Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for initially unresectable locally advanced colon cancer: short-term outcomes of an open-label, single-centre, randomised, controlled, phase 3 trial.

Background: Neoadjuvant chemotherapy (NACT) is commonly used to downstage the tumor in locally advanced colon cancer (LACC) and improve the R0 resection rate. Neoadjuvant chemoradiotherapy (NACRT) is the standard treatment for locally advanced rectal and esophageal cancers, but its benefits in LACC remain poorly understood. This study aimed to compare the effects and safety of NACRT and NACT on R0 resection and survival rates in initially unresectable LACC. Methods: This was an open-label, single-center, randomized, controlled trial conducted between May 11, 2019 and May 30, 2022. Forty-five patients with initially unresectable LACC were randomly allocated to the NACT (control, n = 20) or NACRT (research, n = 25) group. The NACT group received XELOX (oxaliplatin 100-130 mg/m2, qd, d1, every 3 weeks; and capecitabine 1000 mg/m2, bid, d1-d14, every 3 weeks) for 4 cycles. The NACRT group, in addition to chemotherapy, received daily irradiation (GTV 45-50 Gy/25 F; CTV 42.5-45 Gy/25 F). Surgery was scheduled 6-12 weeks after neoadjuvant treatment and adjuvant chemotherapy was administered if the patient developed resectable LACC. The primary endpoint was the 5-year overall survival (OS) rate. The secondary outcomes included the 3-year progression-free survival (PFS) and R0 resection rates. This study was registered with ClinicalTrials.gov (NCT03970694). Findings: In short-term outcome analysis, NACRT significantly improved the R0 resection rate (80% for NACRT vs. 20% for NACT, P < 0.001). The NACRT and NACT groups had a 3-year OS of 87.6% and 75% (P = 0.037) and a 3-year PFS of 76% and 45% (P = 0.049), respectively. The 5-year OS was not reached. In the NACRT group, no local or regional recurrence was observed in patients who underwent surgery during the follow-up period, compared to two patients in the NACT group. Both NACT and NACRT were well tolerated, with no significant differences in severe adverse events. The most commonly observed grade 3-4 AE was myelosuppression (39% for NACRT and 47% for NACT, P = 0.609). No grade 5 AEs were observed between the two groups. Interpretation: Adding radiation to NACT increased the R0 resection rate, prolonged the PFS, and potentially improved OS in selected patients with initially unresectable LACC. The trial findings indicate that this approach is safe, feasible, and may confer a survival benefit. Funding: This study was supported by grants from the National Natural Science Foundation of China (82373213 to Dr Gao, 82202952 to Dr Wang); and the Natural Science Foundation of Guangdong Province (2023A1515010290 to Dr Chang). Funding sources were not involved in the study design, data collection, analysis and interpretation, writing of the report, or decision to submit the article for publication.

Significant reduction in full-thickness pressure injuries through the quality improvement project that implements alternating pressure air mattresses.

To assess a quality improvement project using alternating pressure air mattresses' impact on reducing full-thickness pressure injuries by enhancing setting accuracy and device utilization. We retrospectively evaluated adult acute care unit patients with inclusion criteria (Braden scores ≤12 or existing full-thickness pressure injuries) between May 2020 and August 2023. A wound team attempted to enhance the accuracy, utilization and effectiveness of alternating pressure air mattress implementation. The implementation outcomes were setting accuracy and accurate utilization rates. The clinical outcome was the full-thickness pressure injury proportion. Utilization and allocation gaps were also calculated. The setting accuracy and accurate utilization rates increased (0.59 to 0.88 and 0.15 to 0.37, respectively). The full-thickness pressure injury proportion decreased (0.17 to 0.06), with a strong negative correlation coefficient (-0.789) (p < 0.001) with accurate utilization rates. The full-thickness pressure injury proportion declined faster during the project's complete phase than the partial phase (-0.0046 vs. -0.0016; p < 0.05). The utilization gap narrowed (99 to 60); however, the allocation gap increased (1 to 13), suggesting increased alternating pressure air mattress usage among ineligible patients. Targeting high-risk patients for alternating pressure air mattress utilization and ensuring correct settings, both performed by a dedicated team, substantially reduces the full-thickness pressure injury incidence.

Modulating Electrical Properties of Ti64/B4C Composite Materials via Laser Direct Manufacturing with Varying B4C Contents.

The modulation of electrical properties in composite materials is critical for applications requiring tailored electrical functionality, such as electromagnetic shielding and absorption. This study focuses on Ti64/B4C composites, a material combination promising enhanced electromagnetic properties. Laser direct manufacturing (LDM) was utilized to fabricate coaxial samples of Ti64 blended with TiB and TiC in various mass ratios, with sample thicknesses ranging from 0.5 mm to 3.5 mm. The electrical characterization involved assessing the dielectric and magnetic permeability, as well as impedance and reflectance, across a frequency spectrum of 2 to 18 GHz. The result reveals that TiC, when incorporated into Ti64, exhibits strong dielectric polarization and achieves a reflectivity as low as -40 dB between 7 and 14 GHz. Conversely, TiB demonstrates effective electromagnetic absorption, with reflectivity values below -10 dB in the frequency band of 8.5 to 11.5 GHz. The study also notes that a lower B4C content enhances electronic polarization and increases the dielectric coefficient, while higher contents favor ionic polarization. This shift can lead to a timing mismatch in the establishment of electron and ion polarization, resulting in a decreased dielectric coefficient. In addition, adjusting the B4C content in Ti64/B4C composites effectively modulates their electrical properties, suggesting a strategic approach to designing materials for specific electromagnetic functions.

Patients with hidradenitis suppurativa are associated with risk of new-onset glaucoma: a propensity-score-matched cohort study.

Background: Ocular comorbidities of hidradenitis suppurativa (HS) has been widely evaluated; however real-world evidence was scarce. Moreover, risk of glaucoma in HS patients remained unclear. This study aimed to evaluate the 5-year glaucoma risk in HS patients. Methods: This retrospective cohort study used the TriNetX database covering 2005-2017. In total, 53,281 HS patients were propensity score matched 1:1 to controls based on demographics, including comorbidities, medications, healthcare utilization, etc. Patients were followed for 5 years post-index date. Glaucoma risks were calculated based on hazard ratios and 95% confidence intervals (95% CI). Stratified analyses by sex and age were performed. Results: After matching, baseline characteristics were similar between groups. HS was associated with a 1.25 times higher 5-year glaucoma risk (95% CI, 1.10-1.42). The risk was significant within 1 year (HR=1.37; 95% CI, 1.03-1.82), 3 years (HR=1.31; 95% CI, 1.12-1.54), and 5 years post-index. In subgroup analysis, women had a 1.28 times higher risk (95% CI, 1.10-1.49). Patients aged 18-64 years (HR=1.33; 95% CI, 1.14-1.55) and ≥65 years (HR=1.33; 95% CI, 1.05-1.67) also presented elevated glaucoma risks. Conclusion: This real-world data analysis demonstrated a significantly increased 5-year glaucoma risk in HS patients versus matched controls. Ocular complications should be concerned while managing HS patients.

Ethanol extract of Vanilla planifolia stems reduces PAK6 expression and induces cell death in glioblastoma cells.

Glioblastoma multiforme (GBM) is a malignant tumour with a poor prognosis. Therefore, potential treatment strategies and novel therapeutic targets have gained increased attention. Our data showed that the ethanol extract of Vanilla planifolia stem (VAS) significantly decreased the viability and the colony formation of GBM cells. Moreover, VAS induced the cleavage of MAP1LC3, a marker of autophagy. Further RNA-seq and bioinformatic analysis revealed 4248 differentially expressed genes (DEGs) between VAS-treated GBM cells and the control cells. Protein-protein interactions between DEGs with fold changes less than -3 and more than 5 were further analysed, and we found that 16 and 9 hub DEGs, respectively, were correlated with other DEGs. Further qPCR experiments confirmed that 14 hub DEGs was significantly downregulated and 9 hub DEGs was significantly upregulated. In addition, another significantly downregulated DEG, p21-activated kinase 6 (PAK6), was correlated with the overall survival of GBM patients. Further validation experiments confirmed that VAS significantly reduced the mRNA and protein expression of PAK6, which led to the abolition of cell viability and colony formation. These findings demonstrated that VAS reduced cell viability, suppressed colony formation and induced autophagy and revealed PAK6 and other DEGs as potential therapeutic targets for GBM treatment.

Association of neutrophil-to-lymphocyte ratio with age and 180-day mortality after emergency surgery.

BACKGROUND: To examine the relationship between neutrophil-to-lymphocyte ratio (NLR), age, and mortality rates after emergency surgery. METHODS: In this observational study, a total of 851 patients undergoing emergency surgery between January 2022 and January 2023 were retrospective examined. Using 30 and 180 days mortality data, NLR differences and receiver operating characteristic (ROC) curves were analyzed using a 65-year threshold. A multiple logistic regression model was constructed incorporating age and NLR. Finally, Kaplan-Meier curves were constructed for mortality. RESULTS: Among 851 patients, the 30 and 180 days mortality rates were 5.2% and 10.8%, respectively. Median NLR in 30 days was 5.6 (3.1 to 9.6) in survivors and 8.7 (4.6 to 13.4) in deceased patients (p < 0.0001); in 180 days, it was 5.5 (3.1 to 9.8) and 8.8 (4.8 to 14.5), respectively (p < 0.0001). In the 30- and 180-days mortality analyses, median NLRs were 5.1 (2.9 to 8.9) and 4.9 (2.9 to 8.8) in survivors and 10.6 (6.9 to 16.6) and 9.3 (5.4 to 14.9) in deceased patients aged < 65 years, respectively. The ROC AUC in patients younger than 65 years was higher for 30 days (AUC 0.75; 95% CI 0.72 to 0.87) and 180 days (AUC 0.73; 95% CI 0.64 to 0.81). Multivariate logistic regression revealed that the NLR (odds ratio, 1.03 [95% CI 1.005 to 1.053; p = 0.0133) and age (odds ratio, 1.05 [95% CI 1.034 to 1.064; p < 0.0001) significantly contributed to the model. Survival analysis revealed differences in the 180 days mortality (p = 0.0006). CONCLUSION: We observed differences in preoperative NLR between patients who survived and those who died after emergency surgery. Age impacts the use of NLR as a mortality risk factor. TRIAL REGISTRATION: NCT06549101, retrospectively registered.

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function.

Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically-evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered - swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.

Insulinoma-associated protein 1 (INSM1) immunohistochemical expression in normal, hyperplastic, and neoplastic canine neuroendocrine tissues.

Insulinoma-associated protein 1 (INSM1), a recently identified neuroendocrine marker, is a transcriptional regulator with highly conserved INSM1 homologues in various species. This study investigated the immunohistochemical reactivity of the INSM1 antibody in 20 normal canine neuroendocrine tissues from various anatomical locations, 87 hyperplastic or neoplastic tissues of neuroendocrine origin, and 62 non-neuroendocrine neoplasms and compared the results with those of chromogranin A and synaptophysin in neuroendocrine neoplasms. Western blot was performed on fresh canine pituitary glands and canine parathyroid glands to confirm the specificity of the anti-INSM1 antibody. The results showed that the anti-INSM1 antibody could detect nuclear expression in normal canine neuroendocrine tissues, except for the parathyroid glands. INSM1 was detectable in 79/87 (91%) of the hyperplastic and neoplastic neuroendocrine lesions, but all parathyroid carcinomas and parathyroid adenomas (three samples each) were negative for INSM1. In contrast, INSM1 was detected in only one of 62 (2%) non-neuroendocrine neoplasms. The overall percentage of neuroendocrine neoplasms that immunolabeled positively for all three markers was 89%. In addition, the nuclear expression of INSM1 was easier to interpret than that of chromogranin A or synaptophysin. These findings confirm that INSM1 is a useful immunohistochemical marker for diagnosing canine neuroendocrine neoplasms, except for parathyroid neoplasms, and should be considered as part of immunohistochemistry panels to improve diagnostic capability.

Herpes Zoster Risk After Total Knee Replacement: a multicenter, propensity-score-matched cohort study in the United States.

Background: Total knee replacement (TKR) is a common surgical procedure for osteoarthritis (OA) patients. TKR may increase susceptibility to herpes zoster (HZ) by inducing immunosuppression, surgical stress, and nerve injury. However, limited data exist on the relationship between TKR and HZ. This study examined the risk of HZ over time among OA patients who underwent TKR and those who did not, using a large population-based cohort. Method: Utilizing the TriNetX research network, people with OA and underwent TKR were recruited as case group. After 1:1 propensity score matching, OA patients who never experienced TKR were included as control group. Covariates, including demographics, comorbidities, and laboratory data, were balanced using propensity score matching. A 5-year follow-up assessed the hazard ratio of incident HZ and related complications. Results: Compared to the control group, a significantly elevated risk of HZ was observed in the TKR cohort across 5-year follow-up period, with the hazard ratio of 1.223 (95% CI: 1.089-1.373). Zoster without complications presented 1.173-fold risk in TKR patients while comparing with non-TKR controls. However, most other secondary outcomes related to HZ complications-such as encephalitis, neurological involvement, ocular disease, and disseminated zoster-did not show a significant increase in risk. The risk of HZ was statistically significant for females and older adults in the TKR cohort than in the control cohort. Conclusions: OA patients who underwent TKR had an increased risk of HZ compared to those who did not receive the procedure, especially females and older adults. These findings highlight the need for HZ monitoring/prevention protocols and further research on mitigating viral reactivation after major joint surgery.

Thyroid Diseases After Total Knee Replacement: A Multi-center, Propensity-score-matched Cohort Study.

BACKGROUND/AIM: Thyroid diseases are prevalent endocrine disorders that significantly affect overall health. Although the impact of pre-existing thyroid dysfunction on total knee replacement (TKR) outcomes has been studied, the potential for TKR to increase the risk of developing thyroid disorders remains unexplored. PATIENTS AND METHODS: We examined electronic medical records from a large U.S. research network in the TriNetX research network. The study focused on patients with osteoarthritis, comparing those who had total knee replacement surgery (TKR) between 2005 and 2018 to a non-TKR group who did not have the surgery. Propensity score matching was employed to control for critical confounders. The hazard ratios (HRs) for the risk of thyroid diseases in TKR patients versus non-TKR controls were assessed. RESULTS: Post-matching, the TKR cohort demonstrated a significantly higher risk of developing thyroid diseases compared to the non-TKR cohort (unadjusted HR=1.218, 95%CI=1.169-1.269). This elevated risk persisted after adjusting for confounders (adjusted HR=1.126, 95%CI=1.061-1.196). Stratification analysis indicated that female TKR patients and those aged ≥65 years were at higher risk of developing thyroid diseases than their respective control groups. CONCLUSION: This study suggests a potential link between TKR and an increased risk of thyroid diseases, particularly among older adults and females. Potential mechanisms include inflammatory processes, surgical stress, autoimmune responses, and pharmacological effects. Healthcare providers should be vigilant in monitoring and managing thyroid dysfunction in TKR patients. Further research is necessary to elucidate the underlying mechanisms and develop preventive strategies.

Establishment and validation of a risk stratification model for stroke risk within three years in patients with cerebral small vessel disease using a combined MRI and machine learning algorithm.

BACKGROUND: Cerebral small vessel disease (CSVD) is a major cause of stroke, particularly in the elderly population, leading to significant morbidity and mortality. Accurate identification of high-risk patients and timing of stroke occurrence plays a crucial role in patient prevention and treatment. The study aimed to establish and validate a risk stratification model for stroke within three years in patients with CSVD using a combined MRI and machine learning algorithm approach. METHODS: The assessment encompassed demographic, clinical, biochemical, and MRI-derived parameters. Correlation analysis, logistic regression, receiver operating characteristic (ROC) curve analysis, and nnet neural network algorithm were employed to evaluate the predictive value of machine learning algorithms and MRI parameters for stroke occurrence within 3 years in patients with CSVD. RESULTS: MRI-derived parameters, including average WMH volume, perfusion deficit volume, ischemic core volume, microbleed count, and perivascular spaces, exhibited strong correlations with stroke occurrence (P < 0.001). MRI-derived parameters demonstrated high sensitivities (0.719 to 0.906), specificities (0.704 to 0.877), and AUC values (0.815 to 0.871). The combined model of machine learning algorithms and MRI parameters yielded an AUC value of 0.925, indicating significantly high predictive accuracy for identifying the risk of stroke within three years in CSVD patients. CONCLUSION: The integrated risk stratification model, incorporating machine learning algorithms and MRI parameters, demonstrated strong predictive potential for stroke within three years in patients with CSVD. This model offered valuable insights for personalized interventions and clinical decision-making in the management of CSVD.

Desmodium intortum (Mill.) Urb. Protein Isolate Aggregates as Pickering Stabilizers: Physicochemical Characteristics and Emulsifying Properties.

This work aimed to investigate the feasibility of fabricating Pickering emulsions stabilized by Desmodium intortum protein isolate (DIPI) aggregates. The DIPI aggregates were formed using heat treatment, and the effects of ionic strength and pH on their properties were investigated. The heat-treated protein exposes its hydrophobic groups due to structural damage, resulting in rapid aggregation of the protein into aggregates with a size of 236 nm. The results showed that the aggregates induced by ionic strength had larger particle size and higher surface hydrophobicity and partial wettability. Moreover, this study explored effective strategies for bolstering Pickering emulsion stability through optimized DIPI aggregate concentration (c) and oil fraction (ø). The DIPI Pickering emulsion (DIPIPE) formed at c = 5% and ø = 0.7 was still highly stable after 30 days of storage. As confirmed by laser confocal microscopy, DIPI aggregates could be adsorbed onto the oil-water interface to form a network structure that could trap oil droplets in the network. Collectively, the Pickering emulsion stabilized by DIPI aggregates exhibited excellent stability, which not only deeply utilizes the low-value protein resources in the Desmodium intortum for the first time, but also demonstrates the potential of DIPI for the bio-based field.

Bactofencin YH, a novel bacteriocin with high inhibitory activity against clinical Streptococcus species.

Strain Lactiplantibacillus plantarum D1 with bacteriocin producing ability was found in the intestine of Gambusia affinis. The bacteriocin was found to have high inhibitory activity against multiple Streptococcus species and several other Gram-positive and Gram-negative bacteria. Bacteriocin was purified from culture supernatant by ion-exchange chromatography, Sep-Pak C18 cartridge, and reverse-phase high-performance liquid chromatography (RP-HPLC). Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectral analysis determined that purified bacteriocin has a molecular mass of 2,731 Da. A partial N-terminal sequence KRKKHKXQIYNNGM was obtained from the Edman analysis. The N-terminal sequence was employed to search against a translation of the draft genome of strain D1. The translated full amino acid sequence of the mature peptide is as follows: NH2- KRKKHKCQIYNNGMPTGQYRWC, which has a molecular weight of 2738 Da. A BLAST search revealed that this bacteriocin was most similar to bactofencin A but differed from it with three amino acid residues. No identical peptide or protein has been previously reported, and this peptide, termed bactofencin YH, was therefore considered to be a new bacteriocin produced by Lactiplantibacillus plantarum D1.

Deep learning models for rapid discrimination of high-grade gliomas from solitary brain metastases using multi-plane T1-weighted contrast-enhanced (T1CE) images.

Background: High-grade gliomas (HGG) and solitary brain metastases (SBM) are two common types of brain tumors in middle-aged and elderly patients. HGG and SBM display a high degree of similarity on magnetic resonance imaging (MRI) images. Consequently, differential diagnosis using preoperative MRI remains challenging. This study developed deep learning models that used pre-operative T1-weighted contrast-enhanced (T1CE) MRI images to differentiate between HGG and SBM before surgery. Methods: By comparing various convolutional neural network models using T1CE image data from The First Medical Center of the Chinese PLA General Hospital and The Second People's Hospital of Yibin (Data collection for this study spanned from January 2016 to December 2023), it was confirmed that the GoogLeNet model exhibited the highest discriminative performance. Additionally, we evaluated the individual impact of the tumoral core and peritumoral edema regions on the network's predictive performance. Finally, we adopted a slice-based voting method to assess the accuracy of the validation dataset and evaluated patient prediction performance on an additional test dataset. Results: The GoogLeNet model, in a five-fold cross-validation using multi-plane T1CE slices (axial, coronal, and sagittal) from 180 patients, achieved an average patient accuracy of 92.78%, a sensitivity of 95.56%, and a specificity of 90.00%. Moreover, on an external test set of 29 patients, the model achieved an accuracy of 89.66%, a sensitivity of 90.91%, and a specificity of 83.33%, with an area under the curve of 0.939 [95% confidence interval (CI): 0.842-1.000]. Conclusions: GoogLeNet performed better than previous methods at differentiating HGG from SBM, even for core and peritumoral edema in both. HGG and SBM could be fast screened using this end-to-end approach, improving workflow for both tumor treatments.