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Background: To prospectively evaluate the technical efficacy and safety of the double-lumen eustachian tube (ET) balloon catheter in patients with ET dysfunction., Methods: Patients who were diagnosed with ET dysfunction and needed balloon eustachian tuboplasty (BET) were prospectively enrolled. A double-lumen ET balloon catheter was used to dilate the ET and inject medicine. Efficacy results were assessed by the injection channel patency (ICP) rate, the injection reached the expected site (IRES) rate, and the improvement in eustachian tube function was evaluated by the seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) score. Safety results were assessed in terms of adverse events and device defects., Results: BET was successfully attempted in 87 patients from April 2022 to August 2022 at two academic medical centers in China (01, 02). The ICP rate was 100%, and the IRES rate was 88.51%. The overall ETDQ-7 score was significantly reduced ( p < 0.001) postsurgically at both centers. There were no major complications or device defects., Conclusion: The double-lumen ET balloon catheter is technically effective and safe for the treatment of ET dysfunction., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Background: Preservation of intracochlear structures and residual hearing has become a major concern in modern cochlear implant. Consequently, many efforts have been made to minimize intraoperative trauma, especially while cochlear fenestration and electrode insertion., Methods: Building on the core concept of "soft surgery", a modified approach, described as diving technique for cochlear implant electrode array insertion is proposed. Steps and technical points are presented with figures, video and review of relevant anatomy., Conclusions: This novel diving technique is operationally feasible and safe, promising to minimize intraoperative invasion and thus preserve residual hearing in cochlear implant., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The objective of the present study was to evaluate the effect of dexmedetomidine administration during video-assisted thoracoscopic surgery for lung cancer on perioperative inflammatory response and chronic post-surgical pain., Methods: A cohort of 152 patients with lung cancer scheduled for elective video-assisted thoracoscopic surgery participated in this randomized controlled trial. Patients were randomly divided into 2 groups and administered an equivalent volume of dexmedetomidine (n = 63) or normal saline (n = 63). Dexmedetomidine was administered at a dose of 0.6 μg/kg 10 minutes before anesthesia induction and maintained at 0.5 μg/kg/h until 0.5 hours before surgery completed. Anesthesia and postoperative pain management protocols were standardized for both groups. The analysis included vital signs, numerical rating scales of pain, blood inflammatory and oxidative stress biomarkers, pain type and location, patient-controlled intravenous analgesia usage, consumption of general anesthetics and pain rescue medications, as well as complications., Results: The administration of dexmedetomidine resulted in decreased levels of inflammatory cytokines (interleukin-1 beta, interleukin-6, alongside tumor necrosis factor-alpha) and oxidative stress biomarkers (reactive oxygen species alongside malondialdehyde) but elevated levels of interleukin-10 and superoxide dismutase. In addition, the dexmedetomidine group showed lower postoperative numerical rating scale scores, reduced consumption of anesthetics, faster chest-tube removal, fewer patient-controlled intravenous analgesia presses, and shorter postoperative hospital stays., Conclusion: The administration of dexmedetomidine effectively attenuated surgical inflammation, oxidative stress, and postoperative pain, thereby promoting patient recovery after lung cancer surgery without increasing the risk of adverse effects or complications., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Postmastectomy radiation therapy is a mainstay in the adjuvant treatment of node-positive breast cancer, but it poses risks for women with breast reconstruction. Multibeam intensity-modulated radiation therapy improves dose conformality and homogeneity, potentially reducing complications in breast cancer patients with implant-based reconstruction. To investigate this hypothesis, we conducted a single-arm phase 2 clinical trial of breast cancer patients who underwent mastectomy/axillary dissection and prosthesis-based reconstruction., Methods and Materials: The primary endpoint was the rate of implant failure (IF) within 24 months of permanent implant placement, which would be considered an improvement over historical controls if below 16%. IF was defined as removal leading to a flat chest wall or replacement with another reconstruction. Patients were analyzed in 2 cohorts. Cohort 1 (RT-PI) received radiation therapy to the permanent implant. Cohort 2 (RT-TE) received radiation therapy to the TE. IF rates, adverse events, and quality of life were analyzed. Follow-up/postradiation therapy assessments were compared with the baseline/preradiation therapy assessments at 3 to 10 weeks after exchange surgery. A subgroup underwent serial magnetic resonance imaging (MRI) sessions to explore the association between MRI-detected changes and capsular contracture, a known adverse effect of radiation therapy., Results: Between June 2014 and March 2017, 119 women were enrolled. Cohort 1 included 45 patients, and cohort 2 had 74 patients. Among 100 evaluable participants, 25 experienced IF during the study period. IF occurred in 8/42 (19%) and 17/58 (29%) in cohorts 1 and 2, respectively. Among the IFs, the majority were due to capsular contracture (13), infection (7), exposure (3), and other reasons (2). Morphologic shape features observed in longitudinal MRI images were associated with the development of Baker grade 3 to 4 contractures., Conclusions: The rate of IF in reconstructed breast cancer patients treated with intensity-modulated radiation therapy was similar to, but not improved over, that observed with conventional, 3-dimensional-conformal methods. MRI features show promise for predicting capsular contracture but require validation in larger studies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: After September 11, 2001, nuclear threat prompted government agencies to develop medical countermeasures to mitigate two syndromes, the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS), both lethal within weeks. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS, no mitigator potentially deliverable under mass casualty conditions preserves the GI tract. We recently reported that anti-ceramide single-chain variable fragment (scFv) mitigates GI-ARS lethality, abrogating ongoing small intestinal endothelial apoptosis to rescue Lgr5 + stem cells. Here, we examine long-term consequences of prevention of acute GI-ARS lethality., Methods and Materials: For these studies, C57BL/6J male mice were treated with 15 Gy whole body irradiation, the 90% GI-ARS lethal dose for this mouse strain., Results: Mice irradiated with 15 Gy alone or with 15 Gy + bone marrow transplantation (BMT) or anti-ceramide scFv, succumb to an ARS within 8 to 10 days. Autopsies reveal only mice receiving anti-ceramide scFv at 24 hours post-whole body irradiation display small intestinal rescue. No marrow reconstitution occurs in any group with attendant undetectable circulating blood elements. Mice receiving 15 Gy + BMT + scFv, however, normalize blood counts by day 12, suggesting that scFv also improves marrow reconstitution, a concept for which we provide experimental support. We show that at 14 Gy, the upper limit dose for H-ARS lethality before transition to GI-ARS lethality, anti-ceramide scFv markedly improves marrow take, reducing the quantity of marrow-conferring survival by more than 3-fold. Consistent with these findings, mice receiving 15 Gy + BMT + scFv exhibit prolonged survival. At day 90, before sacrifice, they display normal appearance, behavior, and serum biochemistries, and surprisingly, at full autopsy, near-normal physiology in all 42 tissues examined., Conclusions: Anti-ceramide scFv mitigates GI-ARS lethality and improves marrow reconstitution rendering prolonged survival with near normal autopsies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Left atrial appendage (LAA) closure can prevent stroke in high-risk patients with atrial fibrillation.A bioabsorbable LAA occluder made of degradable polymer materials, such as polydioxanone (PDO) and poly-L-lactic acid (PLA), and nitinol wire was used. Occluders were successfully implanted in 18 Chinese rural dogs, 2 of which died within 48 hours after operation due to pericardial tamponade and hemorrhage, respectively. Follow-up observation was performed after transcatheter LAA closure. New tissue was found on the surface of the occluder 2 months after operation. No adjacent structures such as the mitral valve and the left superior pulmonary vein were affected by the occluder discs. Hematoxylin and eosin (HE) staining was performed at 3 months after operation, which showed intact intimal structure on the occluder surface, and unabsorbed PDO and PLA were observed. Scanning electron microscopy showed irregular arrangement of endothelial cells. New endothelial tissue was observed to completely cover the occluder at 6 months after operation. Most PDOs were replaced by fibrous connective tissue, and scanning electron microscopy showed regularly arranged endothelial cells. Pathological examination at 12 months showed only a small remnant of PDO. The gross specimens of the liver, spleen, and kidneys and pathological examination did not indicate thromboembolism.The bioabsorbable LAA occluder made of PDO, PLA, and nitinol wire was safe and effective for the occlusion of LAA in dogs. The surface of the occluder was endothelialized half a year after operation. The absorbable materials of the occluder were degraded after 1 year.

Two series of heterocyclic steroidal pyrazolo[1,5-a]pyrimidines derived from dehydroepiandrosterone (DHEA) and epiandrosterone (EPIA) were designed and synthesized, and these compounds were screened for their potential antiproliferation activities. The preliminary bioassay indicated that some of target compounds exhibited significantly good antiproliferation activities against human melanoma cell line (A875) and human hepatocellular carcinoma (Huh-7) cell lines compared with 5-fluorouracil (5-FU), and some of which present good antiproliferative activities as potential ALK inhibitors. The detailed analysis of structure-activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5-a]pyrimidine might be affected by the β-hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, CDK9/CyclinT1, CDK5/P25, PIM2, CDK2/CyclinA2, CDK1/CyclinB1, etc., and which displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63 % at the concentration of 10 μM, which induced cell death in A875 cells at least partly (initially), by apoptosis., 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 Elsevier Inc. All rights reserved.)

Individuals with genetic elimination of MLKL (mixed lineage kinase domain like pseudokinase) exhibit an increased susceptibility to neurodegenerative diseases like Alzheimer disease (AD). However, the mechanism is not yet fully understood. Here, we observed significant compromise in macroautophagy/autophagy in the brains of mlkl knockout (KO) mice, as evidenced by the downregulation of BECN1/Beclin1 and ULK1 (unc-51 like autophagy activating kinase 1). We identified UBA52 (ubiquitin A-52 residue ribosomal protein fusion product 1) as the binding partner of MLKL under physiological conditions. Loss of Mlkl induced a decrease in ubiquitin levels by preventing UBA52 cleavage. Furthermore, we demonstrated that the deubiquitinase (DUB) USP7 (ubiquitin specific peptidase 7) mediates the processing of UBA52, which is regulated by MLKL. Moreover, our results indicated that the reduction of BECN1 and ULK1 upon Mlkl loss is attributed to a decrease in their lysine 63 (K63)-linked polyubiquitination. Additionally, single-nucleus RNA sequencing revealed that the loss of Mlkl resulted in the disruption of multiple neurodegenerative disease-related pathways, including those associated with AD. These results were consistent with the observation of cognitive impairment in mlkl KO mice and exacerbation of AD pathologies in an AD mouse model with mlkl deletion. Taken together, our findings demonstrate that MLKL-USP7-UBA52 signaling is required for autophagy in brain through maintaining ubiquitin homeostasis, and highlight the contribution of Mlkl loss-induced ubiquitin deficits to the development of neurodegeneration. Thus, the maintenance of adequate levels of ubiquitin may provide a novel perspective to protect individuals from multiple neurodegenerative diseases through regulating autophagy. Abbreviations : 4HB: four-helix bundle; AAV: adeno-associated virus; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; APOE: apolipoprotein E; APP: amyloid beta precursor protein; Aβ: amyloid β; BECN1: beclin 1; co-IP: co-immunoprecipitation; DEGs: differentially expressed genes; DLG4: discs large MAGUK scaffold protein 4; DUB: deubiquitinase; EBSS: Earle's balanced salt solution; GFAP: glial fibrillary acidic protein; HRP: horseradish peroxidase; IL1B: interleukin 1 beta; IL6: interleukin 6; IPed: immunoprecipitated; KEGG: Kyoto Encyclopedia of Genes and Genomes; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MLKL: mixed lineage kinase domain like pseudokinase; NSA: necrosulfonamide; OPCs: oligodendrocyte precursor cells; PFA: paraformaldehyde; PsKD: pseudo-kinase domain; SYP: synaptophysin; UB: ubiquitin; UBA52: ubiquitin A-52 residue ribosomal protein fusion product 1; UCHL3: ubiquitin C-terminal hydrolase L3; ULK1: unc-51 like autophagy activating kinase 1; UMAP: uniform manifold approximation and projection; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; USP9X: ubiquitin specific peptidase 9 X-linked.

mRNA vaccines have shown great potential in responding to emerging infectious diseases, with their efficacy and stability largely dependent on the delivery vehicles-lipid nanoparticles (LNPs). This study aims to explore the mechanisms by which LNPs encapsulate mRNA, as well as the effects of different N/P ratios and acid types in nucleic acid solutions on the structure and properties of LNPs, using the ethanol solvent injection method as the encapsulation technique. Six systems were designed, based on the composition and proportions of the existing mRNA vaccine mRNA-1273, and molecular dynamics (MD) simulations were employed to investigate the self-assembly process of LNPs. Ethanol was used as a solvent instead of pure water to better mimic experimental conditions. The results indicate that lipid components self-assemble into nanoparticles under neutral conditions, with the ionizable lipid SM-102 predominantly concentrating in the core of the particles. Upon mixing with nucleic acids in acidic conditions, LNPs undergo disassembly, during which protonated SM-102 encapsulates mRNA through electrostatic interactions, forming stable hydrogen bonds. Cluster structure analysis revealed that the four lipid components of LNPs are distributed sequentially from the outside inwards as DMG-PEG 2000, DSPC, cholesterol, and protonated SM-102. Moreover, LNPs constructed under low pH or low N/P ratios using citric acid exhibited larger volumes and more uniform distribution. These findings provide a scientific basis for further designing and optimizing LNP components to enhance the efficacy of mRNA vaccine encapsulation.

Zinc metal batteries have recently emerged as a promising stable and reversible anode aqueous battery. However, due to the serious dendrite problem and hydrogen evolution problem of the zinc metal anode, the practical application of the zinc metal battery is limited. Here, we propose Y 2 O 3 as an effective coating, which inhibits hydrogen evolution and side reactions by physical isolation and simultaneously prevents dendrite growth by ensuring a uniform Zn-ion flux and fast transport channels generated by Maxwell-Wagner polarization, thus improving the stability of batteries. Meanwhile, in situ/ex situ characterizations and different simulations are conducted to investigate in detail the effect of Maxwell-Wagner polarization on the performance of Zn metal batteries. The symmetric Y 2 O 3 @Zn anode system exhibits a stable electroplating/stripping performance over 780 h and enables the Zn battery to achieve a Coulombic efficiency of up to 99.81% over 1000 cycles by reducing side reactions. The Y 2 O 3 @Zn||MnO 2 full cell delivers a high energy density of 301.42 Wh kg -1 at a power density of 205.04 W kg -1 . The work provides insights into the reversibility and stability of zinc anodes and provides a promising way to promote the practical application of Zn metal batteries.

Background: The relationship between human gut microbiota and high-altitude hypoxia acclimatization remains highly controversial. This stems primarily from uncertainties regarding both the potential temporal changes in the microbiota under such conditions and the existence of any dominant or core bacteria that may assist in host acclimatization., Results: To address these issues, and to control for variables commonly present in previous studies which significantly impact the results obtained, namely genetic background, ethnicity, lifestyle, and diet, we conducted a 108-day longitudinal study on the same cohort comprising 45 healthy Han adults who traveled from lowland Chongqing, 243 masl, to high-altitude plateau Lhasa, Xizang, 3658 masl, and back. Using shotgun metagenomic profiling, we study temporal changes in gut microbiota composition at different timepoints. The results show a significant reduction in the species and functional diversity of the gut microbiota, along with a marked increase in functional redundancy. These changes are primarily driven by the overgrowth of Blautia A, a genus that is also abundant in six independent Han cohorts with long-term duration in lower hypoxia environment in Shigatse, Xizang, at 4700 masl. Further animal experiments indicate that Blautia A-fed mice exhibit enhanced intestinal health and a better acclimatization phenotype to sustained hypoxic stress., Conclusions: Our study underscores the importance of Blautia A species in the gut microbiota's rapid response to high-altitude hypoxia and its potential role in maintaining intestinal health and aiding host adaptation to extreme environments, likely via anti-inflammation and intestinal barrier protection., (© 2024. The Author(s).)

Consolidation strategies for primary central nervous system lymphoma (PCNSL) after induction chemoimmunotherapy include whole-brain radiotherapy (≤24Gy reduced-dose [RD], >24Gy standard-dose [SD] WBRT) and cytarabine, non-myeloablative chemotherapy (NMC), or autologous hematopoietic cell transplantation (AHCT); however, comparative outcomes are lacking. PCNSL outcomes from 1983-2020 were stratified by decade and MSKCC recursive partitioning analysis (RPA) class. Clinicodemographic associations with consolidation were analyzed by multinomial logistic regression. Progression-free (PFS) and overall survival (OS) were analyzed by proportional hazards from consolidation. Of 559 patients, 385 (69%) were consolidated. Median follow-up and OS were 7.4 and 5.7 years, respectively. WBRT use declined (61% in 1990s vs. 12% in 2010s), while AHCT (4% in 1990s vs. 32% in 2010s) and NMC (27% in 1990s vs. 52% in 2010s) rose. Compared to RPA 1 (age<50), RPA 2 (age≥50, KPS≥70) was more likely to receive NMC. Those with partial response to induction were less likely to receive AHCT (OR 0.36, p=0.02). Among 351 with complete response to consolidation, only receipt of R-MPV induction was associated with improved PFS (HR 0.5, p=0.006). Among RPA 1, median PFS and OS were not reached for AHCT or RD-WBRT, vs. 2.5 and 13.0 years, respectively, after NMC. Among RPA class 3 (KPS<70), median PFS and OS post-RD-WBRT were 4.6 and 10 years, respectively, vs. 1.7 and 4.4 years post-NMC. No significant adjusted survival differences were seen across consolidation strategies. NMC is increasingly used in lieu of RD-WBRT despite a trend toward less favorable PFS. RD-WBRT can be considered in patients ineligible for AHCT., (Copyright © 2024 American Society of Hematology.)

Background/aims: After 9/11, multiple government agencies instituted programs aimed at developing medical radiation countermeasures (MRCs) for two syndromes lethal within weeks of a limited nuclear attack; the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS). While re-purposing drugs that enhance marrow repopulation treats H-ARS, no mitigator protects GI tract., Methods: We recently reported anti-ceramide 6B5 single-chain variable fragment (scFv) pre-treatment abrogates ongoing small intestinal endothelial apoptosis to rescue Lgr5 + stem cells, preventing GI-ARS lethality in C57B/L6J mice. Here, with US Department of Defense support, we provide evidence that humanized anti-ceramide scFv (CX-01) is a promising prophylactic MRC for first responders, who risk exposure upon entering a radiation-contaminated site., Results: CX-01, when delivered up to 90 min before irradiation, is highly-effective in preventing small intestinal endothelial apoptosis in mice and lethality in both sexes. Unexpectedly, females require an ~2-fold higher CX-01 dose than males for full protection. CX-01 is effective subcutaneously and intramuscularly, a property critical for battlefield use. Increasing the maximally-effective dose 5-fold does not extend duration of bioeffectiveness., Conclusion: While CX-01 prevents GI-ARS lethality, structural modification to extend half-life may be necessary to optimize first responder prophylaxis., Competing Interests: RK holds the following patents: US7195775B1, US7850984B2, and US10052387B2, US10414533B2, US20140205543A1, US8562993B2, US9592238B2, US10450385B2, US20150216971A1, US20170335014A1, US20190389970A1, and US20190046538A1; RK and ZF hold the following patents: US20170333413A1 and US20180015183A1); ZF holds the following patent: US10413533B2. RK and ZF are co-founders of Ceramedix Holding LLC., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Background: Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS)., Objective: To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort., Design, Setting, and Participants: A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021., Intervention: SRS for RCC BMs., Outcome Measurements and Statistical Analysis: Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death., Results and Limitations: Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041)., Conclusions: To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting., Patient Summary: We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: A retrospective single-center analysis of the safety and efficacy of reirradiation to 40 Gy in 5 fractions (reSBRT) in patients previously treated with stereotactic body radiotherapy to the spine was performed., Methods: We identified 102 consecutive patients treated with reSBRT for 105 lesions between 3/2013 and 8/2021. Sixty-three patients (61.8%) were treated to the same vertebral level, and 39 (38.2%) to overlapping immediately adjacent levels. Local control was defined as the absence of progression within the treated target volume. The probability of local progression was estimated using a cumulative incidence curve. Death without local progression was considered a competing risk., Results: Most patients had extensive metastatic disease (54.9%) and were treated to the thoracic spine (53.8%). The most common regimen in the first course of stereotactic body radiotherapy was 27 Gy in 3 fractions, and the median time to reSBRT was 16.4 months. At the time of simulation, 44% of lesions had advanced epidural disease. Accordingly, 80% had myelogram simulations. Both the vertebral body and posterior elements were treated in 86% of lesions. At a median follow-up time of 13.2 months, local failure occurred in 10 lesions (9.5%). The 6- and 12-month cumulative incidences of local failure were 4.8% and 6%, respectively. Seven patients developed radiation-related neuropathy, and 1 patient developed myelopathy. The vertebral compression fracture rate was 16.7%., Conclusion: In patients with extensive disease involvement, reSBRT of spine metastases with 40 Gy in 5 fractions seems to be safe and effective. Prospective trials are needed to determine the optimal dose and fractionation in this clinical scenario., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: Ultrahypofractionated stereotactic body radiation therapy (SBRT) has become a standard treatment intervention for localized prostate cancer., Objective: To report final long-term tumor control outcomes and late gastrointestinal (GI) and genitourinary (GU) toxicities from a single-center phase 1 dose escalation study using SBRT for patients with low- or intermediate-risk prostate cancer., Design, Setting and Participants: Between 2009 and 2012, 136 patients were enrolled and treated. The initial dose level was 32.5 Gy in five fractions. Doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy in five fractions delivered every other day., Outcome Measurements and Statistical Analysis: The primary endpoint was late treatment-related toxicity. Secondary endpoints included prostate-specific antigen (PSA) failure., Results and Limitations: The median follow-up was 10.5 yr for the 32.5-Gy group, 9.9 yr for the 35-Gy group, 8.2 yr for the 37.5-Gy group, and 7.3 yr for the 40-Gy group. The 8-yr cumulative incidence of PSA failure was 26% for 32.5 Gy, 15% for 35 Gy, 3.4% for 37.5 Gy, and 6.6% for 40 Gy. Higher radiation dose (37.5-40 Gy) and favorable intermediate risk (vs unfavorable intermediate risk) were associated with better PSA recurrence rates (p = 0.011 and 0.002, respectively). The 8-yr actuarial probability rates for survival free from late grade ≥2 toxicity were 94% for GI toxicity and 86% for GU toxicity. No grade 4 events were recorded. Higher dose levels were not associated with higher rates of late grade ≥2 GI (p = 0.2) or GU (p > 0.9) toxicity., Conclusions: SBRT doses ranging from 32.5 to 40 Gy were associated with low incidence of moderate or severe toxicities. Higher doses resulted in superior disease control outcomes 8 yr after treatment., Patient Summary: We investigated the association between the radiotherapy dose used and the rate of control of prostate cancer. We found that higher doses resulted in more favorable outcomes without excess toxicity. This trial is registered on ClinicalTrials.gov as NCT00911118., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: (1) To describe existing tools to assess the burden of informal caregivers of people with cancer, (2) to describe how these tools have been validated and (3) to describe the areas of interest of existing assessment tool entries., Background: The caregiver burden of informal caregivers of people with cancer greatly affects their lives. There is a wide variety of relevant assessment tools available, but there are no studies to help researchers to select tools., Methods: A search was conducted using the keywords 'cancer', 'caregiver', 'burden' and 'scale' in Medline (PubMed), CINAHL and EMBASE to include articles that developed or applied tools to assess the burden on informal caregivers of cancer patients. Once eligible tools were identified, we searched their 'primary reference' studies. If the original scale was assessed in a population other than informal caregivers of cancer patients, we again searched for psychometric measures in the population of caregivers of cancer patients., Results: This study retrieved 938 articles on developing or applying the informal caregiver burden instrument for cancer patients, including 42 scales. Internal consistency of the original scales ranged from 0.53 to 0.96. Nineteen scales initially developed to assess caregiver burden for patients with dementia, stroke and other disorders were later used for caregivers of cancer patients, eight of which have not yet been validated. Reclassifying all scale domains of concern revealed that scale assessments focused more on caregivers' physical health, emotional state and caregiving tasks., Conclusion: This review identifies many scales for assessing informal caregiver burden in cancer patients and gives scales recommended. However, a portion still needs to be validated. The development of a new scale proposes to be based on a theoretical framework and to consider dimensions for assessing support resources., Impact: What problem did the study address?: This paper collates assessment tools on the burden of informal carers of people with cancer. It also provides information on the applicable population, reliability and validity. What were the main findings?: 41 scales could be considered for use, eight of which have not been validated. The scales focus more on assessing caregivers' physical health, emotional state and caregiving tasks, and less on the dimension of support resources. Where and on whom will the research have an impact?: There are implications for informal carers of cancer patients in hospitals or in the community, as well as for relevant researchers., Reporting Method: Retrieved with reference to systematic evaluation., Patient or Public Contribution: No patient or public contribution., (© 2024 John Wiley & Sons Ltd.)

Cisplatin is widely employed in clinical oncology as an anticancer chemotherapy drug in clinical practice and is known for its severe ototoxic side effects. Prior research indicates that the accumulation of reactive oxygen species (ROS) plays a pivotal role in cisplatin's inner ear toxicity. Hesperidin is a flavanone glycoside extracted from citrus fruits that has anti-inflammatory and antioxidant effects. Nonetheless, the specific pharmacological actions of hesperidin in alleviating cisplatin-induced ototoxicity remain elusive. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical mediator of the cellular oxidative stress response, is influenced by hesperidin. Activation of Nrf2 was shown to have a protective effect against cisplatin-induced ototoxicity. The potential of hesperidin to stimulate Nrf2 in attenuating cisplatin's adverse effects on the inner ear warrants further investigation. This study employs both in vivo and in vitro models of cisplatin ototoxicity to explore this possibility. Our results reveal that hesperidin mitigates cisplatin-induced ototoxicity by activating the Nrf2/NQO1 pathway in sensory hair cells, thereby reducing ROS accumulation, preventing hair cell apoptosis, and alleviating hearing loss.

Background: Cutaneous metastases (CMs) are a manifestation of advanced cancer and can be treated with oncolytic immunotherapy. Laboratory studies suggest radiotherapy (RT) may facilitate response to immunotherapy. We hypothesized that oncolytic immunotherapy with talimogene lapherparepvec (T-VEC, an oncolytic immunotherapy that expresses granulocyte-macrophage colony stimulating factor) and RT would produce response in non-targeted metastases., Methods: A randomized phase 2 trial of T-VEC+/-RT was conducted. Eligible patients had ≥1 CM from a solid tumor amenable to T-VEC and RT and another measurable metastasis. Tumor and overall response was assessed using modified World Health Organization (mWHO) criteria. Adverse events (AEs) and quality of life (QOL) were characterized using CTCAE v4.0 and Skindex-16, respectively. Correlative analyses of tumor genomics and the immune system were performed., Results: 19 patients were randomized to receive T-VEC (n = 9) or T-VEC+RT (n = 10). One patient in each arm demonstrated complete response in the largest non-targeted metastasis. The trial was closed after the first stage of enrollment because of no overall mWHO responses, slow accrual and the COVID-19 pandemic. AEs were consistent with prior reports of T-VEC. Skin related QOL was poor before and after treatment. Median progression free survival was 1.2 and 2.5 months in the T-VEC and T-VEC+RT arms; median overall survival was 4.9 and 17.3 months in the T-VEC and T-VEC+RT arms. Analyses of peripheral blood cells and cytokines demonstrated responders exhibited several outlying lymphocyte and cytokine parameters., Conclusions: Low overall response rate, slow accrual, and the COVID-19 pandemic led to closure of this trial. Responses in non-injected and non-irradiated metastases were infrequent., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [CAB reports honoraria from Regeneron, his institution receives research funding for clinical trials from Regeneron, EMD Serono, Physical Sciences Incorporated, Amgen, Elekta, Melanoma and Skin Cancer Trials Limited, Merck, Alpha Tau Medical and the University of California San Francisco, and he has received support to attend meetings from the National Comprehensive Cancer Network, University of Washington, and the National Cancer Institute. SPD reports personal fees from Aadi bioscience, Adaptimmune, GI innovation, GSK, Pfizer, and Servier outside the submitted work. MEL has a consultant role with Johnson and Johnson, Novocure, Janssen, Novartis, Deciphera, Kintara, RBC/La Roche Posay, Trifecta, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Roche, Oncoderm, Apricity and research funding from Lutris, Paxman, Novocure, OQL, Novartis and AZ, all outside the submitted work. PBC reports honoraria or personal fees from BMS, GlaxoSmithKline, Genentech/Roche, Provectus, Momenta Pharmaceuticals, Daiichi Sankyo, Merck, Pfizer, Genentech, Takeda, Vanium Group, and Scancell. Consulting or Advisory board: BMS, GlaxoSmithKline, Genentech/Roche, Daiichi Sankyo, Provectus, Momenta Pharmaceuticals, LICR Research, Merck, Immunocore, Cell Medica, Takeda Millennium, Rgenix, Scancell, AstraZeneca, Black Diamond Therapeutics, and Pfizer. Presentations for Medscape. Ownership/equity interests in Molecular MD Corp and Rgenix. Research funding from Pfizer, NCI, and Genentech. ANS reports personal fees from BMS, Immunocore, and Novartis; institutional grant support from BMS, Immunocore, Novartis, Pfizer, AstraZeneca, Xcovery, Checkmate Pharmaceuticals, and Polaris. CA reports consulting fees from Iovance.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Several data sets have demonstrated a correlation between lymphovascular invasion (LVI) and locoregional recurrence (LRR). Whether the observation of "extensive LVI" is a further and incremental determinant of LRR risk is unknown. We describe clinical outcomes in women with invasive breast cancer stratified by (1) absence of LVI (neg), (2) LVI focal or suspicious (FS-LVI), (3) usual (nonextensive) LVI (LVI), and (4) extensive LVI (E-LVI)., Methods and Materials: Between December 2009 and August 2021, 8837 patients with early-stage breast cancer were treated with curative intent and were evaluable. Clinical-pathologic details were abstracted by retrospective review. The description of LVI was abstracted from pathology reports. Recurrence and survival outcomes were compared based on the extent of LVI. A matched propensity score analysis compared outcomes between patients with LVI versus E-LVI., Results: Of the 8837 patients studied, 5584 were negative, 461 had FS-LVI, 2315 had LVI, and 477 had E-LVI. Patients with E-LVI had an adverse risk profile compared with the other groups. The 5- and 10-year LRR cumulative incidence estimates in patients with E-LVI were 9.6% (95% CI, 7.1-13) and 13% (95% CI, 10-17), respectively, which were significantly higher than those observed in the usual LVI group (6.8% [5.7-7.9] and 10% [8.8-12], respectively). A statistically significant difference in LRR was demonstrated in univariable (HR, 1.4; 95% CI, 1.03-1.89; P = .029) and multivariable regression analysis (HR, 1.62; 95% CI, 1.15-2.27; P = .005) compared with nonextensive LVI. In an alternative approach, we performed a 2:1 propensity score matching analysis comparing patients with LVI to those with E-LVI. The hazard ratio for LRR (HR, 1.47; CI 1.02-2.14; P = .041) was suggestive of a higher risk associated with E-LVI., Conclusions: Our work suggests that patients with E-LVI are at a higher risk for LRR than those with usual LVI. For patients who are borderline candidates for regional nodal irradiation or post-mastectomy radiation therapy, the finding of E-LVI might be decisive in favor of intensified treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metabolic dysfunction-associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet-fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.

Purpose: Regional nodal irradiation (RNI) for breast cancer yields improvements in disease outcomes, yet comprehensive target coverage often increases cardiac radiation therapy (RT) dose. Volumetric modulated arc therapy (VMAT) may mitigate high-dose cardiac exposure, although it often increases the volume of low-dose exposure. The cardiac implications of this dosimetric configuration (in contrast to historic 3D conformal techniques) remain uncertain., Methods and Materials: Eligible patients receiving adjuvant RNI using VMAT for locoregional breast cancer were prospectively enrolled in an IRB-approved study. Echocardiograms were performed prior to RT, at the conclusion of RT, and 6 months following RT. Echocardiographic parameters were measured by a single reader and measures were compared pre- and post-RT via the signed-rank test. Changes in echocardiographic parameters over time were compared to mean and max heart doses via the Spearman correlation test., Results: Among 19 evaluable patients (median age 38 years), 89% (n = 17) received doxorubicin and 37% (n = 7) received trastuzumab/pertuzumab combination therapy. All patients received VMAT-based whole-breast/chest wall and RNI. The average mean heart dose was 456 cGy (range, 187-697 cGy) and the average max heart dose was 3001 cGy (1560-4793 cGy). Among salient echocardiographic parameters, no significant decrement in cardiac function was observed when comparing pre-RT to 6 months post-RT: mean left ventricular ejection fraction (LVEF) was 61.8% (SD 4.4%) pre-RT and 62.7% (SD 3.8%) 6 months post-RT ( P = .493); mean global longitudinal strain (GLS) was -19.3% (SD 2.2%) pre-RT and -19.6% (SD 1.8%) 6 months post-RT ( P = .627). No individual patient exhibited reduced LVEF or sustained decrement in GLS. No correlations were observed for changes in LVEF or GLS when compared to mean or maximum heart doses ( P > .1 for all)., Conclusions: VMAT for left-sided RNI yielded no significant early decrement in echocardiographic parameters of cardiac function, including LVEF and GLS, within this limited cohort. No patient exhibited significant LVEF changes, and none exhibited sustained decrements in GLS. VMAT may be a reasonable approach to cardiac avoidance in patients requiring RNI, including those receiving anthracyclines and HER2-directed therapy. Larger cohorts with longer follow-ups will be needed to validate these findings., Competing Interests: The authors have no relevant conflicts of interest to disclose., (© 2024 The Author(s).)

Liver disease has become an important risk factor for global health. Resveratrol (Res) is a natural polyphenol which is widely found in foods and has a variety of biological activities. This study investigated the role of the microbiota-gut-liver axis in the Res relieving the liver fibrosis induced by inorganic mercury exposure. Twenty-eight mice were divided into four groups ( n = 7) and treated with mercuric chloride and/or Res for 24 weeks, respectively. The results showed that Res mitigated the ileum injury induced by inorganic mercury and restrained LPS and alcohol entering the body circulation. Network pharmacological and molecular analyses showed that Res alleviated oxidative stress, metabolism disorders, inflammation, and hepatic stellate cell activation in the liver. In conclusion, Res alleviates liver fibrosis induced by inorganic mercury via activating the Sirt 1/ PGC -1α signaling pathway and regulating the microbial-gut-liver axis, particularly, increasing the relative enrichment of Bifidobacterium in the intestinal tract.

Background: Osteoporotic vertebral compression fractures (OVCF) may necessitate percutaneous vertebral augmentation (PVA), a procedure not without its risks. One notable complication is cement leakage (CL), which can cause significant distress in patients. Despite its clinical importance, there remains a paucity of meta-analyses investigating these complications and their management in the existing literature., Material and Methods: We systematically reviewed PubMed, Cochrane Library, Embase, and Web of Science databases up to February 2024 to identify studies examining CL following PVA treatment in OVCF. We assessed the quality of eligible cohort studies using the Newcastle-Ottawa Scale (NOS), extracted data on incidence, identified risk factors for CL, and conducting meta-analysis with Revman 5.2 software. We calculated odd ratios (OR) and Mean Differences (MD) with 95% confidence interval (CI) applying random effects models., Results: We identified twelve cohort studies that matched our strict inclusion criteria. These studies included a total of 2388 patients and 3392 vertebrae. CL was identified in 1132 vertebrae. Notable risk factors for CL included compromised cortical bone integrity (OR 5.00, 95% CI 3.01~8.29, P<0.00001), presence of intravertebral vacuum clefts (OR 1.68, 95% CI 1.07~2.65, P=0.03), basivertebral foramen sign (OR 1.77, 95% CI 1.09~2.89, P=0.02), and volume of cement used (MD 0.75, 95% CI 0.41~1.10, P<0.0001)., Conclusion: Our findings underscore the significance of cortical bone integrity, intravertebral vacuum cleft, basivertebral foramen sign, and cement volume as principal determinants of CL risk in PVA for OVCF. These insights advocate for tailored surgical strategies to mitigate the risk of CL in this patient population., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLA WFS1 neurons' NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders., Competing Interests: Declaration of interests L.W. is a member of the advisory board for Neuron., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To explore the risk factors and predictive effects of visceral pleural invasion in lung adenocarcinoma patients with mGGN type, in order to identify high-risk groups of visceral pleural invasion early, and to provide more references for targeted intervention and individualized treatment adjustment of high-risk groups based on the analysis of risk factors., Methods: The clinical data of 135 patients with mGGN-type lung adenocarcinoma who received surgical treatment in our hospital from January 2018 to December 2022 were selected from our hospital's medical record database for retrospective analysis. The patient information was entered by a two-person summary and analyzed after verification.The patients were divided into invasion group (60 cases) and non-invasion group (75 cases) according to the invasion of pleural viscera, which was helpful to analyze the difference of clinical features between the two groups. The independent risk factors for visceral pleural invasion in patients with mGGN lung adenocarcinoma were evaluated using univariate and multivariate factor methods, and receiver operating characteristic (ROC) curves were drawn to evaluate the clinical efficacy of these risk factors above alone and in combination in predicting of visceral pleural invasion risk. The larger the area under ROC curve, the higher the corresponding sensitivity and specificity, and the greater the predictive value for the risk of visceral pleural invasion in mGGN lung adenocarcinoma patients., Results: Univariate analysis showed that gender, family history of hypertension, location of focus, maximum diameter of solid component, proportion of solid component, pleural indentation, burr sign, bronchial and nodular route may be related to visceral pleural invasion in lung adenocarcinoma patients with mGGN type (P < .05). Multivariate Logistic regression analysis showed that pleural indentation (OR=2.49, 95%CI:1.17~4.58, P < .001) and abnormal broncho-nodular travel (OR=3.06, 95%CI: 1.35~7.02, P = .01) were the independent risk factors for visceral pleural invasion in lung adenocarcinoma patients with mGGN type (P < .05). ROC curve analysis results showed that pleural indentation (AUC=0.70, 95%CI: 0.65~0.79, P = .02), abnormal bronchial and nodular running relationship (AUC=0.74, 95%CI: 0.69~0.81, P = .01) could both be used to predict the visceral pleural invasion risk in lung adenocarcinoma patients with mGGN type, and combined prediction efficacy of both indexes (AUC=0.90, 95%CI: 0.85~0.97, P < .001) was better than single index., Conclusion: The occurrence of visceral pleural infiltration in patients with mGGN lung adenocarcinoma is related to the relationship between pleural indentation and bronchus and nodules. Combined with the above indicators, the risk of visceral pleural infiltration in patients can be effectively predicted, and early intervention and treatment can be performed on high-risk patients accordingly to effectively prevent and treat visceral pleural infiltration.

Fluidized bed reactor can enhance mass transfer and increase reaction rate. Numerical simulation helps to optimize fluidized bed reactors. The present paper models the photocatalytic oxidation of 2,4-dichlorophenoxy acetic acid in a fluidized bed reactor using the Eulerian-Eulerian model. The drag models have influences on the distribution of catalysts particles. The bed expands under the fluid flow and reaches a quasi-steady height at approximately 3s. The asymmetric distribution of catalysts with respect to the axis plane is predicted. The Gidaspow model predicts the nearly same bed expansion with the experimental data, whereas the Syamlal-O ' Brien model overestimates it. The simulation results at two pH values are in accordance with the experimental data. The removal in the continuous stirred tank reactor decreases with the increase in flow rate., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP., Materials and Methods: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes., Results: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036)., Conclusion: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AR previously consulted for Boehringer Ingelheim. CMR has consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros, and serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. DRJ has consulted for AstraZeneca and serves on the clinical trial steering committee for Merck. All other authors declare no competing interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Object: Chronic otitis media (COM) is an inflammatory disease that commonly presents with otorrhea and hearing loss. Bacteria-induced inflammation can cause inner ear damage, leading to sensorineural hearing loss (SNHL). This study aimed to compare the prevalence and severity of SNHL in patients with gram-negative versus gram-positive cultures and examine associations between the concentrations of circulating monocytes and neutrophils with bacteria species and SNHL., Methods: This was a retrospective study. Cholesteatoma or chronic suppurative otitis media patients with otorrhea were enrolled. Middle ear secretions were collected using sterile swabs under an otoscope, and sent for bacterial detection within 30 min. Pure tone audiometry and circulating leukocyte counts were recorded and analyzed in patients infected with different pathogens. Logistic regression analysis was used to identify the risk factors associated with SNHL., Results: A total of 137 patients were enrolled, including 45 patients infected with gram-negative bacteria, 41 with gram-positive bacteria, 20 with polymicrobial infection, and 31 with no bacterial growth. Logistic regression analysis showed that bacterial culture positive infections (OR = 7.265, 95% CI 2.219-23.786, p = 0.001) were an independent risk factor for SNHL. Patients with gram-negative bacteria had higher risks of SNHL (p < 0.0001) and more severe hearing loss (p = 0.005) than those with gram-positive bacteria. COM patients infected with gram-negative bacteria showed an increase in circulating monocytes, which correlated with the occurrence of SNHL (p = 0.0343)., Conclusion: Gram-negative bacteria are associated with elevated circulating monocyte counts and have a higher risk of severe SNHL., Level of Evidence: 4 Laryngoscope, 134:3335-3341, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase 1 trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3 cm., Methods and Materials: A 3 + 3 dose-escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3 cm (T2-4) were eligible. Select ipsilateral hilar and single-station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute grade (G) 4+ or persistent G3 toxicities (Common Terminology Criteria for Adverse Events version 4.03). Secondary endpoints included local failure (LF), distant metastases, disease progression, and overall survival., Results: The median age was 80 years; tumor size was >3 cm and ≤5 cm in 20 (59%) and >5 cm in 14 patients (41%). In cohort A (n = 9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose-expansion cohort B (n = 25), no radiation therapy-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year overall survival was 53%. A biologically effective dose (BED) <100 Gy was associated with higher LF (P = .006); advanced stage and higher neutrophil/lymphocyte ratio were associated with greater disease progression (both P = .004)., Conclusions: Fifty Gy in 5 fractions is the MTD for SBRT to tumors >3 cm. A higher BED is associated with fewer LFs even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Short stature is one of the most prevalent endocrine disorders in children, and its genetic basis is a complex and actively researched subject. Currently, there is limited genetic research on exome sequencing for short stature, and more large-scale studies are necessary for further exploration., Methods: The retrospective study entailed investigation of 98 Chinese children with short statures (height SDS ≤ -2.5) of unknown etiologies recruited between 2017 and 2021. Whole-exome sequencing (WES) was performed on these patients to identify the potential genetic etiologies. The clinical data were reviewed retrospectively to assess the pathogenicity of the identified mutations. Additionally, 31 patients consented to and received recombinant human growth hormone (rhGH) therapy for 12 months. The short-term effects of rhGH treatment were evaluated across different etiologies of patients with short statures., Results: The WES results were used to identify 31 different variants in 18 genes among 24 (24.5%) patients. Individuals with more severe short statures were more likely to have underlying genetic etiologies. Short stature accompanied by other phenotypes had significantly higher diagnostic yields than simple severe short stature. The rhGH therapy demonstrated efficacy in most children. Nevertheless, the treatment response was suboptimal in a boy diagnosed with 3M syndrome., Conclusion: WES is an important approach for confirming genetic disorders in patients with severe short statures of unknown etiologies, suggesting that it could be used as a primary diagnostic strategy. The administration of rhGH may not be suitable for all children with short statures, and the identification of the genetic cause of short stature by WES has significant guidance value for rhGH treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fang, Li, Zhang, Cai, Wang, Yu, Hu and Ye.)

Ultra-high molecular weight polyethylene/graphene oxide (PE-UHMW/GO) composites have demonstrated potential in artificial joint applications. The tribological behavior of irradiated PE-UHMW/GO composites under water lubrication remained unclear, which limited their application range. In this study, the PE-UHMW/GO composites were gamma irradiated at 100 KGy in a vacuum and subsequently aged at 80 °C for 21 days in air. We assessed their water absorption, and mechanical and tribological properties post-treatment. Notably, gamma irradiation markedly enhanced the mechanical and tribological performance of PE-UHMW/GO composites. Irradiated composites had a 6.11% increase in compressive strength and a 25.72% increase in yield strength compared to unirradiated composites. Additionally, under water lubrication, the irradiated composites showed improved wear resistance and a reduced friction coefficient. The irradiation enhancement can be attributed to the irradiation-induced strengthening of the interface bonding between GO and PE-UHMW. Conversely, accelerated aging led to oxidative degradation, negatively impacting these properties. Aged composites exhibited lower compressive and yield strengths, higher friction coefficients, and diminished anti-wear properties compared to the irradiated composites. The wear mechanism evolved from predominantly fatigue wear in irradiated PE-UHMW/GO to a mix of abrasive and fatigue wear post-aging. While GO and aging influenced water absorption, irradiation had a minimal effect. These insights significantly contribute to the application potential of irradiated PE-UHMW/GO composites in artificial joints., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Ovarian cancer is one of the most common gynecological malignant tumors with insidious onset, strong invasiveness, and poor prognosis. Metabolic alteration, particularly aerobic glycolysis, which is tightly regulated by transcription factors, is associated with the malignant behavior of OC. We screened FOXK2 in this study as a key transcription factor that regulates glycolysis in OC. FOXK2 is overly expressed in OC, and poor prognosis is predicted by overexpression. FOXK2 promotes OC cell proliferation both in vitro and in vivo and cell migration in vitro. Further studies showed that PDK2 directly binds to the forkhead-associated (FHA) domain of FOXK2 to phosphorylate FOXK2 at Thr13 and Ser30, thereby enhancing the transcriptional activity of FOXK2. FOXK2 transcriptionally regulates the expression of PDK2, thus forming positive feedback to sustain glycolysis in OC cells., (© 2024. The Author(s).)

Background: Although there are many reasons for extubation failure, maintaining negative or lower positive fluid balances 24 hours before extubation may be a key measure for successful extubation., Aim: To assess the predictive value of fluid balance before extubation and its outcome in mechanically ventilated cases in the intensive care unit (ICU)., Study Design: This retrospective cohort study involved collecting clinical data from patients undergoing mechanical ventilation in Lanzhou general adult ICU from January 2022 to December 2022. Based on extubation outcomes, the patients were divided into a successful extubation group and a failed extubation group. Their fluid balance levels 24 h before extubation were compared with analyse the predictive value of fluid balance on extubation outcomes in patients undergoing mechanical ventilation., Results: In this study, clinical data from 545 patients admitted to a general adult ICU were collected. According to the inclusion and exclusion criteria, 265 (48.6%) patients were included, of which 197 (74.3%) were successfully extubated; extubation was unsuccessful in 68 (25.7%) patients. The total intake and fluid balance levels in patients in the failed extubation group 24 h before extubation were significantly higher than those in the successful extubation group, with a median of 2679.00 (2410.44-3193.50) mL versus 2435.40 (1805.04-2957.00) mL, 831.50 (26.25-1407.94) mL versus 346.00 (-163.00-941.50) mL. Receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value for predicting extubation outcomes was 497.5 mL (sensitivity 64.7%, specificity 59.4%) for fluid balance 24 h before extubation. The area under the ROC curve was 0.627 (95% confidence interval [CI] 0.547-0.707). Based on the logistic regression model, cumulative fluid balance >497.5 mL 24 h before extubation could predict its outcomes in mechanically ventilated patients in the ICU (OR = 5.591, 95% CI [2.402-13.015], p < .05)., Conclusions: The fluid balance level 24 h before extubation was correlated with the outcome of extubation in mechanically ventilated patients in the ICU. The risk of extubation failure was higher when the fluid balance level was >497.5 mL., Relevance to Clinical Practice: Tracheal intubation is a crucial life support technique for many critically ill patients, and determining the appropriate time for extubation remains a challenge for clinicians. Although there are many reasons for extubation failure, acute pulmonary oedema caused by continuous positive fluid balance and volume overload is one of the main reasons for extubation failure. Therefore, it is very important to study the relationship between fluid balance and extubation outcome to improve the prognosis of patients with invasive mechanical ventilation in ICU., (© 2024 British Association of Critical Care Nurses.)

Background: Medullary sponge kidney (MSK)is rare in association with glomerulonephritis. We report a patient with medullary sponge kidney, and the kidney biopsy revealed a diagnosis of IgA nephropathy., Case Presentation: A 27-year-old female presented with hematuria and proteinuria, and imaging studies indicated the presence of medullary spongy kidney. With appropriate preparation, a kidney biopsy was performed. Considering the patient's clinical and pathological characteristics, the final diagnosis was determined to be medullary sponge kidney associated by IgA nephropathy. The combination of corticosteroids and angiotensin receptor blockers (ARBs) proved to be significantly effective in reducing proteinuria in the current case. To the best of our knowledge, this is the first reported case that demonstrates the coexistence of MSK and IgA nephropathy., Conclusions: Administering precise therapy based on renal pathology can potentially enhance outcomes for patients with renal conditions, necessitating the need for clinicians to be vigilant about differential diagnosis in order to reduce the rates of missed diagnoses and misdiagnosis., (© 2024. The Author(s).)

Thiacloprid (THI) is a neonicotinoid insecticide, and its wide-ranging use has contributed to severe environmental and health problems. Dendrobium officinale polysaccharide (DOP) possesses multiple biological activities such as antioxidant and antiapoptosis effect. Although present research has shown that THI causes kidney injury, the exact molecular mechanism and treatment of THI-induced kidney injury remain unclear. The study aimed to investigate if DOP could alleviate THI-induced kidney injury and identify the potential molecular mechanism in quails. In this study, Japanese quails received DOP (200 mg/kg) daily with or without THI (4 mg/kg) exposure for 42 days. Our results showed that DOP improved hematological changes, biochemical indexes, and nephric histopathological changes induced by THI. Meanwhile, THI exposure caused oxidative stress, apoptosis, and autophagy. Furthermore, THI and DOP cotreatment significantly activated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway, restored antioxidant enzyme activity, and reduced apoptosis and autophagy in quail kidneys. In summary, our study demonstrated that DOP mitigated THI-mediated kidney injury was associated with oxidative stress, apoptosis, and autophagy via activation of the Nrf2/HO-1 signaling pathway in quails., (© 2024 Wiley Periodicals LLC.)

Inorganic arsenic (iAs) is a well-recognized environmental pollutant that induces severe brain injury in humans and animals. The antioxidant, anti-inflammatory, and anti-ferroptotic effects of resveratrol (Res) were demonstrated in multiple animal experiments. In order to investigate the protective effect of Res on iAs-induced chicken brain injury, the 40 chickens (19-d-old, female) brain injury model was established by oral administration of iAs (30 mg/L NaAsO 2 ) for 6 weeks. All chickens had free access to both food and water during the experiment. The biochemical indices, hematoxylin-eosin staining, and related protein levels of oxidative stress, inflammation and ferroptosis were then determined. Our results indicated that Res (1000 mg/kg) alleviated the iAs-induced brain injury after 6 weeks of oral administration, primarily by reducing the interleukin-1β mRNA expression and nuclear factor kappa B and malondialdehyde level, and increasing the antioxidant enzyme activity and the mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, our study demonstrates that Res effectively inhibits iAs-induced oxidative stress and ferroptosis by mediating the Nrf2 signaling pathway, thereby alleviating iAs-induced brain injury in chickens. This is the first time that the amelioration effects of Res on the iAs-induced brain have been investigated from multiple perspectives., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The rate of isolated locoregional recurrence after surgery for pancreatic adenocarcinoma (PDAC) approaches 25%. Ablative radiation therapy (A-RT) has improved outcomes for locally advanced disease in the primary setting. We sought to evaluate the outcomes of salvage A-RT for isolated locoregional recurrence and examine the relationship between subsequent patterns of failure, radiation dose, and treatment volume. Methods : We conducted a retrospective analysis of all consecutive participants who underwent A-RT for an isolated locoregional recurrence of PDAC after prior surgery at our institution between 2016 and 2021. Treatment consisted of ablative dose (BED10 98-100 Gy) to the gross disease with an additional prophylactic low dose (BED10 < 50 Gy), with the elective volume covering a 1.5 cm isotropic expansion around the gross disease and the circumference of the involved vessels. Local and locoregional failure (LF and LRF, respectively) estimated by the cumulative incidence function with competing risks, distant metastasis-free and overall survival (DMFS and OS, respectively) estimated by the Kaplan-Meier method, and toxicities scored by CTCAE v5.0 are reported. Location of recurrence was mapped to the dose region on the initial radiation plan. Results : Among 65 participants (of whom two had two A-RT courses), the median age was 67 (range 37-87) years, 36 (55%) were male, and 53 (82%) had undergone pancreaticoduodenectomy with a median disease-free interval to locoregional recurrence of 16 (range, 6-71) months. Twenty-seven participants (42%) received chemotherapy prior to A-RT. With a median follow-up of 35 months (95%CI, 26-56 months) from diagnosis of recurrence, 24-month OS and DMFS were 57% (95%CI, 46-72%) and 22% (95%CI, 14-37%), respectively, while 24-month cumulative incidence of in-field LF and total LRF were 28% (95%CI, 17-40%) and 36% (95%CI 24-48%), respectively. First failure after A-RT was distant in 35 patients (53.8%), locoregional in 12 patients (18.5%), and synchronous distant and locoregional in 10 patients (15.4%). Most locoregional failures occurred in elective low-dose volumes. Acute and chronic grade 3-4 toxicities were noted in 1 (1.5%) and 5 patients (7.5%), respectively. Conclusions : Salvage A-RT achieves favorable OS and local control outcomes in participants with an isolated locoregional recurrence of PDAC after surgical resection. Consideration should be given to extending high-dose fields to include adjacent segments of at-risk vessels beyond direct contact with the gross disease.

Background: Electromagnetic transponders bronchoscopically implanted near the tumor can be used to monitor deep inspiration breath hold (DIBH) for thoracic radiation therapy (RT). The feasibility and safety of this approach require further study., Methods: We enrolled patients with primary lung cancer or lung metastases. Three transponders were implanted near the tumor, followed by simulation with DIBH, free breathing, and 4D-CT as backup. The initial gating window for treatment was ±5 mm; in a second cohort, the window was incrementally reduced to determine the smallest feasible gating window. The primary endpoint was feasibility, defined as completion of RT using transponder-guided DIBH. Patients were followed for assessment of transponder- and RT-related toxicity., Results: We enrolled 48 patients (35 with primary lung cancer and 13 with lung metastases). The median distance of transponders to tumor was 1.6 cm (IQR 0.6-2.8 cm). RT delivery ranged from 3 to 35 fractions. Transponder-guided DIBH was feasible in all but two patients (96% feasible), where it failed because the distance between the transponders and the antenna was >19 cm. Among the remaining 46 patients, 6 were treated prone to keep the transponders within 19 cm of the antenna, and 40 were treated supine. The smallest feasible gating window was identified as ±3 mm. Thirty-nine (85%) patients completed one year of follow-up. Toxicities at least possibly related to transponders or the implantation procedure were grade 2 in six patients (six incidences, cough and hemoptysis), grade 3 in three patients (five incidences, cough, dyspnea, pneumonia, and supraventricular tachycardia), and grade 4 pneumonia in one patient (occurring a few days after implantation but recovered fully and completed RT). Toxicities at least possibly related to RT were grade 2 in 18 patients (41 incidences, most commonly cough, fatigue, and pneumonitis) and grade 3 in four patients (seven incidences, most commonly pneumonia), and no patients had grade 4 or higher toxicity., Conclusions: Bronchoscopically implanted electromagnetic transponder-guided DIBH lung RT is feasible and safe, allowing for precise tumor targeting and reduced normal tissue exposure. Transponder-antenna distance was the most common challenge due to a limited antenna range, which could sometimes be circumvented by prone positioning.

Purpose: Intravascular tumor emboli in axillary soft tissue (ITE) is a rare pathologic finding in breast cancer and is associated with higher axillary nodal disease burden. The independent prognostic and predictive value of this entity is unknown, as is the role of radiation therapy for ITE., Methods and Materials: We analyzed a prospectively maintained database of breast cancer patients treated from 1992 to 2020. Patients with ITE were matched to those without (1:2) based on propensity scores to control for potential confounding factors. Locoregional (LRR) and distant recurrence (DR) were evaluated using competing risks methods accounting for death as a competing event. Overall survival (OS) and disease-free survival (DFS) were evaluated by Cox regression models. Among patients with ITE, we also evaluated whether RT improved outcomes., Results: Among 2377 total patients, 129 had ITE, of whom 126 were propensity score matched to 252 without ITE. Median follow-up from time of surgery was 5.5 years (IQR 2.3, 9.7). There were no statistically significant differences in the 5-year incidence of LRR between groups (5.4% [95% CI, 1.6%-13%] with ITE vs 10% [95% CI, 6.7%-15%] without, P = .53) or DR (24% [95% CI, 15% 35%] with ITE vs 21% [95% CI, 16%-27%] without, P = .51). Five-year OS and DFS did not differ between groups ( P > .9 for both comparisons, patients with ITE vs without ITE). In analyzing the effect of RT among patients with ITE, receipt of RT was associated with significantly improved DFS (HR, 0.34, 95% CI, 0.12-0.93, P = .04)., Conclusions: Patients with ITE do not exhibit significantly worse LRR, DR, DFS, or OS compared with a propensity-score-matched cohort without ITE. However, among patients with ITE, those who received RT demonstrated significantly improved DFS. Larger studies with longer follow-up are needed to evaluate the prognostic and predictive implications of ITE., (© 2024 The Author(s).)

Deep-learning-based medical image segmentation techniques can assist doctors in disease diagnosis and rapid treatment. However, existing medical image segmentation models do not fully consider the dependence between feature segments in the feature extraction process, and the correlated features can be further extracted. Therefore, a recurrent positional encoding circular attention mechanism network (RPECAMNet) is proposed based on relative positional encoding for medical image segmentation. Multiple residual modules are used to extract the primary features of the medical images, which are thereafter converted into one-dimensional data for relative positional encoding. The recursive former is used to further extract features from medical images, and decoding is performed using deconvolution. An adaptive loss function is designed to train the model and achieve accurate medical-image segmentation. Finally, the proposed model is used to conduct comparative experiments on the synapse and self-constructed kidney datasets to verify the accuracy of the proposed model for medical image segmentation., 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. Published by Elsevier B.V.)

Background: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease., Aims: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients., Methods: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction., Results: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%., Conclusions: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic., (© 2024. The Author(s).)

Introduction: R0 resection and radiation therapy have been associated with improved overall survival (OS) in patients with thymic carcinoma (TC). Here, we analyzed which subgroups of patients derive the greatest benefit from postoperative radiation therapy (PORT)., Methods: Clinical, pathologic, treatment, and survival information of 462 patients with TC from the International Thymic Malignancy Interest Group/European Society of Thoracic Surgeons database were analyzed. Variables included age, sex, continent of treatment, paraneoplastic syndrome, carcinoma subtype, tumor size, pathologic Masaoka stage, resection status, and use of chemotherapy. OS was the primary end point using the Kaplan-Meier method. Time to recurrence (TTR) was the secondary end point using a competing risk analysis. A 3-month landmark analysis was performed., Results: PORT was associated with a significant OS benefit (5-y OS 68% versus 53%, p = 0.002). In patients with R0 resection, PORT was associated with increased OS for advanced (stages III-IV, p = 0.04), but not early (stages I-II, p = 0.14) stage TC. In patients with an R1/2 resection of advanced-stage TC, PORT was associated with significantly longer OS (5-y OS 53% versus 38%; p < 0.001). Subset analyses did not reveal clear associations of PORT with TTR. On multivariable analysis, lower pathologic stage, PORT, and R0 resection status were associated with an OS benefit, whereas only higher age and lower pathologic stage had an association with longer TTR., Conclusions: In the largest individual patient data set on patients with TC reported to date, PORT was associated with a meaningful OS benefit in patients with advanced-stage TC after an R0 or R1/2 resection., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Src homology 2-domain-containing tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase that is widely expressed in a variety of cells and regulates the immune response of T cells through the PD-1 pathway. However, the activation mechanism and allosteric effects of SHP2 remain unclear, hindering the development of small molecule inhibitors. For the first time, in this study, the complex structure formed by the intact PD-1 tail and SHP2 was modeled. The molecular recognition and conformational changes of inactive/active SHP2 versus ITIM/ITSM were compared based on prolonged MD simulations. The relative flexibility of the two SH2 domains during MD simulations contributes to the recruitment of ITIM/ITSM and supports the subsequent conformational change of SHP2. The binding free energy calculation shows that inactive SHP2 has a higher affinity for ITIM/ITSM than active SHP2, mainly because the former's N-SH2 refers to the α-state. In addition, a significant decrease in the contribution to the binding energy of certain residues ( e.g. , R32, S34, K35, T42, and K55) of conformationally transformed SHP2 contributes to the above result. These detailed changes during conformational transition will provide theoretical guidance for the molecular design of subsequent novel anticancer drugs.

Purpose: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy., Methods: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18 F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin., Results: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia., Conclusion: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Objectives: To determine the morphologies and effect of the round window niche veil (RWNV) on local drug delivery efficacy and develop diagnostic criteria on high-resolution computed tomography (HRCT)., Methods: Patients diagnosed with otosclerosis, bilateral profound sensorineural hearing loss or vestibular schwannoma were enrolled from 2019 to 2022, receiving temporal bone HRCT scanning, and anatomic variations of RWMV were summarized intraoperative. For patients with vestibular schwannoma, 1 mL of dexamethasone solution (4 mg/mL) was administered via facial recess during operation, and samples of perilymph were collected to analyze. The diagnostic criteria of RWNV on HRCT were developed and verified., Results: A total of 85 patients were enrolled. RWNV was observed in 54 cases intraoperatively with an incidence of 63.5% (95% CI, 52.9%-73.0%). The median perilymph concentrations were 4.86-fold higher in the group without RWNV than with RWNV (p < 0.0001). RWNV could be visualized on HRCT with a window width of 3500-4500 HU and a window level of 300-500 HU. The characteristic features were as follows: (1) a thin soft tissue shadow could be seen at the entrance of the round window niche (RWN); (2) it was visible in at least 2 consecutive layers along the upper margin of RWN from top to bottom; (3) it was discontinuous with the adjacent bone margin. The sensitivity and specificity of the diagnostic criteria were 77.8% and 93.6%, respectively., Conclusion: RWNV could reduce local dexamethasone diffusion efficacy to the inner ear, which could be diagnosed on HRCT and used as a predictor of local drug delivery efficacy to the inner ear., Level of Evidence: 3 Laryngoscope, 134:1396-1402, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

The cGAS-STING pathway and the Mevalonate Pathway are druggable targets for vaccine adjuvant discovery. Manganese (Mn) and bisphosphonates are known to exert adjuvant effects by targeting these two pathways, respectively. This study found the synergistic potential of the two pathways in enhancing immune response. Risedronate (Ris) significantly amplified the Mn adjuvant early antibody response by 166-fold and fortified its cellular immunity. However, direct combination of Mn 2+ and Ris resulted in increased adjuvant toxicity (40% mouse mortality). By the combination of doping property of hydroxyapatite (HA) and its high affinity for Ris, we designed Ris-functionalized Mn-HA micro-nanoparticles as an organic-inorganic hybrid adjuvant, named MnHARis. MnHARis alleviated adjuvant toxicity (100% vs. 60% survival rate) and exhibited good long-term stability. When formulated with the varicella-zoster virus glycoprotein E (gE) antigen, MnHARis triggered a 274.3-fold increase in IgG titers and a 61.3-fold surge in neutralization titers while maintaining a better long-term humoral immunity compared to the aluminum adjuvant. Its efficacy spanned other antigens, including ovalbumin, HPV18 VLP, and SARS-CoV-2 spike protein. Notably, the cellular immunity elicited by the group of gE + MnHARis was comparable to the renowned Shingrix®. Moreover, intratumoral co-administration with an anti-trophoblast cell surface antigen 2 nanobody revealed synergistic antitumor capabilities. These findings underscore the potential of MnHARis as a potent adjuvant for augmenting vaccine immune responses and improving cancer immunotherapy outcomes., Competing Interests: Declaration of competing interest The authors hereby declare that there are no known competing financial interests or personal relationships that could have potentially influenced the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)