsiveness Scale™, Second Edition (SRS™-2) are two measures for identifying autism symptoms. The CARS™-2 has two versions: Standard (CARS-ST) and High-Functioning (CARS-HF). To better understand their properties, this study aimed to investigate: (1) the associations among the CARS-ST, CARS-HF and the SRS™-2, and (2) the severity consistency between the CARS-ST and the CARS-HF. A sample of 125 children with autism spectrum disorder was recruited (mean age: 80.98 months, SD = 16.08). Based on Verbal Comprehension Index (VCI), children were divided into two groups: low severity level of autism spectrum disorder (LSL-ASD: VCI ≥ 80) and high severity level of autism spectrum disorder (HSL-ASD: VCI < 80). All children were evaluated with the CARS-ST and the SRS™-2, and the HF group, with the CARS-HF as well. In the LSL group, the CARS-ST and the CARS-HF had high correlation (r = 0.852, p < .001). Both versions had small to moderate correlations with the SRS™-2 (r = 0.130-0.491). In the HSL group, no significant correlations were found between the CARS-ST and SRS™-2 (p > .05). The CARS-HF and the CARS-ST had low severity consistency (Kappa = 0.376, p < .01). The CARS-ST and the CARS-HF had high correlations but low severity consistency. Different correlation patterns were found between the CARS™-2 and the SRS™-2 in the LSL and HSL groups. The results should help clinicians better understand the properties of the measures and choose appropriate measures when assessing autism symptoms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

We report a case of vaccine-induced Sweet syndrome in a female patient in her 50s presenting with fevers and a scattered red patchy rash on the lower limbs. Seven days prior, she had received the first dose of AstraZeneca ChAdOx1-S vaccine. A skin biopsy confirmed Sweet syndrome. She did not respond to high doses of prednisolone and required methotrexate therapy to induce remission. This is one of the first reports of Sweet syndrome caused by the ChAdOx1-S vaccine and provides further evidence for vaccine-induced dermatosis. This case demonstrates that methotrexate can induce remission in cases of Sweet syndrome resistant to corticosteroids. This report also describes an approach to the differential diagnosis of patients presenting with a rash, fever and malaise., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)